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Page 1: DIASTEREOSELECTIVE INTERMOLECULAR · A ROUTE TO ENANTIOMERICALLY ENRICHED CYCLOADDUCTS ... Single Crystal X-Ray Detemination of 80 182 ... [3.7.1 ]octa-2.6-diene- karboxy lates Diastereoselective
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DIASTEREOSELECTIVE INTERMOLECULAR [4 + 31

CYCLOADDITIONS BETWEEN CHIRAL FURANS AND

OXYÂLLYL CATIONS: A ROUTE TO ENANTIOMERICALLY

ENRICHED CYCLOADDUCTS

by

Renee Aspiotis

A thesis subrnitted in conformity with the requirements

for the degree of Master of Science

Graduate Department of Chernistry

University of Toronto

O Copyright by Renee Aspiotis ( 1997)

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National Library of Canada

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Acquisitions and Acquisitions et Bibliographie Services services bibliographiques

395 Wellington Street 395. nie Wellington Ottawa ON K I A ON4 Ottawa ON K1A ON4 Canada Canada

The author has granted a non- exclusive licence allowing the National Library of Canada to reproduce, loan, distribute or sell copies of this thesis in microform, paper or electronic formats.

The author retains ownership of the copyright in ths thesis. Neither the thesis nor substantial extracts from it may be printed or otherwise reproduced without the author's permission.

L'auteur a accorde une licence non exclusive permettant à la Bibliothèque nationale du Canada de reproduire, prêter, distribuer ou vendre des copies de cette thèse sous la fornie de rnicrofiche/filrn, de reproduction sur papier ou sur format électronique.

L'auteur conserve la propriété du droit d'auteur qui protège cette thèse. Ni la thèse ni des extraits substantiels de celle-ci ne doivent être imprimés ou autrement reproduits sans son autorisation.

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Objective

The overall objective wa5 to develop a practical and generd strategy for the synthesis of

unsymmetrical oxabicyclo[3.2.1] octenes as single enantiomers. Moreover if the methodology is

to be applicable to the synthesis of various natural products and their analogues. diastereomeric

cycloadducts to those previously prepared must be made available.

Our pt-imary objective focussed on developing a diastereoselective intemolecular [4+3]

cycloaddition reaction between chiral 2-furylcarbinols and oxyailyl cations. To this end. the

conditions io effect the cycloaddition as well as its scope and limitations were addressed. The

issues of facial-. stereo- and regioselectivity of the reaction were also exarnined.

In order to demonstrate their synthetic potential in organic synthesis. the methodology

was applied toward the synthesis of enantiomericdly enriched cycloheptenols. Hence. various

nucIeophilcs were screened in an effort to induce highly regioselective ring opening reiictions.

Both inter- and intramolecular versions of the ring opening reaction were investigated.

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Abstract

Diastereoselec tive Intermolecular [4+3] Cycloadditions Be tween

Chiral Furans and Oxyallyl Cations: A Route to Enantiornerically

Enriched Cycloadducts

Renee Aspiotis, Master of Science (1997)

Department of Chemistry, University of Toronto

Oxabicyclo[3.2.1] octenes have served as valuable intermediates for the constmction of

various natural products and their analogues. Un ti 1 recentl y. methods for their asymmetric

construction have been limited to desymrnetrization reactions. Thus. if their scope and utility are

to be expanded in organic synthesis. then the development of alternative strategies for their

iisymrnetric construction is warranted.

This thesis describes a practicd and general strategy for the synthesis of unsymmetrical

oxabicyclo[3.2. I ] octenes as single enantiomers via a diastereoselective intermolecular [4+3]

cycloaddition reaction between chiral 2-furylcarbinols and oxyallyl cations. It was tound that

deprotonation of the furylcarbinol's hydroxyl moiety with a divalent organometallic reagent and

subsequent cycloaddition with the oxyailyl cation provides access to cycloadducts in high

diastereomeric excess (290%). Interestingly, the stereochemistry of the products dictates that the

reaction not only arises from a chelate controlled facially selective cycloaddition but also from an

unprecedented extended fransilion state. Hence. previously unavailable cycloadducts can be

made in good yields (580%).

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Acknowledgements

First. my deepest appreciation is extrnded to my supervisor. Professor Mark Lautens. for

his guidance. encouragement and support throughout my course of study. His knowledge in

chernistry and his enthusiasm as a teacher has helped immensely in my development as a chemist.

1 would also like to thank the members of the Lautens' group. both past and present. for

their friendship. assistance and helpfui discussions. In particular. John Colucci. Tom Rovis. Dr.

Sophie Kumanovic. Eric Fillion. Dr. Yi Ren. and Dr. Wolfgang Klute are jratefully

acknowledged for thrir extra help and guidance throughout the course of this project.

The technical assistance of Dr. Alan Lough. Dr. Alex Young, Nick Plavac. Tim Burrows

Patricia Aroca-OuIlette and Dan Mathers is appreciated. In addition. Edward Grabowski and

David Mathre from Merck (Rahway) are thanked for their generous donation of the m i n o

indanol and oxazaborolidine-borane reagents.

To rny older broiher. Jim. I would like to extend my deepest love and thanks for k i n g

there when needed most. A best fnend you will always be. 1 would also like to welcome my

cool new sister Mary into Our family. Finally, 1 am very grateful to my parents who have

supported me throughout my university years. Their immeasurable Iove and understanding will

ülways be cherished deeply. Zaq E q a p t a r o j~ o)crl q v ~apha pou. ME ayaicq,

Oupav~a.

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tn rny mothrr.

farher and Jim.

rr*ittt love

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Table of Contents

Objective

Abstrrict

Acknow ledgemen ts

Dedication

Table of Contents

List of Abbreviations

List of Tables

1. GENERAL INTRODUCTION

1 . 1 Racemic Routes to Oxabicycl0[3.2.1] Substrates

1 .Z Asymmetnc Routes to Unsymrnetrical Oxabicyclo[3.Z.l] Substrates

1.2.1 Asymmetric Desymmetnzation Reactions

1.2.2 Asyrnrnetric Tandem Cyclopropanation/Cope Remangement

1.2.3 Diastereoselective IntrarnolecuIar [4+3] Cycloadditions

1.2.4 Diastereoselective Intermolecular [4+3] Cycloaddi tions Using Chiral

Oxyallyl Cation Precursors

1.2.5 Diastereoselective Intermolecular [4+3] Cycloadditions Between Chiral

Furans and Oxyallyl Cations

2. AN INTRODUCTION TO THE [4+3] CYCLOADDITION REACTION

AND ITS MECHANISM

2.1 Preparation of Oxyallyf Cations

2.2 Mode of Attack of 1,3-Terminaily Substituted 2-Oxyailyl Cations

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2.3 Electrophilicity and the .Mode of the Cycloaddition

2 -4 Precedent for W-Configured Oxyally l Cations

2 .5 Structural Assignments by I H NMR Spectroscopy

3. DIASTEREOSELECTIVE INTERMOLECULAR [4+3] CYCLOADDITIONS

BETWEEN CHIRAL FURANS AND OXYALLYL CATIONS:

A ROUTE TO ENANTIOMERICALLY ENRICHED CYCLOADDUCTS

Introduction

Synthesis of Chiral 2-Furylcarbinols and Sulfoxides

Attempted As ymmetric Reduction of a Proc hiral Ketone

Preparation of Enantiornerically Enriched 2-Furylcarbinols by Kinetic

Resdution

Diastereoselective Fury llithiurn Additions to Chiral Aldehydes

Synthesis of a Chiral 3-Furylcarbinol Using a Diastereoselective Aldol

Attempted Preparation of a Chiral Furylsulfoxide

Resul ts and Discusion

Intermolecular [4+3] Cycloadditions With 2.4-Dibromo-3-pentanaone

Using Zn-Ag Couple

lntermolecular [4+3] Cycloadditions With 2.4-Dibromo-3-pentanaone

Using Diethylzinc

Diastereoselective [4+3] Cycloadditions With 1,1,3,3-Tetrabrornoacetone

Attempted Diastereo- and Regioselective [4+3] Cycloadditions With

1.3-Dibromo-2-butanone

Cycloaddi tions With Furfury 1 Alcohol

Further Support for the Observed Diastereofacial Selectivity: Ab Initio Studies

vii

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3 .1 Summary

4. APPLICATIONS: SYNTHESIS OF CYCLOHEPTENOLS V A R I N G

OPENING REACTIONS 59

4- i Introduction

4.2 Preparation of S tating Materials

4.3 Organoiithium Induced Ring Opening Reactions

4.4 Reductive Ring Opening of Di01 123

4.5 Zirconium-Catalyzed Ethylmagnesiation of Compound 126

4.6 Intramolecular Ring Opening of lui Enantiomerically Enriched Unsy mmetncd

Oxabicyclo[3.2. i ] Substrate

4.7 Summary

5. EXPERIMENTALS 77

5.1 General Experimentai 77

5.2 Synthesis of Chiral 2-Furyl Carbinols 78

5.3 Intermolecular [4+3] Cycloadditions With 2.4-Dibrom-3-pentanone Using

Zn-Ag Couple 87

5.4 Intemolecular (4+3] Cycloadditions With 2.4-Dibrom-3-pentanone Using

Diethy lzinc 99

5.5 Diastereoselective [4+3] Cycloadditions With 1.1.3.3-Tetrabromoacetone 1 07

5 -6 Attempted Diastereo- and Regioselective [4+3] Cycloadditions With

1,3-Dibromo-2-butanone 112

5 -7 Preparation of Oxabic yclic S ubstrates for Ring Opening Reactions 115

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5.8 Intermolecular Nucleophilic Ring Openings of Unsyrnmetrical

Oxabicyclic Compounds Csing Organolithiurn Reagents 127

5.9 Reductive Ring Opening of Oxabicyclic Compound 123 Using DIBM-H 138

4.5 Zirconium-Catalyzed Ethyimagnesiation of Oxabicyclic Compound 126 139

4.6 Intrarnolecular Nucleophilic Ring Opening of an Enantiomerically

Enriched of lin Unsy mmetrical Oxabicycio[3.Z. 1 Substrate I 40

REFERENCES AND NOTES

APPENDIX 1 SELECTED SPECTRA OF REPRESENTATIVE COMPOUNDS 1 54

APPENDIX 2 X-RAY CRYSTAL DATA FOR COMPOUNDS 76b. 80.85

AND 92 175

Single Crystal X-Ray Determination of 76b 176

Single Crystal X-Ray Detemination of 80 182

Single Crystal X-Ray Determination of 85 188

Single CrystaI X-Ray Determination of 92 1 94

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List of A bbreviations

ID

Ac

Anal.

Ar

B INAP

Bn

BOC

calcd

CBZ

chx

COD

CP

d

DBU

DBP

DEAD

de

DIBAL-H

DIPT

DMAP

D m

DMF

DMSO

dppb

ee

equiv

specific rotation measured nt 589 nm

acety l

anaiysis

aryl

2.2'-bis(dipheny1phosphino)- 1.1'-binapthyl

benzy l

N-tert-butoxycarbony l

caiculated

carbobenzy Ioxy

cyclohexy 1

1 5-cyclooctadiene

cyclopentadieny l

day

1 -8-diazabicyclo[5.4.0]undec-7-ene

2.4-dibromo-3-pentanone

diethy l azodicarbox y late

diastereoisomeric excess

diisobutylaluminum hydride

diisopropy l tartrate

4-(dimethy1arnino)pyridine

1,2-dimethoxyethane

di rnethy l formamide

dirnethylsulfoxide

1 -4-bis(dipheny1phosphino)butane

enantiomeric excess

equivalen t

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i ~ r

L

LDA

L-Selectride

M

Me

NMO

NMR

NOE

Nu

Oct

Ph

PMB

p-NBA

PY

R

TBA

TB AF

TBHP

TBS or TBDMS

CBu

eihy l

Fourier trmsform

gas chromatography

hour

hexamethylphosphoric triamide

high resolution m a s spectrum

infrared

isopropy l

ligand

lithium diisopropyl amide

lithium tri-sec-butyl borohydnde

generic metal or metal ion

meihyl

4-methylmorpholine N-oxide

nuclear magnetic resonance

nuclear Overhauser effect

nucleophile

oc ty 1

phenyl

paru-methoxybenzyl

para-nitrobenzoic acid

pyridine

generic alky l group

1,1,3.3-tetrabromoacetone

tetrabutylammonium fluoride

tert-butyl hydroperoxide

tert-butyldimethylsilyl

ter?- bu ty l

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TFE

THF

TIPS

TLC

TMEDA

TMS

TPAP

tr i fluoromethanesulfonyl

2.32-trifluoroethanol

tetrahydrofuran

triisopropylsiIy l

thin layer chrornatogrriphy

tetramethy lethy lene diamine

trimethylsilyl

tetrapropy t ammonium pemthenate

room temperature

generic hdide

xii

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List of Tables

Table 1

Table 2

Table 3

Table 4

Table 5

Tabie 6

Table 7

Table 8

Table 9

Table 10

Table I l

Table 12

Table 13

Table 14

Table 15

Table 16

Table 17

Table 18

Table 19

Table 20

Enantioselective Desyrnmetrization by Deprotonation With a Chiral Base 1

Diastereoselective Synthesis of 3-Siloxy-8-oxabicycl0[3.7.1 ]octa-2.6-diene-

karboxy lates

Diastereoselective [4+3] Cycloadditions From Chiral a-Chloro [mines

Cornparison of Furan and Cyclopentadiene

Energies of Oxyallyl Configurations [kJ mol 3)

Enantioselective Reduction of Prochiral Ketone 57 CataIyzed by 58

Kinetic Resolution of 59 or 50c Using TBHP. Ti(O-i-Pr)4 and L-(+)-DIPT

[4+3] Cycloadditions Using Zn-Ag Couple

[4+3] Cycloadditions Using Zn-Ag Couple: Counter Ion Effecr

Scope of the [4+3] Cycloadditions Using Zn-Ag Couple

Epi merization S tudies

[4+3] Cycloadditions Using Diethylzinc: Initial Studies

[4+3] Cycloadditions Using Diethylzinc: Optimization Studies

[4+3] Cycloadditions Using Diethylzinc and Other Furans

Effect of an Additive on the Diastereoselectivity

[4+3] Cycloadditions Using Tetrabromoacetone

[4+3] Cycloadditions With Furfuryl Alcohol

Attempted Stereoselective Reductions of 77c

Organolithium Induced Ring Openings of Unsymmetrical Oxabicycl0[3.2.1]

Compounds

Reductive Ring Opening of Compound 123

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1. GENERAL INTRODUCTION

Oxabicyclo[3.2.1 Ioctenes have been extensively used as building blocks for the

synthesis of a wide variety of naturai products and their analogues, Scheme 1. These

structurally ngid bicyclic templates undergo facile. stereoselective functiond group

introduction a d o r interconversion and this chemistry combined with ring cleavage provides

access to simpler ring systems and acyciic chains.1-7

Scheme 1

O H

Thromboxane An \ Furanether B

Pyrrolkidine alkaloids Muscarine analogue

Rifamycin fragment Nonactic acid

in order to further expand their scope and utility in organic synthesis, however, two

limitations of the existing methods for the preparation of oxabicyclic compounds must be

overcome. The most pressing requirement is the need to develop a practicai and general

method for the synthesis of unsymmetrical oxabicyclo[3.2. lloctenes as single enantiomers.

In addition, if the methodology is to be applicable to the synthesis of stereochemicdly

complex acyclic "pentads" and rings, diastereomeric cycloadducts must be made available.

The focus of my research project has provided a solution to this problem by the development

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of a highIy diastereoselective intermolecular [4 + 31 cycloaddition reaction between chiral 2-

furyl carbinols and oxyaliyl cations generated from a polybromoketone. Before disclosing

the details of this smdy, an overview of alternative asymrnetric smegies to the usymmetricai

oxabicyclic core will be discussed. In addition, a bnef introduction to the [4+3]

cycloaddition reaction wili be provided.

1.1 RACEMIC ROUTES TO OXABICYCL0[3.2.1] SUBSTRATES

A number of useful methods for the construction of racemic unsymmetrical and

symmetrical8-oxabicyclo[3.2. lloctenes have k e n developed over the past 25 years, Scheme

2. The most widely established procedure is the [4+3] cycloaddition between oxyallyl

cations generated from a polybromoketone and a furan. 1.8 Fint developed by ~offmann.8~

this method has since been optimized by various research groups and new ways of

generating allyl cation intermediates continue to be reported. Reviews of this reaction have

covered the synthetic and mechanistic aspectsl-8ac and are briefly summarized in parts 2 and

3 of this thesis. An alternative to the [4+3] cycloaddition strategy is the Lewis acid catalyzed

annulation of 1,4-dicarbonyl compounds with 1-3-bis(trimethylsily1)oxy di en es?^-^

Metastable aromatic pynlium species undergo [5+2] cycloadditons with olefins to also

generate l3.2.11 oxabicyclic denvaùves. This reaction has been reviewed by Sammes and

Kairitzky.9 Recently, rhodium carbenoids have been show to react with furan derivatives to

generate oxabicyclo[3.2.l]octadienes through the formation and remangement of

divinylcyclopropane intemediates. 10 Al1 these reactions and other miscellaneous reactions

have been documented in a comprehensive review by Lautens and Chiu.le

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Scheme 2

TMSO OTMS

U O M e

tandem cyclopropanation /Cope / P+21 \

1.2 ASYMMETRIC ROUTES TO CHIRAL OXABICYCL0[3.2.1]

SUBSTRATES

1.2.1 Asymmetric Desymmetrization Reactions

Previously, asymrnetric derivitkation of meso oxabicyclic cornpounds was the ody

effective way of generating enantiomerically e ~ c h e d oxabicyclic compounds. In 1993,

Simpkins and coworkers were the fmt to report the asymrnetric desymmetrization of a meso

oxabicyclic substrate via an enantioselective deprotonation by a homochiral base 1. Table

1 summarizes the results of their study. Enantiomeric excesses of about 85% could be

achieved after a denvatization reaction and the ee could be m e r improved by successive

recrystallizations.

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Table 1. Enantioselective Desymmetrization by Deprotonation with a Chiral Base 1

.

Entry Product Substrate Reaction Yield ee'

TMSCI,

1 >(Em TMS >em THF. -94 O C

THF, -94 OC

' ee after recrystallization in brackets

Asymrnetric hydrometailation on the alkene hctionality is another effective approach

for generating a chiral oxabicyclic starting material. Recenrly, Lautens and Ma demonstrated

that the oxabicyclic substrate 2 could be asymrnetricaily hydroborated yielding the exo

alcohol 3 with high enantioselectivity, eq 1. l 2 This in tum was converted to

cycloheptadienol4 in three steps in high enantiopurity.

1. (-)-lpc2BH, THF, -25 OC ?- - C Lw' - 2. NaOH, H202 HO

8?%, 95% ee OTBDMS

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While asyrnrnetnc desymmetrization of rneso oxabicyclic alkenes can serve as a

powerful tool for the synthesis of enantiomerically enriched unsymmetrical 8-

oxabicyclo[3.2.1]alkenes, a more efficient and convergent approach would be to develop a

one step enantioselective or diastereoselective annulation method. Within the last year, four

different asymmetric approaches to the unsyrnmetrical oxabicyclic framework have been

reported. One of the methods uses a novel tandem asyrnmetric cyclopropanation/Cope

remangement between a vinyl carbenoid and furan. The other three strategies utilize

diastereoseiective intermolecular [&3] cycloacidition reactions. In addition, diastereoseIctive

intramolecular [4+3] have been reported. These strategies are the subject of discussion in the

following sections.

1.2.2 Asymmetric Tandem Cyelopropanation/Cope Rearrangement

In late November of 1996, two independent yet complementq asymmetric

approaches to the unsymmetrical [3.2.1] oxabicyclic framework were reported. In addition

to the approach described in this thesis, Davies and coworkers employed a tandem

asyrnmetric cyclopropanation/Cope remangement between a vinylcarbenoid and a furan, lob

as illustrated in Table 2. Asymmetric induction in these reactions was achieved by using a

chiral auxiliary on the carbenoid. Table 2 summarizes some of the results of their work.

Based on their experimentai findings, both moderately electrondonating and electron

withdrawing substituents c m be tolerated on the furan (i.e. R2) without an appreciable

change in the diastereoseiectivity or overail yield for the oxabicycie formation. However,

substitution at R3 Ied to a decrease in diasteroselectivity from 94% to 82% with ( R ) - t

pantolactone as the auxiliary (cf enaies 4 and 7 respectively). Endo products were observed

when Rl=Me, even though the starting dinomethane was a 9: 1 ZIE mixture. Thus a third

stereogenic center could be introduced into the oxabicyclic system with a diastereomenc

excess of 95% (entry 8). Overall, (R)-pantolactone was found to be the best chiral auxiliary

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6

because it gave the highest levels of asymmetric induction (82-95% de). The (9-lactate

auxiliary was also promising giving oxabicycles of the opposite absolute stereochemistry

after removal of the chiral auxiliary.

Table 2. Diastereoselective Synthesis of 3-Siloxy-8-oxabicylo[3.2.l]octa-7,6-diene- î-carboxylates

de, % Yie'dv ''O (abs. stereochem)

1 Me H H H 72 2 H Me H 81 3 H COMe H 74 79

4 H H H 82 5 H Me H 9-l 6 COMe H €6 7 H H COOMe 65 82 8 O Me H H 75

The asymmetric induction observed in these reactions is rationalized by assuming that

the carbonyl group of the auxiliary interacts with the carbenoid, Figure 1. The interaction

allows efficient aansfer of the chiral information from the stereogenic center in the auxiliary

to the carbenoid position, but the extent of the interaction is Iimited such that the species stdl

has carbenoid reactivity ratber than ylide reactivity.

Figure 1

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7

The observed regio- and stereochemical outcorne of the reaction is consistent with a

tandem c yclo propanationKope rearrangement in whic h the fm t c yclopropanation occurs in a

non-synchronous mode with initial interaction at the sterically more accessible Zposition of

the furan. The favoured interactions with the carbenoid for the (S)-lactate and (R)-

pantolactone auxiliaries are expected to minimize steric interactions between the aufiary and

the "wall" of the catalyst. Scheme 3. The overall effect is to block one of the two faces of the

vinylcarbenoid intermediate to approach by the furan. Depending on which auxiliary is

chosen, either the (IR) or (13 oxabicycle is formed.

Scheme 3 n

si face attack

1

R+o,xc TBDMSO

OMe

re face - 1

OTBDMS

co2xc

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1.2.3 Diasteroselctive Intramolecular [4+3] Cycloadditions

The intramolecuiar [4+3] cycloaddition reaction of allylic cations with dienes is a

promising reaction for the synthesis of fused seven-mernbered and other ring systems.13

Uniike intermolecular processes, intramolecular cycloadditions are enrxopically favoured and

are inherently supenor in t ems of regio- and stereocontrol. Asymme~c versions of these

reactions have been reported and are discussed below.

Schultz was among the fmt to demonstrate that photogenerated oxyaüyl cations could

undergo an diastereoselecrive intramolecular cycloaddition when terhered to a furan;14 an

example is illustrated in eq 2. Presumably, remangement to the oxyallylic species 5 is

followed by an intramolecular [4+3] cycloaddition. The stereocenter exerts complete

regiocontrol over the facial selectivity of the process, as might be expected. Cornplete endo

selectivity assures the formation of a diastereomericaüy pure product.

O

A c 0 PhH, 3h quantitative OAc

In a related reaction, West and coworkers found that photolysis of pyrone 6 resulted

in the formation of two cycloadducts Sa and Sb in a ratio of 1.5: 1.15 Facial selectivity was

complete, and relative stereocontrol provided by the resident stereocenten in intermediate 7

led to addition anti to the epoxide ring. However steric factors lead to poor endolexo

selectivity .

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Scheme 4

Hannata also demon

b,

VYCOR

strated that high levels of a symmetric induction could be

achieved by placing a stereogenic center three carbons away from a furan tethered to an

oxyaiiyl cation precursor as in 9. Scheme 5-16 The major product is said to arise via a

transition state lob where severe 13-aIiylic interactions are largely avoided (cf figure 10a).

In contrast, substitution at either the Ci* or C2- carbon lead to poor overall

diastereoselectivity .

Scheme 5

OEt

1 Oa (Disfavoured) 10b (Favoured)

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10

1.2.4 Diastereoselective Intermolecular [4+3] Cycloadditioos Using Chiral

Oxyallyl Cation Precursors

While examples of catalytic asymmetnc intermolecular Diels Alder reactions with

furan have recently been reponed. l enantioselective approaches to the bridged seven

membered oxabicyclic skeleton via a [4+3] route have yet to be developed.

Diastereoselective intermolecular [4+3] cycloadditions. on the other hand, have been

reported. Two of the examples reported, which appeared after our initial discovery, rely on

the use of a chiral oxyallyl cation precursor as a source of inducing asymmetry in the

reactions. The third approach developed by Our group utilizes a chiral furan for its source of

c hiraliîy .

Chiral 2-Aminoallyl Cations

In search of a chiral aWLiliary which could mediate the asymmeuic version of a [4+3]

cycloaddition between a furan and a 1.3-dimethyl-2-oxydyi cation, Kende and Huang found

that chiral a-chloro imines 11 could serve as efficient precursors to chiral 2-aminoailyi

cations. These cations are subsequently uapped by furan in a facial endo selective [4+3]

fashion to give iminium salts. 12.18 Mild hydrolysis cleaves the chiral amine auxiliary in the

adducts to yield chird 2,2'-disubstituted-8-oxabicyclo[3.2. lloctenone derivatives 13. The

a-chioro imines were readily obtained from the corresponding a-chloro ketones and

cornrnercially available (S)- 1 -ethyl amines. The "enantioselective" [4+3] sequence was

initiated by treating 11 with 1 equiv of ~ g B F ~ l 9 in CHzC12 in the presence of excess furan.

followed by acid hydrolysis (2 Y aq HC1-acetone, 1: 1). Table 3 illustrates sorne of the

results of their study.

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Table 3. Diastereoselective 1431 Cycloadditions from Chiral a-Chloro m e s

acetone

EntW R Yield, O h ee, O/O

1 Chx 24 2 Ph 37 3 Naphth 17 4 4-NO2+ h 5

For most of the chiral imines examined, rnoderate yields and enantiomeric excesses

(less than 60%) were obtained. Imines having buikier and electron poor substituents (entries

3 and 4 respectiveiy) gave both lower yields and ee's.

A tentative hypothesis for the observed cycloaddition diastereoselectivity was

suggested (Scheme 6). The authors propose the additional enhancement in the ee for the aryl

derived chiral auxiliary is due to a possible aUyl cation-arene x interaction; given the two

possible aliyl cation-arene interactions (rotamers 14 and 15), the furan attacks preferentially

from the less hindered re face of 14 (back face) and not the si face of 15 (front face).

Scheme 6

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Chiral Allylic Cation Derived from a Chiral Allylic Acetal

Following Our report, Harmata and Jones have pubiished a diastereoselective

intemolecular [4+3] cycloaddition reaction using a chiral allylic cation derived From a chiral

(trimethyisi1yi)methyl allylic a ~ e t a l . 2 ~ From their initiai studies using achirai acetal

precursors 16, they found that endo adducts 18 could be prepared in moderate to excellent

yields, eq 3. Mechanistically, a putative transition state as in 17 may explain the endo

selectivity .

The authors then demonstrated the potentiai of their methodology by incorporating the

chiral acetal 19 into their studies. In a single experiment, cycloaddition with 19 and furan

under similar reaction conditions gave 45% yield of cycloadduct 20 with a

diastereoselectivity of 9: 1, eq 4. No mention was made of the absolute stereochemisûy in the

derived product.

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1.2.5 Diastereoselective Intermolecular [4+3] Cycloadditions Between

Chiral Furans and Oxyallyl Cations

As part of our group's ongoing interest in designhg novel synthetic strategies which

would address the need to synthesize stereochemically complex acyclic and polycyclic

systems in a convergent manner. we have explored the synthetic potential of both

symmetrical and unsymmetrical oxabicyclic alkenes. Our earlier efforts have revealed that

compounds of generd structure 21 undergo SN^' ring opening in a stereo- and

regiocontrolled manner, rapidly generating cycloheptenols 22 with up to five contiguous

stereocenten, Scheme 7. Both intermolecu1ar~~-**le and intramole~ular2~ variations of th is

reaction have been reported. What remained was to develop an asymmetric approach based

on the oxabicyclic ring opening. Two possible strategies could be envisioned. One would

be the development of an enantioselective ring opening reaction on a meso oxabicyclic

compound. An alternative strategy would require the development of an asymmetric route to

enantiomerically pure unsymmetrical oxabicyclic stamng rnaterials.

Scheme 7

Nu' C

.c10R2

SN^' ring opening VR, ~4

The focus of this research has been to provide a solution to the latter problem via the

development of a diastereoselective intermolecular 14 + 31 cycloaddition reaction between a

chiral 2-furyl carbinol and an oxyallyl cation, Scherne 8.25 It was found that initial

deprotonantion of the hydroxyl moiety on the furan 23 with a divalent organometallic reagent

followed by cycloaddition with 1,3-dimethyl-2-oxyallyl cation (generated in sim from 2,4-

dibromo-3-pentanone in the presence of a reducing agent) provided access to crystaliine

adducts 25 in high diastereomeric excess. Moreover, the stereochemistry of the product

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14

dictated that the reaction not only arose from a chelate controlled facially selective

cycloaddition but aiso fiom an unprecedented exo transition state, 24. Hence, previously

unavailable cycloadducts could be made in moderate to good yields.

Scheme 8

RMX, Zn-Ag, THF or

Et2&, THF

O

Before discloshg the details of our cycloaddition study (part 3 of this thesis), a brief

ovewiew of the [4+3] cycloaddition mechanism as well as our rationale behind the design of

some of the selected chiral furan starting materials will be presented. The various methods

that were used to synthesize some of Our chirai furans will also be described. These topics

cm be found in parts 2 and 3 of this thesis.

Finally, some applications of the resulting cycloaddition study to the synthesis of

enantiomericdly enriched cycloheptenols using various ring opening reactions that were

developed by Our research group are presented in part 4 of this thesis.

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2. AN INTRODUCTION TO THE [4+3] CYCLOADDITION AND ITS

MECHANISM

2.1 Preparation of Oxyallyl Cations

The [4n(4C) + 2x(3C)] cycloadditon reaction between a furan and an oxyaliyl cation

is a powerful method for the constnicuon of 8-oxabicyclo[3.2.1]octenes.~~~ Of the many

ways to generate 2-oxyallyl cations, the most useful is the reaction of an a,af-dihaloketone

26 with a reducing agent, Scheme 9. lnitially, halopnated metai enolates of type 27 are

formed and the oxyaiiyl cation (28) is then generated by subsequent elimination of the haiide

ion. Scheme 9 illustrates some of the reducing agents which are capable of forming 2-

oxydyl cations fiom a polybromoketone.

Scheme 9

R = Me, Ph, H, Br

Other methods of generating oxyallyl cations and other allyl cations include the

heterolysis of an allylic halide with a Lewis acid. The silver salt route remains perhaps the

most useful and versatile procedure, especiaiiy when very reactive ailyl cations are involved

and all other methods and Lewis acids fail, Scheme 10.26

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Scheme 10

X = CI, OH, 0COCF3 Y = OTMS, alkyl, OR, NR2

Another common method is the combination of a-halo ketones and bases. Readily

available lithium perchlorate-triethyl amine in ether is effective for reactions with a-chloro

and a-bromo ketones, owing to the formation of insoluble triethylammonium halide.Z7

Base-induced reactions of a-halo ketones generate weakly electrophilic 2-oxyallyl cation

intermediates which react specificaliy with nucleophilic dienes such as furans.28

Oxygenated cycloadducts are possible by the reaction between a heteroatorn-stabilized

allylic cation and furan. Albizati and Murray, for example, demonstrated that the

triakylsilylenol ether 29 derived from pyruvaldehyde dimethylacetal reacts with 2-rnethyl

furan in the presence of a Lewis acid to afford one regioisomeric cycloadduct 31, Scheme

1 1 .29 The reactive three carbon intermediate in these cases was the triallcylsilyloxyally1

cation, 30.

Scheme 11

P OTMÇ Lewis Acid

M e 0 -

OMe OMe

30

Lewis Acid = TMSOTf (cat.), SnBr4, SnCI4, TiCI4, SbCI5, BCI3, or Ph3C+BF4-

Other ways of generating three carbon reactive allyl cation intermediates have been

extensively reviewed. l

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2.2 Mode of Attack of 1,3-Terminally Substituted 2-Oxyallyl Cations

Once generated, terminally substituted 2-oxyallyl cations can undergo a [4+3]

cycloaddition reaction with a furan in a stepwise (32) or concerted manner. the latter case

being further subdivided into compact (34) or extended modes (36). Scheme 12. The

terminology endo and exo is also used to describe the compact and extended modes of

addition respectiveiy.

During concerted bond formation, the configuration of the oxyallyl cation remains

intact. Assurning a W-coafigured oxyallyl cation, a compact mode of addition results in "ee"

product formation where both Cz and C4 methyl groups are cis diequatorial in the seven

membered ring (as in 35). Similarly, "an" products in which both C2 and C4 methyl groups

occupy the axial position (38) arise from an extended transition state. A stepwise reaction in

which a cationic intexmediate (32) results may give al1 three aa, ee. ae products (the latter

notation is reserved for the axial/equatorial orientation of methyl groups at C2 and C4).lac

Scheme 12

MLn 'Y+

34 35 (ee)

,MLn O

- a = stepwise

0 b = concerted, compact c = concerted, extended

O 36 37 38 (a)

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2.3 Eletrophilicity and the Mode of the Cycloaddition

Based on knom experimental fmdings, Hoffmann has compiled a wide array of data

and has established a correlation between the electrophilicity of the oxyaiiyl cation and the

mode of the cy~loaddit ioa.~~ In general. the electrophilicicty of oxyallyl intermediates

decreases along the series: iron oxyallyl 2 siloxyalIy1 > zinc oxyallyl > Iithium oxyallyl >

sodium oxyailyl > cyclopropanone ("oxidodlyl"), Furthermore. it has been noted that the

more electrophilic aily 1 cation intermediate has a greater propensity toward exîendedstepwise

attack on the diene. Furan, more than cyclopentadiene. favours the compact mode of

addition, Table 4.

Table 4. Cornparison of Furan and Cyclopentadiene

reducing agent X ee aa ea

NaIfCu, MeCN CH2 13 87 Zn-Cu, DME CH2 37 63 Fe2(CO)9, C6H6 CH;! 54 46

Naf/Cu, MeCN O 91 3 6 Zn-Cu, DME O 74 9 17 Fe2(CO)9 0 44 4 %

It is apparent that the reactions of 2.4-dibromo-3-pentanone with the more electron

ricn cyclopentadiene in the presence of three different reducing reagents are stereoselective:

only ee products and aa products are formed. There is no leakage into the ea series. In

contrat, with furan there is some eu product formed. Based on these findings, it has been

suggested that: a) W-configured allyl cations are generated stereoselectively as the only

significant species, and b) these ions are captured by cyclopentadiene via compact (34) and

extended (36) transition States. In other words, the ee:aa ratio is identical to the steric course

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of attack, i.e. compact vs extended. From the ratios observed, sodium oxyailyl is the

weakest electrophile while iron oxyallyl is the strongest. Any oxyaliyl cation which gives a

ratio smaller than 0.89: 1 is considered to be more electrophilic than the iron oxyallyl species.

In the presence of furan. al1 three products (aa, ee, and ea) are formed. It is

suggested in these cases that W-configured allyl cations are generated initially, but they

partiaüy Iose their configuration once a cationic intemediate of type 32 has been gnerated:

attack at either face of the rc enolate system in 32 is possible, giving d l three epimenc

adducts-

2.4 Precedent for W-Confipred Oxyallyl Cations

Based on the experimental findings with cyclopentadiene. it was suggested that W-

configured oxyallyl cations were formed stereoselectively, regardless of the reducing agent

used. Indeed, it would be advantageous to be able to design experirnents which would

support the hypothesis that W-configured oxyaiiyl cations prevail under the given reaction

conditions.

In one of the earliest reported cases. Schleyer and coworkers had prepared and

characterized al1 three U, S and W shaped 1.3-dimethylailyl cations stereospecificaily using

low temperature NMR techniques.30 From their studies, they were able to caiculate the

energy of activation upon conversion fkom the U shaped allyl cation (39) to the S (40) and

from S to W (41), Scheme 13. Olah had reported sirnilar energy of activation parameters for

the same allyl cations? In addition, they have found that the U shaped allyl cation is

cleanly converted to the sickle shaped S conformer at - 10 OC with a half life of about 10 min,

while conversion from S to W occurs completeiy at 35 OC with about the sarne half Me; the S

form h a been estimated to be more stable than the U form by 6.5 kcai/mol. However, it is

interesting to note that considerable efforts to trap these cation by conjugated dienes have

been unsuccesfil.

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Scheme 13

Ea = 17.5 kWmol Ea = 24.0 W m o l C .

tln = 10 min tlR = 1 O min + -100 OC 35 O C

39 40 41

Preference for a W-configured formyloxyallyl cation has k e n reported by Hoffmann,

Scheme 14.8~ Upon treatment of a m i x m of 2-dirnethylamino4methylene- 1 -3-dioxolanes

42 or 43 witb trace amounts of acid or adventitious water followed by trapping with furan,

cycloadduct 46 was isolated as the only product where both methyl groups were cis

diequatorial. The reaction was monitored by the Liberation of dirnethyl amine gas. The fact

that both 42 and 43 gave the same product implied that the reaction went through a comrnon

intermediate; the obvious rationale intemediate was assigned to the racemic dioxolenium ion

44. This intermediate could open a priori to the 1,3-dirnethyl-2-formyloxy allyl cation of

either W (45a) or S (45b) configuration. However, since the methyl groups in the derived

cycloadduct 46 were ris diequatorial, it was concluded that the W dlylic cation (45a) was

formed stereospecifcally at the exclusion of the sickle shaped ailyl cation, 45b.

Scheme 14

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Recentiy. Hoffmann, Vinter and Goodman calculated the preferred shape of oxyailyl

cations in ring systerns.32 As part of their model studies. they also calculated the energies of

the three possible configurations that an acyclic oxyailyl cation may possess, at three different

levels of theos.. The calcuiations were performed on both the naked oxyallyl zwitterion, and

on the protonated f o m (Table 5). The latter was used to serve as a better model for the metal

oxyallyl cation, which is usuaily the active electrophilic species in cycloadditions to

conjugated dienes. They arbitrarily assigned an energy of zero kJ mol-1 to the S

configuration and calculated the relative energies of the corresponding W and U shaped

oxyaUyI cations.

Table 5. Energies of OxyaUyl Configurations FI mol-']

MM2 1 -446 1 relative to Ç 0.00 18.13

In general, five of the cornparisons showed good correlation (the sixth at the RHF/6-

3 1G** level of optimisation could not be calculated due to a possible coliapse of the naked S

and U shaped oxyallyl cations to three membered rings, presumably by a Favorsky-type

collapse). For both the oxyallyl and the O-protonated species, the W configuration has the

lowest energy, and the U configuration the highest. The W configuration is between 2.5 and

17 kJ mol-' lower than the S; the U configuration is 10 and 30 Id mol-1 higher. The results

may be explained quaiitatively by noting that a U shaped oxyaiiy cation aiways suffers from a

bad steric interaction between the two methyl groups at the tips of the U. The W oxyallyl

RHFI6-31 G" (hartrees)

relative to S - - -

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cation, on the other hand, suffers the least amount of 1,3-strah and thus is the most stable of

the t h e .

While the above combined molecular modelling / ab initio caiculations are

informative, there is no mention of a rotational energy barrier calculation. Moreover, no

solvent or temperature specifications are noted (presumably a vacuum is used as the solvent

in these calculations). In other words. while the above calculations may agree well with

Hoffmann's interpretation of the steric course of the cycloaddition.Ic there still is the

possibility that a sickle shaped cation (S) rnay be responsible for producing ea products in the

cycloaddition with furan, thus they should not be ruled out.

2.5 Structural Assignments by 1H NMR Spectroscopy

The configuration of 1 -substituted-8-oxabicyclo[3.2.1]oct-6-en-3-ones which are

substituted at CZ and Cq c m readily be deduced from the coupling constants 3 ~ ~ ~ 2 . For exo

4-H as in 47, 3J = 4.5 - 5 Hz; for an endo 4-H as in 4 8 . 3 ~ < 1.5 Hz. The fact that there is

such a small coupling constant associated with 48 suggests that the preferred conformation

of a CyC4 diaxial substituted cycloadduct is in fact in its boat form 49. where the angle

between the bridgehead H and pseudo axial H is close to 90 O. This result can be rationalized

qualitatively by noting the 1,3-diaxial interaction of the aikyl groups in 48.

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3. DLASTEREOSELECTIVE INTERMOLECULAR [4+3] CYCLOADDITIONS

BET'WEEN CHIRAL FURANS AND OXYALLYL CATIONS:

A ROUTE TO ENANTIOMERICALLY ENRICfIED CYCLOADDUCTS

3.1 INTRODUCTION

With the need to develop an efficient and general strategy for the preparation of

unsymmetrical oxabicyclo[3.2. lloctenes, we investigated the diastereoselectivity in the

intennolecular [4+3] cycloaddtion reactions between chiral furyl alcohols/ethers or sulfoxides

and 1,3-dunethyl-2-oxyallyl cation. Most of the fûrans that were selected for our snidy are

available as single enantiomen; their preparations are discussed in section 3.2 of this thesis.

Rationale Behind the Design of the Furan : High Diastereofacial Selectivity

The choice of the side chah on the furan was based on the notion that a metal ion

(such as a divalent zinc or magnesium ion) could chelate with the furan and side chah

oxygens thus restricting rotation around the C*-Ci* bond, structure 56 in Scheme 15. The

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steric buik of the R' group would then d i c w the sense and the level of the facial selectivity

in the cycloaddition. Approach of the oxyallyl cation from the side opposite the bulky R'

group would be expected (Le. bonom face) and the relative stereochemisay at the bridgehead

carbons (C* and Cg) would be ultimately controlied by the stereochemistry at Cl-. "Non-

chelated" cycloadducts (53 or N) may arise from rotamer 55.

Scheme 15

"non-chelated" cycloaddition

approach from top face

"c helated" cycloaddition

approach from bottom face

N = non chelated C = chelated

Additionai Criteria for Diastereoselective [4+3] Cycloadditions

In addition to high facial selectivity, a highiy diastereoselective [4+3] cycloaddition

would also require control of the mode of aaack of the oxyaIlyl cation which is respoosible

for setting the stereochernistry at CL and C4. AS illustrated previously in Scheme 12. [4+3]

cycloadditions Ieading to 1 -substituted-2,4-dimethyi-8-oxabicyclo[3.2.1 Ioct-6-en-3-ones

could occur in either a srepwisc or concerted manner, of which the latter is fuaher subdivided

into compacr or extended modes. Overall, one could imagine eight possible diastereomenc

products arising from a cycloaddition with a chiral furan and a 1,3-dimethyl-2-oxyallyl

cation.

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3.2 Synthesis of Chiral 2-Furylcarbinols and Sulfoxides

2-Fiirylcarbinols have shown to be vaiuabIe intermediates for the construction of

various naturd products including carbohydrates,33 macrolides and related compounds,34

pheromones35 and alkaloids36. As a result, extensive efforts have been directed toward their

asymmetric syntheses. Among the various ways optically active 2-furylcarbinols have been

made include: the asymmetric addition to a furan a l d e h ~ d e ; ~ ~ ~ o asymmetric reduction of 2-

f~.ryLketones;~l diasteroselective additions of 2-furyllithium to chiral aldehyde~;~2 and kinetic

resolution of 2-furylcarbinols.~3~

3.2.1 Attempted Asymmetric Reduction of a Prochiral Ketone

The asymrnetnc reduction of prochiral 2-furylketones is one of many ways of

synthesizing chiral 2-furylcarbinols. Both enzymatic43 and c h e ~ n i c a l ~ ~ reductions have k e n

reported with high levels of stereoselectivity.

While access to 2-furylketones have been reported in the literature.45 many of these

methods rely on the use of toxic auxiliaries and often byproduct contamination is

unavoidable. Recently, Luche and coworkers have demonstrated efficient preparations of

these subsuates via a Barbier reaction accelerated by u l t r a ~ o u n d . ~ ~ The one pot reaction

involves the sonication of a mixture 2-furyilithium (generated in situ in the presence of ten-

butyl chioride and lithium metai) and a lithium carboxylate. Interestingly. we were able to

synthesize the bulky tert-butyl furylketone 57 in good yield (83%) using Luche's extension

of the Barbier reaction, eq 5.

Li (3 equiv). 'BUCI (1.5 equiv) O BU COOL^ (1 equiv).THF. O OC

son icatio n (5 equiv) 836x3

57

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26

Oxazaborolidines have been shown to be important catalysts for the reduction of

prochiral ketones." UUnle the air and moisnire sensitive B-H oxazaborolidines, the %-Me

oxazaborolidine-borane complex of 58 is an air stable, free-flowing crystalline s o ~ i d - ~ ~ d

Both catalytic and stoichiometric reductions using this catalyst have k e n reported with high

levels of enant io~elect ivi ty.~~e In particular, aryl ketones with varying electron

donatingJwithdrawing capabilities were shown to be good substrates for this catalyst, with

ee's 1 97.0%. Encouraged by these fmdings, we attempted the enantioselective reduction of

the fqlketone 57 using the same catalyst. The resuits of our findings are shown in Table

6.

Table 6. Enantioselective Reduction of Prochiral Ketone 57 Catalyzed by 58

1) BH3-DMS (Y mol%) solvent, -20 O C

Y-B O

1 100 O toluene nr 2 100 O C H2CI2 c5 3 20 110 CH2CI2 >99 90 - - - -

nr = no reaction

It was found that use of stoichiometric arnounts of 58 (envies I and 2) gave little or

no conversion in either toluene or dichloromethane as solvent. On the otber hand, lowering

the amount of catalyst did result in complete conversion of the ketone to product. Repeated

attempts at this reaction unfortunately gave consistently low ee's (up to 50% ee). Further

investigations using less stencally demanding substituents may prove worthwhile.

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27

3.2.2 Preparation of Enantiomericaliy Enriched 2-Furylcarbinois by Kinetic

Resolution

Afier the discovery that secondary aliylic aicohols could be kinetically resolved using

ten-butyl hydroperoxide (TBHP) in the presence of a chiral titanium/tartrate catalyst (the

Katsuki-Sharpless epo~idation~~), Sato and coworkers demonstrated that the same protocol

could be applied to kineticaily resolve racemic 2-f~rylcarbinols.*~ Depending on the choice

of tartrate (either (+) or (-)-DR) either the (R) or (S)-furylcarbinol is oxidized to give the

corresponding 2H-pyran-3-(6H)-one 60 and the desired unreacted chiral 2-furylcarbinol (R)-

59, eq 6.

TBHP (0.6 equiv), T ~ ( ' P ~ o ) ~ (1 equiv),

L-(+)-DIPT (1 2 equiv) , O H

- - -21 OC

HO

The success of the protocol can be applied to a wide range of substrates (R' = aikyl,

q l , alkenyl and alkynyl) with the exception of a buiky fert-butyl group in which poor

enantioselectivity was observed (6% ee), entry 3 in Table 7. However an isopropyi derived

furylcarbinol could be resolved with >95% ee and 39% yield (entry 2). Encouraged by this

result, we atternpted the kinetic resolution of the cyclohexyl furylcarbinol 50c using a

stoichiometric amount of catalyst (entry 7). The cyclohexyl furylcarbinol gave a 46% yield

(based on racemic 50c) of the desired chiral alcohol with an ee of >99%! John Colucci of

these laboratones later showed that a cataiyuc arnount of Ti(0-i-Pr)4 worked equdly as weli

as the stoichiome~c reaction.

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Table 7. Kinetic Resolution of 59 or 50c Using TBKP. Ti(0-i-Pr), and L-(+)-DIPT

Entry Furan R' Conditions Yield, O/O ee,% (R)

1 59a Me A 2 59b i-Pr B 3 59c t-BU B 4 586 Ph A 5 59e H C=CH2 B 6 5M CECSiMe3 6 7 50c Chx B

a as determined by chiral GC (B TA colurnn) : experiment perforrned by our laboratory ; A = catalytic Ti(O-FPr)4 was used; B = stoichiometric Ti(O-FPr)4 was used

3.2.3 Diastereoselective Furyllithium Additions to Chiral Aldehydes

In order to test the generality of the diastereoselective cycloaddition, we prepared

some functionaiized 2-furytcarbinols with heteroatoms both a and P to the alcohol moiety.

One of the furans we synthesized was the known dibenzylamino alcobol 50e obtained from

a non-chelated diastereoselective addition of 2-fuql lithium to Nfl-dibenzyl alaninal, 63.42b

The authors report high anti selectivity for the reaction (9 1 :9) and that separation of the

diastereomers cm be easily achieved by simple flash chromatography.

Synthesis of the anti furyl amino alcohol was easily obtained fiom (S)-alanine as

follows, Scheme 16. Treatment of the amino acid with a slight excess of benzyl bromide in

the presence of sodium bicarbonate and a phase transfer catalyst (tetrabutylammonium

bromide) followed by refluxing in a biphasic mixture of Hz0 and CHîC12 furnished the

correspondhg Nfl-dibenzylamino benzyl ester 61 in 75% yieldS49 The ester was then

reduced to the dibenzyl alcohol 62 (82%), whose optical rotation was in good agreement

with that reported in the literature.50 Oxidation to the aldehyde (63) using Swern's

conditi0ns5~ was very efficient (96%) and 63 was used without further purification. Finally,

reaction of the crude aldehyde with furyl lithium gave a 90: 10 mixture of anti : syn amino

alcohoIs in 85% combined isolated yield.

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Scheme 16

BnBr (3.2 equiv}, Na2C03 aq. (3.2 equiv),

L Bu4N+ Br' (1 eq), O H LiAIH4, Et20 HO BnO - I,

H20, CH2CI2, reflux O O C N H ~ k3nP N B ~ ~ 75%

(S) alanine 82% 6f 62

(COC1)2, DMSO, CH2CI2 then Et3N , -63 OC

9 : i (anti: syn) - - - --

THF, -78 OC

For Our studies, the furylglycerol acetonides 51 and 50h were also prepared

according to the methods of Suzuki and Sato. The anti-addition product was easily obtained

in 901 de and 74% yield from the reaction of 2-furyllithium with (R)-glyceraldehyde

acetonide52 65 in the presence of zinc bromide, Scheme 17.42~ Preparation of the syn

diastereomer however was not as stereoselective. Sato and coworkers have demonstrated

that phenylcuprate (prepared from PMilgBr and CUI) adds to the sarne glyceraldehyde

acetonide in high syn selectivity (>99: l)? Our attempts with the corresponding

furylcuprate, however. were completely non-selective. giving a 1 : 1 mixture of the syn and

anti diastereomers. Fortunately, the desired syn furylcarbinol could be selectively

crystallized at O OC after column chromatography. The poor selectivity could be explained by

an incomplete formation of the organocuprate (prepared from furyllithium in the presence of

MgBr2 and CUI). Models 66 and 67 in Scheme 17 rationalize the observed anri and syn

selec tivies.

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Scheme 17

MgBr2, Cul (1 -7 equiv) THF-Me2S (5:1), -78 OC

n > 95% anti

74%

1

67

X = MgBr2 or RCu

50h

1 : 1

(anti : syn)

3.2.4 Synthesis of a Chiral 2-Furylcarbinol Using a Diastereoselective Aldol

Ghosh and coworkers previously demonstrated highly diastereoselective aldol

reactions between benzaldehyde and the chiral auxiliary 71 (>99: 1 syn:anrzJ, derived from

the corresponding cis- 1-amino-2-hydroxyindane 70.j4 We envisioned the synthesis of the

fqlcarbinol50f arising from a similar diastereoselective aldol reaction between furfural and

71. Illustrated in Scheme 18 are the steps taken to prepare the furylcarbinol.

Preparation of the N-acylated oxazolidinone (71) is descnbed by Ghosh in the

literature.j4+55 Thus, reaction of 71 with di-n-b~tylborontriflate5~ and triethylamine (-78 OC

to O OC) foilowed by condensation of the resulting boron enolate with furfural gave 64% of

predominantly the aldol adduct 72 (>95:5) as determined by lH NMR. We have shown

that the reaction can be carried out on large scale (3 g) with almost no change in the yield or

ratio. Removal of the auxiliary was achieved with L i B a (84%) and subsequent protection

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of the prirnary alcohol as its TBDMS ether using standard conditions gave 54% of 50f dong

with some of bis-TBDMS ether (23%). Preparation of the opticaily active mono-silared

hirylcarbinol bas k e n made previously via enrymatic reduction of the corresponding ketone

Scheme 18

1 ) Bu2BOTf, CH2C12 -78 OC 2) EbN -78 - O O C then

1) (Eto)$O, K2C03 2) n-BuLi, THF, EtCOCI,

O OC - rt & fl R 67%

> 95% de

1 ) LiBH4, THF, O OC 2) TBSCI, irnidazole,DMF

3.2.5 Attempted Preparation of a Chiral Furylsulfoxide

To add to Our collection of chiral furans, we attempted the asymmeuic synthesis of

the chiral furyl sulfoxide 52. For this synthesis we relied on the chernistry of the (-)-menthol

derived chiral sulfinate ester 73 whose utility in chiral sulfoxide preparation has been

d e m ~ n s t r a t e d . ~ ~ Unfortunately, wlule we found that THF was the optimal solvent for the

preparation of the furyl sulf~xide in terms of yield (eq 7), the optical rotation of the new

furan was only +OS O in CH.313 (c = -0.5). suggesting that racemic sulfoxide had been

formed from the reaction. Our speculation was later confmed after one of our cycloaddition

reactions when X-ray analysis of the major cycloadduct reveded the adduct was racernic.

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Other routes to chiral sulfoxides have been reportedw and may prove to be better alternatives

for the consûuction of 52.

-0 .. C

THF, O OC (2h)

3.3 RESULTS AND DISCUSSION

3.3.1 Intermolecular [4+3] Cycloadditions With 2,4-Dibrorno-3-pentanone

Using Zn-Ag couple

In Our initial studies, we employed reaction conditions fint descnbed by Noyori and

Sato (Zn-Ag couple)8d for the generation of the oxyallyl cation from 7.4-dibromo-3-

pentanone (74 or DBP), Table 8. The reaction, which is reminiscent of a Reformatsky

reaction, liberates zinc bromide through the course of the reaction. We thought that perhaps

the resulting zinc bromide could chelate with the oxygen of the furan and thus the reaction

would occur via the chelate 56 (see Section 3.1).

The fnst furan that we studied was the furyl methyl ether 50a. After considerable

optimization, the best conditions estabiished for the cycloaddition using Zn-Ag couple

resulted in a highly diastereoselective reaction but in poor yield (entry l)? Contrary to our

expectations of a "chelated" cycloaddition, the major diastereomer produced in this case was

the "non-chelated" diequatonal adduct 75a, in accord with the reaction via rotamer 55.

Conversely , cycloaddition with the free alcohol 50b gave predominantly "chelate-

controlled" adducts in moderate yield but lower diastereoselectivity (entry 2). In order to

enhance the diastereofacial selectivity, the hydroxyl group was deprotonated with a divalent

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organometallic reagent followed by cycloaddition with DBP (entry 3). Interestingly, use of

the magnesium alkoxide resdted in preferentid formation of the product with methyl groups

situated at Cs and C4 in a diaxial orientation (adduct 77b). To our knowledge, this was the

frst instance of diaxial products predominating in a [4+3] cycloaddition with a furan and a

1,3-disubstituted-2-oxyallyl cation and thus warranted funher snidy.

Table 8. [4+3] Cycloadditions Using Zn-Ag Couple

1. A , O ° C -

O R 2. 74 (1 equiv) 0°C(2h) O then rt (20 f i )

50a (R = Me) b (R = H)

EntV Furan Conditions, A a Yield 7576:fl

1 SOa Zn-Ag, DME =/O 92: 8:O 2 SOb Zn-Ag, THF 4560?! 27:57:16 3 SOb EtMgCl then Zn-Ag, THF 50% 1 1 :30:59

a Typical conditions: 1.4 equiv furan, 1.4 equiv RMX (Entry 3). 2.5 equiv Zn-Ag couple, 1 equiv 74 (DBP). Deprotonations were camed out at O OC (10 min) and subsequent cycloadditions were done at O O C (2 h) then it (20 h). All reactions were done at 0.8 M with respect to the furan. Combined isolated yield. Measured by capillary GC (HP 5 column).

Structural Proof of Diequatorial Adducts

Fortunately, we were able to obtain crystals of 76b suitable for X-ray andysis which

confirmed the stereochemisvy of the methyl groups and the facial selectivity of the

cycloaddition (Figure 2). Moreover, an independant oxidation of 7Sb and 76b using

catalytic TPAP (10 mol %) and 2.5 equiv MA060 gave the same diketone 78, indicating that

75b and 76b were epimeric at the Cl* hydroxyl. Structural proof of 75a and 76a was

achieved chemically by methylation of 75b and 76b at the C 11 hydroxyl respectively ,

Scheme 19.

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Figure 2

Structure 76 b

Scheme 19

TPAP (10 ml%) TPAP (1 0 rnoPh) , NMO (2.5 equiv) NMO (2.5 equiv)

H Of,.. 2 yv%o M S , Mec"

Wh O

X-Ray (+/ -) 78 75b

1 NaH, Mel. O OC, THF NaH, Mel, O OC, THF

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Structural Assignment of Diaxiai Cycloadduct 77b

1H NMR andysis of 77b gave a singlet for the bridgehead proton at Cs indicative of

an axial orientation of the C4 methyl group (see reference Ic and Section 2.5 of this chesis for

a discussion on how configurational assignments are made for methyl groups situated at C4

in a 1 -substituted-2,4-dimethyl-8-oxabicyclo[3.2.1]oct-6-en-3-ones). Furthermore.

epimerization of 77b using base (!BuOK in BUOH) gave the known adduct 76b and a new

cycloadduct 79b in a 3:l ratio respectively, thus confirming the stereochemisuy at Ci1.

What remained was the assignment of the stereochemistry at C2. We were able to obtain a

crystal of the reduced adduct of 79b (structure 80 in Scheme 70) suitable for X-ray

difiaction thus supporting the assi,pnent of an axial configuration of the methyl group at Cz

in 77b, Scheme 20.

Scheme 20

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Counter Ion Effects

WhiIe enhancernent in the overall facial selectivity was observed with the use of a

magnesium aikoxide. a variety of other counter ions were screened in order to improve the

diastereoselectivity of the cycloaddition (Table 9).

As iUustrated in Table 9, the metallic species are classed as mono-, bi- and polyvalent

according to the charge on the metal ion. From the range of counterions that we studied, al1

gave high diastereofacial selectivity (Le. chelated cycloadducts >> non-chelated). Both

mono- and polyvalent counterions gave poor diastereoselectivities (entries 2-3 and 8-9

respectively). On the other hand, a zinc alkoxide prepared from the deprotonation of the

furan's Cl# hydroxyl group with n-PrZnI was far better than the magnesium salt. resulting in

almost exclusive chelationcontrolled diaxial adduct 77b (enay 5).

Proposed Mechanism

At this stage of our studies, we needed a working hypothesis which would explain

the observed facial (chelated products) and stereoselectivity (aa methyl groups) upon

deprotonation with a divalent organometallic reagent. We proposed that a divalent metal such

as Zn2+ (or perhaps an aggregate containing zinc ions) may act as a tether between the furyl

alkoxide and the oxyallyl cation, resulting in a complex as in 81. This would explain the

observed facial and exo selectivity. Like Hoffmann, we propose initial formation of a W-

configured oxyallyl cation; whether this is uapped in a concerted or stepwise manner is

uncertain at this point and will require funher investigation.

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Table 9. [4+3] Cycloadditions Using Zn-Ag Couple: Effect of the Counter Ion

O H * H*O

1. A , Zn-Ag O

Co O OC, THF 75b 76b

2. 74 (1 equiv) O H 0°C(2h)

then rt (20 h)

50b

Deprotonation Conditions A a

1 Zn-Ag, THF 45-60 27:S:16:0

2 NaH 42 28:60: 12:O

3 monovalent [ MeLi 16 1 029:49: 1 2

4 EtMgCl 50 1 1 : 3 0 : S O

5 49 0:394:3

6 divalent

42 31 :60:9:0

8 polyvalent Ti(0-CP r)4 30 16:6222:0

9 NaH/17(0-i-Pr)4 37 16:55B:O

a Typical conditions: 1.4 equiv furan, 1.4 equiv RMX, 2.5 equiv Zn-Ag couple, 1 equiv 74 (dibromopentanone). Deprotonations were canied out at O OC (10 min) and subsequent cycloadditions were done at O OC (2 h) then rt (20 h). All reactions were done at 0.8 M with respect to the furan. Combined isolated yield. Measured by capillary GC (HP 5 column).

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Cycloadditions With Other Chiral Furans

The scope of the reaction was investigated and other furans were examined under

sirnilar deprotonaùng conditions. Table 10 sumarizes the results.

As illustrated, furans of varying complexity worked as well as we had found for

furan 50b. As for entries 2 and 3, we wanted to determine the effect of an additional oxygen

moiety on the diastereomeric raüu using the both syn and anti furylglycerol acetonides 5Oh

and 51 respectively. These studies were cmied out by John Colucci. It was found that the

presence of the Cy oxygen either enhanced or reduced the diastereoselectivity but the reaction

nonetheless gave diaxial adducts for both b s indicating that the ml alkoxide (i.e. at Cl*)

was the dominant conml element in the cycloaddition.

Table 10. Scope of the [4+3] Cycloadditions Using Zn-Ag Couple

1. EtMgCI, THF. O OC 2. Zn-Ag couple, O O C

/ isomers O

50 (or 51) 74 Br< O 0 OC (2h) - rt (20 h)

77 (or 82)

EntW Furan Major Product a Ratio Yield, %

a Typical conditions: 1.4 equiv furan, 1.4 equiv EtMgCI, 2.5 equiv Zn-Ag couple, 1 equiv 74. Deprotonations were camed out at O OC (1 0 min) and subsequent cycloadditions were done at O OC (2 h) then rt (20 h). All reactions were done at 0.8 M with respect to the furan. Ratio corresponds to major product isolated : al1 other isorners as determined by 'H NMR (400 MHz). Yield in brackets based on recovered starting matenal. Sarne conditions except used ~ P r f n l as deprotonating agent. Results obtained from John Colucci.

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Access to Diequatorial Cycloadducts

Previously, we were able to show that diaxial adduct 77b could be epimerized under

thermodynamic conditions using BuOK in BUOH to give predorninantly the ee adduct 76b

dong with the ae product 79b in a 3: 1 ratio. Other bases were also examined to see if this

ratio could be improved (Table 11). While most other conditions gave aimost the same ratio

as previously established, the use of Mg(OMe)2 gave more of the ae diastereomer 79b in

either MeOH or diethyl ether as the solvent. Subsequent refluxing of the reaction for longer

periods of time eventually lead to increased formation of the diequatonal adduct 76b. No

detectible amounts of the C2-axial/C4-equatorid isomer was formed under any of the

epimerization conditions tried. We can assume that 79b arises in part by an intrarnolecular

deprotonation by the akoxide generated at the Cl* hydroxyl. It would be worthwhile to try

some kinetic deprotonation experiments to see if the unobserved C2-axiaVC4-equatoriai

adduct can be napped.

Table 11. Epimerization Studies

--- - - - - - -- -

KOBU', HOBU', 6 h, rt 1

K2C03, MeOH , 3 d, 40 O C 1

DBU (neat), rt 1

M s ( O M ~ ) ~ , MeOH, 5 h, rt 95 1 d, reflux 39

Mg(OMe)2, Et20, 2 d, reflux 66

5 d, reflux 55

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40

Previously, Hoffmann had shown that the use of a sodium oxyallyl cation generated

from N ~ V C U * ~ gave preferential ee adduct formation with furan as the diene (see Section 2.3

of this thesis). Unfominately, our attempt at the reaction with the furylcarbinol SOb gave a

poor diastereomenc ratio. with al1 three 75b, 76b and 77b adducts fonning, eq 8. A closer

look at the ratio however did reveal some preference for ee product formation over na adducts

(3 9 1 ) Interestingly, a more electrophilic zinc oxyallyl cation gave a larger ee:aa ratio of

( 5 -3 : 1 ), contradic ting the elec trophilicity-mode of cycloaddition trends that are generally

observed in these cycloadditions (compare with entry 2 in Table 8). While no valid

explanation of these fmdings c a . be made at present. further screening of other metal oxyailyl

cations may prove worthwile.

Nal/Cu MeCN rt thenDBPor74,20h (51°) a

3.3.2 IntermolecuIar [4+3] Cycloadditions With 2,4-Dibrorno-3-pentanone

Using Diethylzinc

A more recent development in the generation of oxyallyl cations from

polybromoketones has been the use of diethylzinc.gf Developed by Mann, this procedure is

convenient for the large scale synthesis of oxabicyclic compounds.

Previously we had demonstrated that the use of a zinc alkoxide resulted in highly

diastereoselective [4+3] cycloadditions with Zn-Ag couple (entry 5 in Table 9). The

possibility that diethylzinc could also be used as both a deprotonating agent and a reagent for

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31

the generation of the reactive oxyallyl cation intermediate inspired us to investigate its

potential in our cycloaddiùon reactions.

Our intial attempts at the cycloaddition reaction with furan 50b using Mann's exact

protocol (Le. addition of 2 equiv of diethylzinc to a solution consisting of 1: 1 furan and

dibromopentanone) gave poor overall diasteroselecûvities regardless of the solvent used

(Table 12). In some instances. the results were irreproducible. While chelation controlled

cycloadducts predominated for al1 the cases studied (i.e. very Little or no 75b was observed).

we decided to optimize the conditions in hope that one diastereorner could be formed

preferentially .

Table 12. [4+3] Cycloadditions Using Diethylzinc; Initial Studies

(1 equiv)

(1 equiv)

V ZnEt2 (2 equiv)

solvent 7%

Emf solvent Yield ', 96 75:76:77:79

toluene Et20 DME THF

a Combined isolated yield. Measured by capillary GC (HP 5 column).

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42

From our previous cycloadditions with Zn-Ag couple, we found thar highly facial and

stereoselective reactions were possible when the furylcarbinol was deprotonated initially with

a divalent organornetdic reagent foiiowed by cycloaddition with the polybrornoketone.

Accordingly, we were pleased to find that application of a similar protocol to our diethylzinc

reactions dmaticaiiy improved the diastereoselectivity of the [4+3] cycioaddition reaction,

Table 13. As illustrated, TKF gave the highest selectivity with almost exclusive formation of

the chelated diaxial cycloadduct 77b. (compare entry 4 with entries 1-3). Moreover, an

improvement in the yield was possible by lengthening the reaction Ume, and increasing the

concentration, and the number of equivalents of diethylllnc and dibromopentanone. The

nature of the counterion on the furyl akoxide (Le. aikyl zinc vs metal halide) apparently had

little effect on the diastereoselectivity; both magnesium and zinc halides undergo highly

diastereoselctive cycloadditions (entries 8 and 9). Enty 13 exemplifies optimized conditions

required for high yields and diastereoselectivity: addition of 2 equiv of diethylzinc ro a

solution of the furylcarbinol in THF (0.3M concentration) followed by the addition of 3

equiv dibrornopentanone 74.

An interesting consequence of the optimization study was that in THF, the

diastereoselectivity remained nearly constant regardless of the number of equivaients of

diethylzinc used (entries 4 and 12 in Table 13). However, in a non-polar solvent as in Et20

or toluene, addition of a second equivalent of diethylzinc resulted in a change in product from

77b to 79b. Moreover, only one of the two adducts with axial-equatorial orientation of the

methyl groups was observed (entries 10 and 11).

One could envision a putative aggregated transition state 83 in which a sreric

interaction between an aikyl zinc and one of the methyl substituents on the oxyallyl cation

forces the allyl cation in its less stable sickle shaped configuration. In fact, alkylzinc

alkoxides are known to form stable cubic tetramen in non-polar solvents, regardless of the

size of the alkyl group.61 Noyori has also observed dimer formation between alkylzinc

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Table 13. [4+3] Cycloaddiùons Using Diethyfiinc: Optimization Studies

"O" '- 3 -

0 O°C (1 h)- rt (20 h)

50b 74

(Y equiv) 77b 7%

EntW &Et2 solvent concenttation 74 Yield b. % 75:76:va7g c (X equiv) a (Y eq uiv)

1 1 toluene 0.1 M 1 5 1 :14:71:14

2 1 Et20 0.1 M 1 17 0:0:94:6

3 1 DME 0.1 M 1 0:0:95:5

4 1 THF 0.1 M 1 18 0:0:98:2

5 1 THF 0.1 M 2 32 1 2952

6 1 THF 0.3 M 2 47 0:0:98:2

7 d 1 THF 0.3 M 2 54 0:0:982

8 e THF 0.3 M 2 64 0:3:95:2

g d f THf 0.3 M 2 60 0:3:93:4

I l 2 toluene 0.3 M 1 25 0:026:74

a Deprotonations carried out at O OC for 10 min followed by addition of 74. Cornbined isolated

yield. Measured by capillary GC (HP 5 column). Reaction carried out at O OC (1 d) then rt (1 d).

Initial deprotonation with EtMgCl (1 equiv) followed by addition of 1 equiv of ZnEtn. f Initial

deprotonation with mPrZnl (1 equiv) followed by addition of 1 equiv of Zn&.

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oxides in the Dm-catalyzed ethylation of benzaldehyde, which has been shown to

predominate in non-polar solvents such as ether, toluene andor hexanes-ab

stepwise or

concerted R '

Whether the observed axiaVequatoria1 selectivity in Et20 was the resuit of aggregation

or due to a change in mechanisrn is purely speculation at this point. What is known is that

the degree of axiaYequaotoria1 adduct formation can be suppressed with the addition of zinc

bromide, Table 14. Studies by 'H NMR may prove useful in determining if aggregates are

actually formed.62

Table 14: Effect of an Additive on the Diastereoselectivity

. .

1) A. O OC 1 equiv Br Br,'. 77b et he r

- OH 2) B, O OC 0°C (1 d)

then rt (1 d)

- -- -- -- -

A (equiv) B (equiv) 76b : 77b : 79b a

a Ratios determined by capiliary GC (HP 5 column).

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Cycloadditions With Other Chiral Furans

The scope of the reaction was investigated and other furans were examined under

similar deprotonating conditions, Table 15.

Most of the furans we investigated gave high facial and stereoselectivities with yields

ranging from moderate to good. Yields based on recovered furyl carbinol were usually

285% thus costly starting materials could be easily recycled. Again. an enhancement in the

diastereoselectivity was possible through double stereodifferentiation using the syn

furylglycerol acetonide 50h (compare entry 3 vs 4). Moreover, both furans gave diaxial

products funher justifying rhat the furyl alkoxide at Cil serves as the dominant

diastereocontrol element in the reaction.

The poor selectivity observed for h a n 50g desexves further comment. A reduction

in the overall diastereoselectivity may be attributed to the second alkoxy site generated C3.

under the deprotonating conditions. One could imagine that this site could also effectively

compete for zinc ions in such a way that it begins to intempt the original pathway proposed

for these cycloadditions as illustrared below.

Cycloaddition With a Furyisulfoxide: Access to ee Adducts

We envisioned similar facial and exo selectivities could be achieved with other

stnicturaiiy similar furans as in the furyl sulfoxide 52. Supnsingly however. we found that

the cycloaddition of this furan urder Our optimized diethylzinc conditions did not furnish any

diaxial cycloadducts; only the diequatonal adducts 84 and 85 were isolated in a 1 :4 ratio, eq

9. Moreover, the sarne products and ratios could be obtained using Zn-Ag couple as the

reducing agent.

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Table 15. Scope of the [4+3] Cycloadditions Using Diethylrinc

1. ZnEt2 (2 equiv) THF, O OC v (or,) + Other

C isomers *-A (3 equivi

50 (or 51) Br Br 0 'C (Id) - rt (ld) 74

- - -

Entry Fumn Major Product ratio a yield

50h &?Po 7 7 , * O 95:5 @/O

O F - %O

OH OTBDMS

96:4 56% (95%) TBSO O

a Ratios determined b y 'H NMR spectroscopy (400 MHz). Ratios correspond to TI : ail other isomers; Cornbined isolated yield. Yield in brackets based on recovered starting material. One equiv of Et2Zn and 2 equiv of 74 was used (results in entries 3 and 4 obtained from John Colucci).

Ratio corresponds to 82 : al1 other isomers.

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conditions

1. Zn-Ag (2.5 equiv), THF O O C 2. DBP (1 equiv) O O C (2h) - rt (2Oh) 20

1. ZnEt2 (2 equiv), THF, O O C

2. DBP (1 equiv), O OC(1 d) - rt (1 d) aO

Recall that our reasoning behind exo selective cycloadditions with 2-furylcarbinols

was based on the notion that a divalent zinc ion could act as a tether, covalently linking the

C l 1 alkoxy group of the furan and the 2-oxygen of the oxyallyl cation (cornplex 81). We

suspect that Our furyl sulfoxide's anionic oxygen is incapable of participating in covalent

bond formation with a zinc ion and thus control over the diastereofacial selectivity and the

mode of attack of the oxyallyl cation is lost. An experiment to force chelation was attempted

by adding ZnBr2 salt to the reaction mixture, however, this lead to complete reduction of the

furyl sulfoxide starting matenal in the presence of Zn-Ag couple. One might also argue that

an electronic factor associated with the furan may be responsible for the observed

stereoselectivity (Le. an electron poor fu~yl sulfoxide may have a greater propensity toward a

compact mode of addition). Nevertheless, the stereoselectivity is interesting and is worthy of

further study.

Structural Proof of Diequatorial Adducts 84 and 85

We were fortunate to obtain crystals of 85 suitable for X-ray analysis which

confirmed the stereochemistry of the methyl groups and the facial selectivity of the

cycloaddition, Figure 3. Moreover, an independant oxidation of 84 and 85 using oxone in

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48

Me0H:water (1: 1)63 gave the same sulphone 86, indicating that 84 and 85 were epimeric at

the sulfur atom, Scheme 2 1.

Figure 3

Scheme 21

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49

3.3.3 Diastereoselective [4+3] Cycloadditions With 1,1,3,3-

Tetrabrornoacetone

Previous methods for the construction of racemic [3.2.l]oxabicyclic compounds

lacking C2 and C4 substitution as in 89 have been achieved via a [4+3] cycloaddition reaction

with the polyhalogenated ketone l,1.3.3-tetrabromoacetone (87 or TBA) followed by

reduction with Zn-Cu couple. Scherne 72. Among the various reducing agents which are

capable of generating oxyallyl cations from TBA are z ~ - A ~ ~ ~ and diethykinc8f.

Br Br

87

BEt2 - RbBr MeOH - R or Zn-Ag O NH4CI O

88 89

Having developed a practical method for the asymmetric construction of 2.4-dimethyl

8-oxabicyclo[3.2.1] substrates, we envisioned a sirnilar reaction protocol could be applied

for the construction of unsymrnetrical derivatives of 89 using TBA as the source of the

oxydyl cation. Our prelimùiary studies are summanZed in Table 16.

Our initial studies using Zn-Ag couple and furan 50b under non-deprotonating

conditions gave two cycloadducts 91b and 90b in a 6: 1 ratio with a combined isolated yield

of 35% (enûy 1). A dramatic hprovement in the diastereofacial selectivity was realized with

the use of diethylzinc as both a deprotonating and reducing reagent (entry 3). Moreover,

application of the methodology to other furylcarbinols consistently gave >95:5 selectivity in

favour of the formation of 91 (entries 4 and 5). Our best attempt at optimizing the yields of

the reaction for furylcarbinol50b is depicted in entry 6 where initial deprotonation of 50b

with 2 equiv of diethyl zinc foilowed by the cycloaddition with 3 equiv of TBA afforded both

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90b and 91b in 47% combined isolated yield and 88% de. Further optimization of the

yields would be required if the resulting methodology is to be applicable in organic synthesis.

Table 16. [4+3] Cycloadditions Using Te~abromoacetone

?OH $3 1. conditions

d i , a 2. Zn-Cu, NH4CI

O R ' Br MeOH (4 - 20 h)

50b (R = tert-butyl) c (R = chx) 87

R' d (R = n-heptyl) O

Entry Furan Conditions a 50 : 87 90 : 91 yield

1 50b Zn-Ag (1.5 equiv), THF 411 14 :86 35%

2 5Qb Et2Zn (2 equiv), THF 1 : 1 no reaction -

3 50b EtzZn (2 equiv), toluene 1 : 1 5 : >95 36%

4 50c Et2Zn (2 equiv), toluene 1 :1 5 : >95 =/O

5 50d Et2Zn (2 equiv), toluene 1 : 1 5 : >95 1 P/o

6 50b Et2Zn (2 equiv), toluene 1 :3 4 : 96 47%

a See experimental section for details. Ratios determined by 'H NMR spectroscopy (400 MHz). Combined isolated yields.

Proof of the Stereochemistry at Cl* in 91b

NMR spectroscopic techniques did not prove useful in determining the

stereochemistry at Ci* in 9 l b . However, stereoselective reduction of 91b with L-

SelectrideTM gave only the endo alcohol92 in 83% yield as a white crystalline solid suitable

for X-ray analysis, Figure 4.

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Figure 4

is of the enatiomer)

3.3.4 Attempted Diastereo- and Regioselective [4+3] Cycloaddition With

1,3-Dibromo-2-butanone

In addition to cycloadditions perfomed with the symmetrical dibromoketones, we

incorporated the unsymmetrical 1.3-dibromo-2-butanone 93 into our studies in hope that a

regioselective reaction could be affected. We proposed the major product would arise from a

complex similar to 81, with approach of the unsymmetrical oxyallyl occuring "anti" to the

sterically h i n d e ~ g 2-position of the furan, structure 94 in Scherne 23.

Scheme 23

L

concert4 (or stepwise)

-

94 "anti"

For o u preliminary attempt at the reaction, we used the bulky tert-butyl furan 50b

for optimum diastereofacial selectivity and for facile interpretation of the product(s) by IH

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52

NMR. Thus. cycloaddition of SOb usinp one equiv diethylzinc and two equiv DBP resukd

in not one but rwo cycloadducts 95 and 96 in a ratio of 2.1 : 1 and combined isolated yield

42% yield, eq 10.

1. ZnEt2 (1 equiv), THF O OC (1 Omin) -

(2 equiv)

O O c (1 d)- (1 d) 95 (X=H. Y=Br) or 96 (X=H, Y=Me) or Br Br (%Br, Y=H) (X=Me, Y=H)

506 2.1 1 (@/O)

lH NMR analysis of the bridgehead protons gave a singlet for both adducts

uggesting an axial orientation of the substituent at C4. Moreover, 1H NMR and mass spec

analysis indicated that both compounds contained one bromine atom. The relative

stereochemistry at CI* and at the bridgehead carbons in 95 and 96 were tentatively

hypothesized to arise from a cycloaddition with the chelate 56 (section 3.1) based on

previous facial selectivities observed with furan 50b under similar deprotonaûng conditions.

Funher analysis of the lH NMR spectra indicated mono substitution at Cz and Cq hence the

structures 95 and 96 were proposed as illustrated in eq 10.

Mechanisticaily, we propose the brorninated products arise fiom a cycloaddition with

the oxyallyl cation 99 (Scheme 24). This oxyallyl cation is presumably generated from an

initial proton loss from 97 to form the metal enolate 98 followed by elimination of the

bromide anion. Indeed, similar rlono-debrominated cycloadducts were noted when

cyclopentadiene was allowed to react with 1,3-dibromo-2-butanone in the presence sf

@tO)3B/Zn powder.64 The autkon propose a similar mechanism where a boron enolate 100

is generated and ionization to the oxyallyl cation 101 is achieved with intramolecular

assistance by oxygen.

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Scheme 24

(EtO)351 \ Zn powder I B.

-Br- ~t.2 0 & & p r

We were able to prove the methyl group at CJ in 95 was in an axial position by

reducing the monobrominated compound to 102 quantitatively with Zn-Cu couple, Scheme

25. 1H NMR analysis of 102 gave a singlet for the bridgehead proton thus confirming its

structure. Reduction of the mono-brominated cyctoadduct 96 resulted in a quantitative

formation of 103 where a doublet of doublets was observed in the bridgehead region of the

NMR spectrum. While this conf i ied the axial orientation of the bromine group at Cq in

96, attempts to prove the stereochemistry of the methyl group at Cz in 103 and 96 were

Scheme 25

Zn-Cu, NH4CI, MeOH

100%

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54

Future studies using a bullcier isopropyl or te#-butyl substituted dibrornopropanone

may prove as better alternatives for achieving highly regioselective [4+3] cycloadditions.

3.3.5 Cycloadditions With FurfuryI AlcohoI

Having found an effective diastereoselective method for the asymmetric construction

of unsymmetrical [3.2.l]oxabicyclic substrates, we then m e d to achiral furans in hope that

an enantioselective version using chiral diorganozinc reagents could also be developed. Our

preliminary experiments were carried out on the commercially available hirfuryl alcohol 104

for the simple reason that it too contained a hydroxy alkyl moiety which could potentially

serve as a tether between the furan and the oxyallyl cation as in complex 81 (section 3.3.1).

The results of our snidies are reported in Table 17.

Under non-deprotonating Zn-Ag conditions, both diequatorial 105 and diaxial 108

adducts were formed in a 7.3: 1 ratio respectively with a combined isolated yield of 54%

(entry 1). AxiaVequatorid isomers were not observed. Structural proof of the cycloadduct

105 was achieved chernicaily by converting the primary alcohol to the known TBDMS

ether.65 1H NMR analysis of the'bridgehead proton of adduct 108 indicated axial orientation

of the rnethyl group at C4. The stereochemistry at C2, although not rigorously determined.

was tentatively assigned to be axial as well since treatment with tBuOK in fBuOH almost

completely epimerized the product to the known cyloadduct 105 and its axiaVequatorial

isomers 106 and 107, eq 1 1.

63 17 a0

(+ 3% unreacted 108)

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Table 17. [4+3] Cycloadditions With Fumiryl Alcohol

1. conditions

Entry Conditions 74 Yield ", Sc 105:1û6:107:1ûû (ewiv)

1 Zn-Ag, THF 1 54 88:0:0:12

2 EtMgCl, THF then Zn-Ag 1 49 1 92:5:74

3 Et2Zn (1 equiv) 1 24 7:O: 1 3:81

4 Et2Zn (1 equiv) 2 33 1 5:4:11:70

5 Et2Zn (2 equiv) 3 71 58:0:0:42

- - -

Combined isolated yield. f~ Measured b y 'H NMR (400 MHz). Typical conditions: 1 equiv

furan, 1 equiv RMX (entry 2). 2.5 equiv Zn-Ag couple, 1 equiv 74 (dibromopentanone).

Deprotonations were canied out at O OC (1 0 min) and subsequent cycloadditions were done at O

O C (2 h) then rt (20 h). Al1 reactions were done a i 0.8 M with respect to the furan. Addition of

diethylzinc at O OC (10 min) followed b y cycloaddition with 74, O OC (1 d) then rt (1 d). All

reactions were done at 0.3 M with respect to the furan.

Previously we had demonstrated that the use of a zinc or magnesium furylalkoxide

resulted in highly exo selective cycloadditions. Accordingly, we found that initial

deprotonation of the hydroxyl moiety with EtMgCl followed by cyloaddition with the

polybromoketone 74 in the presence of &-Ag couple gave the expected diaxial cycloadduct

but in poor overall stereoselectivity (49% de). Cycloadditions carried out with diethylzinc

were less selective than with the chiral furylcarbinols and the yields were much lower (entries

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56

3-5). A sacrifice in the overd diastereoselectiviq was made while attempting to opamize the

yield of the reaction by increasing the amount of diethylzinc and DBP added.

During the course of our investigations, a publication by Mann had appeared in the

literanire which reported f a d e construction of unsyrnmetrical diequatorial oxabicylo[3.2.1]

substrates from the cycloaddition with a furylcarbinol using diethylzinc as the reducing

agent.8f Most of the furans which were tested had the hydroxy functionalify located three

carbons away from the furan nucleus. For example, the reaction with the furylcarbinol 109

gave 52% of the diequatorial adduct 110. Contras, to our findings, benzene proved to be

the best solvent for their cycloaddition. Further investigations would be required to

understand why the diastereoselecuvity changes as a function of the position of the hydroxyl

goup on the side chain but one possible explanantion is that the longer chain reduces the

stability of the chelate which would anse from 109.

3.3.6 Further Support for the Observed Diastereofacial Selectivity : A b

Zn itio Studies

Recall a complex as in 81 (see page 36) was proposed which would explain the

observed facial and exo selectivity in Our c ycloaddition reac tions. Moreover, the facial

selectivity was said to arise from a chelate sirnilar to 56 (see page 24), where the covalently

bound metal ion is simultaneously chelated to the oxygen in the furan. ln surveying the

literature. however, we were unable to find any literature precedent which would support our

assumption of chelation to the furan oxygen. Thus some ab iniiio studies were undertaken at

the HF / LANLZDZ level of theory and the energies of the "chelated" and "non-chelated"

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forms of a Civ substituted vs unsubstituted methyl zinc furylalkoxides were calculated.66

Illustrated below are the results of these snidies.

(a) simplest model

- essentially planar backbone

more stable by 5.6 kcafirnol

(b) methyl substituted model

E = -484.020917 a. u.

more stable by 5.9 kcaVmol

- essentially planar backbone

It was found that for both the unsubstituted (a) and methyl substituted (b) models. the

"chelate" was more stable than its "non chelated" form by >5 kcal/mole. Moreover,

substitution at Clw (as in the methyl substituted model) exerts a slightly larger energy

difference between chelated and non-chelated f o m than the simple model. Interestingly, the

backbone in these models was found to be essenûally planar hence the aromaticity of the

furan remains intact; the metal ion therefore interacts with the lone pair located in the sp2

orbital on the oxygen.

It is important to note these preliminary studies fail to take into account THF

molecules, which are also capable of interacting with the zinc metal, but it is interesting to

note that the calculations agree well with Our experimental work and also with Our

interpretation of the diastereofacial selectivity in the cycloadditions. Future studies factoring

in THF as the solvent wouid serve as a better model in these calcuialtions.

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3.4 Summary

We have developed a practical generai strategy for the synthesis of unsyrnmenical

oxabicyclo [3 2.1 ] octenes as single enantiomen via a diastereoselec tive intermolecular [4+3]

cycloadditon reaction between chiral 2-furylcarbinols and oxydyl cations. It was found that

initial deprotonaticn of the furan's hydroxyl moiety with a divalent organometallic reagent

followed by cycloaddition with the polybromoketone were the conditions necessary to affect

a highly diastereoselective [4+3] cycloaddition. Interestingly, the stereochemistry of the

products dictates that the reaction not only arises from a chelate controlled facially selective

cycloaddition but also from an unprecedented extended (or exo) transition state (as in

complex 81). Hence previously unavailable cycloadducts can be made in good yield.

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59

4. APPLICATIONS: SYNTHESIS OF CYCLOHEPTENOLS VIA RING

OPENING REACTIONS

Oxabicyclo[3.2.1 j octenes have k e n used as intermediates in the syntheses of many

nanird products. We and othen have shown that they undergo highly stereo- and regioselective

SN^' ring opening reactions to f-sh cycloheptenois 22 (see aiso Scheme 7 in section 1-25 of

thesis).21-25 Further oxidative cleavage of the double bond cm quickly provide access to

stereochemicaiiy compiex acyclic " pentads" 11 1 Uustrated below. This methodology was used

in a synthesis of the C21-Cz7 fragment of Rifamycin. Scheme 76.6'

Scheme 26

5 equiv MeLi

O H

steps T

If the methodology is to be applicable in the synthesis of stereochemically complex

chahs and rings, then asymmetric approaches based on the oxabicyclic ring opening would

be required. The use of enamiomericaliy e ~ c h e d oxabicyclic compounds is one solution

and strategies for their construction have k e n the main focus of this thesis (part 3 of thesis).

Altematively, access to chiral cycloheptenols would be possible via the development of an

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60

asymmetric ring opening reaction on meso oxabicyclic substrates. Examples based on

enantioselective ring openings have k e n reported and are briefly mentioned below.

The enantioselective ring opening of a meso oxabicyclic cornpound is an attractive

approach for generating chiral cycloheptenols. Und recently, this area was met with Little

success. In 1993, Laurens. Gajda and Chiu demonstrated that a catalytic arnount of a chiral

additive such as sparteine induced the asymmevic organolithiurn ring opening of the

symmetncal oxabicycle 112. eq 12.68 The sparteine was shown to increase the reactivity of

the organolithium reagent toward the ring opening as well as induce modest

enantioselectivities of up ta 52% in the reaction.

15 mol% sparteine, n-BuLi - BU Q.':~ oTBDMs pentane, -40 O C

OTBDMS 52% ee, 60% yield "#

HO

Even more promising was the use of an aluminum hydride reducing agent, such as

DIBAL-H. In 1995, Lautens and coworkers reported that highly enantioselective reductive

ring openings of mes0 oxabicyclo[2.2.1]alkenes could be achieved using catalytic amounts

of Ni(COD)* with either (R) or (S)-BINAP as iigand.2la Recently, Lautens and Rovis

extended this methodology to [3.2.l] systems. Interestingly, they found that higher reaction

temperatures were necessary to induce the asyrnrnetric ring opening (unpublished results), eq

13. Moreover, the reaction has k e n done on 4 1/2 mm01 scale and is currently being used in

a synthesis of the C17-C23 fragment of ionomycin.

HO O m 3 mol% Ni(COD)2, 6 mol% (S)-BINAP

syringe pump addition of 1 -1 equiv DIBAL-H (20 h) OTIPS PhMe, 65 OC

- (J ~~OTIPS

-%

93% ee, >95% yield

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Enantioselective deprotonation followed by ring opening is an alternative strategy for

generating a chiral cycloheptene skeleton. In an attempt to enantioselectively alkylate the

alpha position of tropinone 113 with methyl chloroformate in the presence of the chiral base

1, Simpkins found that a ring opening reaction ensued in which the nitrogen atom was

alkylated in 88% yield. The ee was estimated at 50% following reduction to the allylic

alcohol (relative stereochemisrry unknown) and denvatking to the Mosher ester, eq 11.69

NaBH4, CeCI3

MeOH N ' C02Me C02Me

single diastereomer 95% yield Cam% ee

Majewski later perfected the reaction utiiizing the chiral base 114 in the presence of

0.5 equivalent of LiCl and obtained cyclohexenone 115 with 92% ee, eq 15.~0

2. LiCl (0.5 equiv) 3. CBZ-CI CBz

Recently , Lautens and Filiion have discovered that meso oxabicyclic[3 2.1 ]

substrates can also be enantioselectively ring opened via asyrnmevic deprotonation with a

chiral base. It was found that the sulfide analogue, 116, could be ring opened with ee's up

to 95% while the carbamate derivative 117 gave only 60% ee with sparteine, eq's 16 and

17-71

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Ph M e 0 Li

MeO+S 1 M e 0

3 equiv LiCl toluene, -50 O C = Me(3 D HO

I f 6 79% yield 95% ee

M ~ O S L - B O C Et20, -1 05 OC

M e 0 97% yield

(17)

As mentioned, a complementary strategy to the asymmetric ring opening reaction

would be to develop an efficient merhod for the construction of unsymmetrical

oxabicyclo[3.2.1]a&enes as single enantiorners. We have already descnbed a practical and

general snategy for their construction via a novel diastereoselective intermolecular [4+3]

cycloaddition reaction between chiral fuiylcarbinols and 2-oxydlyl cations (see part 3 of this

thesis). What rernained was to dernonstrate their synthetic utility in organic synthesis. Thus

application of the resulting rnethodology toward the synthesis of enantiomerically e ~ c h e d

cycloheptenols was undertaken and various ring opening reactions that were developed in

this laboratory were explored.

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4.2 Preparatîon of the Starting Materials

The preparation of oxabicycles 118-123 are depicted in Scheme 27. Cornpound

91b was reduced stereoselectively to the endo aicohol in 83% yield (see Figure 4 in part

3.3.3 of this thesis for X-ray of 92). Deprotonations were performed with potassium

hydride in the presence of catalytic amount of 18-C-6 followed by trapping with an

elecuophile. The epimeric oxabicycle 120 was prepared via a Mitsunobu reaction followed

by hydrolysis of the para-nitrobenzoic ester (78%).'2

Scheme 27

I

118 R = TBS, R' = H --l v. 81% OR 119 R = TBS, R' = Bn

ii , iii

7tPh

- 121 R = TBS, R' = f i r 122 R = TBS, R' = Bn

Key: i. L-Selectride (2.2 equiv), THF, -78 OC, 0.5 h then NaOH (8.8 equiv). H202 (8.8 equiv). ii. pNBA (1.5 equiv), PPh3 (1.5 equiv), DEAD (1 -5 equiv). THF, r t 10 min. iii. MeOH, MeONa, rt, 3 h. iv. KH (1.2 equiv), 18-C-6 (cat.), THF, O OC then TBSCl (1 equiv). v. KH (1.2 equiv), 18-C-6 (cat.), THF, O OC then BnBr (1 equiv).

Colucci had demonstrated that the DIBAL-H reduction of oxabicycle 77c at room

temperature gave the endo 124 and exo 123 alcohols as a 4: 1 mixture. Clearly there was

room for optimization. Table 18 illustrates the various reagents that were tried to affect the

stereoselective reduction of 77c.

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Table 18. Attempted S tereoselective Reduc tions of 77c

Entry Conditions 123 : 124 Yield a

DIBAL-H rt, toluene

LiAIH4, THF, -78 OC- O O C

LiAIH(OMeI3 (2 equiv), THF

NaBH4 (2.5 equiv), DME, rt

Diisobutylaluminum-2,6di-t-butyl- 4-methylphenoxide (1 equiv), tol uene

Sm12, THF, CPrOH

Zn(BH4)*, (2 equiv), DME, -15 O - O OC

L-Selectride (4 equiv), THF, -20 O C

LiBH4, (3 equiv), THF, O OC (1 h)- rt (3h)

- nr

- epim

9.8 :1 7p/0

13 : 1 91% . -- -

a combined isolated yield nr = no reaction epim = epimerized starting material

Reduction with lithium aluminum hydride (entry 2) was essentially quantitative

however poor selectivity was observed. Use of a less reactive aluminum hydride reagent

( L ~ A ~ H ( o M ~ ) ~ ) ~ ~ or sodium borohydride gave linle or no product (entries 3 and 4).

Diastereoselective Meerwein-Pondorf-Verley type reactions have been demonstrated on

substituted cyclohexanones using d i i s o b u t y l a l u m i n u m - 2 , 6 - d i - t - b u t y 1 - 4 - m e ~ 7 4

and samarium iodide/isopropanol7? Unfortunately , our attempts with these reagents failed

to give any product (entries 5 and 6). Equaily disappointhg was the stereoselecitve reduction

with a chelating base such as zinc b~rohydride'~, where complete epimerization of the

starting material to 76c was observed (entry 7). Exo selectivity (9.8: 1) was predominant

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65

with the b u e reducing agent L-Selemidem (entry 8). The reaction proceeded smoothly

between -20 O - O OC and higher temperatures caused epirnerizarion of the starting material.

Our best attempt at the stereoselective reduction is depicted in entry 9 where treaunent of a

solution of 77c in THF with 3 equivalents of lithium borohydride at O OC foliowed by

warming to n (4 h total) afforded 9 1% of a 13: 1 ratio of 123 and 124 respectively.

Structural proof of 123 was f d y established by convering it to known cycloheptendiol

125 which has been previously prepared.21~. 25

Scheme 28 illustrates some of the derivatives of 123 that were used in the ring

opening study. Again, protection at C3 and Clm was carried out sequentiaily for compounds

129 and 130.

Scheme 28

i 1- lP R = H , R b = H

12i6 R = Me, R' = Me 2 iii, 79%

R = TBS, R' = H

92%, ii 128 R = TBS, R' = Bn C '" -J ï", 95Oh

129 R = TBS, R' = PMB

Key: i. KH (2.5 equiv), 18-C-6 (cat.), THF 0°C then Mel (2.5 equiv).

ii. KH (1 -2 equiv), 18-C-6 (cat.), THF 0°C then PMBBr (1.2 equiv).

iii. KH (1.2 equiv), 184-6 (cat.), THF 0°C then TBDMSCI (1 -2 equiv).

iv. KH (1 -2 equiv), 18-C-6 (cat.), THF 0°C then BnSr (1.2 equiv).

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66

Access to oxabicycle 131 (Scheme 29) could not be achieved directiy from di01 123.

Its preparation was thus carried out as follows. Ketone 77c was protected as its TBDMS

ether using ten-buryldimethylsilyl triflate and 2.6-lutidine. The reaction proceeded smoothly

at -78 OC to -30 OC furnishing 130 in 91 1 yield. In order to ensure that the product was not

epimerized under the reaction conditions, a blank reaction was carried out in the absence of

the silating agent. Quenching of rhe reaction after 4 h and analysis of the crude mixture by

lH NMR c o n f m e d that the starting material had not epimerized. Thus, subsequent

reducûon of 130 with LiB& under the conditions established for 77c gave predominantly

the exo alcohol 131 dong with its epimer 132 as a 5.8: 1 ratio in 92% yield.

Scheme 29

TBDMSOTf (1 -1 equiv)

I LBH4 (3 equiv) THF. O O C - rt (8 h)

E?! f

4.3 Organolithium Induced Ring Opening Reactions

Organolithium reagenrs have been shown to induce the ring opening of

unsymrnetrical oxabicyclic L3.2.11 compounds bearing a substituent at the bridgehead. e777

Chiu, for example, found that an ethyl group, which is not very sterically demanding,

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induced highly regioselective ring-opening reactions in which the

to the position distal to the bridgehead substituent, eq 18. The

67

nucleophiie was delivered

high regioselectivity was

postulated to arise from complexation of lithium to the bndging oxygen followed by

weakening of the C-O bond to generate the more stable cation. Delivery of the nucleophile

then occurs remote to the bridgehead substituent.

Encouraged by these fmdings, we set out to investigate the scope and limitations of

the organolithium induced ring opening reaction on our oxabicyclic compounds. Table 19

sumarizes the results of this study.

It was found that conditions to induce the ring opening of free diols 92, 120 and

123 always resulted in a complex mixture of products. Changing the solvent or temperature

failed to give a clean ring opening reaction. As with compound 123, ring openings with a

Grignard reagent (MeMgBr) in the presence of different nickel catalysts7g were attempted but

these failed to give any products. Thus, the cycloadducts were mono- and diprotected and

their effect on the ring openings were examined.

In general, it was found that protecting both dcohols lead to enhanced product

formation with al1 the cases studied. In addition, the ring opening of 2,Cdimethyl

oxabicyclic subsnates gave siightly better yields than the unsubstituted cases (compare for

example entry 6 with entry entry 12). A predomuiant side product with the latter substrates

was the formation of dienes and trienes. In the case of ring opening of monodiols 127 and

131, it was found that protection of the Cie hydroxyl gave significantly higher yields than

protection at Cg (compare en tq 1 1 with 14). Furthemore, it was found that the rates of ring

opening were highly dependent on the stereochemistry at C3. For example, the ring opening

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Table 19. Organolithiurn Induced Ring Openinsg of Unsymmetrical Oxabicyclo[3.2.1] Compounds

Emr~ Substrate Product Yield

R J&q; O,..

9 R = H , R 1 = H

118 R = TBS, R' = H

119 R = TBS, R' = Bn

120 R = H , R ' = H

121 R = TBS, R' = H

122 R = TBS, R1 = Bn

la6 R = Me, R' = Me

la R=TBS, R = H

128 R = TBS, R' = Bn

la R = TBS, R' = PMB

131 R = H , R t = T B S

complex mixture

18%

Z / o

complex mixture

Wh

P h

v 139 Fi" = Bu complex mixture

a 5 equiv of RLi in ether at O O C . lsolated yields of analytically pure material. Plus 15% recovered starting material.

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of the endo substrates 118 or 119 were significantly slower (1 day) than the exo compounds

121 and 122 (1-3 h).

We were also able to demonstrate highly successful ring openings with a

functionalized organolirhium reagent (ennies 10 and 13). This was a simcant fmding since

a new site within the cycloheptenol molecule was available for further manipulation.

Applications of these findings to the synthesis of naturally occurring molecules have

been considered. The ring opening of 147 with hexyllithium could potentially Iead to the

synthesis of lipstatin, esterastin, and tetrahydrolipstatin which are potent pancreatic lipase

inhibitors,79 Scheme 30. We have also envisioned the synthesis of the Ci -Cg piece of

ionomycin indirectly arising from 145, Scheme 3 1. Curent methods for its synthesis in our

laboratory rely on a resolution of the methyl Lithium ring opened adduct 148.80

Scheme 30

Lipstatin, Tetrahydrolipstatin, Esterastin

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Scheme 31

OPMB &Om

4.4 Reductive Ring Opening of Di01 123

Lautens and Chiu have introduced DIBAL-H as a reagent for the efficient reductive

ring opening of a wide variety of oxabicyclo[3.2.1] substrates.2lacV 81 The eficiency of this

reagent is attributed to its solubility. reducing ability and Lewis acidity, which enables it to

coordinate to the bridging oxygen and thus facilitate the ring cleavage step. The issue of

regioselectivity has also k e n addressed.81~65 For exampie it was found that the ring opening

of 149a gave 151a as the major product where hydride delivery proximal to the bridgehead

was favoured. No selectivity was observed in the case of the free di01 149b. eq 18.

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DIBAL-H, hexane + C

reflux, 6-24 h OH ,II.--

OR H O

14% R = TBDMS 1 6.4

A milder more more selective reductive ring opening was achieved with nickel

catalysts in the presence of phosphine ligands. eq 19. For example the reaction alcohol

149b in the presence of 10 mol% Ni(COD)2 and 30 mol% triphenylphosphine ligand in

toluene afforded predominantly the uisubstituted cyclodkene 150b in 74% yield. Even

higher selectivities and yields were obtained with the use of 2 equiv of dppb as ligand with

respect to nickel catalyst,

Ni(COD)2 (1 0 moloh)/L 2.5 equiv DIBAL-H,toluene

* rt

O H

dppb (20 mol%)

Encouraged by the above findings, some preliminary studies were tested on the

unsyrnrnetrical oxabicyclic compound 123. The results of the study are surnmarized in Table

20. Our attempts using the established nickel catalyzed reductive ring openings with either

dppb or PPh3 as ligand unfortunately did not give any product with Our substrate.

Furthemore, the themal catalyzed ring opening with 10 equiv of DIBAL-H in the absence of

a nickel catalyst gave cycloalkenols 152 and 1 5 3 in a 6.51 ratio (62%). This result

complements the regioselective heterogeneous hydrostannylation reaction, which has been

shown to predominantly give the minor isomer 153;22925 hence access to both re,. oloisomers

is possible.

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Table 20. Reductive Ring Opening of Compound l23

-

E m Conditions 152 : 153 a Yield

DIBAL-H (3.2 equiv), 10% Ni(COD)2, 20% dppb, - toluene. rt I d

DIBAL-H (3.5 equiv), 10% Ni(COD)2, 30% PPh3, toluene, r t 1 d

DIBAL-H (10 equiv), toluene. reflux, 9 h 6.5: 1

a Ratios detenined by 'H NMR (400 MHz). Combined isolated yields.

4.5 Zirconium-Catalyzed Ethylmagnesiation of Compound 126

The carbomagnesiation of a double bond catalyzed by Cp2ZrC12 is a powerful mol for

generating new carbon-carbon bonds. Since first reported by Dzhernilevg2. eq 20, an

increasing number of groups have investigated this reaction in detail.83

1. Et2Mg, Cp2ZrCI2 (cat.) 1

RecentIy, Ma has demonstmted that diethylmagnesiation in the presence of a catalytic

arnount of Cp$ZrC12 could affect the ring opening of a symme trical oxabicyclo [3.2.l]

substrate 154, eq 2 1.81 The reaction, which is reminiscent of an ethyllithium ring opening

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73

(although it likely proceeds by a completely different mechanism), proceeded in good yield

(73 %). The aspect of regioselecûvity for unsymmetrical substrates, however, had not been

addressed.

OMe

154

15 mol% Cp2ZCI2 3.0 equiv Et2Mg, 40 h

Ln order to uivestigate the possibiiity of a regioselective carbomagnesiation of an

unsymmetrical oxabicyclic substrate. diethylmagnesium was prepared according to the

known procedure.84 The result of Our attempted ethylmagnesiation is illustrated in eq 22.

Thus, treatment of 126 with 5 equiv of Et2Mg in the presence of 15 moi% Cp2ZrC12 in THF

at room temperature for 3 d afforded only a single regioisomer 141 in 42% yield. The

product isoiated was identical to the product obtained fiom the corresponding ethyllithium

ring opening of 126, hence the stereochemical relationship between the ethyl and hydroxyl

group was tentatively assigned to be syn .

15 moloh Cp2ZrCI2 5 equiv Et2Mg, THF

rt, 3 d

430x2

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4.6 Intramolecular Ring Opening of an Enantiomerically Enriched

Unsymmetrical Oxabicyclo[3.2.1] Substrate

The ability to consuuct polycyclic, mulufunctional systems which are sterochemically

rich in a convergent manner is a chailenging task to the synthetic organic chemist. Recently,

Lautens and Kumanovic have developed a novel strategy to bicyclo[5.3.0]decenes via an

anionic iritramolecular ring opening of oxabicyclo[3.2.1] compounds, eq 23-24 The bicychc

systems are generated with complete regio- and stereocontrol via an attack of the olefin in an

SN^' fashion. Oxabicycles bearing either an a-heteroalkyltin or an a-alkyliodo tether at the

bndgehead can undergo the desired anionic ring opening.

The 5,7-fused ring system can be found in a wide variety of natural products.85 Of

particular interest to our research group are the biologically active tumor promoting phorbols

and the stmcturally related daphnane, Figure 5.86 While previous application of the anionic

ring opening strategy for their construction have ai i urilized racernic starting material, access

enantiomerically e ~ c h e d unsymrnetrical oxabicyclic akenes would be necessary if the

methodology is to be directed toward the syntheses of these naniral products.

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Figure 5

Daphnane Phorbol

We have already demonstrated that access to the enantiomerically enriched

unsyrnmetrical oxabicycle 77f was possible via a highly diastereoselective [4+3]

cycloaddition reaction between chiral furylcarbinol50f and 2.4-dibromo-3-pentanone. We

envisioned that the intramolecular anionic ring opening reaction on the corresponding a-

alkyliodo tethered oxabicycle would immediately consmict an analogous 5,7-fused ring

system found in phorbol or daphnane. Scheme 32 Uustrates the steps taken to achieve this

goal.

Reduction of ketone 77f under previously established LiB& conditions afforded

both exo and endo alcohols in 78% yield. 'H NMR integration of the alkene region in the

spectnim indicated that the exo alcohol 155 was formed preferentially over the endo alcohol

by 10: 1. We opted to protect the di01 functionality as its dimethyl ether 156 since an

appLication on a similar unprotected oxabicycle resulted in poor yield.Z4 Thus, dimethylation

of 155 with potassium hydnde and trapping with iodornethane gave 156 in 86% yield.

Subsequent, removal of the TBDMS group followed by conversion of the primary alcohol to

the iodoaIky1 oxabicycle 158 using Lange's conditionsB7 proceeded in 62% overall yield.

With the iodoalkyl tethered oxabicycle in hand, the nexr step was to explore the

in~amolecular Rng opening. Thus treatment of a solution of the iodoalkane 158 in pentane-

ether (3:2) with teri-BuLi at -78 OC followed by wanning to -50 OC afforded the 5,7-fused

bicycle 159 in 50%. The reaction which couid be monitored by TLC was essentially

complete within one hou .

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WhiIe we have demonstrated the synthetic potential of our cycloaddition rnethodology

with the construction of a [5.3.0] bicyclic system, a similar application on the acetone

equivalent of 77f (Le. lacking substitution at Cr and C4) would be warranted if the resulting

methodology is to be applied toward the synthesis of 5,7-hsed ring system found in phorbol

or daphnane.

Scheme 32

Key:

i. LiBH4 (3 equiv), THF O O C - rt (8 h)

ii. KH (2.5 equiv), 18-C-6 (cat.) THF O O C

then Mel (2.5 equiv), O O C - rt iii. TBAF, THF rt iv. PPh3, imidazole, 12, CH2CI2, rt 0.5 h v. tert-BuLi (2.2 equiv), ethedpentane,

-78 O to -50 O C , 1 h

OMe

OMe

iii. nOh c 156 R =TBS 157 R = H

iv, 81%

v, 50% +

OMe

4.7 Summary

We have demonstrated that the diastereoselective [4+3 ] cycloaddition methodology

can be successfully applied to the synthesis of cycloheptenols. For example. we have s h o w

that the orgrnolithium induced ring opening of oxabicycles obtained from the cycloaddition

study can proceed in high yield if both alcohol functionalities at C3 and Cl* are protected.

Thermal reductive ring openings with DIBAL-H are possible on the free diol. It was also

found that the ethylmagnesiation of the alkene in an unsyrnmeuicd oxabicyclo[3.2.1]

compound was regioselective, affording the corresponding ethyllithium ring-opening in

moderate yields. Findly, access to the [5.3.0] bicyclic skeleton was possible via an anionic

intramolecuiar ring opening of an a-alkyliodo tethered oxabicycle.

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NOTE TO USERS

Page(s) not included in the original manuscript are unavailable from the author or university. The manuscript

was rnicrofilmed as received.

UMI

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78

Column chrornatography was performed as "Flash Chromate-aphy" as reported by ~ t i l l g * using

(200-400 mesh) Merck grade silica gel.

5.2 Syntbesis of Chiral 2-Furylcarbinols and Sulfoxides

Solvents and Reagents

Unless otherwise stated, commercial reagents were used without purification. Diethyl

ether, THF, and toluene were distilled immediately prior to use from sodium

wirelbenzophenone. DME, triethylamine and chlorinated solvents were disùlled from calcium

hydride prior to use. (IR. 2s. SR)-(-)-Menthyl-(5')-p-toluenesulfmate (73).j7 and syn and anti

furylglycerolacetonides (50h and 51)42~~53 were prepared according to the methods described in

the literature. (S)-B-Methyloxazaborolidine-borane (58), was obtained from the Merck Researcb

Laboratory in Rahway. N. J. (U.S.A.), and was stored in a $ove box under an atmosphere of

nitrogen. N-ac ylated oxazolidinone (71) was prepared from (1 S. 2R)- 1 -amho-2-hydroxyindane

(70) (obtained from Merck in Rahway ) according to the Literanire procedure.%*j5

Li (3 equiv). 'BUCI (1.5 equiv) A

Ketone 57 was prepared according to the literature46 as foilows: Pivalic acid (1.35 g,

13.1 m o l ) was dissolved in 30 mL THE The solution was cooled to -78 O C and to this was

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79

added 1 equiv of n-BuLi (5.3 mL, 2.5 M in hexanes. 13 m o l ) to generate the Iithium

carboxylate. The mixture was then allowed to warm to rt slowly after which furan (4.8 mL, 66

mmol), ren-butyl chloride (2.1 mL, 20 mmol), and lithium wire (0.27 g, 40 mrnol) were added

in that order. The mixture was then sonicated for 4 - 6 h at rt until the metal was consumed, The

reaction was then inversely quenched with aqueous sanirateci W C 1 and the product extracted

with EQO (3 x). The combined organic layers were dned (MgS04), filtered. and the solvent

removed in vacuo. Purification by flash chromatogaphy (540% Et20 in hexanes) afforded

1.98 g (83%) of the known ketone 57g9. IH NMR (400 MHz, CDCl3) 6 7.48-7.49 (IR, m),

7.16 (IH, d, J = 3.3 fi), 6.44 (lH, dd, J = 3.7, 1.5 Hz), 1.30 (9H, s),

Attempted asymmetric reduction of furyl ketone 57 in CHzCIz:47d-e

To a solution of oxazaborolidine-borane cataiyst 58 (19 mg, 20 mol%, 0.066 mmol) in

0.1 mL CH2Cl2 was added borane-methyl sulfide complex ( 10 M, 0.04 mL, 1 10 mol%, 0.4

mmol) and the mixture was cooled to -20 OC. Neat prochiral ketone 57 (49 mg, 0.33 rnmol) was

added slowly over 2 h via syringe purnp whiie the intemal temperature was rnaintained at < -20

OC. The contents were stirred for an additonal 3 h at -20 OC and cautiously quenched by pouring

the reaction mixture into 5 rnL of precooled MeOH (-20 OC). Removal of the sotvent in vacuo

followed by flash chromatography (15% EtOAc in hexanes) gave a quantitative recovery of furan

carbinol>99% with an ee of 50%, as determined by gc analysis on a P-TA chiral columo.

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80

Kinetic Resolution of Furylcarbinol 50c Using Stoichiometric Amount of Ti(0-i-

TBHP (0.6 equiv) Ti(O-i-Pr)4 (1 equiv), L-(+)-DIPT (1 2 equiv)

-21 OC

- &-fJ (+/-)-soc (R)-50c

To a solution of Ti(0-i-Pr)4 (0.18 mL, 0.62 m o l ) in CHzcl~ (2.7 mL) was added L-

(+)-DDT (174 mg, 0.742 rnmol) at -21 OC. After 10 min, the solution was cooled to -30 O C and

racernic 50c ( 1 12 mg, 0.6 19 rnmol) dissolved in CHzC12 (0.14 mL) was slowly added. After

30 min, TBHP (0.06 mL, 0.4 mmol, 5-6 M in CHîC12) was added slowly, and the solution was

stirred for 25 h at -21 OC. Dirnethylsulfide (0.03 mL) was slowly added and the mixture was

stirred for 30 min at -21 OC. To this mixture were added 10% aqueous tartaric acid (0.03 mL),

Et20 (0.5 mL), and NaF (15 mg), and the resulting mixture was vigorously stirred for 2 h at rt.

The white precipitate was filtered off through a pad of Celite with Et20 as the eluent. The fltrate

was concentrated to give an oil, which was dissolved in Et20 (50 m . ) and ueated with 3 M

NaOH (20 mL) for 30 min at O OC with vigorous stining. The organic layer was washed with

brine, dried (MgS04), and concentrated to give an oil which was purified by flash

chromatography (10% EtOAc in hexanes) to afford (R)-50c (52 mg, 93 %, >99% ee as

detennined by chiral gc with a P-TA column).

(2s)-Dibenzylarnino-propionic acid benzyl ester, (61):

BnBr (3.2 equiv) NazC03 aq. (3.2 equiv)

Bu4N+Br' (1 equiv) BnO

NH* H20, CH2CI2, reflux Nenn (9-alanine 61

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81

To a biphasic mixture of 4 mL water and 3.2 mL CH2C12 was added (S')-alanine ( 1 g, 1 1

mmol), B u o + B r (3.6 g, 11 m o l ) , NazCO:, (3.8 g, 36 -01) and benzyl bromide (4.2 mL.

36 mmo1).49 The mixture was gently refluxed for 8 h. The reaction was then cooled to n and

the aqueous phase extracted with 3 x CH2C12. The combined organic layers were dned

(Na2S04). fdtered, and the solvent removed in vacuo. Purification by flash chromatography (5-

10% EtOAc in hexanes) affordec 3 g (75%) of pure ester 6149: [a]25, = -86.1" (CHCI:,, c = 2);

IR (neat) 3063, 3030, 2936, 2848, 1732, 1494, 1454, 1191, 1142, 1078, 745, 697 cm-1; 1H

NMR (400 MHz, CDC13) 6 7.47-7.23 (15H. m), 5.27 1H. d, J = 12.5 HZ), 5.20 (lH, d, J =

12.5 Hz), 3.88 (2 H, d, J = 14.3 Hz), 3.69 (2 H, d J = 14.3 Hz), 3.62 (1H. q, J = &O), 1.40

(3Hy d, J = 8.0) HZ; 13c NMR (100 MHz, CDC13) 6 173.3, 139.7, 136.0, 128.5, 128.5,

128.4, 128.2, 128.1, 126.8, 65.9, 56.2, 54.4, 14.9.

B.. L LiAIH4. Et20. O OC O

C ha I Ù B ~ ~

6l 62

Dibenzylamino alcohol 62 was prepared according to the literature50 as follows:

Dibenzylamino ester 61 (1.00 g, 2.78 mmol), was dissolved in 28 mL Et20 and to this solution

added L m (264 mg, 6.95 mrnol) slowly. After stining at O OC (1 h) then n (3 h), the reaction

was cooled back down to O O C into which a saturated solution of K+/Na+ tartrate was slowly

added (100 mL). The slu- was stirred for 0.5 h and was diluted with aqueous sodium

bicarbonate solution (100 mL). The product was extracted with CHzCl2 (3 x 200 mL), and the

combined organic layers dned (Va2S04), concentrated and the solvent removed in vacuo. Flash

chromatography (20% EtOAc in hexanes) afforded 582 mg (82%) of pure 62 as a clear

colourIess oil. [a]2SD = -87.7' (CHC13, c = 2) ~ i t . 5 0 [a]25, = -86.9' (CHC13, c = l)]; IH

NMR (400 MHz, CDCl3) G 7.34-7.25 (IOH, m), 3.82 (2H, d, J = 13.4 Hz), 3.46 ( lH, t, J =

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82 10.5 Hz), 3.37 (2H, d, J = 13.2 HZ), 3.34 (1H. dd J = 10.5, 5.1 Hz), 3.17 (lH, br s), 3.02-

1.95 (lH, m), 0.98 (3H, d. J = 6.6 Hz); 13c NMR (100 MHz. CDC13) 6 139.2, 128.9, 128.4.

127.1, 62.7, 54.2, 52.9, 8.9.

fCOC1)2, OMS0 O H then Et3N

CH2CI2 H -

Swem N 8 n p N B ~ ~

Aldehyde 63 was prepared according to the literature5l as foilows: To a solution of

oxalyl chloride (0.10 mL, 1.2 mmol) in 0.9 mL of CH2C12 at -50 to -60 OC was added a solution

of DMSO (0.1 1 mL, 1.6 mrnol) dissolved in 0.6 mL of CHzC12. The reaction mixture was

s h e d for 2 min and a solution of the alcohol62 (200 mg, 0.789 m o l ) in 5 mL CH2C12 was

added within 5 min. Stimng was continued for an additional 15 min. Triethylamine (0.44 mL,

3.2 mmol) was added and the reaction mixture was stirred for 5 min and then ailowed to wann to

a. Water was then added and the aqueous layer was extracted with CHzCl2 (2x). The combined

organic layers were then washed succesively with brine, dilute HCL (1 %), water, Na2C03 (5%)

then water, and the organic phase dried witb Na2S04. The solvent was removed in vacuo to

yield a slightly pale orange oil which was used without further purification: Analysis of the

crude: 1H NMR (400 MHz, CDC13) 6 9.75 (1, s), 7.23-7.45 (10H. m), 3.76 (2H, d, J = 13.8

Hz), 3.58 (2H, d, J = 13.8 Hz), 3.35 (1H. q J = 6.8 Hz), 1.20 (3H, d, J = 6.8 Hz).

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( I S , 2s)-Dibenzylamino-1-furan-2-yl-propan-1-01, (50e):

1. n-BuLi, THF

*- 7 H- 9 : 1 (anti : syn)

N B ~ ~ rn 5oe

The reaction was carried out as described in the literanire pro~edure~~b as follows: To a

solution of furan (2.9 mL, 40 mmol) in THF (50 mL) at -40 OC was added n-BuLi (12 rnL of a

2.5 M solution in hexanes, 30 mmol). The reaction was then warmed to rt for 3 h. The mixture

was then cooled to -78 O C and a solution of the crude aldehyde 63 (2.5 g, 10 mmol) in THF (20

mL) was added. The reaction was stirred for an addtional3 h at -78 OC, and hydrolysed with 50

mL of a saturated NH&1 solution. The aqueous layer was extracted with ether. The combined

organic layers were dried (MgS04). and the solvent removed in vacuo. hirification by flash

chromatography (10-35% EtOAc in hexanes) gave 2.73 g of pure anri furylcarbinol 5 0 e ~ ~ b

(85%) dong with 320 mg of syn diastereomer contamlliated with some other impurity (roughly

9: 1 ratio of anti:syn). [@, = -44.6 (CHC13, c = 1 ) 1H NMR (400 MHz, CDC13) 6 7.20-7.32

(1 lH, m), 6.31 (lH, dd. J = 2.9, 1.5 Hz), 6.22 (lH, d, J = 2.6 Hz), 4.58 (1 H, d, J = 6.6 Hz),

3.62 (1 H, d J = 13.6 Hz), 3.37 (IH, d, J =23.6), 7.20-7.32 (1 lH, m), 1.20 (3H, d, J = 7.0)

Hz; 13c NMR (100 MHz, CDCl3) 5 155.8, 141.4, 139.6, 128.9, 128.3, 127.0, 110.2, 106.8,

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Di-n-butylboron triflates6 (3.2 mL, 13 mmol) was added dropwise with stimbg to a

solution of oxazolidinone 71s4 (3.03 g, 13.1 mmol) in CH;?Cl:! (33 mL) at -78 O C .

Triethylamine (2.2 mL, 15.7 mmol) was added, and the reaction was stirred for 1 h at -78 OC and

then for 1 h at O O C . After the mixture was cooled to -78 OC, a solution of furfural (1.1 mL, 13

m o l ) in CH$& (1 mL) was added dropwise. The reaction was stirred at -78 OC for 30 min

and then at O OC for 1 h, whereupon the reaction was quenched by the addition of 0.25 M

aqueous N a 2 H ~ P 0 4 (pH = 7) (20 mL). Methanol was added until the mixture became

homogeneous. The solution was cooled to O OC, whereupon a mixture of MeOH : 30% Hz02

(2: 1 total volume of 60 mL) was added while the internal temperature was rnaintained d OC, and

the solution was stirred for 2 h at rt. The organic solvents were removed in vacuo and the

aqueous layer was extracted with CH2C12 (3x 200 mL). The combined organic layers were

washed with saturated NaHC03 ( l x 300 mL), dried (MgS04) and concentrated under reduced

pressure. Flash chromatography eluting with 35% EtOAc in hexanes gave 2.72 g (64%) of 72

as a sticky oil ( ~ 9 5 % de by 400 MHz NMR). [a]2SD = +15S0 (CHCl3, c = 1.3); IR (neat)

3483, 1775,1694, 1364, 1 191, 1044,979,756 cm-1; 1H NMR (400 MHz, CDC13) 6 7.5 1 (1H.

d, J = 7.3 Hz), 7.20-7.32 (4H. m), 6.29-6.30 (2H, m), 5.83 (lH, d, J = 7.6 Hz). 5.16-5.19

(lH, m), 5.08 (lH, ci, J = 5.1 Hz), 4.19 (lH, dq, J = 7.0, 5.1 Hz), 3.31 (3H, d, J = 3.3 Hz),

1.24 (3H. d, J = 7.0 Hz); 13c NMR (100 MHz, CDC13) 6 176.2, 154.1, 152.2, 141.6, 139.2,

138.6, 129.6, 128.0, 126.5, 125.0, 110.1, 106.5, 78.2, 68.4, 62.8, 42.2, 37.6, 12.0. HRMS

calcd for C l8H 1705N Fi]+ 327.1 107, found 327.1096.

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A solution of L i B a (4.1 rnL of a 2.0 M in THF, 8.3 m o l ) was slowly added with

stirring to a solution of the syn aldol adduct 72 (2.25 g, 6.88 m o l ) in TKF (5 mL) at -45 OC.

The reaction was stirred for 1 h at - 45 OC and then at O OC for 2 h. Most of the THF was

removed under reduced pressure, whereupon sahirated NH4Cl(25 mL) and CH2Cl:, (25 mL)

were added. The Iayers were separated and the aqueous layer was extracted with CH2C12 (3 x

50 mL). The combined organic layers were dried (Na2S04) and concentrated under reduced

pressure. The solid which fonned was resuspended in a Iitiie CH;?CI2 and the residue was

purifed by flash chromatography (40-55%% EtOAc in hexanes) to give 903 mg (84%) of 5Og

as a clear colourless oil. [a125, = -37.0" (CHC13, c = 0.5); 1H NMR (400 MHz, CDC13) 6 7.28

(1H, dd, J = 1.8, 1.1 Hz), 6.26 (IH, dd, J = 3.3, 1.8 Hz), 6.17 (lH, dm, J = 2.9 Hz), 4.78

(lH, d, J = 3.7 Hz), 3.88 (IH, br s), 3.57 (lH, dd, J = 11.0, 7.3 Hz), 3.48 (lH, dd, J = 11.0,

4.8 Hz), 2.06-2.16 (IH, m), 0.80 (3H. d, J = 7.3 Hz); 1 3 ~ NMR (100 MHz, CDCI3) 6 155.3,

141.5, 110.0, 70.6, 65.7, 39.5, 11.4.

( I S , 2R)-3-tert-Butyldimethylsiloxy-l-furan-2-methyl-propan-o1, (50f):ae

O O H TBDMSCI. imidazole

OH OTBS

DMF

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86

To a solution of the alcohol 50g (900 mg, 5.76 mmol) in 6 mL DMF was added

imidazole (863 mg, 13.7 mmole) foliowed by rert-butyldimethylsilylchloride (955 mg, 6.34

mmole). The reaction was stirred for 18 h at rt, diluted with water and extracted with 10%

CH2C12 in hexanes (3x). The combined organic layers were dned (MgSQ), fdtered, and the

solvent removed in vacuo to give a paie yeiiow oil. The resultant oil was purified by flash

chromatography (10% EtOAc in hexanes) to give 840 mg (54%) of the known compound S e l e

dong with 23% unreacted starting material and 23% of the di-silated furan which could be

recycled back to the starting materiai 50g upon treatment with TBAF in THF at O OC (92%).

[a]25, = -27.0' (CHCI3, c = 1) 1H NMR (400 MHz, CDC13) 5 7.28 (1H. dd, J = 1.8.0.7 Hz),

6.27 (lH, dd, J = 3.3, 1.8 Hz), 6.18 (lH, d, J = 3.3 Hz), 4.82 (lH, br d, J = 3.3 Hz), 3.72

(lH, br s), 3.63 (lH, dd, J = 9.9, 4.4 Hz), 3.59 (lH, dd, J = 9.9, 6.6 Hz), 2.10-2.19 (fW, m),

0.87 (9H, s), 0.85 (3H. d, J = 7.3 Hz). 0.03 1 (3H, s), 0.027 (3H, s); l3C NMR (100 MHz,

CDCI3) G 155.8, 141.1, 109.9, 106.0, 71.2, 66.8, 39.3, 25.8, 18.1, 11.3, -5.66, -5.70.

Furan (0.37 mL, 5.0 mmol) was dissolved in THF (10 rnL) and cooled to O OC. To this

solution was added n-BuLi (1.9 mL, 2.5 M in hexanes, 5.0 mmol) slowly. The resulting

solution was stirred at O OC for 1 h then n (2 h) and cooled back to O OC. The resulting

furyllithium solution was then added to a solution of (IR, 2S, SR)-(-)-menthy 1-(S)-p-

tol~enesulfinate,5~ 73 (729 mg, 2.52 rnmol) in 5 mL THF at n. The reaction mixture was

stirred for an additional 2 h at n and then quenched with saturated NH4CI solution and extracted

with Et20 (2x). The combined organic layers were dried (MgS04), filtered, and the solvent

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87

removed in vacuo. mirification by flash chromatography (20% EtOAc in hexanes) afforded 520

mg (100%) of 52. [a]25, = -0.5 (acetone. c = -0.5); IR ( D r ) 3 1 14. 149 1. 145 1, 1082, 1049,

809, 754 cm- ; 1H NMR ( 4 0 MHz. CDC13) 6 7.57 (7H, d, J = 8.4 HZ), 7.52 ( 1 H. dd, J = 1.8,

0.7 Hz), 7.31 (SH, d, J = 7.7 HZ). 6.78 (1 H, dd J = 3.7, 0.7 Hz), 6.43 ( 1 H, dd J = 3.7, 1.8

Hz), 7-40 (3H, s ) ; 1 3 ~ NMR (100 MHz, CDC13) 6 153.6, 147.0, 141.7, 138.2. 129.8, 124.9,

1 15.7, 1 1 1.2, 2 1.5; HRMS calcd for C 1 1 H 1 102s m+ 207.0480, found 307.0476.

5.3 Intermolecular [4+3] Cycloadditions With 2,4-Dibromo-3-pentanone Using

Zn-Ag Couple

General Solvents and Reagents

The following general soivents and reagents details apply to ail subsequent cycloaddition

experiments.

Unless othewise stated, commercial reagents were used without purification. Diethyl

ether, THF. and toluene were distilled immediately prior to use from sodium

wire/benzophenone. DME and chlorinated solvents were distilled from calcium hydnde prior to

use. Zn-Ag couple,8d Zn-Cu couple.8c 2,4-Dibromo-3-pentanone (DBP or 74).9* n - ~ r ~ n l . ~

1,1,3,3-tetrabromoacetone (TBA or 87)92 and 1,3-dibromo-2-butanone (DBB or 93)93 were

prepared according to methods described in the fiterature. DBP (74), and DBB (93) were stored

at O OC in the dark under an argon atmosphere. Rior to their use. the dibroketones were filtered

through basic alumina, eluting with spectral grade pentane and the solvent removed in vacuo

give a clear colourless oils, free of any residuai acid.

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88

Method A: General Procedure Using Zn-Ag Couple (non-deprotonating

conditions). To a fiame-dried. round bottom flask equipped with a magnetic stir bar and

rubber septum was placed freshly prepared Zn-Ag couple (2.5 mmol), furan (1 -4 m o l ) and

solvent (0.8 M final concentration with respect to furan). The mixture was cooled to O OC and 1

mm01 of DBP 74. was added dropwise. WARNING: the reaction is exothennic therefore care

should be taken not to add the dibromoketone rapidly, especially on a large scale. The reaction

was stirred at O OC (2 h) then n (20 h). The crude mixture was filtered through Ceiite using

EtOAc as the eluent and the organic filtrate was washed with a saturated solution of NazEDTA

(2x). The organic Iayer waç dried (MgS04), filtered and the solvent removed in vacuo to give

an oii which was purified by flash chromatography on silica gel. Roduct ratios were determined

by integration of the bridgehead protons in the 1H NMR specmim between the 4-5 ppm region or

by GC malysis.

Cycloaddition of

Zn-Ag Couple.

(S*)-2-(1-Methoxy-2,2-dimethyl-propy1)-hran, (50a), Using

1. Z n-Ag, THF e OMe

OMe J 2 . A 0

5Oa Br Br 7% 76a

The reaction was carried out as described in the general procedure (Method A) using 50a

(380 mg, 2.32 mmol), Zn-Ag couple (270 mg, 4.14 mmol), DBP 74 (390 mg, 1.66 mmol), and

DME (2.9 rnL). Purification by flash chromatography (2% Et20 in toluene) gave 109 mg (26%

combined isolated yield) of a 92 8 mixture of 75a and 76a, as determined by analytical GC.

[ I R * , l ( I S * ) , 2 S * , 4 R * , 5S*]-(l-(l-Methoxy-2,Z-dimethyI-propyl)-2,4-

dimethyl-8-oxabicyclo[3.2.l]oct-6-en-3-one, (75a). IR (neat) 2933, 2872, 283 1,

1769, 1741, 1458, 1363, 1099, 1083 cm-'; 1H NMR (200 MHz, CDC13) 6 6.28 (1H, d, J =

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89

6.1 Hz), 6.14 (1H, dd, J = 6.1, 1.7 Hz), 4.86 (1H, dd, J = 4.6, 1.7 Hz), 3.48 (3H, s ), 3.10

(lHT s), 2.80-2.66 (2H, m), 1.09 (9H, s), 1.07 (3H. d, J = 5.6 Hz), 0.94 (3H. d. J = 7.0 Hz);

I3C NMR (100 MHz, CDC13) 6 209.3, 136.2, 130.4, 94.8, 88.7, 82.1, 62.5, 53.8, 49.7,

38.2, 28.1, 10.7, 10.6; HRMS calcd for Cl jH24O3 M+ 252-1725. found 252.17 17.

[IS*, I ( I S * ) , ZR) 4S> SR*] -1-(1-Methoxy-2,2-dimethyLpropy1)-2,4-

dimethyl-8-oxabicycio[3.2.l]oct-6-en-3-one, (76a). IR (neat) 2940, 2875. 2830,

1709, 1458, 1378, 1099, 1086, 1023.907,706 cm-'; lH NMR (400 MHz, CDCl3) 6 6.19 (lH,

d, J = 6.2 Hz), 6.06 (IH, dd, J = 6.2, 1.5 Hz), 4.84 (1H. dd, J = 4.8, 1.5 Hz), 3.60 (3H, s ),

3.17 (lH, s), 3.01 (IH, q. J = 7 Hz), 2.76 (lH, dq, J = 4.8, 6.9 Hz ), 1.07 (3H, d, J = 7 Hz),

1.02 (9H, s), 0.93 (3H. d, J = 6.9 Hz); 13C NMR (100 MHz, CDCl3) 6 210.3, 135.6, 129.5,

93.8, 87.5, 81.7, 63.3, 52.2, 49.4, 38.1, 28.3, 10.6, 10.4; HRMS calcd for Ci5H2303 [M-

H]+ 25 1. 1647, found 25 l . 1636.

Cycloaddition of (S*) -1-Furan-2-yl-2,2-dimethyl-propan- 1-01, 50b, Using Zn-

Ag Couple (non-deprotonating conditions).

1. Zn-Ag, THF 3. *.,: O * + W*O +

50b Br Br 7% 76b 77b

The reaction was carried out as described in the general procedure (Method A) using 50b

( 100 mg, 0.645 mmol), Zn-Ag couple (76 mg, 1.2 mmol), DBP 74 ( 1 13 mg, 0.46 1 m o l ) , and

THF (0.8 mL). Purification by flash chromatography (10% Et20 in toluene) gave 66 mg (60%

combined isolated yield) of a 27:57:16 mixture of 75b, 76b and 77b, as determined by

analytical GC.

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90 [IR*, I(IS*) , ZS*, 4R*, 5S*]-1-(1-Hydroxy-2,2-dimethy!-propy1)-2,4-

dimethyl-8-oxabicycloU.2.l]oct-6-en-3-one, (75b). Mp = 83.5-84 OC (pentane); R

(KBr) 3557, 2952, 1699, 1455, 1054, 973, 913, 766 cm-'; 1H NMR (400 MHz, CDCl3) G

6.21 (lH, d, J = 6.2 Hz), 6.13 (lH, dd, J = 6.2, 1.8 Hz), 4.86 (lH, dd, J = 4.4, 1.8 Hz), 3.56

(lH, d, J = 9.5 Hz), 2.82 (lH, q, J = 7.0 Hz), 2.76 (1H, dq, J = 4.4, 7.0, Hz), 2.01 (lH, d, J

= 9.2 Hz ), 1.08 (9H, s), 1.07 (3H. d, J = 7.0 Hz), 0.95 (3H, d, J = 7.0 Hz); l3C NMR (100

MHz, CDC13) 6 208.7, 137.8, 130.3, 94.3, 83.1, 76.9, 53.1, 49.8, 36.9. 27.8, 10.6, 10.5;

Anal. calcd for C 14H22O3 : C, 70.56; H, 9.30. Found: C, 70.3 1, H, 9.12.

[IS*, I (IS*) , 2R*, 4S*, SR*]-1-(1-Hydroxy-2,2-dimethyl-propy1)-2,4-

dimethyl-8-oxabicycl0[3.2.l]oct-6-en-3-one, (76b). Mp = 104.5- 105 OC (pentane);

IR ( D r ) 3566, 2997, 1694, 1466, 1378, 1011, 979, 908, 746 cm-'; 1H NMR (200 MHz,

CDC13) 6 6.18 (lH, d, J = 6.1 Hz), 6.06 (lH, dd, J = 6.1, 1.6 Hz), 4.82 (lH, dd, J = 4.5, 1.6

Hz), 3-48 (lH, d, J = 10 Hz), 3.07 (lH, q, J = 7.0 Hz), 2.67 (1H. dq, J = 4.5, 7.0 Hz), 2.17

(lH, d, J = 10.0 HZ ), 0.99 (3H9 d, J = 7.1 Hz), 0.97 (9H9 s), 0-91 (3HT d, J = 7-0 HZ); ' 3 ~

NMR (200 MHz, CDCl3) 8 209.9, 135.4, 129.7, 93.6, 81.7, 76.7, 52.7, 49.4, 36.7, 27.7,

10.2, 9.7; Anal. Caicd. for C1&12203 : C, 70.56; H. 9.30. Found: C, 70.31, H, 9.00.

dimethyl-8-oxabicyclo[3~2.l]oct-6-en-3-one, ( 7 7 IR (neat) 3522, 297 1, 2882,

1702, 1217, 1085, 944, 747 cm-I; l H NMR (400 MHz, CDC13) 6 6.26 (lH, d, J = 6.3 Hz),

6.22 (lH, ddd, J = 6.3. 1.4, 0.8 Hz), 4.68 (lH, d, J = 0.8 Hz), 3.65 (lH, d, J = 0.8 Hz), 2.87

(lH, d. J = 1.8 Hz). 2.56 (1H. dd, J = 7.3, 0.8 Hz), 2.25 ( lH, q, J = 7.7 Hz ), 1.32 (3H, d, J

= 7.3 Hz), 1.30 (3H, d, J = 7.7 Hz), 1.05 (9H, s); 1 3 ~ NMR (50 MHz, CDCl3) 8 213.6,

134.5, 133.0, 90.9, 81.1, 75.9, 53.9, 49.2, 34.9, 27.9, 17.4, 15.7; Anal. Calcd for C14H2203

: C' 70.56; H, 9.30. Found: C, 70.60, H, 9.46.

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[ I S * , ZR*, 4S*, SR*]-1-(2,2-Dimethyl-propiony1)-2,4-dimethyl-8-

oxabicyclo[3.2.l]oct-6-en-3-one, (78):

O H f iqPq 0. H%O TPAP (cat-), NMO, +

O 4 À MS. MeCN

TPAP (7 mg, 0.02 mmol) was added to a sthed solution of 76b (50 mg, 0.2 1 mmol),

NMO (62 mg, 0.53 rnmol) and powdered 4 A molecular sieves (50 mg) in MeCN (0.4 r n ~ ) . o O

After 5 hours, the reaction was filtered through a plug of silica using CH2C12 as the eluant.

Evaporation of the solvent and flash chromatography of the residue over silica gel (5%

EtOAchexanes) gave 30 mg (60%) of pure 78 dong with 40% unreacted starting matenal.

Similady for 75b, TPAP (8 mg, 0.02 m o l ) was added to a s h e d solution of 75b (54 mg,

0.23 mmol), NMO (66 mg, 0.57 mmol) and powdered 4 A molecular sieves (55 mg) in MeCN

(0.4 mL). Purification as for 76b gave 45 mg (85%) of diketone 78 dong with 15% unreacted

starting material: IR ( D r ) 2963, 1733, 1705, 1652, 910, 734 cm-l; IH NMR (400 MHz.

CDCl3) 6 6.45 (lH, d, J = 5.9 Hz), 6.24 (1H. dd, J = 5.9, 1.8 Hz). 4.93 (lH, dd, J = 4.8, 1.8

Hz), 2.84 (lH, q, J = 6.6 Hz). 2.82 (lH, dq, J = 4.8, 7.0 Hz). 1.28 (9H, s). 0.97 (3H, d, 1 =

7.0 Hz), 0.94 (3H, d, J = 7.3 Hz); 13C NMR (100 MHz. CDCl3) G 209.5, 207.1, 135.0.

132.1, 96.1, 83.0, 53.6, 50.1, 45.4, 26.5, 10.3, 9.9; HRMS calcd for C14H2003 [Ml+

236.14 12, found 236.14 14.

Epimerization Experiments:

base

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Epimerization of 77b With tBuOK in tBuOH: Ketone 77b (10 mg, 0.04 m o l )

was dissolved in BUOH (0.1 mL), tBuOK (2.2 mg, 0.02 mmol) was added and the mixture

stirred for 6 h at rt - 35 O C . The reaction was quenched with water and the products extracted

into ether. The organic layer w ~ d r i e d (MgS04) and filtered and the solvent removed in vacuo.

GC anaiysis of the crude mixture indicated a ratio of 1:25:74 of 77b, 79b and 7 6 b

respectively.

Epimerization of 77b With &CO3 in MeOH: Ketone 77b (30 mg, 0.13 mmol)

was dissolved in MeOH (0.13 mL), K2C03 (87 mg, 0.63 mmol) was added and the mixture

stirred for 3 d at 40 OC. The reaction was quenched with water and the products extracted into

ether. The organic layer was dned (MgS04) and filtered and the solvent removed in vacuo. GC

analysis of the crude mixture indicated a ratio of 1:25:74 of 77b, 79b and 76b respectively.

Epimerization of 77b With DBU: Ketone 77b (10 mg, 0.04 rnrnol) was dissolved

in DBU (1 mL) and the mixture s h e d for 3 h at 60 OC. The reaction was quenched with water

and the products extracted into ether. The organic layer was dried (MgS04) and filtered and the

solvent removed in vacuo. GC anaiysis of the crude mixture indicated a ratio of 1 :2 1:79 of 77b,

79b and 76b respectively.

Epimeruation of 77b With Mg(0Me)z in MeOH: Ketone 77b (10 mg, 0.04

m o l ) was dissolved in a solution of Mg(0Me)z in MeOH (0.5 mL, 0.2 M solution, 0.1 rnrnol)

and the reaction mixture was stined for 1 d at reflux. The reaction was quenched with water and

the products extracted into ether. The organic layer was dried (MgS04) and fütered and the

solvent removed in vacuo. GC analysis of the crude mixture indicated a ratio of 39:39:22 of

77b, 79b and 76b respectively.

Epimerization of 77b With Mg(0Me)z in EtzO: Ketone 77b (10 mg, 0.04

rnrnol) was dissolved in Et20 (0.1 mL), Mg(0Me)z in MeOH was added (1 mL, 0.2 M solution,

0.2 mmol) and the mixture was s h e d for 5 d at reflux. The reaction was quenched with water

and the products extracted into ether. The organic layer was dried (MgS04) and filtered and the

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solvent removed in vacuo. GC analysis of the cmde mixture indicated a ratio of 552320 of

77b. 79b and 76b respectively.

[ IS* , I ( IS*) , 2S*, 3R*, 4S*, 5R*]-l-(l-Hydroxy-2,2-dimethyl-propyl)-2,4-

dimethyl-8-oxabicyclo [3 .L lloct-6-en-3-01, (80).

To a O OC solution of the ketone 79b (275 mg, 1.15 mmol) in Et20 (12 rnL) was added

LiAIH4 (131 mg, 3.45 mmol) portion-wise. After 3 h, the reaction was quenched with a

saturated solution of K+/Na+ tartrate and the mixture was aliowed to stir for 1 h. The products

were extracted into EtOAc (3x), and the organic layer dried (MgS04), fdtered. and the solvent

removed in vacuo to give a pale yellow oil. hirification by flash chromatography on silica gel

(25% CH3CN in CH2C12) gave 235 mg (85%) of 80 and recrystaiiization from CH2C12 gave

pure white crystais suitable for X-ray crystaiiography (See Appendix 2 for X-Ray crystai data for

compound 80): Mp 106.5-107 OC (CH2Cl2); IR (KBr) 3424,2928, 1472, 1376, 1056,960 cm-

; IH NMR (400 MHz, CDCl3) 6 6.03 (lH, d, J = 6.2 Hz), 5.97 (lH, dd, J = 6.2, 1.5 Hz),

4.55 (lH, s), 3.43 (lH, d, J = 10.3 Hz), 3.34 (lH, m), 2.09 (lH, d, J = 10.6 Hz), 1.96 (lH,

dq, J = 9.5, 7.0 Hz ), 1.80 (lH, ddq, J = 7.0, 7.0, 1.5 Hz), 1.06 (3H, d, J = 7.3 Hz), 0.94

(9H, s), 0.93 (3H, d J = 7.0 Hz); 13C NMR (100 MHz, CDCl3) 8 131.4, 129.2, 92.3, 82.9,

76.7, 73.1, 38.0, 36.6, 34.2, 27.7, 13.2, 11.6. HRMS calcd for C14H2403 M+ 240.3456,

found 240.345 1.

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94 Cycloaddition of (S)-2-(Toluene-4-sulfiny&furan, (52), Using Zn-Ag Couple

(non-deprotonating conditions).

The reaction was canied out as described in the generai procedure (Method A) using 52

(193 mg, 0.936 mmol), Zn-Ag couple (109 mg, 1.67 mmol), DBP 74 (163 mg, 0.667 m o l ) ,

and THF (1.2 mL). Purification by flash chromatography (35% EtOAc in hexanes) gave 39 mg

(20% combined isolated yield) of a 80:20 mixture of 8584 dong with 169 mg of unreacted

starhg material.

[ I S , I ( I S ) , ZR, 4S, 5R]-2,4-DimethyI-l-(toluene-4-sulfiny1)-8-

oxabicyclo[3.2.l]oct-6-en-3-one, (85): [a]25, = +0.4 (CHC13. c = 1); IR (KBr) 3058,

297 1, 1726, 1370, 1052. 1033. 980,966, 804, 750 cm-l; NMR (400 MHz, CDC13) 6 7.49

(2H, d, J = 8.1 Hz), 7.27 (2H, d. J = 8.1 Hz), 6.26 (lH, dd. J = 6.2, 1.5 Hz), 6.22 (lH, d J =

6-2 HZ), 4-83 (1H. dd J = 4-89 1.1 HZ), 3-19 (1H. q J = 7.0 HZ), 2.79 (lHT dq, J = 7.0. 5.1

Hz), 2.39 (3H, s), 1.28 (3H, d J = 7.0 Hz), 0.91 (3H. d J = 7.0 Hz); l3C NMR (100 MHz,

CDCl3) 8 207.3, 142.0, 135.9, 134.4, 129.7, 129.2, 126.1, 102.9, 83.5, 51.0, 49.3, 21.5,

2 1-5, 10.3, 9.5; HRMS calcd for C1&g03S [w+ 290.0977, found 209.0963.

[ I R , I ( I S ) , 2R, 4R, 5S]-2,4-Dimethyl-l-(toluene-4-suIfinyl)-8-

oxabicyclo[3.2.l]oct-6-en-3-one, (84): [a]25, = M.6 (CHC13, c = 2); IR ( D r ) 3056.

2946, 1702, 1456, 1077. 978. 890 cm-l; IH NMR (400 MHz, CDCl3) 6 7.56 (2H, d, J = 8.1

k), 7.29 (2H, d, J = 8.1 Hz), 6.47 (lH, d, J = 6.2 Hz), 6.45 (lH, dd, J = 6.2, 1.5 Hz), 4.96

(lH, dd J = 5.1, 1.5 Hz), 2.68 (lH, dq J = 7.0, 5.1 Hz), 2.54 (lH, q, J = 7.3 Hz), 2.39 (3H,

s), 1.20 (3H, d J = 7.0 Hz), 0.90 (3H, d J = 7.0 Hz); 13c NMR (100 MHz. CDC13) 6 206.3,

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142.5, 136.7, 134.8, 130.3, 129.4, 126.5, 103.2, 83.8, 52.3, 49.6, 21.6, 10.4, 9.8; HRMS

cdcd for C 16H 1903s m]+ 29 1.1055, found 29 1.1055.

Cycloaddition of Furfuryl Alcohol, (104), Using Zn-Ag Couple (non-

deprotonating conditions).

1. Zn-Ag, THF O A \k

The reaction was carried out as described in the general procedure (Method A) using 104

(200 mg, 2.31 mmol), Zn-Ag couple (380 mg, 5.79 mmol), DBP 74 (566 mg, 2.3 1 mmol), and

THF (20 rd). Purification by flash chromatography (15% MeCN in CH2C12) gave 226 mg

(54% combined isolated yield) of a 88: 12 mixture of 105108 as determined by IH NMR (400

MHz) .-

(IS*, 2R*, 3S*, 4R * ) - 1 - H y d r o x y m e t h y l - 2 , 4 - d i m e t h y i - 8 -

oxabicyclo[3.2.l]oct-6-en-3-one, (105): H NMR (400 MHz, CDC13) 6 6.3 1 ( 1 H, dd,

J=6.3, 2.2 HZ), 6.11 (lH, d, J = 6.3 HZ), 4.87 (lH, dd, J = 4.8, 1.8 HZ), 3.84 (2 H, s), 2.71-

2.78 (2H, m), 2.32 (lH, br s), 0.96 (3H, d J = 6 . 9 Hz), 0.94 (3H, d, J = 7.0Hz); I ~ c NMR

(100 MHz, CDCl3) 8 208.8, 134.8, 133.4, 91.0, 82.8, 63.5, 50.8, 49.7, 10.4, 9.4.

(IS*, 2S*, 3R*, 4RC)-1-Hydroxymethyl-2,4-dimethy1-8-

oxabicyclo[3.2.l]oct-6-en-3-one, (108): IR (neat) 3422, 2939, 1701, 1456, 1043,

948, 738 c m - l ; l ~ NMR (400 hlHi , CDCl3) G 6.26 (1H. ddd, J =6.2, 1.5, 0.7 Hz), 6.14 (lH,

d, J = 6.2 Hz), 4.69 (lH, d, J = 1.5 Hz), 3.91 (IH, d, J = 11.7 Hz), 3.68 (1H. d, J = 12.1

Hz), 2.33 (2H, m), 1.83 (1H. br s), 1.32 (3H, d J = 7.7 Hz), 1.20 (3H, d, J = 7.3 Hz); 1 3 ~

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NMR (100 MHz, CDCl3) 6 213.3, 134.9, 134.8, 88.1, 82.7, 62.5, 50.7, 49.3, 17.5, 14.4;

HRMS calcd for C10H1403 Ml+ 182.0943, found l82.094I.

Method B: General Procedure Using Zn-Ag Couple (deprotonating

conditions). To a O OC solution of the furan (1.4-2 equiv) in THF was added 1.4-2 equiv of

the organometallic reagent (0.8 M final concentration with respect to furan) and the reaction was

stirred at O OC for 15 min. The solution was then transferred to another dry round bonom flask

containing freshly prepared dry Zn-Ag couple (2.5 m l ) via canula To this mixture was added

dibromopentanone DBP 74 dropwise (1 equiv) and the reaction was s h e d at O OC (2 h) then rt

(20 h). WARNZNG: the reaction is exathermic therefore cure should be taken not tu add the

dibromoketone rapidly, especially on a iarge scale. The reaction was then quenched with a srnall

portion of a sanirated solution of Na2EDTA and the mixture was fdtered through Celite using

EtOAc as the eluent. The final stages of the workup and purification were carried out as in the

general procedure described above (Method A). Product ratios were detemiined by integration

of the bridgehead protons in the 1H NMR specmim in the 4-5 ppm region or by GC analysis.

Cycloaddition of (S*)-l-Furan-2-yl-2,2-dimethyl-propan-1-oi, 50b, Using n-

PrZnI and Zn-Ag Couple (deprotonating conditions):

1. n-PrZnl, THF 2. Zn-Ag, THF

50b Br Br 76b 7% 77b

The reaction was carried out as described in the generai procedure (Method B) using SOb

(104 mg, 0.68 mmol), n-PrZnI (0.3 mL, 0.7 mmol, 2 M in THF), Zn-Ag couple (1 11 mg, 1.69

mmol), DBP 74 (1 18 mg, 0.493 mmol), and THF (0.5 mL). Purification by flash

chromatography (10% Et20 in toluene) gave 57 mg (49% combined isolated yield) of a 3:3:94

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mixture of 76b, 79b, and 77b, as determined by analyticd GC. Spectroscopie data of the

minor adduct, 79b, is given below.

[IS*, I ( l S * ) , 2R*, #R*, SR*]-1-(1-Hydroxy-2,2-dimethyl-propy1)-2,4-

dimethyl-8-oxabicycI0[3.2. îJoct -6-en-3-0 , (79b). IR (neat) 3507, 2976, 2943,

1707, 1459. 1382, 1066, 975, 904 cm-'; IH NMR (400 MHz, CDC13) 6 6.18 (IH, d, J = 6.2

Hz), 6.09 (lH, dd, J = 6.2, 1.9 Hz), 4.67 (lH, s), 3.48 (IH, d, J = 10.6 Hz), 3.19 (IH, q, J =

6.9 HZ), 2.25 (lH, q, J = 7.3 Hz), 2.1 1 (lH, d, J = 10.9 HZ ), 1.30 (3H. d, J = 7.3 Hz), 1.01

(3H. d, J = 6.9 Hz), 1.00 (9H, s); 13C NMR (100 MHz, CDCI3) 6 212.5, 133.7, 131.6,

110.3, 92.9, 81.7, 76.8, 60.0, 48.7, 36.7, 15.9, 9.6; Anal. Calcd for C[4H2203 : C. 70.56;

H, 9.30. Found: C, 70.72, H, 9.26.

Cycloaddition of ( I S , 2R)-l-Furan-2-yl-2-methyl-3-(ter~butyldimethylsiioxy)-

propan-1-01, 50f, Using n-PrZnI and Zn-Ag Couple (deprotonating conditions):

1. n-PrZnl, THF 2. Zn-Ag, THF - other

isomers O H 3. O

The cycloaddition was canied out as in the general procedure described above (Method

B) using 50f (127 mg. 0.469 m o l ) , n-PrZnI (0.25 mL, 0.50 rnmol, 2 M in THF), Zn-Ag

couple (64 mg, 0.98 mmol), DBP 74 (92 mg, 0.39 mmol), and THF (0.34 mL). Purification

by flash chromatography (20% EtOAc in hexanes) gave 67 mg (40% combined isolated yield) of

a 93:7 mixture of 77f to aU other isomers, as determined by lH NMR (400 MHz). In addition,

isolated 69 mg of unreacted 50f.

[ZS, l ( I S , 2R), 2S, 4R, SR]-1-[1-Hydroxy-2-methyl-3-(tert-

butyldimethylsiloxy)-propyi]-2,4-dibromo-8-oxabicyclo[3.2.l]oct-6-en-3-one,

(770: [a]25, = +26.5 (CC4, c = 2); IR (neat) 3498, 2931, 1712, 1472, 1258, 1094, 838,

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777 cm-'; I H NMR (400 MHz, CDC13) 6 6.24 (lH, dm, 1 = 6.2 Hz), 6.20 (1H. d, J = 6.2 Hz),

4.64 (lH, s), 4.20 (1H. s), 3.62 (1H. dd. J = 9.5, 8.1 HZ), 3.53 (1H. dd, J = 9.9, 4.8 Hz),

2.36-2.47 (1H. brs), 2.36 (lH, q, J = 7.3 Hz), 2.25 (lH, q, J = 7.3 Hz), 1.75-1.85 (1H. m),

1.32 (3H, d, J = 7.7 Hz), 1.25 (3H. d J = 7.3 Hz), 0.93 (3H. d, J = 7.0 Hz), 0.86 (9H. s),

0.03 (6H, s); 13c NMR (100 MHz, CDC13) 6 213.4, 135.2, 133.7, 90.8, 81.1, 69.8, 66.9,

51.3, 49.0, 35.1, 25.9, 18.2, 17.5, 14.4, 10.5, -5.49, -5.50; HRMS calcd for CigH3104Si

[MI+ 339.1992, found 339.2004.

Cycloaddition of Furfuryl AIcohol,

(deprotonating conditions):

1. EtMgCl 2. Zn-Ag, THF

10Q Br Br

(104), Using EtMgCl and Zn-Ag Couple

The cycloaddition was camed out as described in the generai procedure (Method B) using

104 (200 mg, 2.31 mmol), EtMgCl (1.2 mL, 2.3 m o l , 2 M in TIIF), Zn-Ag couple (380 mg,

5.79 mmol), DBP 74 (565 mg, 2.31 mmol). and THF (0.7 rnL). Purification by flash

chromatography (15% MeCN in CH2C12) gave 207 mg (49% combined isolated yield) of a

19:2:5:74 mixture of 105, 106, 107 and 108, as determined by *H NMR (400 MHz).

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Epimerization of 108 With 'BuOK in 'BuOH:

base - HO

Ketone 108 (20 mg, 0.20 m o i ) was dissolved in 'BUOH (0.1 mL), [BuOK (2.2 mg,

0.02 mmol) was added and the mixture was stirred for 1 d at 35 OC. The reaction was quenched

with water and the products extracted into ether. The organic layer was dried with MgS04 and

filtered and the solvent evaporated. GC analysis of the crude mixture indicated a ratio of

63: 17:20 of 105, 106 and 107 respectively dong with 3% unreacted starting material (108).

5.4 Intermolecular [4+3] Cycloadditions With 2,4-Dibromo-3-pentanone:

Using Diethylzinc

Method C: General Procedure Using ZnEt2. To a solution of the furan (1

equiv) in THF or Et20 (0.3 M final concentration) was added neat ZnEt2 (1-2 equiv) under N2 at

O O C . The resulting mixture was stirred for 10 min at O OC prior to the dropwise addition of 74

( 1 -3 equiv) . WARNING: the reaction is exothemic therefore care should be taken not to add

the dibromokerone rapidly, especially on a large scale. The mixture was then stirred at O OC (1 d)

then n (1 d) followed by quenching with EtOAc and a saturated solution of Na2EDTA (1: 1). The

products were extracted into the organic layer (2x EtOAc), and the organic layer dried (MgS04),

filtered and the solvent removed in vacuo to give an oil. The cmde oil was then purifed by flash

chrornatography on silica gel. Product ratios were determined by integration of the bridgehead

protons in the 1H NMR s p e c m between the 4-5 ppm region or by gc analysis.

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Cycloaddition of (S*)-l-Furan-2-yl-2,2-dimethyl-propan-l-o1, SOb, Using 1

Equiv ZnEtz in TH%.

+ other isomers

The cycloaddition was carried out as described in the general procedure (Method C) ushg

50b (85 mg, 0.55 mmol), ZnEt2 (0.06 mL. 0.55 mmol), DBP 74 (271 mg, 1.1 1 mmol), and

THF (1 -8 mL). Purification by flash chromatography (10% Et20 in toluene) gave 71 mg (54%

combined isolated yield) of a 98:2 mixture of 77b to al1 other isomen. as determined by

analyticd GC.

Cycloaddition of (S*)-1-Furan-2-y1-2,Z-dimethyl-propan-1-01, SOb,

Using 2 Equiv ZnEt2 in THF: Optimized Procedure for High Yields and High

Diastereoselectivity. The cycloaddition was carried out as described in the general

procedure (Method C) using 50b (86 mg, 0.56 mmol), ZnEt2 (O. 1 1 mL, 1.12 rnmol). DBP 74

(410 mg, 1.68 mmol), and THF (1 -9 mL). Purification by flash chromatography (10% Et20 in

toluene) gave 107 mg (80% combined isolated yield) of a 95:s mixture of 77b to ail other

isomers, as detennined by analytical GC.

Cycloaddition of (S*)-1-Furan-2-yl-2,Z-dimethyl-propao-l-01, 50b, Using 1

Equiv ZnEtz in Et2O:

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101 The cycloaddition was canied out as described in the general procedure (Method C) using

50b (91 mg. 0.59 mmol), ZnEt2 (0.06 mL, 0.59 mmol), DBP 74 (144 mg, 0.59 mmol), and

Et20 (2 mL). Purification by fiash chromatography (10% Et20 in toluene) gave 34 mg (24%

combined isolated yield) of a 94:6 mixture of 77b. and 79b. as determined by analytical GC.

Cycloaddition of (S*)-1-Furan-2-yl-2,2-dimethyl-propan-1-01, 50b,

Using 2 equiv ZnEt2 in EtzO. Preparation of the Major Axial-Equatorial

Cycloadducî, (79b). The cycloaddition was carried out as described in the general procedure

(Method C) using 50b (89 mg, 0.58 mmol), ZnEt2 (0.12 mL, 1.15 mmol), DBP 74 (141 mg,

0.58 1 m o l ) , and E-0 (1.9 mL). Purification by flash chromatography (10% Et20 in toluene)

gave 36 mg (26% combined isolated yield) of a 86: 14 mixture of 79b, and 7% dong with 46

mg (52%) of unreacted starting material. The product ratios were obtained by analytical GC.

Cycioaddition of (R)-Cyclohexyl-furan-2-yl-methanol, (50c), Using 2 Equiv

Z nE t 2 in THF: Optimized Procedure for High Yields and High

Diastereosetectivity.

1. ZnEt2, THF isomers

50c Br Br 77c

The cycloaddition was caxried out as descnbed in the general procedure (Method C) using

50c (98 mg, 0.55 mmol), ZnEt2 (0.1 1 mL, 1.1 mmol), DBP 74 (398 mg, 1-63 mmol), and 1.8

mL THF. Purification by flash chromatography (25% EtOAc in hexanes) gave 12 1 mg (83%

combined isolated yield) of a 9 5 5 mixture of 77c to d l other isomers, as determined by IH

NMR (400 MHz).

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[ IS , I ( IS ) , 2S, 4R, 5R]-l-(l-C~~l0hex~l-hydroxy-methyl)-2,4-dim~th~l-

8-oxabicyclo[3.2.1]octt6-en-3-one, (77c). Mp = 93 OC (pentane); [a125~ = +0.5 l0 (c =

2.0, CHCl3); IR ( D r ) 3490, 2933, 1712, 1455, 1373, 1120 cm-1; 1~ NMR (400 MHz,

CDC13) 6 6.24 (lH, ddd, J = 6.2, 1.8. 0.7 HZ). 6.19 (lH, d, J = 6.3 Hz), 4.64 (1H. ci, / = 1.1

HZ), 3.71 (lH, s), 2-44 (lHT q, J = 7-0 HZ), 2.23 (lH, s ) , 2.22 (lH, q, J = 7.3 HZ ), 1.80-

1.10 ( 1 IH, m), 1.32 (3H, d, J = 7.7 Hz), 1.23 (3H. d, J = 7.3 HZ); 1 3 ~ NMR (100 MHz,

CDCI3) 8 213.4, 135.3, 133.7, 90.9, 81.3, 74.5, 51.7, 49.0. 38.7, 31.2, 27.0, 26.7, 26.2,

26.0, 17.5, 14.9; Anal. Calcd for Cl6H2403 : C, 72.69; H, 9.15. Found: C, 72.66, H, 9.18.

Cycloaddition of (R*)-1-(Furan-2-y1)-octan-1-01, (50d), Using 1 Equiv ZnEt2 in

THF.

The cycloaddition was canied out as described in the general procedure (Method C) using

50d ( 10 1 mg, 0.5 12 mmol), ZnEt2 (0.05 mL, 0.5 mrnol). DBP 74 (250 mg, 1-03 mrnol), and

THF (1.7 mL). Purification by flash chromatography (35% EtOAc in hexanes) gave 57 mg

(48% combined isolated yield) of a 955 mixture (lH NMR (400 MHz)) of 77d to dl other

isomen dong with 47 mg (47%) unreacted starting material.

[IS*, I(ZS*), 2S*, 4R*, SR*]-1-(1-Hydroxy-octy1)-2,4-dimethyl-8-

oxabicyclo[3.2.l]oct-6-en-3-one, (77d). Mp = 73.5-74 O C (pentane); IR (KBr) 3376.

2928, 1712, 1376, 1216, 1104,960 :m-l; N M R (400 MHz, CDC13) 6 6.25 (2H, dm, J =

6.2 Hz), 6.13 (IH, d, J = 6.2 Hz), 4.69 (lH, d, J = 1.5 Hz). 3.87 (lH, br t, 6.23 Hz), 2.82

(lH, q, J = 7.3 Hz), 2.28 (3H m), 1.66 (lH, br s), 1.18-1.42 (16H, m), 0.87 (3H. br t, J

=7.0 Hz); 13C NMR (100 MHz, CDCl3) 6 213.3, 134.9, 132.8, 90.8. 82.2, 70.0, 50.6, 49.0,

31.8, 30.7, 29.5, 29.3, 26.3, 22.7, 17.5, 14.3, 14.1; And. Cdcd for C17H2803: C, 72.82; H,

10.06. Found: C, 72.82, H, 10.14.

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103

Cycloaddition of ( I S , 2s)-Dibenzylamino-1-furan-2-yl-propan-1-01 (50e),

Using 2 Equiv ZnEt2 in THF': Optimized Procedure for High Yields and High

Diastereoselectivity.

1. ZnEt2, ' other isomers

The cycloaddition was canied out as described in the generd procedure (Method C) using

50e (197 mg, 0.6 10 mmol). ZnEt2 (0.13 mL, O. 1.2 mmol), DBP 74 (446 mg, 1.83 m o l ) , and

TW (2 mL). Purification by flash chromatography (40% EtOAc in hexanes) gave 118 mg (488

combined isolated yield) of a 9223 mixture of 77e to al1 other isomers, as determined by IH

NMR (400 MHz).

[ I S , I ( IS , 2S), 2S, 4R, SR]-1-(2-Dibenzylamino-1-hydroxy-propy1)-2,4-

dimethyl-8-oxabicyclo[3.2.l]oct-6-en-3-one, (77e): [a]25, = + 13.4 (c = 1. CHC13);

IR (neat) 349 1, 3098, 2976, 2934, 1709. 1455, 1373, 1242, 1090. 747, 700 cm-1; 1H NMIC

(400 MHz, CDC13) 6 7.20-7.37 (lOH, m), 6.14 (lH, dm, J = 6.2 Hz), 5.83 (IH. d. J = 6.2

Hz), 4.62 (lH, s), 4.15 ( lH, s), 3.95 (2H, d J = 13.6 Hz), 3.42 (2H, d J = 13.6 HZ), 2.86

(1H, dq, J = 6-69 2-2 Hz), 2-40 (lH, s), 3-19 (lH, q, J = 7.3 HZ), 1.93 (lH, q, J = 7.3 HZ),

1.28 (3H, d, J = 7.7 Hz), 1.17 (3H, d. J = 7.0 Hz), 0.99 (3H, d, J = 7.3 Hz); 1 3 ~ NMR (100

MHz, CDC13) 6 213.1, 139.9, 135.0, 132.7, 128.8, 128.1, 126.9, 90.5, 81.7, 74.1, 54.4,

51.4, 51.1, 48.9, 27.5, 14.7, 6.9; HRMS calcd for C26H3103N [Ml+ 405.2304, found

405 -2303.

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104

Cycloaddition of (IS, 2R)-l-Furan-f-yl-2-methyl-3-(tert-butyldimethylsiloxy)-

propan-1-01, (509, Using 2 Equiv Zn& in TE@': Optimized Procedure for High

Yields and High Diastereoselectivity.

1. ZnEt2, THF - rn + other

O TBSO - isomers 2.

II - O

The cycloaddition was canied out as described in the general procedure (Method C) using

SOf (187 mg, 0.691 mmol). ZnEt2 (0.14 rnL, 1.4 mmol), DBP 74 (506 mg, 2.07 mmol), and

TW (2.3 mL). mirifkation by flash chromatography (20-30% EtOAc in hexanes) gave 138 mg

(56% combined isolated yield) of a 96:4 mixture of 77f to al l other isomers dong with 76 mg of

unreacted starting material. Ratios were determined by lH NMR (400 MHz).

Cycloaddition of ( I S , 2R)-l-Furan-2-yl-2-methyl-propane-1,3-diol Using 2

Equiv ZnEt2 in THF: Optirnized Procedure for High Yields and High

Diastereoselectivity.

1. ZnEt2, THF + other isomers

O H

509 B r Br n g

The cycloaddition was canied out as described in the general procedure (Method C) using

50g ( 109 mg, 0.698 mmol), Zn& (0.16 mL, 1.5 mmol), DBP 74 (5 1 1 mg, 2.09 mmol), and

THF (2 rd). Purification by flash chromatography (45-60% EtOAc in hexanes) gave 64 mg

(38% combined isolated yieid) of a 67:33 mixture of 77g to al1 other isomers dong with 68 mg

of unreacted starting materiai. Product ratios were determined by 1H NMR.

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IR (neat) 3480, 3033, 2980, 2944. 1701, 1465, 1242, 1013, 767 cm-'; IH NMR (400 MHz,

CDC13) 6 6.29 (lH, dm, J = 6.2 Hz). 6.24 (1H. d, J = 6.1 Hz), 4.66 (lH, br s), 4.21 (1H, d, j

= 1.1 Hz), 3.65-3.74 (2H, m), 2.41 (1H. q, J = 7.3 Hz), 2.20-2.36 (3H. m), 1.82-1.92 (lH,

m), 1.35 (3H, d, J = 7.7 Hz), 1.27 (3H. d J = 7.3 Hz), 1.03 (3H, d, J = 7.0 Hz); 1 3 ~ NMR

(100 MHz, CDCl3) 6 213.2, 135.7, 133.6, 90.8, 81.1, 71.6, 67.5, 51.2, 49.0, 34.8, 17.5,

14.5, 10.7; HRMS caicd for C13H2004 [Ml+ 240-1362, found 240-1359.

Cycloaddition of (S)-2-(Toluene-4-su1finyl)-furan, (52), Using 2 Equiv ZnEtz

in THF:

1. ZnEt2, THF

The cycloaddition was cmied out as described in the general procedure (Method C) using

52 (150 mg, 0.727 mmol), ZnEtî (0.15 mL, 1.45 mmol), DBP 74 (532 mg, 2.18 rnrnol), and

THF (2.4 mL). hirification by flash chromatography (30% EtOAc in hexanes) gave 64 mg

(30% combined isolated yield) of a 80:20 mixture of 8S:84, as deterrnined by 1H NMR.

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106

Syntbesis of (IS, ZR, 4S, 5R)-2,4-dimethyl- 1-(toluene-4-suIfony1)-8-

oxabicyclo[3.2.l]oct-6-en-3-0ne (86):

Sulfoxide 85 (20 mg, 0.071 mrnol) was dissolved in MeOH (0.3 mL) and cooled to O

O C . To this was added a solution of 49.5% KHSO5 (85 g, 0.14 rnrnol) in water (0.18 rnL).63

The resulting cloudy slurry was stirred for 4 h at rt, diiuted with water (10 mL), and extracted

with CH2Cl2 (3x 20 mL). The combined organic layen were washed with water (20 mL) and

bnne (20 mL), dried over Na2S04, and the solvent rernoved Ni vacuo to give an oil. The cmde

oil was then purified by flash chromatography on silica gel (5-10% EtOAc in hexanes) to give 9

mg (40%) of sulphone 86 dong with 60% unreacted starting material. Similarly. sulfoxide 84

(25 mg, 0.086 mmol) was dissolved in MeOH (0.34 mL) and cooled to O O C . To this was added

a solution of 49.5 % KHS05 (106 mg, 0.173 m o l ) in water (0.23 mL). The resulting cloudy

slurry was stirred for 4 h at rt. Workup followed by purification as for 85 gave a quantitaive

yield of 86. [a125~ = M . 5 (CHC13, c = 1) from the oxidation of sulfoxide 85; IR (KBr) 3085,

2959, 1721, 1288, 1 142. 1M8,998, 8 1 1,687, 603 cm-'; lH NMR (400 MHz, CDCI3) 6 7.74

(2H, d, J = 8.1 Hz), 7.30 (SH, d, J = 8.1 Hz), 6.47 (lH, d, J = 5.9 Hz), 6.33 (lH, d d , J =

5.9, 1.5 Hz), 4.84 (1H. dd J = 4.8, 1.5 Hz), 3.12 (1H. q, J = 7.0 Hz), 2.78 (1H. dq J = 7.0,

4.8 Hz), 2.42 (3H, s), 1.35 (3H, d J = 7.0 Hz), 0.91 (3H, d J = 7.0 Hz); 1 3 ~ NMR (100 MHz.

CDC13) 6 205.8, 145.2, 136.7, 132.3, 130.2, 129.8, 129.3, 102.7, 84.2, 51.2, 49.5, 21.7,

10.3, IO. 1; HRMS calcd for C lgHl 804s M+ 306.0926, found 306.0934.

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107

Cycloaddition of Furfuryl Alcohol, (104), Using 1 Equiv ZnEt2 in THF:

The cycloaddition was canied out as described in the generai procedure (Method C) using

104 ( 104 mg, 1 .O7 mmol). ZnEtz (O. 1 1 mL. 1 .O7 mrnol). DBP 74 (260 mg, 1 .O7 mmol), and

THF (9 mL). Purification by flash chromatography (15% MeCN in CH2C12) gave 46 mg (24%

combined isolated yield) of a 7: 1 3 9 1 mixture of 105, 107 and 108 respectively, as determined

by IH NMR.

5.5 Diastereoselective [4+3] Cycloadditions With 1,1,3,3-Tetrabromoacetone:

Method D. General Procedure for the Cycloaddition of Furylcarbinols

with 1,1,3,3-Tetrabromoacetone Using Zn-Ag couple: To a flarne-dried, 7 or 3 neck

round bonom flask equipped with a magnetic st i r bar and dropping fume1 was placed freshly

prepared Zn-Ag couple (1.5 equiv), furan carbinol(4 equiv) and THF (1.3 M fuial concentration

with respect to furan). Into the dropping hinnel was placed 1.1,3.3-tetrabromoacetone or TBA

(1 equiv) and this was dissolved in THF (1.8 M final concentration with respect to TBA). The

round bottom flask was cooled to O OC and the solution of TBA was added dropwise over a 0.5- 1

h period. WARNZNG: the reaction is exothemic therefore care should be taken nor t o add the

tetrabromoacetone rapidly, especially on a large scale. M e r complete addition of TB A, the

reaction was stirred for an additional 2 h at O OC then 20 h at rt. The crude mixture was filtered

through Celite using EtOAc as the eluent and the organic fdtrate was washed with a saturated

solution of Na2EDTA (2x). The organic layer was dried (MgS04), filtered and the solvent

removed in vacuo to give an a dark brown oil. The crude oil was redissolved in MeOH (roughly

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108

1 mL MeOH per 1 mg of cmde oil) and subjected to reductive debromination using Zn-Cu

couple, as follows: To a methanolic solution of the brominated oxabicycle was added enough

N&Cl to saturate the solution. To th is mixaire was added Zn-Cu couple portionwise (3-5 equiv

with respect to furan) and the reacùon was stirred at rt for 2-5 h. The solid was removed by

fütration through a Celite pad, eluting with methanol and the organic fdtrate was concentmted to

remove most of the MeOH. The resultant brown oil was then diluted with CH2C12 and washed

with a saturated solution of Na2EDTA (2x). The organic phase was dried (MgS04). filtered, and

the solvent removed in vacuo to give a dark brown oil. The crude oil was then purified by flash

chromatography on silica gel. Product ratios were determined by htegration of the bridgehead

protons in the IH NMR s p e c m between the 4-5 ppm region or by gc analysis.

Method E. General Procedure for the Cycloaddition of Furylcarbinols

with 1,1,3,3-Tetrabrornoacetone Using EttZn (Conditions Described by

~ann):Sfi To a solution of the furylcarbinol (1 equiv) in toluene (0.3 M with respect to furan)

was added neat Zn& (2 equiv) under N2 at O OC. The resdting mixture was stirred for 10 min

at O OC prior to the dropwise addition of a solution of TBA in tolune (1 equiv, 0.5 M with respect

to TBA). WARNIZNG: the reaction is exothermic therefore care should be taken not to add the

tetrabrornoacetone raprdly, especially on a large scale. The mixture was then s h e d at O OC (1 d)

then rt (1 d) followed by quenchmg with EtOAc and a sanirated solution of Na2EDTA (1: 1). The

producü were extracted into the organic layer (2-3 x EtOAc), and the organic layer dried

(MgS04), filtered and the solvent removed in vacuo to give an oil. The crude oil was then

redissolved in MeOH, saturated with NH4Cl and Zn-Cu couple was added ponionwise.

Workup as described in Method D followed by purification by flash chromatography on silica gel

afforded the desired debrominated cycloadducts.

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1 O9

Cycloaddition of (S*)-1-Furan-2-yl-2,2-dimethyl-propan-l-O, (SOb), using Zn-

Ag couple:

1. Zn-Ag,THF - 0 O H 2. H*o +

O H Br& Br

Br Br

31 (6 : 1) 50b 3. Zn-Cu couple, NH4CI, 91 b 90b

MeOH

The cycloaddition was carried out as in the general procedure described above (Method

D). To a 3 neck round bottom flask containing Zn-Ag couple (319 mg, 4.86 mmol) and

equipped with a dropping fume1 was added furan job (2.00 g, 13.0 mmol) and 2 mL THF.

Into the dropping funnel was placed TBA 87 (1 20 g, 3.21 mmol) dong with 4.2 mL TEE.

The flask was cooled to O OC and the TBA solution was added dropwise over 1 h. Workup as

described gave a brown coloured oil which was resubjected to further reductive debromination

by the portionwise addition of Zn-Cu couple (5 g, 76 mmol) to the saturated methanolic mixture

of NH.&I containing the crude brorninated oxabycle (roughly 30 mL MeOH). Purification by

flash chromatography (25% EtOAc in hexanes) gave 204 mg of pure 91b dong with 34 mg of

pure 90b (combined isolated yield of 3 5 2 ) .

[ I S * , Z(IS*) , SR*]-l-(l-Hydroxy-2,2-dirnethyl-propyl)-8-oxa-

bicyclo[3.2.l]oct-6-en-3-one, (91b): Mp = 83-83 OC; IR (neat) 3461, 2939, 1708, 1045,

927, 672 cm-1; 1H NMR (400 MHz, CDCI3) 8 6.21 (lH, d. J = 6.3 Hz), 6.13 (lH, dd, J = 6.3,

1.4 Hz), 5.05 (lH, d, J = 5.1 Hz), 3.38 (1 H, d J = 5.8 Hz), 2.93 (lH, d,J = 16.4 Hz), 2.67

(lH, dd, J = 16.1, 5.1 Hz), 2.40 (IH, d J = 16.1 Hz), 3.33 (lH, d J = 6.2 Hz), 2.27 (lH, dd,

J = 16.2, 0.8 Hz), 1.03 (9H, s); 1 3 ~ NMR (100 MHz, CDCI,) 6 205.9, 134.2, 131.9, 89.9,

80.1, 76.4, 50.1, 45.5, 35.7, 27.7; Anal. Calcd for C12H1 8 0 3 : C, 68.55; H, 8.63. Found: C,

[ I R * , I ( I S * ) , SS*]-1-(1-Aydroxy-2,2-dimethyl-propy1)-8-oxa-

bicyclo[3.2.l]oct-6-en-3-one, (90b): Mp = 60-61 OC; IR (neat) 34 12, 2923, 1697,

1035, 928, 758 cm-'; IH NMR (400 MHz, CDC13) 6 6.25 (lH, d, J = 6.2 Hz), 6.1 1 ( lH, dd, J

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1 IO = 6.2. 1.8 Hz), 5.01 (1H. d. J = 5.1 Hz), 3.47 (1 H, d J = 4.4 Hz), 2.68 (1H. d J = 16.5 Hz),

2.64 (1H. dd. J = 16.5, 4.8 Hz), 2.56 (1H. d J = 16.5 Hz). 2.41 (1H. d J = 4.4 Hz). 2.24 (lH,

dd, J = 16.5 Hz), 0.99 (9H. s); 13C NMR (100 MHz, CDCl3) G 206.2, 134.6, 132.1, 89.3,

80.4, 76.4, 49.4, 45.3, 35.4, 27.4; Anal. Calcd for C12H 1 8 0 3 : C. 68.55; H, 8.63. Found: C ,

Optimized Preparation of 91b Using Diethylzinc: Altematively. the major oxabicycle

91b prepared above could be prepared in high diastereoselectivity using Et& as follows:

Furan 50b (2.0 g, 13 m o l ) was diluted in 40 mL of toluene, and to this was added at O "C neat

ZnEt2 (2.7 mL, 26 mrnol) foilowed by the slow addition of a solution of TBA 87 (15 g, 40

mmol) in toluene (40 mL). Workup as described for Method E gave a brown coloured oïl. The

cmde oil was then redissolved in a saturated methanolic solution of W C 1 (roughiy 30 mL

MeOH) and reductively debrominated by the portionwise addition of Zn-Cu couple (5 g, 76

mmol). Purification by flash chromatography (25% EtOAc in hexanes) gave 1.6 g (47%

combined isolated yield) of a 96:4 ratio of 91b to other isomer(s).

[ IS* , I ( IS* ) , 5R*]-1-Cyclohexyl-hydroxy-methyl)-8-oxa-bicyclo[3.2.l]oct-6-

en-3-one, (91c):

1. ZnEt2, toluene H O,,.. other

2. ~ n - C U couple - fiO +

isomer(s)

Br Br 80. 50c + 87 NH4CI, MeOH

91 c

The cycloaddition was carried out as in the general procedure described above (Method

E). Furan 50c (155 mg, 0.880 mmol) was diluted in 2.9 rnL of toluene, and to this was added

at O OC neat ZnEt2 (0.18 mL, 1.8 mmol) followed by the slow addition of a solution of TBA 87

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1 1 1

(329 mg, 0.88 1 mrnol), in toluene ( 1.8 d). Workup as usual gave a brown coloured oïl. The

crude oil was then redissolved in a saturated methanolic solution of N%Cl (roughly 10 mL

MeOH) and to this mixture was added Zn-Cu couple (145 mg, 2.2 mrnol) portionwise. Workup

as described in Method E followed by purification by flash chrornatography (30% EtOAc in

hexanes) gave 48 mg (23% cornbined isolated yield) of a >95:5 ratio of 91c to other isomer(s).

IR (neat) 343 1, 2924, 17 1 1, 1450. 1019 cm-'; lH NMR (400 MHz, CDC13) 6 6.13 (1H. dd, J

= 5.9, 1.8 Hz), 6.09 (lH, d, J = 5.9 HZ), 4.97 (IH, d, J = 5.1 Hz), 3.46 (1 H, d J = 3.7 Hz),

2.65 (lH, d,J = 15.7 Hz), 2.61 (IH, dd, J = 16.5. 5.1 Hz), 2.37 (lH, br s), 2.28 (LH, d J =

16.1 Hz), 2.2 1 (lH, d 1 = 16.1 HZ), U.98- 1-78 (1 lH, m); 13c NMR (100 MHz. CDCI3) 6

206.2, 134.2, 134.1, 90.2, 77.7, 77.2, 49.0, 45.8, 40.2, 31.7, 27.4. 27.0, 26.7; HRMS calcd

for C 14H2003 [Ml+ 236.3 137, found 236.3 130.

[ IS* , I ( I S * ) , SR*]- l-(l-Hydroxy-octyI)-8-oxa-bicyclo[3.2.l]oct-6-en-3-one,

1. ZnEt2, toluene other

2. Zn-Cu couple isorner(s)

Br NH4CI, MeOH

The cycloaddition was carried out as in the general procedure described above (Method

E). Furan 50d (160 mg, 0.8 15 rnrnol) was diluted in 2.7 rnL of toluene, and to this was added

at O OC neat Zn& (0.17 mL, 1.6 m o l ) followed by the slow addition of a solution of TBA 87

(305 mg, 0.8 15 mrnol), in toluene (1.6 mL). Workup as usual gave a brown coloured oil. The

crude oil was then redissolved in a saturated methanolic solution of W C 1 (roughly 30 mL

MeOH) and reductively debrominated by the portionwise addition of Zn-Cu couple (132 mg,

2.04 mmol). Purification by flash chromatography (25% EtOAc in hexanes) gave 21 mg (10%

combined isolated yield) of a >95:5 ratio of 91d to other isomers as detemiined by 'H NMR

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112

(400 MHz). IR (neat) 3480, 2929, 1697, 1061, 101 8, 856, 766 cm-* ; 'H NMR (400 MHz,

CDC13) 6 6.24 (1H. dd, J = 5.9, 1.8 Hz), 6.11 (lH, d, J = 5.9 Hz), 5.09 (1H. d, J = 5.5 Hz),

3.72 (1 H, t J = 6.2 Hz). 2.71 (1H. d d J = 16.5, 5.1 Hz), 2.61 (1H. d. J = 16.1 Hz), 2.38

(1H. d J = 16.5 Hz), 2.31 (IH, d J = 16.5 Hz), 2.20 (1H. br s), 1.22-1.68 (12H, rn), 0.87

(3H, t, J = 7.0 Hz); 1 3 ~ NMR (100 MHz, CDC13) 8 205.5, 134.2, 132.5, 89.4, 77.3, 73.3,

47.8, 45.3, 31.8, 31.6, 29.5, 29.2, 26.1, 22.6, 14.1; HRMS calcd for C1~H2403 [Ml+

252.1725, found 252.1735.

5.6 Attempted Diastereo- and Regioselective [4+3] Cycloaddition With 1,3-

Dibromo-2-butanone:

Cycloadditon of Furan 50b Using 1 equiv ZnEt2 in THF:

The reaction was carried out as in the general procedure described previously for

cycloadditions carried out on 2-4-dibromo-3-pentanone (see Method C in experimental section

5.4) using 50b (985 mg, 6.39 mmol), Zn& (0.65 mL, 6.4 mrnol), DBB (2.94 g, 12.8 mmol),

and THF (21 d). hification by flash chromatography (20% EtOAc in hexanes) gave 408 mg

of pure 95 and 194 mg of pure 96 (42% combined isolated yield).

[Is*, Z(lS*), ZR* or 2S*, 4R*, SR*]-2-Bromo-1-(1-hydroxy-2,2-

dimethyl-propyl)-4-methyl-8-oxa-bicyclo[3.2l]oct-6-en-3-one, (95): IR (neat)

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113

3530, 2958, 1720, 1005,977 cm-'; IH NMR (400 MHz, CDC13) 6 6.42 (1H. dm, J = 6.2 Hz),

6.26 (1H, d, J = 6.2 Hz), 4.76 (1H. s), 4.12 (1H, s), 4.00 (1H, s). 2.73 (IH. br s), 2.43 (IH,

q, J = 7.3 Hz), 1.61 (3H, d, J = 7.3 HZ), 1.10 (9H, s); 13C NMR (100 MHz, CDC13) 6 202.5,

138.1, 129.0, 89.9, 81.4, 77.2, 53.0, 49.3, 34.5, 27.8, 19.1; HRMS calcd for C13H2003Br

[MH]+ 303.0596, found 303.0599.

[IS*, Z(IS*), ZR* or 2S*, 4Ry SR*]-4-Brorno-1-(1-hydroxy-2,2-

dimethyl-prop yl)-2-methyl-8-oxa-bieyclo[3-2.l]oct-6-en-3one, (96): IR (neatj

3538,2958, 1717. 1080, 1044, 967 cm-l; lH NMR (400 MHz, CDCI3) 6 6.52 (1H. d, J = 5.9

Hz), 6.21 (lH, dm. J = 5.5 Hz), 5.09 (lH, s), 3.90 ( 1 H, s). 3.74 (1H. s), 7.79 (1H. q J = 7.3

Hz), 2.74-2.82 (lH, br s), 1.62 (3H. d J = 7.3 Hz), 1.08 (9H, s); l3C NMR (100 MHz,

CDCl3) 6 203.1, 136.7, 131.0, 91.6, 81.0, 75.8, 54.4, 45.3, 34.9, 27.9, 17.1; HRMS calcd

for C9H 1003Br w - C d g ] + 244.98 13, found 244.9825.

Reductive Debromination of a-Bromoketone 95 Using Zn-Cu couple:

Zn-Cu couple, NH4CI, H Ott..

MeOH

The reaction was carried out as in the general procedure described previously (see

Method D in experimental section 5.5). a-Bromoketone 95 (170 mg. 0.561 rnmol) was

dissolved in MeOH (30 mL) and NH4C1 was added until the solution becarne saturated. To this

mixture was added %-Cu couple (73 mg, 1.1 rnmol) portionwise and the reaction was stirred for

4 h at rt. Workup as descnbed foIlowed by purification by flash cbromatography (30% EtOAc in

hexanes) gave a quantitative recovery of 102.

[ IS* , Z(lS*), 4R5 SR*]-1-(1-Hydroxy-2,2-dimethyl-propy1)-2-methyl-

8-oxa-bicyclo[3.2.1]oct-6-en-3-one, 102: IR (neat) 3493, 2956, 1715, 1482, 1365,

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114

1010, 923, 749 cm-i; 'H NMR (400 MHz, CDCI3) 6 6.19 (lH, d, J =5.8 Hz), 6.12 (lH, dd, J

= 6.2, 1.5 Hz), 4.67 (1 H, s), 3.35 (1 H, s), 2.93 (1H. d, J = 16.5 Hz), 2.40-2.50 (1H. br s),

2.29 (lH, d, J = 16.5 Hz), 2.23 (lH, q, J = 7.3 HZ), 1.26 (IH, d, J = 7.3 Hz), 1.01 (9H, s);

13C NMR (100 MHz, CDC13) 6 210.0, 134.2, 132.4, 89.9, 81.2, 80.1, 48.8, 47.8, 35.6,

27.7, 15.6; Anal. Calcd for C 3H2003 : C, 69.60; H, 8.99. Found: C, 69.2 1, H, 8.52.

Reductive Debromination of a-Bromoketone 96

Zn-Cu couple, NH4CI, I

MeOH

Using Zn-Cu couple:

The reaction was carried out as in the generai procedure described previously (see

Method D in expenmental section 5.5). a-Bromoketone 96 (200 mg, 0.660 m o l ) was

dissolved in MeOH (60 mL) and m C 1 was added until the solution becarne saturated. To this

mixture was added Zn-Cu couple (86 mg, 1.3 rnmol) portionwise and the reaction was stirred for

4 h at rt. Workup as described followed by purification by flash chromatography (35% EtOAc in

hexanes) gave a quantitative yield of 103.

[ I S * , l ( I S * ) , 2R* or 2S*, 5R*]-l-(l-FIydroxy-2,2-dimethyl-propyl)-2-

methyl-8-oxa-bicyclo[3.2.1]oct-6-en-3-one, (103): IR (neat) 3468, 2958, l ï 1 1,

1401, 1008, 754 cm-'; 1H NMR (400 MHz, CDCl3) 8 6.30 (lH, d, J =6.2 Hz), 6.23 (lH, dm,

J = 6.2 Hz), 5.01 (lH, dd, J = 4.8, 0.7 Hz), 3.65 (1 H, s), 2.83 (lH, dd, J = 15.7, 7.8 Hz),

2.65-2.80 (1H, br s), 2.62 (lH, q, J = 7.0 Hz), 2.17 (lH, d, J = 15.7 Hz), 1.28 (3H, d, J =

7.3 Hz), 1 .O6 (9H, s); 1 3 ~ NMR (100 MHz, CDC13) 6 209.3, 134.5, 133.2, 9 1.4, 76.5, 76.1,

54.0, 43.4, 34.9, 28.0, 13.2; Anal. Calcd for C 13H2003 : C, 69.60, H, 8.99. Found: C,

69.35, H, 8.81.

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5.7 Preparation of Oxabicyclic Substrates for Ring Opening Reactions

Reagents

Organolithium reagents were purchased from the Aldrich Chernical Company: n-BuLi

(2.5 M in hexanes). t-BuLi (1.6 M in pentanes). Ethyl. hexyl and 3-

triisopropylsiloxypropyiIithium were prepared by lithium-iodine exchange beween the

correspondhg iodoalkane and tert-~uLi.94

Method F: General Procedure for the Stereoselective Reduction of 1-

substituted-2,4-diniethyl-8-oxabicyclo[32.1]oct6e-3oes: To a 0.3 M solution

of oxabicyclic compound in THF was added dropwise 3 equiv of a 2 M solution of LiBH. in

THF at O OC. The reaction is stirred at O OC for 1 h then warmed to rt and stined for an additional

3-24 h. The reaction mixture was quenched by pouring it into water and the aqueous phase is

extracted with EtOAc (3 to 6 times). The combined organic extracts are dried (Nafi04), filtered

and the solvent removed in vacuo. Purification was then done by flash chromatography on silica

gel.

Method G: General Procedure for the Protection of Oxabicyclic Alcohol as its

Ether: Potassium hydride (1.2-2.2 equiv, 35 % wt in oil), washed three times with pentane

and dried under argon, was suspended in THF and cooled to O OC. To diis mixture was then

added a solution of the alcohol (1 equiv) in THF (0.2 - 0.5 M). After stimng for 1 h (O OC). a

catalytic amount of 18-C-6 ether (one crystal) was added followed by the addition of the

electrophiie. Completion of the reaction was monitored by TLC. The reaction was quenched

with aqueous W C 1 at O OC and the aqueous layer extracted with EtOAc (3x). The combined

organic layen were dried (MgS04), filtered and concentrated in vacuo. Purification by flash

chrornatography (EtOAc in hexanes) afforded the desired protected alcohol.

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Il6

[ I R * , I ( I S * ) , 3S*, SS*]-1-(1-Hydroxy-2,2-dimethyl-propy1)-8-

oxabicyclo[3.2.l]oct-6-en-3-ol, (92):

L-Selectride, THF, -78 O C

To a -78 OC solution of oxabicycle 91b (40 mg, 0.19 rnmol) in THF (1.9 mL) was

added dropwise L-SelectrideTM (0.42 mL of 1.0 M solution if THF, 0.42 mrnol). After the

addition was complete, stimng was continued for an additional 0.5 h at -78 OC (the reaction was

monitored by TLC). The reaction was then warmed to O OC. quenched cautiously with 5 M

NaOH (0.4 mL), stirred 10 min, then treated with 30% H202 (0.3 mL). The reaction mixture

was extracted with Et2O. The combined organic layers were washed with brine, dned

(Na$304), filtered, and concenvated in vacuo. Purification by flash chromatography (308

EtOAc in hexanes) afforded 27 mg (83%) of pure 92 (see Appendix 2 for conesponding X-ray

of this compound): Mp = 145 OC; IR (neat) 3343,2923,1355, 1035,872 cm-1; IH NMR (400

MHz, CDC13) 6 6.39 (lH, d, J = 5.9 Hz), 6.11 (lH, d d J = 5.9, 1.5 Hz), 4.75 (IH, d, J = 1.5

Hz), 3.97 (1 H, dt, J = 6.2, 0.7 Hz), 3.27 (lH, s), 2.39 (2H, br s), 2.24 (lH, dd, J = 14.3,

6.2 Hz), 2.14 (lH, ddd, J = 14.7, 4.0, 5.9 Hz), 1.85 (IH, d, J = 14.3 HZ), 1.63 (lH, dd, J =

14.7, 1.1 Hz), 1.00 (9H, s); 1 3 ~ NMR (100 MHz, CDCl3) 6 135.9, 135.3, 89.6, 80.9, 77.1,

65.2, 39.4, 35.5, 35.0, 27.8; Anal. Calcd for C 12H2003 : C, 67.88; H, 9.50. Found: C,

67.75, H, 9.53.

[IR*, I ( I S * ) , 3S*, SS*] - 1 -(3-tert-Buty1dimethylsiloxy-8-oxabicycIo[3.2.l]oct-

6-en-1-y1)-2,2-dimethyl-propan-1-01, (1 18):

KH. 184-6. THF then

TBDMSCI O H

- \ OTBS

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117

The reaction was carried out as described in the general procedure (Method G) using

potassium hydnde (430 mg, 3.75 mmol) in 1 1 mL TEIF, a solution of alcohol92 (398 mg, 1.87

mmol) in 8 mL THF, 18-C-6 ether (one crystal) and ten-butyldimethylsilyl chlonde (3 10 mg,

2.06 mmol) as the electrophile. The reaction was complete after 10 h and quenched with

aqueous NH&1 at O OC. Workup as described previously followed by purification by flash

chromatography (10% EtOAc in hexanes) gave 473 mg (77%) of 129: IR (neat) 3488,2953,

1372, 1255, 1039, 836, 773 cm-'; IH NMR (400 MHz, CDC13) 6 6.12 (IH, d, J = 6.2 HZ),

6.09 (IH, dd, J = 6.2 1.5 Hz), 4.70 (lH, d. J = 3.7 HZ), 4.05 (1 H, dt, J = 5.5, 1.1 Hz), 3.26

(lH, s), 2.56 (lH, s), 2.14 (lH, dd, J = 13.9, 5.9 fi), 2.07 (IH, ddd, J = 13.9. 5.5. 4.1 Hz),

1.66 (IH. d, J = 13.9 HZ). 1.44 (lH, dd. J = 13.9, 1.1 HZ), 1.01 (9H, s ) , -0.04 (3H. s), -0.05

(3H, s); 13C NMR (100 MHz, CDCS) 8 133.87, 133.91, 89.5, 81.3, 76.3, 64.4, 39.8, 35.6,

35.1, 27.9, 25.6, 17.8, -4.9; HRMS cdcd for Cl8H3403Si FI]+ 326.2277, found 326-7261.

KH, 18-C-6, THF then

BnBr - OTBS - \ OTBS

The reaction was carried out as descnbed in the general procedure (Method G) using

potassium hydride (83 mg. 0.720 mmol, 35% wt dispersion in oil) in 'MF (3 mL), a solution of

alcohol 118 (129 mg, 0.395 mmol) in THF (1 a), 18-C-6 (5 mg, 0.02 mmol), and benzyl

brornide (0.06 rnL, 0.48 m o l ) as the electrophile. The reaction was complete afier 1 h and

quenched with aqueous N a C l at O OC. Workup as described previously followed by

purification by flash chromatography (5% EtOAc in hexanes) gave 134 mg (8 1%) of 119: IR

(neat) 3010, 2916, 1464, 1253, 1074, 837 cm- l ; lH NMR (400 MHz, CDCl3) 6 7.22-7.37 (5H.

m). 6.10 ( lH, d, J = 5.9 Hz), 6.00 (lH, dd, J = 5.9, 1.0 Hz), 4.73-4.77 (2H, m), 4.60 ( 1 H,

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118

d, J = 11.2 Hz), 4.07 (1 H, br t, J = 6.4 Hz), 3.13 (1H. s). 2.33 (1 H, dd, J = 13.7, 5.6 Hz).

2.06 (IH. dt, J = 14.2, 4.6 HZ), 1.62 (1H. d. J = 13.7 Hz), 1.42 (1H. d. J = 14.2 Hz). 1.06

(9H. s), 0.84 (9H. s), -0.04 (3H, s). -0.05 (3H. s); I3C NMR (100 MHz, CDC13) 6 139.2,

136.1, 131.5. 128.1, 127.2, 127.1, 90.3. 89.6. 78.3. 76.3. 64.8. 38.6, 37.3, 35.5, 28.3.

25.7, 17.7, -4.9; H R M S calcd for C21 H3 1 O3Si [M-C4H9 ]+ 359.2042, found 359.2054.

[ I R * , I ( I S * ) , 3R*, SS*]-1-(1-Hydroxy-2,2-dimethyl-propy1)-8-

oxabicyclo[3.2.l]oct-6-en-3-ol, (120):

1. Mitsunobu H O,,..

2. NaOMe, MeOH

To a solution containing oxabicycle 92 (32 mg, 0.15 mmol), PPh3 (59 mg, 0.23 rnmol),

and para-nitrobenzoic acid (38 mg, 0.23 m o l ) was added under N2 diethyl azodicarboxylate

(39 mg, 0.23 mmol) in 0.3 mL of THF over a penod of 1.5 h. The reaction was then stined for

3 h and concentrated Ni vacuo. The residue was triturated with ethyl acetate:hexanes (1 :4) to

remove most of the triphenylphosphine oxide. The filtrate was concentrated in vacuo and the

residue was redissolved in 0.8 mL MeOH. To this solution was added sodium methoxide (4

mg, 0.06 mmol) and the reaction was stirred for 16 h. The reaction was neutralized with acetic

acid, and the solvent removed in vacuo. Purification by flash chromatopgraphy (35 % EtOAc in

hexanes) gave 30 mg (78%) of pure 120: IR (KBr) 3249. 2949, 1362, 1044, 1010, 941, 761

cm-]; lH NMR (400 MHz. CDC13) 6 6.07 (1H. d. J = 6.2 Hz), 6.01 (lH, dd, J = 6.2, 1.8

Hz), 4.80-4.83 (1H. m), 3.83 (1 H, a, J = 9.5, 6.2 Hz), 3.33 (1H. s), 2.07 (1 H, dd, J = 12.8,

6.2 Hz), 1.90 (lH, br dq, J = 12.8, 6.2 Hz), 1.70-1.92 (2H. br s), 1.64 (lH, dd, J = 12.8, 9.5

HZ), 1.52 (lHT ddd, J = 12-83 9-99 3-7 HZ), 1.03 (9H9 s); 13c N M R (100 MHz, CDCl3) G

131.9, 130.4, 90.4, 80.9, 77.1, 65.2, 38.8, 35.4, 35.0, 27.8; Anal. Calcd for C12H2003 : C,

67.88; H, 9.50. Found: C, 67.79, H, 9.37.

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[ I R * , I ( IS* ) , 3R*, 5S*]-1-(3-tert-ButyIdimethyIsiIoxy-8-

oxabicyclo[3.2.l]oct-6-en-l-yI)-2,2-dimethyl-propan-l-ol, (121):

KH, 18-C-6, THF

TBDMSCI

The reaction was carried out as described in the general procedure (Method G) using

potassium hydride (156 mg, 1.39 mmoi. 35% wt dispersion in oil) in 1 mL TW, a solution of

alcohoi 92 (14 1 mg, 0.664 mmol) in 0.7 mL THF, 18-C-6 (5 mg, 0.02 mmol), and rert-

butyldimethylsilyl chlonde (1 10 mg, 0.730 m o l ) as the electrophile. The reaction was

complete afier 20 h and quenched with aqueous W C 1 at O OC. Workup as descnbed previously

followed by purifkation by flash chromatography (10% EtOAc in hexanes) gave 86 mg (404) of

121: IR (neat) 3481, 2946, 1253, 1090, 880, 835, 775 cm-'; 'H NMR (400 MHz, CDCl3) G

6.03 (lH, d, J = 5.9 Hz), 5.98 (lH, dd, J = 5.9, 1.8 Hz), 4.78-4.79 (lH, m), 3.81 (1 H, tt, J

= 9.2, 6.2 Hz), 3.34 (lH, s), 1.97 (1 H, dd. J = 12.8, 6.2 Hz), 1.72 (1H. br dq, J = 12.5, 9.2

Hz), 1.63 (lH, dd, J = 12.5, 9.2 Hz), 1.58 (lH, ddd, J = 12.8, 9.5, 3.7 Hz), 1.01 (9H, s),

0.85 (9H. s), 0.00 (6H, s); 13C NMR (100 MHz, CDC13) 6 133.4, 129.8, 89.7, 80.8, 78.2,

65.7, 38.3, 35.6, 35.1, 27.5, 25.8, 18.0, -4.5; HRMS calcd for C1gH3302Si [M-OH]+

309.2250, found 309.2350.

[ IR*, I(IS*), 3R*, SS*]-l-(l-Benzyloxy-2,2-dimethyl-propyl)-3-tert-

Butyldimethylsiloxy-8-oxabicyclo[3.2.l]oct-6-ene, (122):

KH, 18-C-6, THF then 5

BnBr

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The reaction was carried out as described in the general procedure (Method G) using

potassium hydride (23 mg, 0.20 mmol, 35% wt dispersion in oil) in 1 mL THF, a solution of

alcohol 121 (49 mg, 0.15 mmol) in 0.5 mL THF. 18-C-6 (5 mg, 0.02 mmol), and benzyl

bromide (0.03 mL. 0.23 m o l ) as the electrophile. The reaction was complete afier 1 h and

quenched with aqueous N a C l at O OC- Workup as described previously followed by

purification by flash chromatography (5% EtOAc in hexanes) gave 63 mg (100%) of 122: IR

(neat) 29 16, 1464. 1252, 1068, 837, 696 cm-'; 'H NMR (400 MHz, CDC13) 8 7.22-7.36 (5H.

m), 6.03 (1H. d, J = 6.2 Hz), 5.93 (1H. dd, J = 6.0, 1.5 HZ), 4.784.79 ( lH, m). 4.76 (1H. d,

J = 11.4 Hz), 4.60 (1H. d. J = 11.4 Hz), 3.79 (1 H, tt, J = 9.2, 6.2 Hz), 3.16 (IH, s), 1.92 (1

H, dd, J = 12.5. 6.2 Hz), 1.79 (1H, dd, J = 12.5. 9.2 Hz), 1.69 (1H. ddd, J = 12.8. 5.6, 0.7

Hz), 1.58 (lH, ddd, J = 13.2, 9.5, 3.7 HZ). 1.01 (9H. s), 0.84 (9H. s). 0.00 (6H. s); 13C

NMR (100 MHz, CDCl3) 6 139.9, 133.3, 129.9, 128.7, 126.9, 89.9, 85.8, 79.9, 78.4, 65.5,

38.6, 33.8, 30.0, 27.7, 26.0, 18.7, -4.4; HRMS calcd for Ci gH3302Si [M-OH]+ 309.2250,

found 309.2250.

The reaction was canied out as in the general procedure descnbed above (Method F)

using cycloadduct 130 (26 mg, 0.01 mmol), THF (0.2 mL), and L i B h (0.15 mL of a 2 M

solution in THF, 0.3 mrnol). The reaction was complete after shmng for 1 h (O OC) then 3 h (a).

1H NMR (400MHz) analysis of the crude mixture after workup indicated a 13:l ratio of

123:124 by integration of the vinylic protons. mirification by flash chromatography (50% Et20

in hexanes) afforded 24 mg (91%) of 123 and 124. Recrystdization with pentane-ether (3:2)

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121

gave pure 123 as white crystals: Mp = 1 10 OC (EtzO); = +0.32 O (c = 1.4, CHC13); IR

(KBr) 3457, 2933, 1715, 1455, 1377, 11 17, cm-l; NMR (400 MHz, CDC13) G 6.12 (lH,

ddd, J = 6.2, 1.8. 0.7 Hz), 6.08 (lH, d. J = 6.2 HZ). 4.55 (lH, s), 4.08 (lH, t, J = 6.6 Hz),

3.68 (lH, d, J = 1.8 Hz), 2.00-1.10 (15H, m), 1.12 (3H. d, J =7.3 Hz), 1.05 (3H, d, J = 7.0

Hz); 13C NMR (100 MHz, CDC13) 6 132.5, 131.3, 92.2, 82.6, 75.3, 67.4, 38.4, 36.5, 34.3,

31.3, 26.9, 26.8, 26.3, 26.1, 13.5, 10.0 ; Anal. Calcd for C16H26O3: C, 72.14; H, 9.84.

Found: C, 72.02; H, 9.70.

The minor dcohol 124 was prepared via a non-stereoselective reduction of the

corresponding ketone with DIBAL-H to give 80% yield of a 4: 1 mixture of 124 and 123

respecti~ely.~

[IS,I(lS),2R,3S,4S,SR]-1-(Cyclohexyl-hydroxy-methyI)-2,4-dimethyl-

8-oxabicyclo[3.2.l]oct-6-en-3-ol, (124): 1H NMR (400 MHz, CDC13) 6 6.12 ( 1 H,

ddd, J = 6.2, 1.8, 0.7 Hz), 6.08 (IH, d, J = 6.2 Hz), 4.55 (lH, s), 4.08 (lH, t, J = 6.6 Hz),

3.68 (1H. d, J = 1.8 Hz), 2.00-1.10 (25H, m), 1.12 (3H, d, J =7.3 Hz), 1.05 (3H, d, J = 7.0

Hz); 13C NMR (100 MHz, CDCl3) 6 132.5, 131.3, 92.2, 82.6, 75.3, 67.4, 38.4, 36.5, 34.3,

31.3, 26.9, 26.8, 26.3, 26.1, 13.5, 10.0 : Anal. Calcd for C16H26O3: C, 72.14; H, 9.84.

Found: C, 72.02; H, 9.70.

[ I S * , I ( I S * ) , ZR*, 3R*, 4S*, SR*]-1-(Cyclohexyl-methoxy-methy1)-3-

methoxy-2,4-dimethyl-8-oxabicyclo[3.2.l]oct-6-ene, (126):

n , l KH. 1 8-C-6. THF I

. I I Y.. ,..YI

The reaction was carried out as described in the general procedure (Method G) using

potassium hydride (238 mg, 2.08 mmol, 35% wt dispersion in oil) in 8.3 mL THF, a solution of

alcohol 123 (218 mg, 0.810 mmol) in 0.4 mL THF, 18-C-6 (15 mg, 0.06 mrnol), and

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122

iodomethane (0.16 mL. 2.5 mmol) as the electrophile. The reaction was complete after 4 h and

quenched with aqueous NH&1 at O OC. Workup as described previously followed by

purification by flash chrornatography (5% EtOAc in hexanes) gave 185 mg (78%) of 126: IR

(neat) 2920. 1443, 11 15, L095, 1069, 981, 949, 712 cm-'; NMR (400 MHz. CDC13) 6

6.01-6.08 (2H, m), 4.51 (IH,s), 3.49 (lH, t, J = 6.2 Hz), 3.45 (3H. s), 3.23 (3H, s), 3.19

(lH, s), 1.00-1.92 (13H, m). 1.08 (3H, d, J = 7.0 Hz), 1.02 (3H, d J = 7.0 Hz); 13C NMR

(100 MHz, CDCl3) 6 132.0, 131.2, 93.0, 86.5, 82.2, 76.9, 62.1, 55.6, 38.9, 34.6. 31.5,

31.4, 26.9, 26.6, 26.5, 26.1, 13.9, 10-2; And. Calcd for ClgH3003 : C, 73.43; H, 10.27.

Found: C, 73.29, H, 10.1 1.

[IS*, I ( IS*) , ZR*, 3R*, 4S*, SR*]-(3-tert-Butyldimethylsiloxy-2,4-dimethyl-

8-oxabicycto[3.2.l]oct-6-en-l-yl)-cyclohexyl-methanol, (127):

The reaction was c d e d out as described in the general procedure (Method G) using

potassium hydnde (362 mg, 4.52 m o l , 35% wt dispersion in oil) in 4 rnL THF, a solution of

alcohol 123 (48 2 mg, 1.8 1 rnmol) in 2 mL THF, 18-C-6 (10 mg, 0.04 mmol), and tert-

butyIdimethylsilyl chloride (327 mg, 2.17 mmol) as the electrophile. The reaction was complete

after 17 h and quenched with aqueous NH&l at O OC. Workup as described previously followed

by purification by flash chromatography (15% EtOAc in hexanes) gave 544 mg (79%) of 127:

IR (neat) 3490, 2929. 1460, 1360, 1254, 1084, 976, 886, 836,776,674 cm-1; 1H NMR (400

MHz, CDCl3) 5 6.07 (1H. ddd, J = 6.2, 1.8, 0.7 Hz), 6.02 (LH, d, J = 6.2 Hz), 4.46 (lB, br

s), 3.98 (IH, t, J = 6.2 Hz), 3.62 (lH, s), 2.12 (lH, d, J = 1.4 Hz), 1.08-1.76 (13H, m), 1.04

(3H, d J = 7.3 HZ), 0.98 (3H, d J = 7.0 Hz), 0.84 (9H, s), -0.057 (3H, s), -0.061 (3H, s); 13C

NMR (100 MHz, CDC13) 6 132.6, 131.3, 92.2, 82.5, 75.4, 67.9, 38.3, 35.3, 31.4, 26.9,

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123

26.8, 26.4, 26.2, 25.9, 18.2, 13.9, 10.3, -4.7, -4.8; HRMS calcd for C22H4003Si [Ml+

380.2747, found 380.2750.

[IS*, I(IS*), 2R*, 3R*, 4S*, 5R*]-1-(Benzyloxy-cyclohexyl-methy1)-3-terc-

Butyldimethylsiloxy-2,4-dimethyl-8-oxabicyclo[3.2.1]oct-6-ene, (128):

KH, 1 8-C-6, THF

The reaction was carried out as described in the general procedure (Method G) using

potassium hydride (20 mg, 0.14 mrnol, 35% wt dispersion in oil) in 0.5 mL THF, a solution of

aicohol 127 (36 mg, 0.095 m o l ) in 0.5 mL THF, 18-C-6 (2.5 mg, 0.010 rnmol), and benzyl

brornide (0.02 rnL, 0.14 m o l ) as the elecuophile. The reaction was complete after 4 h and

quenched with aqueous NH4Cl at O OC. Workup as described previously followed by

purification by flash chromatography (5% EtOAc in hexanes) gave 42 mg (95%) of 128: IR

(neat) 2930, 1453, 1254, 11 14, 1060,887,836,774,697 cm-l; lH NMR (400 MHz, CDC13) 6

7.18-7.37 (5H, m), 6.14 (lH, d, J = 6.2 Hz), 6.05 (lH, ddd, J = 6.2, 2.5, 0.7 Hz), 4.93 (lH,

d, J = 11.7 Hz), 4.52 (lH, s), 4.86 (lH, d, J = 12.1 Hz), 4.05 (lH, t, J = 6.2 Hz), 3.48 (lH,

s), 1.44-1.80 (lOH, m), 110-1.13 3 , m ) 1.13 (3H, d, / = 7.0 Hz), 1.09 (3H, d J = 7.0

Hz), 0.91 (9H. s), 0.00 (6H, s); l3C NMR (100 MHz, CDCl3) 6 140.1, 132.6, 130.8, 127.9,

127.2, 126.8, 93.4, 84.7, 82.0, 75.2, 68.1, 39.0, 38.2, 35.1, 31.5, 26.9, 26.9, 26.5, 26.2,

25.9, 18.2, 14.3, 10.4, -4.7, -4.8; HRMS calcd for C25H3703Si [M-C4HgJ+ 413.25 12. found

413.251 1.

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The reaction was carried out as descnbed in the general procodure (Method G) using

potassium hydride (24 mg, 0.2 1 mmol) in 0.5 mL THF, a solution of alcohol 127 (66 mg, 0.17

mmol) in 0.3 mL THF, 18-C-6 (2.5 mg, 0.01 mmol), and para-methoxybenzyl bromide (0.03

rnL, 0.2 m o l ) as the electrophile. The reaction was complete after 3 h and quenched with

aqueous m C I at O OC. Workup as descnbed previously followed by purification by flash

chromatography (5% EtOAc in hexanes) gave 78 mg (92%) of 129: IR (neat) 293 1. 161 1,

1513, 1463, 1304, 1248, 1113, 1031,887,832 cm-'; 'H NMR (400 MHz, CDCl3) 6 7.25 (2H,

d, J = 8.4 Hz), 6.83 (2H. d, J = 8.4 Hz), 6.14 (lH, d, J = 6.2 Hz), 6.06 (1H. br d, J = 5.9

Hz), 4.84 (lH, d, J = 11.4 Hz), 4.53 (lH, s), 4.41 (lH, d, J = 11.0 Hz), 4.05 (1H. t, J = 6.6

Hz), 3.78 (3H, s), 3.47 (lH, s), 1.42-1.79 (lOH, rn), 1.08-1.38 (3H, m), 1.14 (3H. d, J = 7.3

Hz), 1.09 (3H, d J = 7.0 Hz), 0.91 (9H. s), 0.01 (6H, s); ' 3 ~ NMR (100 MHz. CDC13) 8

158.5, 132.6, 132.2, 130.8, 128.9, 113.3, 93.4, 84.2, 82.0, 74.9, 68.1, 55.2, 38.9, 38.2,

35.1, 31.5, 26.9, 26.8, 26.5, 26.2, 25.9, 18.2, 14.3, 10.4, -4.7, -4.8; HRMS caicd for

C3&804Si [Ml+ 500.3322, found 500.3309.

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TBDMSOTf, 2.6-lutidine, I

CH2CI2, -78 "C

Oxabicycle 77c (8 1 1 mg, 3.07 mrnol j was dissolved in 15 mL CH2CIl and the solution

cooled to -78 OC. To this solution was added 2.6-lutidine (0.43 mL. 3.7 mmol) followed by

freshiy distilled ten -butyldimethyIsilyI tnflate (0.78 mL, 3.4 mmol). Completion of the reaction

was monitored closely by TLC. After 3 h, the reaction was warmed to O OC and quenched by the

addition of a saturated sodium bisulfate solution and the products extracted with CH2C12 (2 x).

The combined organic extracts were dried (MgS04), fdtered, and the solvents removed in vacuo

to give a paie yellow oil. Purification by flash chromatography (10% EtOAc in hexanes)

afTorded 1.06 g (91%) of 130: IR (neat) 2933, 1711, 1251, 1125, 837 cm-'; 1H NMR (400

MHz, CDC13) 6 6.16 (1H. d, J = 5.9 Hz), 6.08 (1H. ddd. J = 6.2, 1.8, 1.1 Hz), 4.49 (1H. d, J

= 1.5 HZ), 3.70 ( lH, s), 2.37 (1H, q, J = 7.3 HZ). 2.22 (lH, q, J = 7.7 HZ), 1.00-1.80 (1 lH,

m). 1.32 (3H. d, J = 7.7 Hz), 1-37 (3H. d J = 7.3 Hz). 0.85 (9H. s), 0.04 (3H. s), -0.02 (3H.

s); 13C NMR (100 MHz, CDC13) 6 214.7, 135.2, 133.8, 91.2, 80.5, 76.9, 52.1, 49.0, 39.0,

32.1, 26.9, 26.3, 26.1, 18.7, 17.7, 14.7, -3.5, -5.1; H R M S calcd for C21H35O3Si [M-CH3]+

363.2355, found 363.2363.

Reduction of ketone 130 with La&:

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126

The reaction was carried out as described in the generai procedure (Method F) using

cycloadduct 130 (681 mg, 1.80 mmol), THF (6 mL). and LiB- (2.7 mL of a 2 M solution in

THF, 5.4 mmof). The reaction was complete after stirring for 1 h (O OC) then 3 h (n). 'H NMR

(400MHz) analysis of the crude mixture afier workup indicated a 5.8:l ratio of 131:132 by

integration of the vinylic protons. Purification by flash chromatography (25% EtOAc in hexanes)

afforded 540 mg of 131 dong with 90 mg of 132 (92% combined isolated yield).

[ I S * , I ( I S * ) , ZR*, 3R+, 4S*, SR*]-1-(tert-Butyldimethylsiloxy-

cyclohexyl-methyl)-2,4-dimethyl-8-oxabicyco[3.2.l]oct-6-en-3-oI, (131): IR

(neat) 3410. 2930, 1252, 1 124, 1009, 835, 777 cm-[: IH NMR (400 MHz. CDC13) 6 5.99

(IH, d, J = 6.2 Hz), 5.90 (IH, ddd, J = 6.2. 1.8, 1.1 HZ), 4.37 (lH, s), 1.01-4.07 (IH, m).

3.62 (IH, s), 0.88-1.86 (14H. m), 1.09 (3H, d, J = 7.3 Hz), 1.00 (3H, d J = 7.0 Hz), 0.84

(9H, s), -0.01 (3H. s), -0-07 (3H, s); 13C NMR (100 MHz, CDCls) 8 132.8, 130.3, 92.1,

8 1.9, 77.7, 68.1, 39.0, 37.1, 34.2, 3 1.9, 27.0, 26.4, 26.3, 26.24, 26.22, 18.7, 13.7, 9.9,

-3.6, -5.2; HRMS calcd for C22H4o03Si M+ 380.2747, found 380.2762.

[ I S * , I ( I S * ) , 2R*, 3S*, 4S*, SR*]-1-(tert-ButyIdimethylsiloxy-

cyclohexyl-methyl)-2,4-dimethyl-8-oxabicyclo[3.2.1]oct-6-en-3-ol, (132): 1 R

(neat) 3475. 2926, 1450, 1246, 1 125, 1W7, 834, 776 cm1; 1H NMR (400 MHz, CDCl3) 5

6.33 (lH, d. J = 6.2 Hz), 6.26 (lH, ddd, J = 6.2, 1.8, 0.7 Hz). 4.37 (1H. m), 3.55 (lH, s).

3.33 (lH, s), 2.34-2.18 (lH, br s), 1.20-1.84 (13H. m), 1.20 (3H. d, J = 7.3 Hz). 1.10 (3H, d

J = 7.3 Hz), 0.84 (9H. s), 0.00 (3H, s), -0.07 (3H, s); l3C NMR ( 100 MHz, CDC13) 6 137.1,

135.0, 91.1, 81.7, 79.6, 77.8, 41.8, 39.9, 38.8, 32.0, 26.9, 26.4, 26.33, 26.27, 26.2, 19.7,

18.8, 16.6, -3.6, -5.2; HRMS calcd for C22&003Si [Ml+ 380.2747. found 380.2760.

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5.8 Intermolecular Nucleophilic Ring Openings of Unsymmetrical Oxabicyclic

Compounds Using Organolithium Reagents

Method R: General Procedure for the Nucleophilic Ring Opening of

Unsymmetrical Oxabicyclic Substrates Using Organolithium Reagents. To a 0.3

M solution of oxabicyclic atkene in ether (precooled to O OC) was added 5-10 equiv of the

organolithium reagent dropwise with stirring. The progress of the reaction was monitored by

TLC. When the reaction was complete. the reaction mixture was diluted with ether and quenched

by pouring it into a saturated aqueous solution of NH4Cl. The organic layer was separated and

the aqueous layer was exuacted 4 x with Eno. The combined organic extracts were dried

(MgS04), filtered, and the solvent removed in vacuo. The crude product was puified by flash

chromatopphy on silica gel.

Method 1: General Procedure for the Nucleophilic Ring Opening of

Unsymmetrical Oxabicyclic Substrates Using Iodine-Lithium Exchange. To a 0.3

M solution of iodoakane in ether (precooled to -78 OC) was added 2.2 equiv of t-BuLi ( 1.7 M in

pentane). After stirring at -78 "C for 1 h. the reaction was allowed to warm to rt and concentrated

to half the volume under a Stream of N2. The mixture was then cooled to O OC and the

oxabicyclic alkene was added as a 0.5 M solution in ether. The progress of the reaction was

rnonitored by TLC. When the reaction was complete, the reaction mixture was diluted with ether

and quenched by pouring it N2t0 a saturated aqueous solution of Nl&Cl. The organic layer was

separated and the aqueous layer was extracted 4 x with EtzO. The combined organic extracts

were dried (MgS04), filtered, and the solvent rernoved in vacuo. The crude product was

purifed by flash chromatography on silica gel.

Note: Cycloheptenol 146 showed broad 'H NMR signal and the 1 3 ~ NMR was particularly

poorly resolved. Thus, its 1% NMR was obtained at T = 60 OC and only the major peaks are

listed.

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OTBS

The reaction was carried out as described in the general procedure (Meihod H) using

oxabicyclic substrate 118 (39 mg, 0.12 m o l ) , Et20 (0.2 mL) and n-BuLi (0.24 mL, 2.5 M

solution in hexanes, 0.60 mmol). Mer 24 h, the reaction was diluted with ether (10 di) and

invenely quenched with sanirated aqueous solution of NfiCl (10 mL). Purification by flash

chromatography (15% EtOAc in hexanes) afforded 8 mg (18%) of 134: IR (neat) 3369, 2914.

1464, 1253, 1061, 836, 776. 735 cm1; NMR (400 MHz, CDC13) 6 5.37 (1H. br d. J = 5.1

Hz), 3.79-3.85 (2B, m), 3.75 (lH, s), 2.70-3.20 (lH, br s), 2.45 (IH, ddd, J = 13.7, 10.5,

1.2 Hz), 2.63 (lH, dt, J = 10.0, 5.1), 2.10-2.22 (2H, mj, 1.74 (IH, ddd, J = 13.4, 10.3, 2.7

Hz), 1.38- 1.62 (2H, m), 1.20- 1-34 (5H, m), 0.88 (9H. s), 0.85-0.89 (3H. m), 0.06 (3H. s),

0.05 (3H, s); 1 3 ~ NMR (100 MHz. CDCI3) 6 141.5, 129.8, 83.7, 71.9, 64.8, 48.5. 42.9,

42.7, 35.6, 33.6, 30.1, 26.3, 25.9, 22.8, 18.2, 14.1, -4.5; HRMS calcd for C1gH3503Si [M-

C4H9]+ 327.2355, found 327.2370.

[ I S * , 2R*, 4(1S*), 6R*]-4-(Benzyloxy-2,2-dimethyl-propyl)-6-tert-

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129

The reaction was carried out as described in the generai procedure (Method H) using

oxabicyclic substrate 119 ( 130 mg, 0.3 1 1 mmol), Et20 ( 1 mL) and n-BuLi (0.64 mL, 2.5 M

solution in hexanes, 1.6 mmol). Mer 1 hour, the reaction was diluted with ether (10 mL) and

invenely quenched with saturated aqueous solution of NH4C1(10 mL). Purification by flash

chromatography (5% EtOAc in hexanes) afforded 33 mg (22%) of 135: IR (neat) 3488. 294 1.

1463, 1253, 1075- 837, 775 cm-l; l H NMR (400 MHz, CDC13) 6 7.22-7.34 (5H, m), 5.27

(IH, br d, J = 4.4 Hz), 4.51 (lH, d, J = 12.0 Hz), 4.20 (1H. d, J = 11.9 Hz), 3.73-3.81 (2H,

m), 3.36 (1 H, s), 2.20-2.50 (4H, m). 1.00- 1-83 (8H, m), 0.84-0.96 (3H, m), 0.9 1 (9H, s),

0.85 (9H. s), 0.04 (3H, s), 0.03 (3H. s); 13C NMR (100 MHz, CDCL3) 6 138.9, 138.6. 132.0.

128.1, 127.6, 127.3, 91.4, 72.1, 70.7, 64.2, 48.8, 43.1, 35.7, 34.3, 30.0, 26.8, 25.9, 22.7,

18.1, 14.2, -4.3, -4.5; HRMS calcd for C25H4103Si [M-C&lg]+ 417.2825, found 417.2836.

[ IS* , 2R*, 4(IS*) , 6S*]-6-tert-Butyldimethylsiloxy-2-butyl-4-(l-hydroxy-2,2-

dimethyl-propy1)-cyclohept-3-en01, (137):

The reaction was canied out as descnbed in the general procedure (Method H) above

using oxabicyclic substrate 121 (37 mg, 0.1 1 mmol). Et20 (0.1 1 mL) and n-BuLi (0.22 mL,

2.5 M solution in hexanes, 0.56 rnrnoi). After 1 d, the reaction was diluted with ether (10 mL)

and inversely quenched with saturated aqueous solution of hWC1 (10 mL). Purification by

flash chromatography (25-40% EtOAc in hexanes) afforded 8.3 mg ( 19%) of 137: IR (neat)

3442,2922, 1465, 1254, 1079, 1012,835,776 cm-1; IH NMR (400 MHz. CDC13) 6 5.59 ( lH,

br d, J = 4.4 Hz), 4.08-4.13 (IH, m), 3.74-3.77 (lH, m), 3.74 ( lH, s), 2.51 (IH, d, J = 14.3

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130

Hz), 3.22-2.42 (3H, m), 1.90-2-18 (lH, br s), 1.71 (lH, dt, J = 14.3, 2.6 Hz), 1.63-1.71

(IH. m), 1.47-1.57 (lH, m), 1.21-1.38 (5H, m), 0.86-0.90 (ZlH, m), 0.10 (3H, s), 0.09 (3H,

s); 1 3 ~ NMR (100 MHz. CDC13) 6 141.8, 129.9, 84.4, 71.6, 68.4, 43.9, 43.6, 40.7, 35.6.

33.9, 29.9, 26.1. 25.8, 22.8, 17.9, 14.1, -5.0, -5.3; HRMS calcd for Ci8H3s03Si [M-

C&Ig]+ 327.2355, found 327.2362.

[ I S * , 2R*, 4 ( I S * ) , 6S*]-4-(Benzyloxy-2,2-dirnethyl-propy1)-6-tert-

H O

n-BuLi, EtaO OTBS B *,TB, n Olt..

The reaction was camied out as in the general procedure descnbed above (Method H)

using oxabicyclic substrate 122 (21 mg, 0.049 mmol), Et20 (0.05 mL) and n-BuLi (0.1 mL.

2.5 M solution in hexanes, 0.2 mmol). After 1 hour, the reaction was diluted with ether (10 mL)

and inversely quenched with saturated aqueous solution of NH&l (10 mL). Purification by

flash chromatography (100% toluene) afkrded 13 mg (47%) of 138: IR (neat) 3508, 2930.

1461, 11 10,978, 840, 762 cm-'; 1H NMR (400 MHz, CDCl3) 6 7.15-7.30 (SH, m), 5.53 (1H.

d, J = 5.5 Hz), 4.63 (lH, d, J = 11.7 Hz), 4.17 (1H, dl J = 11.7 Hz), 3.954.08 (lH, m),

3.68-3.82 (lH, m), 3.34 (lH, s), 2.91 (lH, br s), 2.17-2.46 (4H, m), 1.05-1.82 (7H, m),

0.65-0.85 (ZlH, m), 0.01 (3H, s), 0.00 (3H. s); 1 3 ~ NMR (100 MHz. CDCl3) 6 138.9, 137.4,

128.2, 127.7, 126.1, 125.8, 86.0, 75.6, 70.2, 68.2, 43.0, 42.1, 39.8, 34.8, 32.7, 29.9, 26.3,

26.1 23.8, 18.7, 13.8, -4.9, -5.0: HRMS calcd for C25H4103Si [M-C4H9]+ 417.2825, found

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13 1

[IR*, 2R*, 4(IS*), 5S*, 6S*, 7R*]-2-Butyl-4-(cyclohexyl-methoxy-methyl)-6-

The reaction was carried out as described in the pneral procedure (Method H) using

oxabicyclic substrate 126 (22 mg, 0.078 m o l ) . Et20 (0.16 mL) and n-BuLi (0.16 mL, 2.5 M

solution in hexanes, 0.39 rnmol). After 4 hour, the reaction was diluted with ether (10 rnL) and

inversely quenched with saturated aqueous solution of W C 1 (10 mL). Purifcation by flash

chromatography (10% EtOAc in hexanes) afforded 24 mg (92%) of 140: IR (neat) 3533,2924,

1450, 1093, 800 cm- ; IH NMR (400 MHz, CDC13) 6 5.32 (1H. br d. J = 4.8 Hz), 3.49 (4H,

br s), 3.40 (lH, br s), 3.21 (3H, s), 3.18 (lH, br d. J = 1.8 Hz), 2.62-2.72 (2H, m), 2.16

(1H, dt, J = 8.8, 5.5 Hz), 1.44-1.78 (8H, m), 0.90-1.34 (10H. m); 1 3 ~ NMR (100 MHz,

CDC13) 6 138.7, 129.7, 91.4, 86.1, 75.7, 62.9, 56.8, 46.1, 44.2, 43.0, 40.5, 35.0, 31.1,

30.0, 26.9, 26.69, 26.66, 25.9, 22.8, 18.7, 18.2, 14.1; HRMS calcd for C22H~003 [Ml+

352.2977, found 352-2968.

[IR*, ZR*, 4(IS*), 5S*, 6S*, 7R*]-4-(cyclohexyl-methoxy-rnethy1)-2-ethyi-6-

methoxy-5,7-dimethyl-cyclohept-3-enol, (141):

OMe

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The reaction was carried out as described in the general procedure (Method 1).

Iodoethane (0.08 mL, 0.95 m o l ) was dissolved in 3.2 mL of Et20 and the solution cooled to

-78 OC. To this solution was added tert-BuLi dropwise ( 1.2 mL, 1.7 M in pentane, 2.1 mmot).

Afier stirring at -78 O C for I h, the reaction was allowed to warm to rt and concenmted to h d f the

volume under a Stream of N3. The mixture was then cooled to O OC and the oxabicyclic alkene

(56 mg, 0.19 mmol) was added as a solution in 0.38 mL EtzO. After 2 h, the reaction was

diluted with ether (20 mL) and inversely quenched with saturated aqueous solution of NH&1(20

mL). Purification by flash chromatography (10-20% EtOAc in hexanes) afforded 46 mg (75%)

of 141: IR (neat) 3529,2917, 1453, 1096 cm-'; 'H NMR (400 MHz, CDC13) 8 5.33 !1H, br

d, J = 4.0 Hz), 3.50-3.52 (IH, br s), 3.50 (3H, s), 3.43 (lH, br d, J = 6.1 Hz), 3.22 (3H, s),

3.20 (lH, br d, J = 2.2 Hzj, 2.76 (IH, br d, J = 8.1 Hz), 2.65 (lH, m), 2.08 (IH, dt, J = 9.0,

5.4 Hz), 1.50-1.78 (9H, m), 0.96-1.30 (5H. m), 1.26 (3H, d, J = 7.7 Hz), 1.21 (3H, d, J =

7.3 Hz), 0.90 (3H, t, J = 3.3 Hz); 1 3 ~ NMR (100 MHz, CDC13) 6 138.6, 129.4, 91.3, 86.6,

75.4, 62.9, 56.9, 46.2, 46.0, 42.9, 40.4, 31.2, 28.0, 26.9, 26.7, 25.7, 18.7, 18.2, 12.4;

HRMS calcd for C~oH3603 FI]+ 324.2664, found 324.2662.

NaH, TiPSCl H 0 ~ 0 H TIPSO-OH

To a solution of 1,3-propanediol(1 g, 13 rnrnol) in 60 rnL THF was added a suspension

of NaH (780 mg, 32.5 mmol) in 40 rnL THF at O OC. After stimng for 1 h (O OC) then 0.5 h (rt),

the reaction was cooled back to O OC to which triisopropylsilylchloride was added (3 rnL, 14

mmol). The mixture was stimd for an additional 4 h (a) then quenched with a sanirated solution

of l W & I (100 mL) at O O C . The product was extracted with EtOAc (3x) and the combined

organic layers were dned (MgSO4), fütered and concentrated in vacuo. Purification by flash

chrornatography (15% EtOAc in hexanes afforded 160 (2.6 g, 85%) as a clear colourless oil: IR

(neat) 3362, 2942, 1463, 1068, 882 cm-'; lH NMR (200 MHz, CDC13) 6 3.9 1 (2H, t, J = 5.9

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Hz), 3.81 (2H. t, J = 5.9 Hz), 3.93 (1H. s), 1.79 (3H, quintet. J = 5.5 Hz), 1.15-1.03 (21H.

m); l3C NMR (50 MHz, CDCI3) 6 63.5, 62.5, 34.3, 18.0, 1 1.8: HRMS calcd for C12H2902Si

[MH]+ 233.1937, found 233.1929.

Triphenylphosphine (3.5 g, 13.2 mmol), imidazole (898 mg, 13.2 mrnol) and Iz (3.4 g,

13.2 m o l ) were added to 44 mL of CH2C12 respectively. After formation of a white precipitate

(20 min), a solution of dcohol 160 (2Sg, 1 1 mmol) in dry CH2CI2 (1 1 mL) was added and the

mixture was stirred at rt under argon for 1 h. Once the reaction was cornplete, the solvent was

removed in vacuo and the cmde product purified by Bash chromatography (04% Et20 in

pentane) to afford 161 (3.5 g, 944) as a clear colourless oil. IR (neat) 2941, 2865, 1462,

1 105, 882 cm-l; IH NMR (400 MHz, CDCl3) 8 3.73 (2H, t, / = 5.5 Hz), 3.3 1 (2H, t. J = 6.6

Hz), 2.00 (2H, tt, J = 5.5, 6.6 Hz), 1.13-1.02 (21 H, m); 13c NMR (100 MHz, CDCI3) 8

62.6, 36.5, 18.1, 12.0, 4.0; HRMS calcd for Ci lH240SiI [M-CH3 ]+ 327.0641, found

327.0629.

[ I R * , 2R*, 4 ( I S * ) , 5S*, 6S*, 7R*]-2-(3-triisopropylsiloxy-propy1)-4-

(cyclohexyl-methoxy-methyl)-6-methoxy-5,7-dimethyl-cyclohept-3-enol, (142):

TiPSO Li

OMe

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The reaction was carried out as described in the general procedure (Method r). Iodide

161 (376 mg, 1.10 mmol) was dissolved in 3.7 mL of Et20 and the solution cooled to -78 OC.

To this solution was added ten-BuLi dropwise (1.4 mL, 1.7 M in pentane, 2.4 mmol). After

stimng at -78 OC for 1 h, the reaction was aiiowed to warm to n and concentrated to half the

volume under a Stream of Nî. The mixture was then cooled to O OC and the oxabicyclic alkene

(65 mg, 0.22 m o l ) was added as a solution in 0.4 mL EtzO. After 2 h, the reaction was diluted

with eiher (10 mL) and invenely quenched with saturated aqueous solution of W C 1 (10 mL).

Purification by flash chromatography (5-10% EtOAc in hexanes) afforded 106 mg (94%) of

142: IR (neat) 3535,2933, 1463, 1382, 1094,883 cm-'; IH NMR (400 MHz, CDCl3) S 5.32

(lH, br d, J = 4.0 Hz), 3.63-3.68 (2H. m), 3.49 (4H. br s), 3.44 (1H. d, J = 12.0 Hz), 3.21

(3H, s), 3.19 (1H. d, J = 1-8 HZ), 2-76 (1H. d, J = 12.0 HZ), 2-64 (lH, dq, J = 7-07 1-1 HZ),

2.19-2.23 (1H. m), 1.48-1.80 (12H, rn), 1.25 (3H, d. J = 7.7 Hz), 1.21 (3H, d, J = 7.0 Hz),

0.98-1.30 (25H. m); 13C NMR (100 MHz. CDC13) 6 138.8, 129.5, 91.4, 86.0. 75.8, 63.6,

62.9, 56.9, 46.1, 44.1, 43.0, 40.5, 31.5, 31.3, 31.2, 27.0, 26.73, 26.70, 25.9. 18.7, 18.2,

18.1, 12.1 ; HRMS calcd for C2gH5403Si LM-CH30H]+ 478.3842, found 478.3840.

[IR*, 2R*, 4(IS*) , SS*, 6S*, 7R*]-6-tert-Butyldirnethylsiloxy-2-butyl-4-

(cyclohexyl-hydroxy-methyl)-5,7-dimethyl-cyclohept-3-enol, (143):

H O

OTBS

The reaction was cmied out as described in the general procedure (Method H) using

oxabicyclic substrate 127 (54 mg, 0.14 mmol), Et20 (0.48 mL) and n-BuLi (0.28 mL, 2.5 M

solution in hexanes, 0.71 mmol). After 8 h, the reaction was diluted with ether (10 mL) and

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invenely quenched with saturated aqueous solution of NH&l(10 mL). Purification by flash

chromatography (15% EtOAc in hexanes) afforded 20 mg (3 1%) of 143: IR (neat) 35 19.3405.

29 10. 1460, 1254, 998, 836, 774 cm-1; IH NMR (400 MHz, CDCl3) 6 5.59 ( IH, br d. J = 5.1

Hz). 3.78 (lH, d. J = 6.6 Hz), 3.66 (1H. d, J = 1.1 Hz), 3.41 (lH,br s), 2.79 (1H. dq, J =

7.3, 1.1 Hz), 2.65 (IH, br d, J = 8.1 Hz), 2.25 (lH, dt, J = 8-8, 5.5 Hz), 1.99 (lH, br d, J =

13.2 Hz), 1.10-1.80 (18H, m), 1.19 (3H. d, J = 5.1 Hz), 1.17 (3H, d, J = 5.1 Hz), 0.88-0.90

(12H. m), 0.17 (3H. s), 0.15 (3H, s); 13C NMR (100 MHz, CDClj) 6 144.4, 129.9, 80.9,

75.9, 73.6, 46.4, 44.1, 43.5, 41.7, 34.6, 30.6, 29.9, 27.8, 26.7, 26.6, 26.4. 26.3, 22.8.

19.4, 18.6, 18.0, 14.2, -2.2, -4.4; H M S calcd for C26H5~O3Si [Ml+ 438.3529, found

438.3528.

[IR*, 2R*, 4(IS*), 5S*, 6S*, 7R*]-4-(Benzyloxy-cycIohexy1-rnethy1)-6-tert-

butyldimethyIsiioxy-2-butyi-5,7-dimethyi-cyclohept-3-enol, (144):

The reaction was carried out as described in the generai procedure (Method H) using

oxabicyclic substrate 128 (44 mg, 0.096 mmol), Et20 (0.4 mL) and n-BuLi (0.2 mL, 2.5 M

solution in hexanes, 0.48 mmol). After 1 h, the reaction was diluted with ether (10 mL) and

inversely quenched with saturated aqueous solution of NH4CI (10 rnL). Purification by flash

chromatography (10% EtOAc in hexanes) afforded 30 mg (59%) of 144: IR (neat) 3525,2928.

1452. 1255, 1088, 997, 835 cm-l; 'H NMR (400 MHz, CDC13) 6 7.20-7.34 (SH, m), 5.49

(1H. br d, J = 3.4 Hz), 4.65 (lH, d, J = 11.4 Hz), 4.20 (lH, d, J = 11.4 Hz), 3.84 (lH, s),

3.74 (lH, s), 3.53 (1H.br d, J = 8.4 Hz), 2.76 (IH, br d), 2.61 ( lH, br q, J = 7.3 Hz), 2.25-

2.30 (IH, m), 1.00-1.81 (18H, m), 1.26 (3H, d, J = 7.3 Hz), 1.23 (3H. d, J = 7.3 Hz), 0.90

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(9H, s), 0.88 (3H. t, J = 7.0 Hz). 0.17 (3H, s). 0.14 (3H. s); I3C NMR (100 MHz, CDC13) 6

139.4, 138.0, 128.3, 128.1. 127.2, 127.0, 84.4, 81.3, 75.6, 71.5, 46.3, 44.3, 43.4, 41.4,

35.3, 31.4, 30.0, 27.1, 26.71, 26.69, 26.6, 25.5, 22.8, 18.9, 18.3, 16.9, 14.2, -2.0, -4.9;

HRMS calcd for C33H5603Si CM]+ 528.399, found 528.4009.

The reaction was carried out as descnbed in the general procedure (Method I). Iodide

161 (249 mg, 0.73 mmol) was dissolved in 2.4 mL of Et20 and the solution cooled to -78 OC.

To this solution was added te^-BuLi dropwise (0.94 mL, 1.7 M in pentane, 1.6 mmol). After

stining at -78 OC for 1 h, the reaction was allowed to warm to rt and concentrated to hdf the

volume under a Stream of N?. The mixture was then cooled to O OC and the oxabicyclic alkene

129 (75 mg, 0.15 mrnol) was added as a solution in 0.5 mL Et20. After 2 h, the reaction was

diluted with ether (20 mL) and inversely quenched with saturated aqueous solution of NH4Cl(20

mL). muification by flash chrornatography (540% EtOAc in hexanes) afforded approximately

97 mg (>go%) of 145: IR (neat) 3524, 2938, 1514, 1464, 1249, 1102 cm-'; 1H NMR (400

MHz, CDC13) 6 7.25 (2H, d, J = 8.5 Hz), 6.85 (2H, d. J = 8.6 Hz), 5.50 (lH, br s), 4.59 (IH,

d, J = 10.7 Hz), 4.13 (lH, d, J = 11.0 Hz), 3.83 (ZH, br s), 3.79 (3H, s), 3.74 (IH, br s),

3.67-3.70 (2H, m), 3.55 (IH, br d, J = 6.1 Hz), 2.87 (lH, br s), 2.59-2.66 (IH, m), 2.33

(lH, br s), 1.40-1.83 ( l lH, m), 1.19-1.36 (2H. m), 1.27 (3H, d, J = 7.7 Hz), 1.24 (3H, d, J

= 7.3 Hz), 1.00-1.19 (24H, m), 0.89 (9H. s), 0.18 (3H. s), 0.14 (3H, s) ; 1 3 ~ NMR (100

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MHz, CDCI3) 8 158.6, 138.6, 131.6, 128.8, 128.2, 113.5, 84.1, 75.7, 71.2, 65.8, 63.5,

55.2, 46.3, 44.1, 43.3, 41.3, 31.7, 31.6, 31.3, 31.1, 27.0, 26.64, 26.62, 26.5, 25.3, 18.8,

18.0, 17.7. 14.1, 12.0, -1.9, -5.0; HRMS cdcd for C 4 2 H f 6 0 5 S i 2 [Ml+ 716.523 1, found

7 16.~229.

[IR*, 2R*, 3S*, 4S*, 5(ZSx), 7R*]-5-(tert-butyldimethylsiloxy-cyclohexyl-

methyl)-7-butyl-2,4-dimethyl-cyclohept-5-ene-l,3-diol, (146):

The reaction was carried out as descnbed in the general procedure (Method H) using

oxabicyclic substrate 131 (103 mg, 0.271 mmol), Et20 (0.9 mL) and n-BuLi (0.54 mL, 2.5 M

solution in hexanes, 1.4 mmol). After 9 hours, the reaction was diluted with ether (10 m . ) and

inversely quenched with sanirated aqueous solution of (10 mL). Purification by flash

chromatography (25-35% EtOAc in hexanes) afforded 85 mg (72%) of 146: IR (neat) 3535,

2922, 1460, 1212,956,877,712 cm-l; 1H NMR (400 MHz, DMSO, T = 100 O C ) 6 5.32 (lH,

br s), 3.95 (lH, br s), 3.40-3.85 (2H, br s), 3.37 (1H,br s), 3.32 (lH, br s), 2.52-2.60 (lH,

m), 2.13-2.20 (lH, m), 0.82-1.76 (21H, m), 1.21 (3H, d, J = 7.3 Hz), 1.10 (3H, d, J = 7.0

Hz), 0.90 (9H, s), 0.03 (3H, s), -0.01 (3H, s); 13c NMR (100 MHz, benzene, T = 60 O C - only

major peaks are listed) 6 79.9, 76.2, 45.7, 35.7, 32.4, 30.4, 27.5, 27.3, 26.9, 26.8, 26.6,

26.0, 23.2, 18.8, 18.0, 14.5, -4.6; HRMS calcd for C26H50o3Si [Ml+ 438.3529, found

438.3528.

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5.9 Reductive Ring Opening of Oxabicyclic Compound 123 Using DIBAL-H

DIBAL-H (1 0 equiv) - toluene, reflux

[IR*, 2R*, 3S*, 4S*, 5(lS)]-5-(Cyclohexyl-hydroxy-methy1)-2,4-

dimethyl-cyclohept-5-ene-1,3-diol, (152): To a flame dned round bottom flask

equipped with a reflux condenser and stir bar was placed oxabicyclic compound 123 (25 mg,

0.095 m o l ) in 0.2 mL of toluene. The mixture was stirred until the substrate dissolved then the

solution was cooled to O OC. To thîs solution was slowly added DIBAL-H dropwise (0.6 rnL.

0.95 mrno1, 1.5 M in toluene) and the reaction mixture was then heated to reflux for 2 d. The

reaction mixture was diluted with ether, cooled to O OC and quenched with a saturated solution of

NH4C1. Stimng at room temperature for about 15 minutes produced a white gel which was

dissolve by the addition of dilute HCI (10%). The organic layer was separated and the aqueous

layer was extracted 5 times with hot EtOAc The combined organic layers were dried (Na2S04),

filtered, and the solvent removed in vacuo. Purification by flash chromatography (50-60%

EtOAc in hexanes) afforded a 6.5: 1 mixture of 152 and its regioisorner (15 mg total, 62%

combined isolated yield). The minor regioisomer has been previously prepared via the

regioselective hydrostannylation/transmetallation of 123? IR (neat) 334 1, 2908, 1447, 993,

733 cm-'; 'H NMR (400 MHz, CDCI3) 6 5.86 (lH, br t, J = 6.6 Hz), 3.75 (1 H. br d, J = 5.5

H z ) , 3.66 (lH, d, J = 9.2 Hz), 3.50-3.75 (3H, m), 3.52 (IH, s), 2.88 ( lH , br q, J = 7.3 Hz),

2.68 (lH, ddd, J = 15.0, 8.4, 6.6 HZ), 2.31 (lH, dd, J = 14.6, 5.1 Hz), 2.10 (ZH, br d, J =

12.5 Hz), 1.60-1.81 (6H, m), 0.72-1.32 (5H, m), 1.22 (3H. d, J = 7.7 Hz), 1.19 (3H, d, J =

7.0 Hz); 1 3 ~ NMR (100 MHz, CDCI3) 8 143.0, 123.8, 77.6, 73.0, 71.0, 45.3, 41.3, 40.2,

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33.8, 30.2, 29.2, 26.5, 75-94? 25.93, 17.8, 17.5; HRMS calcd for Ci6H2803 [Ml+ 268.2038.

found 268.2028.

5.10 Zirconium-Catalyzed Ethylmagnesiation of Oxabicyclic Compound 126

Et2Mg (5 equiv) CpzZrC12 (cat.)

THF OMe

To oxabicyclic compound 126 (18 mg, 0.062 m o l ) and Cp2ZrC12 ( 1 mg, 0.004 m o l )

was added Et2Mg ( 1 M in Et20, 6.3 mL. 0.3 1 m o l ) dropwise. The mixture was stirred at rt

for 3 d, cooled to O OC and quenched by the addition of saturated aqueous NH4C1. The organic

layer was separated and the aqueous layer was extracted 3 times with ethyl acetate. The

combined organic layers were dried ( N a ~ S 0 4 ) ~ filtered, and the solvent removed in vacuo.

Purification by flash chromatography (10% EtOAc in hexanes) afforded 8.5 mg (42%) of 141

whose spectroscopie data was identical from that obtained in the corresponding EtLi ring

opening.

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5.11 Intramolecular Nucleophilic Ring Opening of an Unsyrnmetrical

Oxabicyclic Compound

[ I S , I ( IS72S) , 2R, 3% 4S, SR]-1-(3-tert-Butyldimethylsiloxy-1-hydroxy-2-

methy1-propyl)-2,4-dimethyl-8-oxabicyclo[3.2.1]oct-6-en3-o1, (155):

The reaction was carried out as described in the pneral procedure (Method F) using

cycloadduct 77f (215 mg, 0.61 mmol), THF (2 mL), and LiBH4 (0.9 mL of a 2 M solution in

TH' , 1.8 mmol). The reaction was complete after stimng for 1 h (O OC) then 3 h (n). 1H NMR

(400MHz) analysis of the crude mixture after workup indicated a 10: 1 ratio of 155 to the endo

dcohol by integration of the vinylic protons. by flash chromatography (30% EtOAc

in hexanes) afforded xx mg (78%) of pure 155: [a]25, = +27.9 O (c = 2, CC4); LR (neat)

3460, 2930, 1471, 1258, 1091,985,837,776 cm-1; IH NMR (400 MHz, CDClj) 8 6.1 1 (lH,

dm, J = 6.2 Hz), 6.08 (lH, d, J = 6.2 Hz), 4.53 (lH, s), 3.12 (lH, s), 4.06 (lH, t, J = 6.2

Hz), 3.62 (IH, dd, J = 9.5, 7.7 Hz), 3.52 (IH, dd, J = 9.5, 5.1 Hz), 1.90-2.10 (2H, br s),

1.80-1.90 (ZH, m), 1.75 (lH, dqn, J = 7.0. 0.7 Hz), 1.10 (3H,d, J = 7 . 3 Hz), 1.03 (3H, d J =

7.0 Hz), 0.93 (3H, d, J = 7.0 Hz), 0.86 (9H, s), 0.03 (6H, s); 1 3 ~ NMR (100 MHz, CDCI3) 6

132.4, 131.3, 92.1, 82.4, 70.7, 67.4, 67.0, 36.2, 35.1, 34.3, 25.9, 18.2, 13.5, 10.6, 9.5,

-5 .5 .

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*OH 1. KH, 18-C-6,THF C

M* OMe TBSO : 2- Mei TBSO = - -

The reaction was canied out as described in the general procedure (Method F) using

potassium hydride (80 mg, 0.70 mmol, 35% wt dispersion in oïl) in 1 mL THF, a solution of

alcohol 155 (113 mg, 0.32 m o l ) in 0.8 mL THF, 18-C-6 (5 mg, 0.02 mmol), and

iodomethane (0.04 mL, 0.8 mmol) as the electrophiie. The reaction was complete after 6 h and

quenched with aqueous NH4C1 at O OC. Workup as described previously followed by

purification by flash chromatography (5% EtOAc in hexanes) gave 106 mg (86%) of 156:

[a125, = +24.6 O (c = 2, CHC13); IR (neat) 2920, 1088, 839, 784 cm-1; IH NMR (400 MHz,

CDCI3) 6 6.05-6.10 (2H, m), 4.53 (lH, s), 3.75 (lH, d, J = 1.1 Hz), 3.53 (lH, t, 3 = 9.5 Hz),

3.50 (lH, t, J = 6.2 HZ), 3.47 (3H, s), 3.38 (lH, dd, J = 9.5, 5.5 Hz), 3.22 (3H. s), 1.64-

1.91( 3H, m), 1.10 (3H, d, J = 7.3 Hz), 1.04 (SH, d J = 7.0 Hz), 0.88 (9H, s), 0.85 (3H, d, J

= 7.0 Hz), 0.04 (6H. s); I3C NMR (100 MHz, CDC13) 6 131.9, 131.4, 93.2, 82.3, 79.8, 76.9.

65.6, 61.6, 55.6, 36.3, 34.3, 31.8, 25.9, 18.2, 14.0, 10.9, 9.6, -5.4, -4.4; HRMS calcd for

C2 1 H40O3Si [Ml+ 384.2696, found 384.2690.

TBAF, THF

OMe

-

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To a solution of the oxabicycle 156 (103 mg, 0.271 m o i ) in 1 rnL of THF was added

TBAF ( 106 mg, 0.4 1 mmol). The reaction was stirred for 18 h at rt, then quenched with water.

The products were extracted with EtzO (3 x 20 mL) and the combined organic layers were dried

(Na2S04), filtered and the solvents removed in vacuo. Flash chromatography on silica gel (35

% EtOAc in hexanes) afforded 56 mg of pure 157 (77%) as a clear colourless oil. [ a ] 2 5 , =

+29.3 O (c = 2, CHC13); IR (neat) 3418, 2928, 1459, 1382, 1094, 1042, 7 15 cm-'; 1H NMR

(400 MHz, CDC13) 6 6.02-6.11 (2H, m), 4.52 (1H. s), 3.69 (IH. d. / = 1.8 Hz). 3.59-3.68

(2H, m), 3.48-3.51 ( lH, m), 3.48 (3H, s), 3.22 (3H, s), 2.15 (lH, br sj , 1.77-1.96 (3H, rn),

1.09 (3H, d, J = 7.3 Hz), 1.03 (3H. d J = 7.0 Hz), 1.00 (3H, d. J = 7.0 Hz); ' 3 ~ NMR (100

MHz, CDC13) 6 131.7, 131.4, 93.0, 83.0, 82.2, 76.7, 67.7, 61.3, 55.6, 35.5, 34.3, 31.5,

14.0, 1 1 -3, 10.0; HRMS cdcd for C 15H2604 CM]+ 270.183 1, found 270.1834.

[ I S , I ( I S , Z S ) , ZR, 3R, 4S, SR]-1-(3-lodo- 1-methoxy-2-methyl-propy1)-3-

methoxy-2,4-dimethyl-8-oxabicyclo[3m2m1]oct-6-ene, (158):

PPh3, imidazole, 12, OMe

CH2CI2

Triphenyiphosphine (24 mg, 0.093 mmol), imidazole (6.3 mg, 0.093 mmol) and 12 (24

mg, 0.093 rnmol) were added to 0.3 mL of dry CH2C12 respectively. After formation of a white

precipitate (10 min). a solution of alcohol 157 (21 mg, 0.078mmol) in dry CH2C12 (0.1 rnL)

was added and the mixture was stirred at rt under argon for 0.5 h. Once the reaction was

complete, the solvent was removed in vacuo and the crude product purified by flash

chromatography (04% EbO in pentane) to afford 158 (24 mg, 8 1%) as a clear colourless oil:

[ c ~ ] * 5 ~ = +68.3 O (c = 1, CHCl3); IR (neat) 2910. 1453, L 195, 1097,953,613 c d ; NMR

(400 MHz, CDC13) 6 6.11 (lH, ddd, J = 6.2, 1.8, 0.7 Hz), 6.05 (1H, d, J = 6.2 Hz), 4.53

(lH, br s), 3.74 (IH, d, J = 1.5 Hz), 3.53 (3H, s), 3.49 (lH, t, J = 6.2 Hz), 3.36 (IH, t, J =

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143

9.5 Hz), 3-23 (3H. s), 3.17 (lH, dd, J = 9.5. 5.5 HZ), 2-00-2.10 (IH, m), 1.78-1.89 (2H, m),

1.11 (3H. d, J = 7.3 Hz), 1.08 (3H. d J = 7.0 Hz). 1.07 (3H, d, J = 7.0 Hz); '3C NMR (LOO

MHz. CDC13) 6 131.8, 131.0, 93.2, 82.33, 82.26, 76.7, 61.9, 55.6, 37.4, 34.4, 31.6. 15.0,

14.0, 12.7, 10.1 ; HRMS calcd for C15H25031 FI]+ 380.0848, found 380.0841.

( I S , 2R, 3R, ?R, 7S, 9R, 10S)-3,10-Dimethoxy-2,4,9-trimethyl-

bicyclo[5.3.0]dec-5-en-1-01, (159):

'BUL~ (2.2 equiv) pentane-Et20 (3:2)

- .GoMe To a solution of oxabicyclic alkene 158 (30 mg, 0.078 mmol) in dry pentaneether (3:2.

0.8 ml total) was added 2.2 equiv of t-BuLi (1.7 M in pentane. 0.10 mL, 0.17 m o l ) at -78 OC.

After stimng at -78 OC for 1 h, the reaction was allowed to warrn to O O C . After 15 min, the

reaction was diluted with ether and quenched by pouring it into a saturated aqueous solution of

NH4Cl. The organic layer was separated and the aqueous layer was extracted 3 x with EbO.

The combined organic extracts were dried (MgS04), filtered, and the solvent removed in vacuo.

Purification by flash chromatography (15% EtOAc in hexanes) afforded 10 mg (50%) of

compound 159: [a125, = +23.7 O (c = 1, CHCI3); IR (neat) 3475, 2925, 1453, 1086, 9 19,

85 1, 758, 643 cm-1; 1H NMR (400 MHz, CDC13) 6 5.44 (1H. ddd, J = 10.3, 2.4, 3.9 Hz),

5.39 (lH, dddd. J = 10.3, 2.2, 3.9, 0.5 Hz), 3.58 (lH, s), 3.50 (3H, s), 3.38 (3H, s), 3.13

(lH, s), 2.88 (lH, d, J = 4.2 Hz), 2.42-2.53 (2H. m), 2.13-2.25 (2H, m), 1.66 (lH, dq, J =

7-3, 1-7 HZ), 1-57 (IH. s), 1.25 (3H9 d. J = 7-3 HZ), 1.2 1 (3H. d J = 7.3 Hz), 1-08 (3H7 d9 J

= 7.1 Hz); 1% NMR* (100 MHz, CDC13) 6 134.5, 132.5, 95.9, 90.8, 80.6, 65.8, 63.1, 57.7,

49.4, 45.4, 39.4, 37.0, 35.7, 22.4, 21.3, 16.2, 15.3 ; HRMS calcd for C15H2603 [Ml+

254.188 1, found 254.1885.

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REFERENCES AND NOTES

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145 REFERENCES AND NOTES

1 ) For reviews on [4+3] cycloadditions, see: (a) Hosomi. A.; Tominaga, Y. [4+3j

Cycloadditions. In Comprehensive Organic Synthesis; Trost, B. M. ; Fleming, L,

Eds.; Pergamon: Oxford. U. K., 1991; Vol. 5 , Chapter 5.1. p 593. (b) Mann, J.

Tetrahedron 1986.42. 461 1. ( c ) Hoffmann, H. M. R. Angew. Chem. Int. Ed.

Engl. 1984.23, 1. (d) Noyori, R-; Hayakawa, Y. Org. React. 1983, 29, 163. (e)

Chiu. P.: Lautens, M. Top. Curr. Chem. 1997, 190, 1.

(2) Bowers. K. G.; Mann, I. Tetrahedron Len 1985.26, 441 1.

(3) (a) Brownbridge, P.; Chan, T. H. Tetrahedron Lett. 1979, 4437. ( b ) Lee, S.;

Chan, T. H . Tetrahedron 1984,40, 361 1. (c) Molander, G. A.; Carey, J. S. J.

Org. Chem. 1995.60, 4845. (d) Molander, G. A.; Swallow, S. J. Org. Chem.

1994,59, 7148. ( e ) Molander, G. A.; Eashvood, P. R. J. Org. Chem. 1995. 60,

8382. (0 Molander, G. A.; Cameron, K. O. J. Am. Chern. Soc. 1993, 115, 830.

(4) Wilson, S. R.; Sawicki, R. A. J. Org. Chem. 1981.46, 3887.

( 5 ) Cowling, A. P.; Mann, J.; Usmani. A. J. Chem. Soc. Perkin. Trans. 1 1981,

21 16.

(6 ) (a) Yadav, J. S.; Rao, C. S.; Chandrasekhar, S.; Rama Rao, A. V. Tetrahedron Let?.

1995,36, 77 17. (b) Lautens, M.; Belter, R. K. Tetrahedron Lett. 1992,33, 2617.

(7) Arco, M. J.; Trammel, M. H.; White, J. D. I. Org. Chem. 1976.41, 2075.

(8) For the preparation of oxyallyl cations frorn polybromoketones using (a) Cu/NaI:

Rawson, D. L; Carpenter, B. K. Hoffmann, H. M. R. J. Am. Chem. Soc. 1979,

101, 1786. (b) Zn/(Et0)3B: Hoffmann. K. M. R.; Iqbal, M . N. Tetrahedron

Lett. 1975, 4487. ( c ) Zn-Cu couple: Hoffmann, H. M. R.; Clemens, K. E.;

Srnithers, R. H. 3. Am. Chern. Soc. 1972, 94, 3940. (d) Zn-Ag couple: Sato,

T.; Noyori, R. Bull. Chem. Soc. Japon 1978, 51, 2745. (e) Fez(C0)g: (i)

Takaya, H.; Makino, S.; Hayakawa, Y.; Noton, R. J. Am. Chem. Soc. 1978, 100.

1765. (ii) Chidgey, R.; Hoffmann, H. M . R. Tetrahedron Lett. 1977, 2633. (0

EtzZn: (i) Mann, J; Barbosa, L. C. A. J. Chem. Soc.. Perkin Trans. 1 1992, 787.

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146 (ii) Mann, J.; Barbosa L. C. A. Synthesis 1996 , 3 1 . ( g ) CeCI3-SnCI2:

Fukuzawa, S.; Fukushima, M.; Fujinami, T.; Sakai. S. Bull. Chem. Soc. Japan

1989.62, 2348.

Katritzky. A. R.; Dennis, N. Chem. Rev. 1989.89, 827.

(a) Davies, H. M. L.; Clark, O. M.; Alligood, D. B.; Eiband, G. R. Tetrahedron

1987,43, 4265. (b) Davies, H. M. L.; h e d , G.; Churchill, M. R. J. Am. Chem.

Soc. 1996,118, 10774.

BUM. B. J.; Cox, P. J.; Simpkins. N . S . Tetrahedron 1993,49. 207.

(a) Lautens, M.; Ma, S. Tetrahedron Lez 1996, 37, 1727. See dso (b) Uozumi,

Y.; Hayashi, T. Tetrahedron Lett. 1993,34, 2335.

For a recent review on intrarnolecular [4+3] cycloaddition reactions, see: Harmata,

M. Intramolecular [4+3] Cycloaddition Reactions. In Advances in Cycloaddition;

Lautens, M . Ed.; Jai Press Inc.: London. England, 1997; Vol. 4, p 4 1.

(a) Schultz A. G.; Macielag, M.; Plummer, M. J. Org. Chem. 1988, 53, 391. (b)

Schultz A. G.; Reilly, J. J. Am. Chem. Soc. 1992, II4 , 5068.

West, F. G.; Hartke-Karger, C.; Koch, D. J.; Kuehn, C. E.; k i f . A. M . J. Org.

Chem. 1993,58, 6795.

Harmata, M.; Galmath, C. B.; Barnes, C. L.; Jones, D. E. J. Org. Chem. 1995.60.

5077.

For examples of catalytic asymmetric intermolecular Diels Aider reactions, see: (a)

Evans, D. A.; Barnes, D. M. Tetrahedron Lett. 1997,38, 57. (b) Corey, E. J.;

Loh, T'.-P. Tetrahedron Lett. 1993-34, 3979. ( c ) Yamamoto, 1.; Narasaka, K.

Chemistv Let!. 1995, 1 129.

Kende, A. S.; Huang, H. Tetrahedron Lett. 1997,38, 3353.

De Kimpe, N.; Palamareva, M.; Verhe, R.; De Buyck, L.; Schamp, N. J. Chem.

Res. ( S ) 1986, 190.

Harmata, M.; Jones, D. E. J. Org. Chem. 1997,62, 1578.

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147 Nucleophilic ring opening on oxabicyclo[3.2.1] systems: (a) Lautens, M.; Chiu, P.;

Ma, S.; Rovis, T. J. A m Chem. Soc- 1995,117. 532. (b) Arjona, O.; de Dios, A.;

Femandez de la Pradilla, R.; Plumet. J.; Viso, A. J. Org. Chem. 1994.59 , 3906

and references therein. k) Lautens, M.: Chiu. P; Coiucci, I. T. Angew. Chem. Inr.

Ed. Engl. 1993.32, 28 1. (d) Lautens, M.; Abd-El-Aziz. A. S.; Lough, A. J. Org.

Chem. 1990,55, 5305.

Lautens, M.; Klute, W. Angew. Chem. Inr. Ed. Engl. 1996,35. 442.

For recent reviews on S$ and SN^' like" ring openings of oxa-n-cyclo systems,

see: (a) Keay, B. A.; Woo. S. Synthesis 1996, 669. (b) Lautens, M. Synlett

1993, 177. ( c ) See also reference 1 (e).

For intramolecular ring opening of oxabicyclo[3.2.1] substrates, see: Lautens, M.;

Kumanovic, S. J. Am. Chem. Soc. 1995,117, 1954.

Lautens, M.; Aspiotis, R.; Colucci, J. J. Am. Chem. Soc. 1996, 118, 10930.

(a) Mann, J.; Usmani, A. J. Chem. Soc., Chem. Commun. 1980, 1 1 19. (b)

Fohlisch, B.; Herter, R. Synthesis 1982, 976. ( c ) Shimizu, T.; Tanaka, M.; Tsuno,

Y. J. Am. Chern. Soc. 1982,104, 1330. (d) Hill, A. E.; Hoffmann, H. M. R. J.

Am. Chem. Soc. 1974, 96, 4597.

Fohlisch, B.; Flogaus, R.; Oexie, J.; Schadel, A. Tetrahedron Lett. 1984, 25,

1773.

Matzinger, P.; Eugster, C. H. Helv. Chim. Acta 1979,62, 2325.

Murray, D. H.; Albizati, K. F. Tetrahedron Len. 1990,31, 4109.

Schieyer, P. v. R.; Su, T. M. J. Am. Chem. Soc. 1969.91, 5174.

Bollinger, J. M.; Brinich, 3. M.; Olah, G. A. J. Am. Chern. Soc. 1970, 92, 4025.

Goodman, J. M.; Hoffmann, H. M. R.; Vinter, J. G. Tetrahedron Lett. 1995,36,

7757.

Achmatowitcz, O.; Bukowski, P; Szechner, B.; Zwienchowska, 2.; Zamojski, A.

Tetrahedron 1977,27, 1973.

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148 (a) DeShong, Ph.; Ramesh, S.; Elango, V.; Perez, J. J. J. Am. Chem. Soc. 1985,

107, 5219. (b) Martin S. F.; Guinn, D. E. J. Org. Chem. 1987.52 , 5588. (c)

Martin S. F.; Gluchowski, C.; Campell, C. L.; Chapman, R. C. Tetrahedron

1988,44. 3171,

(a) Mori, K.; Kisida. H. Terrahedron 1986,42, 5281. (b) DeShong, Ph.; Lin. M.

T.; Perez, J. J. Tetrahedron Let?. 1986, 2 7. 709 1. (c) DeShong, Ph.; Waltermire.

R. E.; Ammon. H. L J. Am. Chem. Soc. 1988,110, 1910. ( d ) Kametani, T.:

Tsubuki, M.; Honda, T. Chern. Pham. Bull. 1988.36, 3706.

(a) Ciufolini, M. A.; Wood C. Y. Tetrahedron Lett. 1986, 27. 5085. (b)

Drueckhammer, D. G.; Barbas, C. F.; Nozaki. K.; Wong, C. H.; Wood. C. Y.:

Ciufolini, M. A. J. Org. Chem. 1988, 53, 1607. (c) Ali, A.; Saxton, J. E.

Terrahedron Le tt. 1989,30, 3 197.

For the preparation of chiral 2-hrylcarbinols via enantioselective aldol, see: (a)

Patterson, 1.; Lister, M. A.; McLure, C . K . Tetrahedron Len. 1986,27, 4787. (b)

Kobayashi, S.; Horibe, M. J. Am. Chern. Soc. 1994,116, 9805. (c) Mukaiyama,

T.; Shiina, 1.; Uchiro, H.; Kobayashi, S. Bull. Chem. Soc. Japan 1994.67, 1708.

(d) Kobayashi, S.; Uchiro, H.; Fujishita, Y.; Shiina, 1.; Mukaiyarna, T. J. Am.

Chem. Soc. 1991, 113, 4247. (e) Corey, E. J.; Cywin, C. L.; Roper, T. D.

Tetrahedron Lett. 1992, 33, 6907. For a diastereoselective aldol, see: (f)

Denmark, S.; Griedel. B. D. J. Org. Chern. 1988, 53, 1607. (g) Martin, S. F.;

Lee, W.-C.; Pacofsky, J.; Gist, R. P. and Mulhern, T. A. J. Am. Chem. Soc.

1994,116, 4674.

For the preparation of chiral 2-furylcarbinols via enantioselective allylation, see:

(a) Keck. G. E.; Krishnamurthy, D.; Grier, M. C. J. Org. Chem. 1993,58, 6543.

(b) Racherla, U. S.; Liao, Y.; Brown, H. C. .I. Org. Chem. 1992,57, 66 14. For

an enantioselective allenylation, see: (c) Keck, G. E.; Krishnamurthy, D.;

Chen, X. Tetrahedron Lest 1994,35, 8323.

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149 (39) For the preparation of chiral 2-furylcarbinols via an enantioselective ene, see:

Tanino, K.; Shoda, H.; Nakamura, T.; Kuwajirna, 1. Tetrahedron Len- 1992,33,

1337.

(40) (a) For the preparation of chiral 2-furylcarbinols via an enantioselective addition of

HCN to furfural, see: Nitta, H.; Yu. D.; Kudo. M.; Mori. A.; houe, S. J. Am.

Chem. Sec. 1992,114. 7969. (b) For enantioselective alkylation of furfural with a

diorganozinc reagent, see: Noyon, R.; Suga, S.; Kawai, K.; Okada, S.; Kitamura,

M. J. Organornetal. Chem. 1990,382. 19,

(4 1) For the preparation of chiral 2-furylcarbinols via chemical reductions, see: (a)

Buynak, J. D.; Strickland, J. B.; Lamb, G. W.; Uasnis, D.; Modi, S.; Williams,

D.; Zhang, H. J. Org. Chem. 1991,56, 7076. @) Sammes. P. G.; Thetford. D. J.

J. Chem. Soc., Perkin Truns. 1 1988, 1 1 1. (c) Llera, J.-M.; Trujillo. M.; Blanco.

M.-E.; Alcudia, F. Tetrahedron: Asymmerry 1994,5, 709. ( d ) Ticozzi. C.;

Zanarotti, A. Tetrahedron Len. 1988.29. 6167. For the preparation of chiral 2-

furylcarbinols via enzymatic reduction. see: (e) Akita, H.; Furnichi, A.; Koshiji,

H.; Horikoshi, K.; Oishi, T. Chem. Pham. Bull. 1984,32. 1242. (f) see reference

36b.

(42) For diastereoselective furyllithium additions to 2-furylcarbinols, see: (a) Poss, M.

A.; Reed, J. A. Tetrahedron Lett. 1992,33, 14 1 1. (b) Raczko, J.; Golebiowski,

P.; Jurczak, J. Tetrahedron Lett. 1990, 31, 3793. (c) Suzuki, K.; Yuki, Y.;

Mukaiyama, T. Chern. Lett. 1981, 1529.

(43) For the kinetic enzymatic resolution of 2-hrylcarbinols: (a) Fantin, G.; Fogagndo,

M.; Guerzoni, M. E.; Medici, A.; Pedrini, P.; Poli. S. J. Org. Chem. 1994, 59,

924. (b) See ref. 41e.

(44) For the kinetic resolution of 2-fus>lcarbinols via a diastereoselctive hydrogenarion,

see: (a) Brown, J. M.; Cutting, 1. J. Chem. Soc., Chem. Commun. 1985, 578.

Using Sharpless' methodology: (b) Kusakabe, M.; Kitano, Y.; Kobayashi, Y.; Sato,

F. J. Org. Chem. 1989.54. 2085.

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150 (45) (a) Scholz, S.; Marshall-Weyerstahi, H.; Weyerstahl, P. Liebigs Ann. Chem. 1985,

1935. (b) Antonioletti, R.; Arista, L.; Bonadies, F.; Locati, L.; Suttri, A.

Tetrahedron L m . 1993,34, 7089. (c) Fayed. S.; Delmas, M.; Gaser, A. J. Mol.

Cotai. 1985.29, 1931. (d) Fischer, K.; Hünig, S. J. Org. Chem. 1987, 52, 564.

(e) Hirao, T.; Misu, D.; Agawe, T. J- Am. Chem. Soc. 1985, 107, 7179. (f)

Friour, G.; Cahiez. G.; Mormant, J. F. Synthesis. 1985, 50. ( g ) Kerdesky, F. A.

J.; Basha, A. Tetrahedron L e z 1991,32,2003. (h) Bumagin, N. A.; More, P. G.;

Beietskaya, 1. P. J. Organometal. Chem. 1989, 365. 379.

(46) Aurell, M. J.; Einhorn, C.; Einhorn, J., and Luche, J. L. J. Org. Chem. 1995, 60.

8 .

(47) (a) Corey, E. J.; Link, J. O. Tetrahedron Lett. 1992,33, 4 141. (b) Qualich, G. J.;

Woodall, T. M. Tetrahedron Let?. 1993,34, 4145. (c) Qualich, G. J.; Woodall, T.

M. Synletr, 1993, 929. (d) Mathre, D. J.; Jones, T. K.; Xavier, L. C.; Blacklock.

T. J.; Reamer, R. A.; Mohan, J. I.; Turner Jones, E. T.; Hoogsteen, K.; Baum. M.

W.; Grabowski, E. J. J. J. Org. Chem. 199 1 , 56, 75 1. (e) Mathre, D. J.;

Thompson, A. S.; Douglas, A. W.; Hoogsteen, K.; Carroll, J. D.; Corley. E. G.;

Grabowski, E. J. J. J . Org. Chem. 1993 , 58, 2880. For a review on

enantioselective reduction of unsymmetrical ketones using oxazaborolidines, see: (0

Singh, V. K. Synthesis, 1992, 605.

(48) (a) Martin, V. S.; Woodward, S. S.; Katsuki, T.; Yarnada, Y.; Ikeda, M.; Sharpless,

K. B. J. Am. Chem- Soc. 1981,103, 6237. (b) Gao, Y.; Hanson, R. M.; Klunder.

J. M.; Ko, S. Y.; Masamune, H.; Sharpless, K. B. J. Am. Chem. Soc. 1987, 109.

5765.

(49) For preparation and characterization of N,N-dibenzylamino ester 61, see: (a) Reetz,

M. T.; Drewes, M. W.; Schmitz, A. Angew. Chem. Int. Ed. Engl. 1987,26, 1 141

and references therein. (b) Dis, D.; Imming, P. Arch. Pham. ( Weinheim Ger.)

1995,328(2), 203.

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151 For preparation and characterization of N, N-dibenzylamino alcohol62, see: (a) Ref.

49a. (b) Razenberg, J. A. S. J.; Nolte. R. J. M. Drenth, W.; Kanters. J. A.;

Duijneveldt, F. B. van J. Mol. Strucr. 1984,112, 1 1 1.

Mancuser, A. J.; Huang, S. L.; Swem, D. J. Org. Chem. 1978,43, 2480.

Schmid, C. R.; Bryant, J. D. In Organic Syntheses; Coffen, D. L.. Ed.; Organic

Syntheses, Inc.: U.S., 1993; Vol. 72, p 6.

Sato, F.; Kobayashi, Y.; Takahashi, O.; Chiba, T.; Takeda, Y.; Kusakabe, M. J.

Chem. Soc., Chem. Comm. 1985, 1636.

For the preparation of the N-propionyl oxazolidinone 71, see: Gosh, A. K.; Duong,

T. T.; McKee, S. P. J. Chem Soc., Chem. Commun. 1992, 1673.

For standard preparation of N-acylated oxazolidinones from their corresponding 1-

amino-2-alcohols, see: Evans, D. A.: Gage, J. R. 0rg.Synth. 1989,68, 83.

For exact preparation of di-n-butylboryl trifluoromethanesulfonate, see: Evans, D.

A.; Nelson, J. V.; Vogel, E. Taber, T. R. J. Am. Chem. Soc. 1981,103, 3099.

For preparation and characterization of [1 R. ?S. SR] -(-)-Men thy 1-(S)-p-

toluenesulfinate 73, see: (a) Solladié, G.; Hutt, J.; Girardin, A. Synthesis, 1987,

173. (b) Anderson, K. K.; Gaffïeld, W.; Papanikolaou. N. E.; Foley, J. W. J. Am.

Chem. Soc. 1964,86, 5637. (c) Anderson, K. K. Tetrahedron Lett. 1962, 93.

For leading references in the preparation of chiral sulfoxides from chiral sulfmate

esters, see: (a) Whitsell, J. K.; Wong, M.-S. J. Org. Chern. 1994. 59, 597. (b)

Drabowicz. J.; Bujnicki, B.; Mikolajczyk, M. J. Org. Chem. 1982.47. 3325. (c)

Andersen, K. K. Tetrahedron Lett. 1962,93. (d) See aiso reference 57a.

Results were obtained from K. Aspiotis, fourth year research project.

Ley, S. F.; Norman, J.: Griffith, W. P.; Manden, S. P. Synthesis, 1994, 639.

Olmstead, M. M.; Pover, P. P.; Shoner, C. S. J. Am. Chem. Soc. 1991, 113,

3379.

Kitamura, M.; Suga, S.; Niwa, M.; Noyori, R. J. Am. Chern. Soc. 1995, 11 7.

4832.

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152 Trost, B. M.; Curran, D. P . Tetrahedron Lett. 1981,22, 1287,

Hoffmann, H. M. R.: Iqbd, M . N . Tetrahedron Lem 1975,4487.

The TBDMS ether of cycloadduct 105 has been previously prepared and

charactenzed: Chiu, P., Ph.D. thesis, University of Toronto, 1 994.

Pericas, M. University of Barcelona, Spain (personal communication).

Lautens, M.; Belter, R. K. Tetrahedron Le#. 1992,33, 26 17,

Lautens, M.; Gajda, C.; Chiu, P. J. Chem. Soc., Chem. Commun. 1993, 1 193.

Simpkins, N. S. Chem. Soc. Rev. 1990,19. 335.

Majewski, M.; Lamy, R. Tetrahedron L m . 1994,35, 3653.

Fillion, E. University of Toronto, 1997 (unpublished results).

Hsu, C.-T.; Wang, N,-Y.; Latimer. L. H.; Sih, C. J. J. Am. Chern. Soc. 1983,

105, 593.

Ashby, E. C.; Boone, J. R. 1. Org. Chem. 1976,41, 2890.

(a ) Haubenstock, H. Tetrahedron 1990,46, 6633. (b) Brunne, J.; Hoffmann, N.;

Scharf, H.-D. Tetrahedron 1994,50, 68 19.

Evans, D. A.; Kaidor, S. W.; Jones, Tt K. J. Am. C'hem. Soc. 1990,112, 7001.

( a ) Sarkar, D. C.; Das, A. R.; Ranu, B. C. J. Org. Chem. 1990,55, 5799. (b)

Crabbé, P.; Garcia, G. A.; Rius, C. J. Chem. Soc., Perkin Trans. 1 1973, 8 10.

(a) Lautens, M.; Chiu, P. Tetrahedron Lett. 1993, 34, 773. (b) Lautens, M.;

Fillion, E. J. Org. Chem. 1996,61, 7994.

Lautens, M.; Ma, S. J. Org. Chem. 1996,61, 7246.

For a review on the synthesis of naniral 2-oxetanes, see: Pommier, A.; Pons, J.-M.

Synthesis, 1995, 729.

Colucci, J. University of Toronto, 1997 (unpublished results).

Ma, S. Ph. D. thesis, University of Toronto, 1996.

(a) Dzhemilev, U. M.; Vostrikova, O. S. J. Organomet. Chem. 1985,285, 43. (b)

Dzhemilev, Li. M.; Vostrikova, O. S.; Tolstikov, G. A. J. Organomet. Chem. 1986,

304, 17.

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153 (a) Hoveyda, A. H.; Xu, 2. J. Am. Chem. Soc. 1991.113, 5079. (b) Hoveyda, A.

H.; Xu, Z.; Morken. J. P.; Houri, A. F. J. Am. Chern. Soc. 1991, 113, 8950. (c)

Hoveyda A. H.: Morken, J. P.; Houri, A. F.; Xu, 2. J. Am. Chem. Soc. 1992, 114,

6692. (d) Morken, J. P.; Didiuk, M. T.; Hoveyda. A. H. /. Am. Chem. Soc. 1993,

115, 6997. (e) Didiuk, M. T.; Johannes. C. W.; Morken, J. P.; Hoveyda, A. H. J. Am.

Chem. Soc. 1995, 11 7 , 7097. (0 Takahashi, T.; Seki. T.; Nitto, Y.; Saburi. M.;

Rousset. C. J.; Negishi, E. -1. J. Am. Chem. Soc. 1991, 113, 6266. (g) Knight. K.

S.; Waymouth, R. M. J. Am. Chem. Soc. 1991,113. 6268. (h) Knight, K. S.; Wang,

D.; Waymouth. R. M.; Ziller, J. J. Am. Chem. Soc. 1994, 116. 1845.

Strohmeier, W.; Seifert, F. Chem. Ber. 1961, 94, 3356.

(a) Rigby, J. H. Stud- Nat. Prod. Chem. 1988, 1, 545. (b) Fraga, B. M . Nat.

Prod. Rep. 1992, 9. 2 17.

For references on the isolation, structure determination. biological activity and total

synthesis of Phorbol, see ref. 24 and references therein.

Lange, G.; Gottardo, C. Synthetic Communications. 1990,20(10), 1473.

Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978,43, 2923.

For the characterization of furyl ketone 57, see: Abele. E. M.; Gol'berg, Y. S.;

Popelis, Y. Y.; Shimanskaya, M. V . J. Org. Chem. USSR (Engl. Transl.) 1990,

26, 1545.

Ashcroft, M. R.; Hoffmann. H. M. R. Organic Syntheses 1978,58, 17.

Knochel. P.; Yek, M. C. P.; Berk, S. C.; Talbert, J. J. Org. Chem. 1988,53,

2392.

Acta. Chem. Scand. 1962, 16(10), 2467.

(a) Orfanopoulos, M.; Smonou. 1.; Foote. C. S. J. Am. Chem. Soc. 1990, 112.

3607. (b) de Kimpe, N.; D'Hondt, L.; Moens, L. Tetrahedron 1992.48, 3 183.

(a) Bailey, W. F.; Punzalan, E. R. J. Org. Chem. 1990.55, 5404. (b) Negishi. E.;

Swanson, D. R.; Rousset, C. J. J. Orn. Chern. 1990.55. 5406.

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APPENDIX 1

SELECTED SPECTRA OF REPRESENTATNE COMPOUNDS

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NOTE TO USERS

Page(s) not included in the original manuscript are unavailable from the author or university. The manuscript

was microfilmed as received.

UMI

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- r S.& l6.S

5.a II. A

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Tl PSO SoMe

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APPENDIX 2

X-RAY CRYSTAL DATA FOR COMPOUNDS

76b, 80, 85, AND 92

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X-RAY CRYSTAL DATA FOR COMPOUND 76b

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Table 1. Crystal data and structure refinement f o r 1.

I d e n t i f i c a t i o n code

Empir ica l formula

Formula we i g h t

Temperature

Wave length

Crys ta1 sys tem

Space group

U n i t dimensions

Volume, Z

Dens i t y ( ca lcu la ted)

Absorpt ion c o e f f i c i e n t

F(000)

C r y s t a l size

8 range for data c o l l e c t i o n

L i m i t ing indices

R e f l e c t i o n s co l l ec ted

Independent r e f l e c t i o n s

Absorpt ion cor rec t ion

Refinement method

Data / r e s t r a i n t s / parameters

Goodness-of-f i t on F 2

F i n a l R i n d i c e s [I>2u(I) ]

R i n d i c e s ( a l 1 data)

Absolute s t r u c t u r e parameter

E x t i n c t i o n c o e f f i c i e n t

L a r g e s t d i f f . peak and hole

Orthorhombic

P212121

a = 6.8513(8) A alpha - 90'

b - 11.8253(4) A beca - 90°

c - l6.3271(8) À gamma = 90'

1322.8(2) A ~ , 4

1 . 1 9 7 Xg/m 3

0.661 mm-l

Full-matrix leas t -squares on F 2

O . O26 ( 3 )

0.220 and -0.160 e ~ - ~

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4 Table 2. Atomic coordinates [ x 10 j and equivalent isotropic

- 2 3 displacement parameters [A x 10 1 f o r 1. U(eq) is defined as

one third of the trace of the orthogoaal ir id U tensor. i j

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Table 3 . Bond lengths [A] and angles [ O ] f o r 1. 179

Symmetry transformations used to generate equivalent atoms:

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3 Table 4. Anisotropic displacement parameters [ À ~ x 10 ] for 1.

The anisotropic displacement f ac to r exponent takes the fom: 2 * 2 * *

-2n [ (ha ) Ull + ... + 2hka b U12 ]

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Table 5 . Hydrogen coordinates ( x 1 0 4 ) and i sotropie =O 2 3 displacernent parameters (A x 10 ) fox 1.

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X-RAY CRYSTAL DATA FOR COMPOUND 80

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T a b l e 1. Crystal data and structure refinexnent for 1.

Ident i f i ca t i on code

Empirical formula

Formula weight

Temperature

Wavelength

Crystal system

Space group

Unit ce11 dimensions

Volume, Z

Density (ca lcu lated)

m s o r p t i o n coefficient

Crystal s i z e

8 range for data c o l l e c t i o n

L i m i t i n g h d i c e s

Reflections collected

Independent ref lect ions

Absorption c o r r e c t i o n

Re f inement method /

Data / restraints / parameters

Goodness-of-fit on F 2

ina al R indices [I>~u(I)]

R indices ( a i l data) i

Extinction coefficient

Largest diff, peak and ho le

Triclinic

PT

a = 10.148(2) A alpha = 7 6 . 6 8 3 ( 6 ) O

b = 11.4109(10) A beta = 87.191(9)O

E = 12.2255(11) À gamma = 77.518(9)O

1345.1(3) A , 4

3 1-18? Mg/m

b

0.081 6'

528

Full-matrix least-squares on F 2

0.306 and -0.198 e ~ - ~

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4 Table 2 . A tomic coordinates [ x 10 ] and equivalent isotropie 3

displacenent parameters [ À ~ x 10 ] for 1. U ( q ) is definad as

one third of the trace of the orthogonalized U i j tensor.

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Table 3 . Bond lengths [A] and angles [O] for 1.

S y m m e t r y transformations used to generate equivalent atoms :

9

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- 2 3 T a b l e 4 . Anisotropic displacement parameters [ A x 10 1 for 1.

The anisotropic displacement factor exponent takes the fonn: 2 * 2 * *

-Zn [ (ha ) Ul l + ... + 2hka b U12 1

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T a b l e 5 . Hpdrogen coordinatas ( x 104) and isotropie 3

displacemant parameters ( À ~ x 10 ) for 1.

H H(3AA) H ( 4AA) H(5AA)

( 6AA) H(7AA) H ( 9 w H(9AB) H(9AC) H ( 1OA) H(11A) H(11B) H ( 11C) H ( 12A) H( l3A) H ( l S A ) H ( 15B) H( 1SC) H ( l6A) W ( l6B) H ( l6C) H ( l7A) H ( l7B) H ( l7C) H(28A) H.( 3BA) H ( 4BA) H ( 5BA) H ( 6BA) H ( 7BA) H ( 9BA) H(9BB) H(9BC) H ( IOB) H(1lD) H(1lE) H( 11F) H ( 12B) H(13B) H ( lSD) H ( ISE) H ( 1SF) H ( l 6 D ) H(16E) H ( l6F) H(17D) H(17E) H ( l7F)

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X-RAY CRYSTAL DATA FOR COMPOUND 85

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Table 1. Ctpstal data and structure refinemeat for 1.

Identification code s9747a

Empirical formula

Formula weight

Temperature 173(2) K

Wavelength 0.71073 À

Space group

Unit ce11 dimensions

V o l u m e , 2

p 2 p

O a = 18.088(3) A alpha = 90

b = 5.7986(11) A bata = 108.706(9)~

c = lQ.844(2) A gamma = 90°

1474.6(4) A ~ , 4

Density (calculated) 1.308 Mg/= 3

Absorption coefficient

Cqstal size 0.21 x 0.24 x 0.34 mm

9 range for data collection 2.38 to 27.00~

L i m i t i n g indices -23 I h S 22, -1 I k 1 7 , -1 I l I l 8

Reflections collected 4295

Independent reflections

Absorption correction Semi-empirical from psi-scans

Max. and m i a . transmission 0.5450 and 0.5214

Ref inemeat method Full-matrix hast-squares on F 2

D a t a / restraints / parameters 3225 / O / 184

F i n a l R indices [3>2a(I)] R1 = 0.0501, wR2 = 0.0985

R indices (al1 data) R1 = 0.0886, wR2 = 0.1142 t

Largest diff. peak and hole 0.236 and -0.256 e ~ - ~

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4 T a b l e 2 . Atomic coordiaates [ x 10 ] and equivalent isotropie

2 3 displacement paramaters [A x 10 ] for 1. U(eq) is defined as

one third of t h e trace of th8 orthogonalized U teasor. i j

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Table 3 . Bond lengths [A] and angles [O ] for 1.

Symmetrp transformations used to generate equivalent atoms:

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3 Table 4 . Aniootropis displaïement parameters [ A ~ x 10 ] for 1.

The anisotropic displacement factor exponsnt takes the form: 2 2 t +

-2n [ (ha ) Ull + ... + 2hka b U 12 ]

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Table 5 . Bydrogen coordinates ( x 104) and isotmpic 193 2 3

displacement parameters (A x 10 ) for 1.

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X-RAY CRYSTAL DATA FOR COMPOUND 92

- \ O-H

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Table 1. C r p s t a l data and structure refinement for 1.

Identification code

Empirical formula

Formula weight

Temperature

Wavelength

Crystal system

Space group

Unit ce11 dimensions

Volume, Z

Density (calculated)

Absorption coefficient

F(000)

Crystal s i ze

8 range for data collection

Limiting indiceç

Reflections collected

Independent reflections

Refinement method

Data / restraints / parameters

Goodness-of -f i t on F 2

Final R indices [1>2c(I) 1

R indices (al1 data)

Largest diff. peak and h o l e

a =- 9.453(2) À alpha = 119.397(10)~

b = 12.055(3) À beta = 94.969(9)0

c = 12.235(3) À gamma = 104.333(8)O

1141.7(4) À ~ , 4

1.235 Mg/m 3

0.087

3722 (Rint = 0.0305)

Full-matrix least-squares on F 2

R1 = 0.0955, wR2 = 0.1166

0.379 and -0.185 e~.~

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4 Table 2 . A t o m i c coordinates [ x 10 ] and equivalent isotropie 3

displacemant paramaters [ Â ~ x 10 ] for 1. U(eq> is defined as

one third of the trace of the orthogonalized Uij tensor.

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Table 3 . Bond lengths [A] and angles fa] for L. 197

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Symmetry transformations used to generate equivalent a t o m s :

#1 -x,-y+l,-z+l #2 -x+l,-y+l,-z+l a3 -x+l,-y+2,-z+2

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200

XP - Molecular Graphics - Ver 5.03 C o p y r i g h t (C) Siemens Analytical Xray 1994

Tors ion angles for s9568 in

-54 - 3 C7A C1A C2A C3A 54 -7 0 8 A C1A C2A C3A 172.1 ClOA C1A C2A C3A -34 .O C1A C2A C3A C4A

8 9 . 2 C U C2A C3A 0 9 A 3 4 . 6 C2A C3A C4A C5A

-87 -6 0 9 A C3A C4A C5A 53 - 4 C3A C4A C5A C6A

- 5 7 . 0 C3A C4A C5A 0 8 A - 8 9 . 0 C4A C5A C6A C7A

2 4 . 6 0 8 A C5A C6A C7A 88.7 C2A C1A C7A C6A

-22-9 0 8 A C1A C7A C6A - 1 4 3 . 3 C l O A C1A C7A C6A

-1.1 C5A C6A C7A C1A -76.2 C2A C1A 08A C5A

3 7 . 6 C7A C1A 08A C5A 1 6 5 . 6 ClOA C1A OSA C5A

78 - 7 C4A C5A 08A C1A -38.3 C6A C5A 0 8 A C I A -64.9 C2A C l A ClOA O l l A 1 6 8 . 1 C2A C1A ClOA C12A 1 6 7 . 6 C7A C1A ClOA O l l A 40-6 C7A C1A ClOA C12A - 4

0 8 A C1A C lOA C12A C1A ClOA C12A C13A C1A ClOA C12A C14A C1A ClOA C12A C15A O l l A ClOA C12A C13A O l l A ClOA C12A C14A O l l A ClOA C12A C15A C7B C1B C2B C3B 0 8 B CTB C2B C3B ClOB C1B C2B C3B C1B C2B C3B C4B C1B C2B C3B 0 9 B C2B C3B C4B C5B 0 9 B C3B C4B C5B C3B C4B C5B C6B C3B C4B C5B 0 8 B C4B C5B C6B C7B 08B CSB C6B C 7 8 C2B C l B C7B C6B 0 8 B C1B C7B C6B ClOB C1B C7B C6B C5B C6B C7B C1B C28 C1B 088 C5B C7B C1B 08B C5B ClOB C1B 0 8 B C5B C4B C5B 0 8 B C1B C6B C5B 0 8 B C1B C2B C1B ClOB O l l B C2B C1B C l O B C12B C7B C1B C l O B O l l B

,178.3 C7B C l O B C l B C l 2 B -164.8 0 8 B C1B C l O B 0 l l f

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67.6 08B CIB ClOB C12B -55.3 ClB C l O B C12B C13B 69.9 C 1 B ClOB C12B C14B

-172 . 4 C1B ClOB C12B C15B 179.2 OllB ClOB C12B C13B -55.6 OllB ClOB C12B C14B 62.0 OllB ClOB C12B C15B

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Table 5 . Hydrogen coordinates ( x 10') and isotmpic 3

203 -2 displacement parameters (A x 10 ) for 1.

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