TANDEM SYNTHESIS OF POLYSUBSTITUTED OLEFINS: AN APPROACH TOWARD THE FIRST TOTAL SYNTHESIS

OF ASTAXANTHIN P-D-DIGLUCOSIDE

FARIBA SOLEYMANZADEH

A thesis submitted to the Faculty of Graduate Studies in partial fidfillment of the requirements

for the degree of Master of Science

Graduate program in Chernistry York University

North York, Ontario

June 2000

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Tandem Synîhesis of Poly-substituted Olefins: An Approach Toward the First Total Synthesis of

Astaxanthin-P-D-diglucoside

by Fanba Soleymanzadeh

a thesis submitted to the Faculty of Graduate Studies of York University in partial fulfillrnent of the requirements for the degree of

MASTER OF SCIENCE

Permission has been granted to the LIBRARY OF YORK UNIVERSITY to lend or self copies of this thesis, to the NATIONAL LIBRARY OF CANADA to microfilm this thesis and to lend or seIl copies of the film. and to UNiVERSITY MICROFILMS to publish an abstract of this thesis. The author reserves other publication rights. and neither the thesis nor extensive extracts from it may be printed or otherwise reproduced without the author's written permission.

ABSTRACT

The synthesis of conjugated polyenes via tandem cross-couplings reactions of

alkenyl halides and organometallic reagents was investigated in this project. The alkenyl

halide, &ans-1-chloro-2-iodoethene, which contains two different sites with varied

reactivity, was prepared to couple with organometals. Akenylboronic acids were

prepared via hydroboration of alkyles and cross-coupled with the olefin template, Pans-

1-chIoro-2-iodoethene. These coupling were also performed in tandem sequences and it

was found that they give good yield as non-tandem ones.

The strategy of one-pot synthesis was then applied in the first total synthesis of

Astaxanthin P-D-diglucoside, using the olefin template trans- 1-chloro-2-iodoethene. To

synthesize this natural product, the key targets, tram- 1 -chlore-2-iodoethene and 2,6-

dunethyl-cyclohexanone were used. The syrnmetry in this natural product gives the

ability to use the olefin template as the middIe key building block and use it several tirnes

to constnict the polyene chain via a series of cross-coupling reactions with boronic acids

and allcynes.

A series of reactions were applied on the 2,6-dimethylcyclohexanone to f o m the

suitably metalated ring part, which can later couple with the chain intermediate.

To My Parents And

My Husband Whose encouragement was my inspiration

m - O WLEDGEMENT

1 would like to take this opportunity to thank my supervisor Prof: Michael G. Organ, for his invaluable assistance and support throughout the course of this work. 1 am also very grateful tu my cornmittee rnembers, ProJ C. C. Lemoff and Prof: P. G. Potvin for their guidance in this research. 1 would also like to thmk aZl the people in Our group, especially Debasis MalZik, Svetoslav Bratovanov and Daniel J. Parh for their intellectual and material heEp. Without thern, my studies a f York would have been Zen enjoyable and mernorable.

Table of Abbreviations

APT

DBN

DCM

D m

DMSO

HMPA

(IPC), BH

LDA

NMO

TBDMS

TRIS

TLC

TBAF

THF

TLC

TMS

r. t.

attached proton test

1,8-diazabicyclo[S.4.0]undec-7-ene

dichloromethane

N,Nt-dimethylformamide

dimethylsulfoxide

hexamethylphosphoramide

diisopinocamphenylborane

lithium diisopropylamide

N-methyl rnorpholine oxide

r-butyldirnethylsilyl

triisopropylbenzenesulfonyl

thin layer chromatography

tetrabutylammonium fluoride

te trahydro fbran

thin layer chrornatography

trimethy k l y 1

roorn temperature

Table of Contents

List of figures

List of tables

Chapter one

Introduction

1.2. Carotenoids and their importance

1.2.1. Background

1.3. Strategies for building the olefinic structure

1.3.1 Conventional olefination methods

1.4. Olefin templates and their importance

1.5. Cross-coupling reaction

1.6. Organoboranes as coupling partners for olefin template

1.7. Role of palladium-catalysis in cross-coupling reactions

1.9. Importance of the tandem sequence

1.10. HighLights of the project

Chapter two

Synthesis of conjugated polyenes

2.1. Synthesis of the olefin template

2.2. Synthesis of alkenyl boronic acids

2.3. Tandem and independent cross-couplings

of organoboranes with the olefin template

Summary

Chapter three

Application of the tandem strategy to the

total synthesis of Astaxanthin p-D-diglucoside

Introduction

3.1. Retrosynthetic analysis

3.2. Synthesis of polyene c h a h key intermediates

3.3. Approaches toward the synthesis of the ring key intermediates

Summary 53

Chapter four 54

Experimental section for the synthesis of dienes:

tandem and independent studies 54

Experirnental section for the snythesis of Astaxanthin P-D-diglucoside 68

References 77

List of Fiqures

FIGURE 1: Astaxanthin P-D-diglucoside

FIGUICE 2: Structure of p-carotene

FIGURE 3: A general catalytic cycle for cross-coupling reaction

FIGURE 4: Major disconnections for Astaxanthin PD-diglucoside

FIGURE 5: Selective synthesis of an alkene

List of Tables

TABLE 1: Results and conditions for the synthesis of boronic acids

TABLE 2: Results for tandem and independent reactions

CHAPTER ONE

Introduction

Stereoselective syntheses of conjugated polyenes are of great importance

in organic chernistry.' A number of new methods for the preparation of conjugated

dienes and polyenes have been developed by using various organometallic

reagentsZ7' Among these procedures, the most promising ones are those based on

cross-coupling reactions, between stereodefined alkenyl metals and haloa~kenes.~ The

development of tandem (one-pot) sequences using simple starting matenals c m provide a

powerful method to produce useful organic molecules.

1.1 . Plan of The Study

There are different issues that this research would focus on:

1. To develop a strategy by which polysubstituted olefine can be prepared via the

formation of a carbon-carbon single bond between an alkenylhalide and alkenyl

metals.

2. To synthesize a suitable aikenyl halide (olef5n template) which can be applied in

tandem reactions.

3. To apply the strategy of the tandem synthesis in the total synthesis of a natural

product containhg a polyene structure, using the prepared olefin template.

The natural product of interest in this project is astaxanthin P-D-diglucoside (1).

Like other carotenoids, this nahiral product can be used in pharmaceutical, medicinal and

food ind~stries.~ The anti-cancer activity of astaxanthin P-D-diglucoside is the most

important reason for chemists to choose it as a synthetic target.' It was also speculated

that the presence of two glucose moieties in the molecule would increase the solubility of

the compound in aqueous media. This feature would potentially increase the

physiological activity of the molecule.

Figure 1. Astaxanthin P-D-diglucoside

1.2. Carotenoids and Their Importance

Arnong the different classes of natural products, carotenoids are one of the

most widespread and important ones containing a polyene structure. The olefinic

chah has a major role in their biological activities. Recent discoveries in the

biological function and medicinal application of retinoids and carotenoids has sparked

a renewed interest in the stereoselective synthesis of polyenes, especially those

containing an all-tram (E) structure.

In order to study the biological activities of single isomers of carotenoids, such as

their interaction with proteins or their role in photosynthesis, it is essential to isolate each

isomer separately. The isolation of one isomer is usually difficult and it rnight isornerize

during the process. This requires chemists to synthesize carotenoids in one single f0m.1.~

In the field of medicine, it is now clear that the provitamin A activity of

p-carotene may not be the only beneficial effect of carotenoids. Several carotenoids

found in the human diet, especiaily lycospene, Iutein, and zeaxanthin, are considered to

be involved in combating diseases such as cancer, heart disease, and degenerative eye

diseases. 6

1.2.1. Background

In the laboratory of Willstatter, after the accurate combustion analyses and

classical molecular weight measurernents of the compounds extracted fiom green Ieaves,

the correct molecular formulae of carotene C40H56 and xanthophyl C40H5& were found.'

Attempts to reveal the molecular structures by the classical method of chemical

degradation to significant identifiable fragments remained unsuccessfûl for several years.

Using catalytic hydrogenation, it was Iater confirmed that these pigments have a highly

unsaturated nature and the t e m 'polyene' was fïrst used to name these structures.* In the

laboratories of Kuhn and Karrer, the isoprenoid nature of carotenoids was found for

bixing and cr~cet in. '~ The first carotenoid whose structure was £ûlly identified was

p-carotene (Figure 2).6

END PART CHAIN PART

Figure 2. Structure of p-carotene

The long conjugated polyene chah part present in the carotene required the

development of new strategies and methods for its synthesis. The syntbesis of p-carotene

was achieved independently by the labs of Karrer, Inhoffen, and Milas, in 1950, a year

which can therefore be regarded as a milestone in carotenoid researcha6

The research in this field was continued extensively, so that by 1976, 98 naturally

occurring carotenoids had been synthesized. During this time, many reactions were

applied to construct the polyene chah (Julia or Wittig olefination). The synthesis of

carotenoids propelled the development of organophosphorous chemistry through the

Wittig and the Horner-Emmons reactions.

Although a large number of carotenoids have been made, the synthesis of carotenoids

is still a popular practice because of their enormous commercial value. Such syntheses

are also routinely exercised in academic and industrial scale processes.

1.3. Strategies For Building The Olefinic Skeleton

Modem synthetic organic chernistry permits the preparation of polyenes via a

number of strategies. However, a few methods established early in this century have

been used and fürther developed to an industrial scale.

There are two approaches to prepare olefinic structures. In the first strategy

(method A), the building bIocks are connected +hou@ the formation of double bonds, by

a Wittig reaction or elimination of a sulfone group (Julia olefination). The second

approach involves the establishment of a single bond between two double bonds (rnethod

B). This approach has not been examined until recently, due to the difflculty in

establishing C-C bonds between two sp2 centers (Scheme I ) . ~ However, cross-coupling

methodology would enable one to build a polyene chah with a defined ( E l 9

stereochemistry.

Method B: single bond formation Z

Y

X

z Method A: double bond formation

Scherne 1

1.3.1 Conventional Olefination Methods

There are different methods leading to the formation of an olefmic structure like

I I , 12 en01 ether and aldol condensations, Wittig olefhation," sulfone c ~ u ~ l i n ~ ' ~ * l5 and

organometallic reactions.16 A large amount of ivork has been done on the

thennodynamics and kinetics of double bond-making processes that helps chemists

predict a reaction profile which leads to an olefin with a desired stereoche~nistr~.'~

In Wittig reactions, a carbonyl functionality can be converted into an o l e f i c

bond by reactions with phosphonium salts.13 The conformational distribution of the

be taine

intermediate often decides the fate of an olefination reaction that leads to a (2) or (E)

double-bond. The synthesis of fucoxanthin employed a Wittig strategy and is shown in

Scheme 2. '' However, th is configurational distribution vastly depends on the proximal

fùnctional group on the substrate. As a result, reactions are, in most cases, substrate

specific. Unstabilized ylides give predominantly the 2-alkene while stabilized ylides give

mainly E-alkene. Besides, the nucleophilic attack of the ylide on the carbonyl system c m

often be a challenge if the carbonyl carbon is sterically crowded with proximal

functionalities.

A modification of Wittig olefination reactions gained a wide popularity as it

attempted to solve a few of the many problems described above.

The Horner-Emmons-Wordsworth method (also known as the modified Wittig reaction)lg

provided a tool to prepare relatively stable (sometirnes isolable) ylides using phosphonate

esters. This method usualiy leads to an E-isomer. However, a slight modification of

steric requiremenis at the proximal carbon atom can lead to a ~-isorner.*~ As a result, the

problem of "substrate-specific success" remains the same for the synthesis of a broad

range of natural products.

&hicl

1 ) NaOMe

2)OH-

A

Scheme 2

Another relatively tess cornmon method where a a-halosulfone can be used to

generate olefins ( hown as the Ramberg-Biicklund rearrangement)20 gained little success

due to rather a reactive intermediate containhg a sulfone functionality. Besides, the use

of strong bases (usually potassium hydroxide) during the reaction-sequence is always a

concern for many natural products containhg sensitive fünctional ~ O U ~ S . ~ A relatively

popular sulfone-based olefination method is Julia olefination. This olefination method

was fïrst applied by Julia for the synthesis of vitamin A. 21* 22 h this method, the double

bond is generated via alkylation of the a-carbanion of a sulfone and then, base-induced

eiïmination,

Like the Wittig reaction, Julia olefmation does not always lead to the

desired stereochernistry of the olefm due to conformational restrictions in the reaction

intermediate. An example of this methodology is shown in Scheme 3.

Scheme 3

A philosophical aspect that challenges these conventional synthetic methods

(specially Wittig ole£ination methods) is the lack of "atom-economy" in these processes.

The molecular mass involved in the triphenyl phosphonium moiety (Wittig type

reactions) or sulfone moiety (Julia olefmation) does not contribute to the product mass

creating a large amount of mass for waste-disposal. Considering the amount of money

spent for industrial waste-disposal, the lack of "atom economy" is a serious

disqualification for conventional olefmation methods."

Today, one of the main methods in carbon-carbon bond formation is based on

the usage of organometallics. Among the various organornetallic reactions employed

for this bond formation, the metal a~etylide?~ ~ri~nard?' and ~eformatskJ~ reactions

have been used in the synthesis of Vitamin A and other carotenoids. In these senes of

reactions, different metals can be used. This includes metals of group LA, IIA, and IIIB

or transition metals in the penodical table. Meta1 acetytides (aikymdes) have featured

prominently in the synthesis of vitamin A and other carotenoids, principally by the

nucleophilic addition of metal acetylides RCCM (M= Li, Na, K, MgX) to aldehydes

and ketones to produce the corresponding a-hydroxyalkynes.24

Scheme 4

In the f i s t synthesis of vitamin A by Isler and his CO-workers, the Grignard

acetylide reacts with aldehydes to give the desired structure (Scheme 4)?

1.4. Olefm Templates and Their Importance

The term "Olefin template" refers to a target which contains a stereodefined

olefinic structure and two or more reactive sites and can be used in tandem reactions on

the double bond with specific stereochemistry. The reactive site is usually a halogen,

which can cross-couple with other molecules. This way a new carbon-carbon bond will

be formed while the stereochemistry of the template remains the same. This method will

reduce the synthetic problems associated with the formation of an undesired

stereochernistry of the double bond.

The synthesis of a suitable template however, dernands the following features:

a) A template must have different groups with varied reactivity to rnaintain the regio-

selectivity in step-wise reactions.

b) A template should be synthesized fiom a commercially available inexpensive

substrate.

c) The preparation of the template shouId be convenient and reaction conditions must be

amenable to large-scale productions.

In the light of these properties, the designed template can be used in cross-

coupling reactions to provide a structure with a defhed stereochemistry of the double

bond,

1.5. Cross-coupiing Reaction

Cross-coupling reactions of organometallic reagents with an alkenyl halide is one

of the best methods to form a carbon-carbon single bond (Scheme 5). There are different

cross-coupling reactions, which can provide carbon-carbon bond formation, such as the

~uzuki ; ~ e c k , ~ ~ or Stille 29 reactions.

Different organometallic reagents have been applied in the cross-coupling

reactions. ~ o ~ ~ e r , ~ ' nickel:' m a g n e s i d and titanim3' 33 c m be used in the

preparation of organometallic reagents and have shown good results in synthesis. These

organometallic intemediates undergo Ni situ transmetallation with their cross-coupling

partner followed by a reductive elirnination where the rnetal is released back into the

catalytic cycle and the carbon-carbon bond forms.

A wide range of transition-metal catalysts have been used (such as Pd, Ni, Pt, Rh,

Cu) and a variety of cross-coupkg partners like ~ r ~ a n o r n a ~ n e s i u m , ~ ~ ~ r ~ a n o c o ~ ~ e r ~ ~

32.33 organoboron? ~ r ~ a n o z i n c ? ~ organonicke13' and organotitanium have been reported.

The vast research in this field allows tuning the reaction-conditions and template-

functionality so that the method can be adjusted to suit a large nurnber of target

molecules. The reactivity of nucleophilic coupling partners c m be tuned with synthetic

precision by changing the metal involved.

1.6. Organoboranes as Coupling Partners For The Olefin Template

Many organometallic reagents undergo cross-coupling reactions, but much

attention has recently been focused on the use of organoboranes by researchers in

university and industrial laboratories. These reagents are generally thermally stable and

inert to water and oxygen, thus allowing their handling without special precautions.34

Allcenylboronic acids show high reactivity towards the alkenyl halides, These

boronic acids can be prepared f?om the hydroboration of alkynes (Scheme 6). The

hydroboration of terminal alkynes with stoichiometric arnounts of hydroborating

reagent gives the predominant formation of the corresponding E-trialkenylborane. The

hydroboration usually gives the alkenyl borane with the boron moiety on the less

hindered end of the triple bond.35

Scheme 6

The choice of catalyst is another important aspect in cross-coupling reactions.

The cross-coupling reaction of organoboranes with haloaikenes proceeds best in the

presence of the catalytic amount of a palladium cataiyst ( S d reaction).

1.7. Role of Palladium Catalysis in Cross-coupiing Reactions

The importance of palladium chemistry was recognized in 1958 when Walker et

ai. introduced palladium metal as the solution for a much-needed hydroformylation

r e a ~ t i o n . ~ ~ Gradually palladium as a catalyst, became the choice of chemists for industrial

as well as academic purposes. The preference of palladium metal in cross-coupling

reactions to other transition metals for exarnple Ni, Rh and Pt, is widespread. Early

research on Pd-catalyzed cross-couplhg reactions mainly focused on the solubility issue

of heterogeneous c a t a ~ ~ s i s . ~ ~ In the case of Pd, the problem was minimized since several

Pd salts or ligated species have been found to be water-soluble.37 Another important

aspect of choosing Pd is its electronic configuration. Because of its electronically

saturated d'O conf~guration at its "0" oxidation-states, palladium is prevented from any

M e r reduction of the metal system. Thus the first step in the oxidative insertion of Pd

into an organic bond becomes a lot more unambiguous than other metals. A general

cycle of base-catalyzed

cross-coupling is shown in Figure 3.

In this cross-coupling reaction, the o bond in a haloalkene is activated by the

assistance of a metal-catalyst via an oxidative insertion process.

Figure 3. A general catalytic cycle for cross-coupling reaction

The oxidative addition of 1-alkenyl halides to a palladium (0) complex gives a

R ' - P ~ 0 - X intermediate which can be isolated. The reaction proceeds with cornplete

retention of configuration of this halide. This step is often the rate-determining step

in a catalytic cycle. The reactivity of vinyl halide in the reaction decreases in the

order of 1 > Br » The reductive elimination of the organic partner from

R'-~d @)-RI produces the palladium (O) complex and the desired product RI-R'."

Modem synthetic methods are now focused on the usage of palladium

catalysts. An example of a palladium-mediated reaction is shown in Scheme 7.39

ko-ms

Scheme 7

1.9. Importance of The Tandem Sequence

The word tandem means "in conjunction " which in the chexnical sense translates to a

sequence of reactions performed one after the other without the isolation of the

inter me dia te^.^^ The wide-spread popularity of tandem reaction sequences is probably

due to the fact that it reduces the labor-cost and enhances the efficiency of the synthesis

in A tandem sequence also reduces the amount of solvent required to

perfonn a reaction and purifjr the product. This c m be of great importance in industry,

where to produce a compound on a large scale, a large volume of solvent is required,

which then becomes the waste." However, to employ a complex reaction scheme in a

tandem sequence a few issues need to be resolved:

a) The reagents must react selectively, meaning one reagent must not interfere with

other functionalities that are present in the moiecule.

b) Chemicals used for the early steps must not inhibit or interfere in the later steps.

c) The reagents a d the reactive intermediates must be fairIy stable under the reaction

conditions so that the reaction proceeds cleanly.

1.10. Highlights of The Project

This research focused on the development of a tandem cross-coupling of alkenyl

halides and alkenyl metal to make polyenes and the application of the strategy to the total

synthesis of Astaxanthin B-D-diglucoside. The choice of alkenyl halide used in these

reactions is very important, so that it could be applied in the total synthesis of

Astaxanthin B-D-diglucoside (1). A suitable olefm (trans- 1-chloro-2-iodoethene)

template was synthesized for tandem Suniki reactions to prepare a range of olefinic

compounds. This tempIate, which contains two active sites, was used for selective cross-

coupling with alkenylboronic acids. A range of alkenylboronic acids was prepared via

the hydroboration of terminal a m e s using dibromoborane as hydroborating agent.

M e r the optimal conditions for these reactions were obtained, the olefin template tram-

1-chloro-2-iodoethene was used in the synthesis of Astaxanthin p-D-diglucoside (1). The

olefm template can be used several times to build the chah part of this natural product

via ~ 0 n o ~ a s h i 1 - a ~ ~ and carboal~mination~~' " reactions.

The ring part can be formed starting fiom 2,6-dimethylcyclohexanone (14). A

series of reactions can be applied to obtain the best alkenyl metal that can be coupled

with the olefin template. It was found that the alkenylboronic acid is the best coupling

partner for trans- 1-chloro-2-iodoethene (Figure 4). The conversion of starting material

2,6-dimethylcyc1ohexanone to vinylboronic acid was performed via formation of a vinyl

iodide intermediate using the Shapiro reaction. 46.47

Figure 4. Major disconnections for astaxanthin P-D-diglucoside

CHAPTER TWO

Synthesis of the Conjugated Polyenes

2.1. Synthesis of the Olefin Template

Polyenes were prepared via cross-coupling reactions of an akenyl halide and

organometallic reagents. This demanded first the preparation of a suitable alkenyl halide

as the olefin template. Trans-1-chloro-2-iodoethene was prepared and applied in the

synthesis of polyenes. Having two halogens with different reactivity gives the ability to

build the olefin A via cross-coupling of organometallics RM and R'M', respectively

(Scheme 10).

Scheme 10

Compound 2 was obtained by slowly bubbling acetylene gas (4) into an acidic

solution of ICI (3) at ambient temperature (Scheme 1 1).49

6N HC1 ICI i- --

O O c T

Scheme 11

The assignment of configuration (E) was c o n f i e d by the c o u p h g constants of

tram-vin ylic pro tons (J = 1 4 Hz).

To build the C-C single bond in a polyene chah, the coupling of different

organomatallics with compound 2 was investigated. Organomagnesium and

organoborons were coupled with compound 2. The results indicated that cross-coupling

of organoboronic acids (Suniki) happens smoothly in the presence of the small amount of

Pd-based catalyst and gives a better yield than Grignard reagents catatyzed with Ni

(Scheme 12).

2, Pd (0) ,THF R-B(OW2

base, 60 OC R*Cl

5 R= Ph, para-OMe-Ph (68 %)

Scheme 12

Reaction of organoboron reagents with 2 was also found to proceed smoothly

when the reagents were activated with aqueous bases, and gave the product in better

yields.

The next attempt was to develop a rnethodology that works selectively with the

olefin template and to produce a series of substrates (alkenylboronic acids) for this study.

2.2. Synthesis of the Alkenylboronic acids

Although several methods for the synthesis of aikenylboronic acids are available,

the hydroboration of terminal a i m e s is one of the best methods to make vinyl boronic

a ~ i d s ? ~ This reaction is especially valuable for the synthesis of stereodefined or

functionalized alkenylboronic acids and their esters.

Three different reagents, catechol-borane." diisopinocampheny lborane

[ (T~C)~BW~' and halob~ra.nes '~*~~ were used to make these boronic acids (Scheme 13).

In the first method, terminal allynes were hydroborated with catechol-borane to

produce 1-alkenyl esters. These esters were then converted to boronic acids by

hydrolysis. The presence of catechol, produced during the hydrolysis, was a

contaminant in the boronic acid products. Thus the reaction of (?l?C)aBH and haloboranes

were examined with a m e s . The best hydroboration results were obtained using

dihaloborane, and in particular dibromoborane (Table 1). This reagent exhibits extremely

high reactivity toward akenes and allcynes, allowing the hydroboration to proceed at low

ternperatures.

Scheme 13

Table 1 shows the reaction conditions and yields for different aikynes.

In th is method, a slight excess of allcyne was utilized to prevent dihydroboration.

Many of the akenylboronic acid products exist in solid form and are hygroscopic. The

hydroboration of the aikynes resulted in single products on which the boron moiety is in

the least sterically hindered place and these were confirrned by spectroscopie methods.

The coupling of these boronic acids with the olefm template were examined.

Reaction

a R=C,H,, . tert-butyl- b R=C5H, 1

R=C&Ig- R=Ph- c X=Br C3H7- Ph- ca9-

c6H13' t-butyl- CH2Cl- HO-CH2- TBDMSOCH2- MeO-Ph-CH2-

Solvent

THF

DCM

Yield (%)

Table 1. Results and conditions for the synthesis of boronic acids

2.3. Tandem and Independent Cross-couplings of Organoboranes With

The Olefin Template

A series of Su& reactions were performed on cornpound 2 using the optimized

condition of 3-7 % of Pd catalyst and sodium or potassium hydroxide in refluxing THF.

lndependent sequence 7 KOH, Pd(F'P6j)4 (3-7%)

R- B(O& * &Cl THF, 60 OC, 8 hours R

R'-B(OW2 KOH, Pd(PP6j)4 (3-7%) &R' * R

THF, 70 OC, ovemight

Tandem sequance I

L ITP, 60 OC, 8 hours ' THF, 70 OC, ovemight

R- B(OH)2 &Cl 1

KOH, pd(PPl~)~ (3-7%)

Scheme 14

Different boronic acids were examined in these cross-couplings using tandem and

independent sequences. In the independent sequence, the resulting product of the f ï s t

cross-coupling was isolated and purified for the second cross-coupling, while in the

tandem sequence, the product of first cross coupling was not isolated, but rather carried

through the second coupluig. Scheme 14 shows the general method of these couplings.

In these reactions after completion of the first cross-coupling, the second alkenylboronic

acid was added to the same pot, along with a fiesh batch of catalyst and base and heated

to reflux. The results obtained fiom tandem reactions are comparable with sequential

ones (step 1 yield x step 2 yield) (Table 2).

&Cl R

K-B(OW2 - &R' KOH, Pd(PPq)4 (3-7%)

By changing the sequence of the boronic acid addition, the ease of the separation

of the product and yield would change. It should be noted that, for the one-pot c o u p h g

sequence to work, attention must be given to the order of addition. Sorne examples are

shown in Schemes 15, 16 and 17. For exarnple, if the coupling starts by the addition of

octenylboronic acid (10) to cornpound 2 and then coupling of 4-methoxyphenylboronic

acid (9b), the isolation of the fmal product (11) as a clean cornpound is difficult. By

changing the order of addition, compound (11) can be purified more easily, resulting in

higher yield (Scheme 16). This c m be due to the reactivity of the first boronic acid

chosen for couphg. If this boronic acid is very reactive, the chance of its coupling with

the chlorine site is higher, and therefore bis-couplîng products will be groduced during

the first reaction. Less reactive boronic acids can diminish the formation of these

byproducts while being reactive enough for the formation of first intemediate.

Sequence A u P-M~O-P~-B(OH)~

KOH, Pd(PPh3)4 (3-7%) KOH. Pc~(PP$)~ (3-7%)

THF, 60 OC. ovemight THF, 65 OC, overnight Me0

KOH. Pd(PPh3)j (3-7%) - THF, 60 OC. overnight

OMe

9b

Scheme 15

* Tandem and independent yields are shown in table 2.

Ph-B(OW2 KOH, Pd(PPh3)4 (3-7%)

THF, 65 OC. ovemight - MeO Q""

Once the structure o f the polyenes were confirmed by spectroscopie methods, the

methodology was applied in the synthesis of natural product (1).

Sequenee A O Pd(PPbl4 (3-7%). THF.

-eco% + 2 KOY 60 OC. overnight

Pd(PPh), (3-7%). T'HF, - KOH, 65 OC. ovemight

M e 0 I I

Sequence B n

OMe t Sb J

Scheme 16

* Tandem and independent yields are show in table 2.

Sequence A n -B(OB(OH +

Pd(PPb)4 (3-7%). THF, C

KOH, 60 OC. overnight

Ph-B(0W Pd(PPh3)j (3-7%). THF,

* KOH, 65 OC. overnight

Sequence B C I

+ 2 KOH. 60 OC. ovemight

8 Sa

Scheme 17

Octenyl boronic acid pd(PPt~ )~ (3-7%). THF

KOH, 65 OC, ovemight

Table 2. Results for tandem and independent reactions

Summary

The olefin template pans-1-chloro-2-iodoethene (2) was prepared fiom the

reaction of acetylene gas and ICI (3). This cornpound was subjected to tandem cross-

couplings with alkenylboronic acids to provide olefinic structures. The akenylboronic

acids with (E) conformations were prepared fiorn the reaction of hydroborating reagents

with terminal -es. Among different hydroborating reagents for hydroboration,

dibromoborane-dimethylsulfide complex gave the best results. Cross-coupling reactions

gave the highest yield in the presence of 3-7% palladium catalyst and an aqueous solution

of potassium or sodium hydroxide in refluxing THF.

Tandem experiments were applied to the o l e k template and it was found that the

order of the alkenylboronic acid addition is very important. Reactive alkenylboronic

acids in the fnst cross-coupling reduce the regioselectivity of the reaction as they rnight

also react on the chlorine site to fonn the bis-coupling product.

The yields ftom tandem reactions are comparable with the overall yield for

sequential reactions, which makes it possible to use the tandem strategy in the synthesis

of natural product.

CHAPTER THREE

Application of the Tandem Strategy to the Total Synthesis of

Astaxanthin p-D-diglucoside

Introduction

The second part of this project focuses on the first total synthesis of astaxanthin P-

D-diglucoside (1). The strategy of tandem synthesis can be applied in the preparation of

this compound, using the sarne o le f i template, tram- 1-chloro-2-iodoethene (2).

3.1. Retrosynthetic Analysis

The synthesis of astaxanthin P-D-diglucoside (1) involves a series of cross- coupling

reactions requiring complete control of regio- and stereochemistry of double bonds in the

polyene chain. The retrosynthetic analysis leads back to two key intermediates, tram- 1 -

chloro-2-iodoethene (2), a substrate for selective palladium- catalyzed cross-coupling

reactions, and 2,6-dimethylcyclohexanone (14). The symrnetry in this natural product

gives the ability to use 2 several times to construct the polyene chain via a series of

stereo- and regioselective cross-coupling reactions with boronic acids

and akynes. The one-pot methodology described in the previous chapter is ideal to get a

desired product with good yield while it reduces the time, waste and cost associated with

the synthetic chemistry.

Disco~ections on Cls- Cl4 and Cis*- Ci4 of the chah part allows one to use

pans-1-chloro-2-iodoethene (2) as the key building block (Figure 5).

Figure 5. Setective synthesis of alkene

The ring part of the h a 1 product c m be obtained fiom a metalated target starting

fiom 2,6- dimethylcyclohexanone (14). Compound 14 can be then converted to the

intermediate 17 via a series of reactions. The intermediate 17 then will be cross-coupled

to trimethylsilylacetylene under Sonogashira coupling condition^!^ Allylic oxidation5'

and a-hydroxylation52 following the TMS group removal would provide intermediate 18.

Carboalumination of 18 with trimethylaluminum and an organozinc reagent will provide

the methylated diene 19 with the desired stereochemistry. By repeating the coupling of

13 to the metaiated compound 19 foilowed by the TMS group removal, and

carboalumination again, compound 20 would be obtained. Two equivalents of compound

20 with 2 in the same pot, would give the natural product of interest (Scheme 18).

Scheme 18

3.2. Synthesis of the Polyene Chain Key Intermediates

The synthesis of the centrai part of the astaxanthin compound consists of the

synthesis of compound 2 as the binder of two identical parts and the chloro-enyne 13,

which can be made fiom the same compound 2. Compound 13 can undergo M e r

cross-coupling to intermediate 19 to provide compound 20.

The first attempt was to obtain the chloro-enyne 13a, which does not contain the

TMS moiety, but M e r studies showed that due to its volatility, the isoIation of 13a is

difficult.

To make compound l3a, lithium acetylide (21) was coupled to compound 2

(Scheme 19). Therefore, lithium acetylide was transrnetaiated with dry zinc chloride and

provided intennediate 22. Transmetalation was pex5ormed by sonication and the

resulting intermediate was coupled with compound 2 in the presence of a pailadium

catalyst. The reaction was examined in different solvents and only proceeded (50%) in

THF. The boiling point of the product is close to that of TEIF and, thus, it was difficult to

isolate the product in good yield.

- - Li ZnC12 ,solvent - r- t, 1-2 h

21 sonication

2, 4% 4 solvent, r. t-, overnight Cl d

13a

Scheme 19

In the second method the Sonogashira coupling of compound 2 with a m e s was

exarnined. Allqne 23 was coupled with 2 and the method was applied in the reaction of

the olefin template with TMS-acetylene. This provided product 13 which has a higher

boiling point than 13a, and which is easier to handle and isolate (Scherne 20).

r// 2,4%CuI, 4%Pd(PPbI4

/ Piperidine , EtrO. 40 OC. 6h Me0

Piperidine, Et20, 40 OC, 8h 25 13 (70 %)

Scheme 20

To rernove the TMS group, compound 13 was reacted with different bases and

provided 13a (Scheme 2 l).". " The best results were obtained using potassium fluoride

as a base. However, the volatility of the product and its susceptibility to polymerization

forced the abandonment of the preparation of compound 13a. Instead, atternpts were

made to couple 13 directly to the end group, planning to remove the TMS group later.

TBAF

1

Scheme 21

3.3. Approaches toward the Synthesis of the Ring Key Intermediates

The synthesis of the ring part began by using 2,6-dirnethylcyclohexanone (14),

which is inexpensive and commercially available. It was decided to examine several

pathways in order to get the desired ring moiety.

It was considered that the organometal species (25) provides suitable candidates

for cross-coupling reactions with compound 2. This allows us the generation of these

species via a general method shown in Scheme 22.

Scheme 22

A methyl group was introduced on the starting material 2,6-dimethyl-

cyclohexanone as described in Scheme 23. In this way, ketone 14 was fkst deprotonated

using LDA and the resulting enolate was quenched with excess methyl iodide at O O C .

The existing carbonyl moiety can be used to f o m the olefinic conjugation in the ring.

The enolate of IS reacted with diphenyl disulfide producing thio-ether 26

(Scheme 23). The formation of double bond was effected by oxidation of 26 using Na104

in situ and heating the resulting sulfoxide 2 P 5 This provided the desired enone 28, but in

low yield (10-15%). The yield of 28 was poor, so a new method for its preparation was

attempted.

1) LDA, -78 OC. THT, Ih 1) LDA, -78 OC, THF, Lh

2 ) Me1 (excess), O OC 2) Ph-S-S-Ph, O O C

14 15

es-ph 26

(93%) (-70%)

Scherne 23

In the second method, the desired unsattmted structure was produced by

introducing bromine on the starting ring and then elirninating HBr. Cornpound 30 is a

mild and effective reagent which introduces bromine on carbon even on hindered sites in

good y ie~ds .~~ ' 57 It was made by the addition of sodium hydroxide to 1,4-dimethyl-2,s-

dioxane (29) (Meldrum's acid) at O OC and then slow addition of bromine to the mixture

(Scheme 24). Addition of 30 to the ketone 15 in CC4 at 70 O C provided bromo-ketone 31

in 85% yield. Compound 31 was then heated in the presence of LiBr and Li2C03 and

converted to enone 28 in 70% yield (Scheme 25). 58, 59

Scheme 24

I) LDA, -78 OC, THF

2) Me1 (excess), O'C

LiBr, L5CO3, DMSO

i 15 OC, 12 h

Scheme 25

The next objective was to fom the remaining hydroxy ketone on the ring (compound 24).

Thus, the extended enolate form of compound 28 formed using LDA and it was quenched

with diethyl c h l ~ r o ~ h o s ~ h a t e ~ ~ (Scheme 26). In uis way the desired double bond was

formed on the ring (compound 32). It was found that the yield of the reaction was

enhanced dramatically when HMPA was used to solvate the lithium base.

O II

O-P-(O-Et), L) LDA, HMPA, THF, -78OC

2) O II

28 Cl-P-(O-Et)2 ->O/ 32

(70%)

Scheme 26

To make the chiral alcohol, the synthesis of optically active building blocks which

can be achieved via asymmetric hydroboration was examined. In this mode1 study,

compound 32 reacted with diisopinocamphenylborane, that was made in situ by the

reaction of two equivalents of the optically pure isomer of a-pinene and a borane-

dimethyl sulfide cornplex, which gave alcohol24a (Scheme ~ 7 ) . ~ ' Heating the reaction

was necessary, as no reaction was observed between diisopinocamphenylborane and the

en01 phosphate at room temperature.

Scheme 27

The en01 phosphate was also examined to give a dihydroxyl compound via

dihydroxylation using osmium tetroxide as a hydroxylating reagent!' Reaction of 32

with a catalytic amount of osmium tetroxide and N-methyl morpholine oxide (NMO)

gave the desired dihydroxylated product (Scheme 28). These studies confinned that we

could introduce chirality on the ring. So the reactivity of the en01 phosphate in reactions

was exarnined.

Scheme 28

To continue the rest of the synthesis, the reactivity of en01 phosphate 32 was

examined in coupling with di fferent partners.

3.3.1 Evaluation of En01 Phosphate Reactivity

33.1.1 Reaction with Grignard Reagent

It is well lcnown that en01 phosphates are good cross-coupling partners for

Grignard reagents? In this study, compound 32 was exarnined to react with the

Grignard reagent generated fiom enyne 13 and rnagnesium (Scheme 29). This reaction

did not provide the desired product. It was believed that the conversion of 32 to an

organotin moiety would provide a more reactive compound for the cross-coupling.

Ether

," 1

M g + CI 13

Scheme 29

3.3.1.2 Conversion of en01 phosphate to organotin

Compound 32 was examined to react with hexabutyldistannane in the presence of

a Pd catalyst. In spite of heating and increasing the reaction t h e , no coupling was

observed. The lack of reactivity could be caused by the stencally encumbered butyl

group on the tin reagent (35). However, the reaction of compound 32 with

hexamethyldistannane (36), which has smaller alkyl group, also did not provide the

desired intermediate (Scheme 30). These series of experiments involving 32 indicaieci

that the reactivity of the en01 phosphate is low, thus the approach was changed.

Scheme 30

Since the e n d phosphate 32 was not sufficiently reactive, the formation of vinyl

borate 41 fiom ketone 15 was considered. This compound can be prepared fiom the

related vinyl halide via halogen-metal exchange. Vinyl iodides have shown the best

results in cross-coupling (chapter two14 or halogen-metal exchange reactions. Vinyl

iodide 38 was prepared from a reported modification of Barton's procedure." The

hydrazone 37 obtained fiom ketone 15 was converted to vinyl iodide using two

equivalents of iodine in the presence of excess 1,8-diazabicyc~o[5.4.0]undec-7-ene

@BN) as base (Scheme 3 1). The resulting oil was confirmed to be vinyl iodide (38)

using spectroscopic methods.

The reactivity of this iodide was then determïned by treatment of this target with a

mode1 octenylboronic acid in the presence of a palladium catalyst. This reaction

produced the cross-coupled product in high yield, indicating that the iodide is reactive

despite being hindered.

EtOH, 100 OC, 2 days

Scheme 31

Compound 38 could aIso be converted to an organostannane to serve as a

coupling partner for compound 2. Since it has been reported that the Suzuki coupling is

more tolerant of steric effects than the Stille c o ~ ~ l i n ~ , 6 ~ the vinyl iodide product was

converted to a vinylboronic ester rather than the correspondhg stannane. Keay et al.

reported the cross-coupling reaction of aryl and vinyl halides with in situ-generated

organoboronates, 67 obtained by treatrnent of the orgrnolithium precursor with

triisopropylborate. To diminish the number of steps in this method, it was decided to

46,47 prepare the vinyllithium derivative of compound 15 ushg the Shapiro reaction

startïng from the corresponding triisopropylbenznesulphonyl (TRIS) hydrazone (Shapiro-

Suzuki). 67 Therefore, compound 39 was prepared by the reaction of ketone 15 and

TRIS-hydrazone. Compound 39 was then reacted with two equivalents of tert-butyl

lithium to produce 40 which was then quenched with triisopropyl borate. The resulting

ester was directly cross-coupled with compound 2 in the hope of generation of the desired

product. The reaction of ester 41 with compound 2 did not provide the cross-coupled

product 42 (Scheme 32). So the methodology was continued using vinyl iodide as the

key intermediate (compound 38).

Scheme 32

The same procedure was applied to vinyl iodide 38. It was treated with 2

equivalents of tert-butyl Iithium and the resulting vinyllithium quenched with triisopropyl

borate, To modie the previous method, the boronic ester was hydrolyzed in situ with

concentrated sodium hydroxide and then coupled with compound 2 in the presence of

palladium catalyst. This produced the desired product 42 in 55% overall yield starting

fiom 38 (Scheme 33).

10 equiv. NaOH,

[IO NJ, r* t., 2 h

2, Pd(PPh3)4 *

THF, reflux

Scheme 33

It is believed that the reactivity of the boronic acid (43) in the cross-coupling

reaction with compound 2 is considerably higher than that of boronic ester 41.

With some of the critical questions answered, the future synthetic pathway should

be possible following the route laid out in Scheme 34. The one-pot synthesis strategy

will be applied to compound 19 to fom the desired natural product in several steps.

I I

Hydroxylation - O

1 Carboalumination

Scheme 34

Summary

The retrosynthetic analysis of the natural product Astaxanthul B-D-diglucoside

leads back to two key targets, lrans- l -chlore-2-iodoethene (2) and 2,6-dimethyl-

cyclohexanone (14). Intermediates for the total synthesis were prepared fiom these key

targets. Trans-1-chloro-2-iodoethene, was used to prepare the olefinic chah intermediate

via coupiing with TMS-acetylene (Sonogashira coupling).

The synthesis of the ring part was atternpted with the formation of a hydrazone

intermediate via the Shapiro reaction. The hydrazone was converted to alkenylboronic

acid and coupled with trans-1-chloro-2-iodoethene. This intermediate can be converted

to the ring part in several steps. M e r the preparation of the ring part, the one-pot

synthesis of the molecule will be applied.

CEFAPTER FOUR

Experimental Section for the Synthesis of Dienes : Tandem and

Independent Studies

General Procedure. Al1 reactions were carrïed out under a positive atrnosphere of dry

nitrogen. Solvents were distilled pnor to use. Et20 and THF were distilled fkorn sodium

and benzophenone; CH2C12 was distilled fiom CaH2. Anhydrous dimethylforrnamide and

anhydrous dimethylsulfoxide were purchased from Aldrich and stored under a nitrogen

atmosphere. Flash chromatography was performed using Whatman 230-400 silica gel 60.

Thin layer chromatography (TLC) was carried out on Merck silica gel 60 F254 pre-coated

glass plates, with detection by W light and permanganate solution. Melting points are

uncorrected. 'H NMR spectra were recorded in CDC13 at 400 MHz, and ')c NMR were

recorded at 100 MHz in CDC13. Chemical shifts are listed relative to CHClp (5 7.28) for

1 H NMR and (6 77.2) for 13c NMR. Low resoiution mass results were obtained with a

mass spectrometer at the Department of Chemistry, York University. High resolution

mass values were obtained with a high resolution mass spectrometer at the Department of

Chemistry, McMaster university. Elemental analyses were obtained at the Guelph

Chemicat Laboratones.

General procedure for preparation of (PPh3)4Pd

A mixture of 650 mg of trïphenylphosphine (2.4 mmol), 85 mg of PdCl2 (0.47 mmc!) and

6 mL dry dimethylsulphoxide was placed in a flame-drïed flask. The yellow slurry was

heated to 140 O C untir al1 the compounds were dissolved and a clear orange solution was

formed. The flask was removed fkom the heatïng bath and after 2 minutes, 0.1 rnL of

hydrazine hydrate (3.2 m o l ) was added drop-wise to the solution. Yellow crystals

were formed upon the addition of the hydrazine. The reaction mixture was cooled to

room temperature (r. t.), filtered and washed several tirnes with ether. The yellow

crystals were dried under vacuum at r. t. for one hour and filled with nitrogen providing

500 mg of (PPh&Pd as yellow crystals. Spectra corresponded to that previously

reported."

General procedure for the preparation of tram-alkenylboronic acids using

catechol-borane

One equivalent of alkyne in THF and one equivalent of catechol-borane was added to a

flame-dried flask, The solution was heated to reflux for 6 h. The reaction was monitored

by TLC. After completion of the reaction, the mixture was cooled to r. t. and 100 mL of

water was added. The white crystals were filtered and recrystallized fkom water to give

the tram-akenylboronic acid. Spectra corresponded to those previously reported. 35

General procedure for the preparation of frans-alkenylboronic acids using

diisocamphenylborane

To a flame-dried flask was added 1.06 eq of borane-dimethylsulnde in THE The solution

was cooled to O OC and 2.4 eq of a-pinene (dried over calcium hydride for 4 h and

distilled prior to use) was added slowly to the mixture and stirred for 1 h at the same

temperature. The mixture was s h e d for another 2 h at r. t. and the resulting white slurry

was cooled to -35 OC. One equivalent of aUcyne was added to the mixture drop-wise at

-35 O C and stirred for one h and then warmed to r. t.. The mixture was stirred for

another 2 h at r. t. and then cooled again to O O C . Distilled acetaldehyde (2.5 eq) was

added to the mixture at O OC. It was warrned to r. t. to and stirred for one h. To the

mixture was added 2 eq of water and it was heated at 55 O C for 3 h. It was cooled to r. t.

and the solvent was removed in vacuo. Hexane was added to the residue and the mixture

was stirred for 10 minutes. The resulting precipitation was filtered, washed several tirnes

with hexane and dried under vacuum to provide the alkenylboronic acid. Spectra

corresponded to those previously reported. 49

General procedure for the preparation of tram-alkenylboronic acids using the

dibromoborane-dimethylsulflde complex

To a flarne-dried flask was added 1.1 eq of akyne which then diluted with

dichloromethane. The solution was cooled to 10 OC and one equivalent dibromoborane-

dimethylsulfide was added drop-wise. After stimng for 4 h at 10 OC, the solvent was

removed in vacuo. The resulting oil was cooled to O OC and 2.2 eq of aqueous sodium

hydroxide was added to the solution to fonn a white solid. The mixture was stirred for 1

hour and water was added. The resulting crystals were filtered, washed severai tirnes

with water and dried under vacuum to give the alkenylboronic acid. Spectra

corresponded to those previously reported. 34.50

Acetylene was bubbled slowly into a dark solution of 8.1 1 g of iodomonochloride

(50 mmol) in 60 rnL of HCl(6 N) at O O C over 3 h. The reaction mixture was extracted 3

times with pentane. The extract was washed with sodium bisulphate and saturated NaCl.

It was dried over MgS04, concentrated Ni vacuo, and distilled to give 5.46 g (60%) of the

product as a pink liquid. Spectra corresponded to that previously reported?

bp= l M ° C

1 H NMR (CDC13, 400 MHz): 6.50 (d, J = 14 Hz, 1 H), 6.70 (d, J = 14 Hz,1 K) ppm.

13c NMR (CDCh, 100 Hz): 124.7,75.3 ppm.

frans-2-Chlorovinylbenzene (5a)

Method A:

Into a 25 mL flame-dried flask was added 99 mg of phenyl boronic acid (0.8 1 mmol), 2.5

mL of THF and 42 mg of tetrakis(ûiphenylphosphine)palladiurn (0) (0.036 rnmol). To

the solution was added 100 mg of trans-1-chloro-2-iodoethene (2) (0.53 rnmol) by

syringe, followed by the addition of 1.62 mL of KOH (1 M, 1.55 rnrnol). The mixture

was heated to reflux overnight and monitored by TLC, until no starting material was left.

The dark yellow solution was cooled to r. t., quenched with water, and extracted with

ether (2x10 mL). The organic layers were combined and dried over anhydrous MgS04.

Following the solvent rernoval in vacuo, the residue was loaded on the top of a pre-

packed silica gel column and flashed @entane, Rr= 0.58) providing 50 mg (68% yield) of

pans-2-chlorovinylbeozene (Sa) as yellowish oil. Spectra corresponded to that

previously reported?

1 HNMR(CDC13, 400 MHz): 7.38- 7.28 (rn, SH), 7.11 (d, J= 16 Hz, lH), 6.7 (d, J= 16 Hz, 1

Hl FPm-

I3c NMR (CDC13, 100 Hz, APT pulse sequence-evens down (-), odds up (+)): 135

(-), 133 (+), 128.9 (+), 128.3 (+), 126.0 (+), 118.0 (+) ppm.

IR (neat): 3028,2921, 1478, 1070,734, 692 cm-'.

MS (M+: 140, 138), 103, 83, 77,63,51.

Method B:

Into a 10 mL flame-dried flask was added O. 17 g of magnesium turnings (7.08 mmol) and

a stirring bar. The flask was flame-dried under vacuum and purged with dry nitrogen. To

the flask was added 0.9 g of bromobenzene (5.7 rnmol) followed by the addition of 5 mL

of THF and 8 pL of distilled dibromoethane as initiator. The reaction mixture was heated

until the cloudy gray Grignard reagent was forrned. To a separate flarne-dried flask

equipped with a stirring bar was added 0.1 g of nickel dichloride diphenylphosphino-

propane (O. 18 rnmol), 5 rnL of THF and the Grignard reagent was transferred to this flask

by cannula followed by the addition of another 5 mL of T m . To this flask was added

0.7 g of pans-1-chloro-2-iodoethene (2) (3.7 mrnol) by syringe. It was heated gently to

40-50 OC for 30 h. The reaction was monitored by TLC until the starting material was

consumed. The mixture was cooled to r. t., quenched wiîh water and diluted with 40 mL

ether. It was transferred to a separatory funnel. After shaking the flask, the layers were

separated and the aqueous layer fiirther extracted with ether (2x10 mL). The organic

layers were then combined and dried over anhydrous MgS04. Following solvent rernoval

in vacuo, the residue was loaded on top of pre-packed silica gel column and

chromatographed @entane, Rf= 0.58) providing 3 10 mg (50% yield) of bans-2-chloro-

vinyl-benzene (5a) as yellow oïl.

tram-1-(4-Met hoxypheny1)-2-p hen ylethene (8)

Method A (Independent):

h t o a 25 mL flarne-ciried flask was added 41 mg of 4-methoxyphenyl boronic acid (0.27

mmol) following the addition of 1.5 mL of THF and 30 mg of (PPh3)$d ( 0.025 mmol).

Trans-2-chlorovinylbenzene (Sa) (25 mg, 0.19 mmol) was then added neat by syringe

followed by the addition of 0.5 rnL of THF and 0.54 mL of KOH (1 M, 0.5 rnmol). The

mixture was then heated to reflux for 12 h. The reaction was monitored by TLC, until no

starting material was left. The solution was cooled to r. t. and quenched with water,then

diluted with 20 mL of ether. Then it was transferred into a separatory b e l . M e r

shaking the flask, the layers were separated and the aqueous layer extracted with ether

(2x10 mL). The organic layers were combined and dried over anhydrous MgS04.

Following solvent removal in vacuo, the residue was loaded on the top of a pre-packed

silica gel column and chromatographed (2% pentane: ether, Rr = 0.13) providing 30 mg

(70-8 1% yield) of trans-1-(4-methoxypheny1)-2-phenylethene (8) as a white solid.

Melting point: 82-83 OC.

1 H NMR (CDCl3,400 MHz): 6 7.49 (d, J = 8 Hz, 2 H), 7.45 (d, J = 8 Hz, 2 H), 7.37 (t, J

= 7.6 Hz, 2 H), 7.26-7.21 (m,l H), 7.05 ( d , J = 16 Hz, 1 H), 6.93 (d, J = 16 Hz, 1 H),

6.70 (d, J = 8 Hz, 2 H), 3.86 (s, 3H) ppm.

13 C NMR (CDC13,100 MHz, APT pulse sequence-evens down (-), odds up (+)): 160.0

(-), 138.0 (-), 130.8 (-), 128.8 (+), 128.3 (+), 127.9 (+), 127.4 (+), 126.8 (+), 126.4 (+),

114.3 (+), 55.5(+) ppm.

IR (mat): 3084,2954.3,2924, 17 15, 1606, 15 1 1, 1460, 1264, lOS2,96L, 797,739,706,

629 cm".

MS (M': 210), 195, 179, 165, 152, 139, 115, 105,83,71.

HRMS calcd for C15H140 210.104, found 210.103.

Method B (Tandem):

Into a 25 mL flarne-dried flask was added 68 mg of phenyl boronic acid (1.05 eq, 0.55

mmol), 2 mL of THF and 30 mg of (PPh3)4Pd (0.025mmol). To the resulting solution

was added 100 mg of tmns-1-chloro-2-iodoethene (0.53 rnmol) and 1.1 mL of KOH (1

M). The mixture was then heated to reflux for 12 h. It was monitored by TLC, until no

starting material was lefi- Then 120 mg of 4-methoxyphenylboronic acid (0.79 mmol),

30 mg of (PPh3)4Pd (0.00259 mmol) catalyst and 1.59 rnL of KOH (1 M, 5 mmol) were

added and the mixture was heated to reflux for 2 days. The reaction mixture was

monitored by TLC, until no starting matenal was lefi. After the completion of the

reaction, the dark mixture was cooled to r. t., quenched with water and diluted with 20

mL of ether. It was transfemed into a separatory b e l . After shaking the flash, the

layers were separated and the aqueous layer extracted with ether (2x10 mL). The organic

layers were combined and dried over anhydrous MgS04. Following solvent removal in

vanto, the residue was loaded on the top of a pre-packed silica gel column and

chromatographed (2% pentane: ether, &= 0.13) providing 56 mg of a white solid of

tram- 1 -(4-methoxypheny1)-2-phenylethene (8) in 50% yield.

Method B (Tandem):

Change in sequence

Into a 25 mL flarne-dried flask was added 84.6 g of 4-methoxyphenylboronic acid

(0.55 mmol), 1.5 mL of THF and 30 mg of (PPh&Pd (0.025 mmol). To the resulting

solution was added bons-1-chloro-2-iodoethene (100 mg, 0.53 mmol) and 1.1 mL of

KOH (1 M, 2.1 equivalents). The mixture was heated to reflux for 12 h. The reaction

was monitored by TLC, until no starting matenal was left. Then 96 mg of phenyl

boronic acid (0.79 mrnol), 10.4 mg of (PPh&Pd (0.0089 mmol) catalyst and 1.59 mL of

KOH (0.5 rnmol) were added. The mixture was heated to reflux for 2 days. It was

monitored by TLC, until no starting material was left. After the cornpletion of the

reaction, it was cooled to r. t., quenched with water and diluted with 20 mL of ether. It

was transferred into a separatory &el. M e r shaking the flash, the layers were

separated and the aqueous layer was extracted with ether (2x10 mL). The organic layers

were combined and dried over anhydrous MgS04. Following solvent removal in vacuo,

the residue was loaded on the top of a pre-packed silica gel column and chrornatographed

(2% pentane: ether, Rf = 0.13) providing 58 mg of trnns-1-(4-methoxypheny1)-2-

phenylethene (8) (5 % yield) as a white solid.

1-(2-C hloro-viny1)-4-methoxy benzene (5b)

into a 25 mL flame-dried flask was added 88 mg of 4-methoxyphenyl boronic acid

(0.57 mmol), 1.5 rnL of THF and 30 mg of ( l?Pl~~)~Pd (0.025 mmol). To the resulting

solution was added 100 mg of trans-1-chloro-2-iodoethene (0.53 mmol) and 1.16 rnL of

KOH (1 M). The mixture was heated to reflux for 12 h. The reaction was monitored by

TLC, until no starting material was left. The mixture was cooled to r. t., quenched with

water and diluted with 40 mL of ether. It was transferred into a separatory funnel. After

shaking the flash, the layers were separated and the aqueous layer extracted with ether

(2x10 mL). The organic layers were combined and dried over anhydrous MgS04.

Following solvent removal in vanto, the residue was loaded on top of a pre-packed silica

gel colurnn and chromatographed (pentane, RF= 0.15 ) providing 74 mg (90 % yield) of

1-(2-ch1orovinyl)-4methoxybenzene (Sb) as a yellow solid. (Yields varied with the

quality of starting materials and catalyst). The spectra corresponded to those previously

reported."

Melting point: 40 OC (decomposed).

1 HNMR (CDC13, 400 MHz): 7.25 (d, J = 8 HZ, 2 H), 6.88 (d, J = 8 HZ, 2 H), 6.79 (d, J =

14&, 1 H), 6.52 (d ,J= 14Hz, 1 H), 3.83 (s,3 H)ppm.

13 C NMR (CDCl3, 100 MHz, APT pulse sequence-evens down (-), odds up (+)): 159.7

(-), 132.8 (+), 127.8 (-), 127.5 (+), 116.5 (+), 114.3 (+), 55.5(+) ppm.

IR (neat): 2917,2844, 1689, l6SO,lSO3, 1455, 1240, 1027, 8 19 cm-'.

MS (M+: 170, L68), 153, 125, 1 18,99,89,75,63,51,39,28.

1-Chloro-1,3-decadiene (Sc)

Into a 25 mL flame-dried flask was added 107 mg of octenylboronic acid (0.68

mmol), 2 mL of THJ? and 42 mg of (PPh&Pd (0.036mmol). To the resulting solution

was added trans-1 -chlore-2-iodoethene (100 mg, 0.53 mmol) and 1.3 8 mL of KOH (1 M)

and the mixture was heated to reflux for 14 h. The reaction was monitored by TLC, until

no starting material was left. M e r completion of the reaction, it was cooled to r. t.,

quenched with water and diluted with 20 mL of ether. Then it was transferred into a

separatory funnel. Afier shaking the flash, the layers were separated and the aqueous

layer extracted with ether (2x10 mL). The organic layers were combuied and dried over

anhydrous MgS04. Following solvent removal in vacuo, the residue was loaded on the

top of a pre-packed silica gel column and chromatographed ('entane, RF = 0.84)

providing 70 mg of 1-chloro-1,3-decadiene (Sc) as a yellowish oil in 80% yield. Spectra

corresponded to those previously reported."

' H N M R ( C D C ~ ~ , ~ O O M H ~ ) : 6.41 (dd, J= 13, 11 Hz, 1 H),6.07(d, J = 13 Hz, 1 H),

5.96 (dd, J = 16, 10 Hz, 1 H), 5.68 (dt, J = 15,7 Hz, 1 H), 2.06 (m, 2 H), 1.37 (m, 2 H),

1.29 (m, 6H), 0.85 (t, J = 6.7 Hz ,3 H) pprn.

(E, E)-1-(4-Methoxypheny1)-13-decadiene (11)

Method A (Independent):

Into a 25 rnL flame-dried flask was added 132 mg of 4-methoxyphenylboronic acid (0.87

mmol), 1.5 rnL of THF and 42 mg of (PPh3)4Pd (0.036mmol). To the resulting solution

was added 100 mg of 1-chloro- 1,3-decadiene (5c) (0.57 -01) and 1.8 mL of KOH (1

M, 1.74 mmol). The mixture was heated to reflux for 14 h. The reaction was monitored

by TLC, until no starting material was left. After the completion of the reaction, it was

cooled to r. t., quenched with water and diluted with 20 mL of ether. Then it was

transferred into a separatory funnel. After shaking the flash, the layers were separated

and the aqueous layer extracted with ether (2x10 mL). The organic layers were

combined and dried over anhydrous MgS04. Foilowing solvent removal in vacuo, the

residue was loaded on top of a pre-packed silica gel column and chrornatographed (2%

pentane: ether, Rr= 0.12) providing 80 mg (57 % yield) of (E, E)-1-(4-methoxypheny1)-

1,3-decadiene (11) as a yellowish oil. 71

1 H NMR (CDCb, 400 MHz): 7.33 (d, J = 8-0 HZ, 2 H), 6.86 (d, J = 8-0 HZ, 2 H), 6.65 (dt,

J = 15.5, 10 Hz, 1 H), 6.41 (d, J = 16 Hz, 1 H), 6.20 (dt, J= 15.0, 9.9 Hz, 1 H), 5.81-5.78

(dt, J = 15.5, 7.5 Hz, 1 H), 3.83 (s, 3 H), 2.13 (q, J= 6.1 Hz, 2 H), 1.61-1.22 (rn, 10 H),

0.87 (t, J= 6.1 Hz, 3 H) ppm.

13 C NMR (CDC13, 100 MHz, APT pulse sequence-evens up (+), odds d o m (-)): 159.1

(+), 135.1 (-), 13 1.0(+), 130.8 (-), 129.6 (-), 127.7 (-), 127.4 (-), 114.0 (-), 55.4 (-), 33.1

(+), 3 1.9 (+), 29.5 (+), 29.1 (+), 22.8 (+), 14.3 (-) ppm.

IR (neat): 3052,2922,2852, 1697, 15 1 1, 1456, 1262,739 cm-'.

Method B (Tandem)

Into a 25 mL flame-dried flask was added 107 mg of octenylboronic acid (0.68

mmol), 3 rnL of THF and 30 mg of (PPh3)ad (0.025 mmol). To the resulting solution

was added 100 mg pans-1-chloro-2-iodoethene (0.53 mmol) and 1.38 mL of KOH (1 M)

and the mixture was heated to reflux for 14 h. The reaction was monitored by TLC, until

no starting material was lefi. Then 120 mg of 4-methoxy-phenyl boronic acid (0.79

mmol), 30 mg of (PPh3)ad (0.0259 mmol) catalyst and 1.58 mL of KOH (1 M, 1.5

mmol) were added. The mixture was heated to reflux for 24 h. The reaction was

monitored by TLC, until no starting material was lefi. After the completion of the

reaction, it was cooled to r. t., quenched with water and diluted with 20 mL of ether. It

was transferred into a separatory fuonel. M e r shaking the flask, the layers were

separated and the aqueous layer extracted twice with ether (2x10 mi,). The organic

layers were combined and dried over anhydrous MgS04. Following solvent removal in

v m o , the residue was loaded on the top of a pre-packed silica gel column and

chromatographed (2% pentane: ether) providing 96 mg of yellowish oil of (E, E)-L(4-

methoxypheny1)- 1,3-decadiene (11) in 74% yield.

(E, E)-1-Phenyi-13-decadiene (12).

Method A (Independent):

Into a 25 mL flame-dried flask was added 99 mg of phenyl boronic acid ( 0.8 1 mmol),

1.5 mL of THF and 42 mg of (PPh3)J'd (0.036 mmol). To the resulting solution was

added 200 mg of 1-chloro-1,3-decadiene (5c) (0.57 mmol) and 1.6 mL of KOH (1.62

mmol). The mixtue was then heated to reflux for 14 h. The reaction was monitored by

TLC, until no starting material was lefi. After the cornpletion of the reaction, it was

cooled to r. t., quenched with water and diluted with 20 mL of ether. It was transferred

into a separatory h e l . After shaking the flash, the Iayers were separated and the

aqueous layer extracted twice with ether (each time 10 mL). The organic layers were

then combined and dried over anhydrous MgS04. Foltowing solvent removal in vacuo,

the residue was loaded on the top of a pre-packed silica gel column and chromatographed

(2% pentane: ether), providing 70% yield of (E, E)- 1-phenyl- 1,3-decadiene (12) as

yeLlow oil.

'HNMR(CDCI~, 400 MHz): 7.38 (d, J= 7.5 Hz, 4 H), 7.19 (t,J=7.4 Hz, 1 H), 6.76

(dd, J = 15.6, 10.3 Hz, 1 K), 6.45 (d, J= 15.7 Hz 1 H), 6.21 (dd, J = 15.7, 10.5 Hz, 1 H),

5.84 (dt, J= 15.1, 7.3 HZ, 1 H), 2.16 (m, 2 H), 1.45-1.27 (m, 8 H), 0.99 (t, J = 6.7 Hz, 3

H) PPm-

"C NMR (CDC13, 100 MHz, APT pulse sequence-evens up (+), odds down (-)): 137.7

(+), 136.0 (-), 130.4 (-), 129.9 (-), 129.5 (-), 128.5 (-), 127.03 (-), 126.1 (-), 32.8 (+), 31.7

(+), 29.3 (+), 28 -9 (+), 22.6 (+), 14.1 (-) ppm.

IR (neat): 3054, 3027,2925,2855, 1680, 1455, 965, 749, 693 cm-'.

MS (M?: 214), 188, 154, 143, 129, 117, 91, 81, 67, 55,41.

HRMS calcd for C i6 HZ2 2 14.172, found 2 14.1 7 1.

Method B (Tandem):

Into a 25 mL flame-dried flask was added 142 mg of phenyl boronic acid (1.16 mrnol),

1.5 mL of THF and 61 mg of (PPh3)ad (0.053 mmol). To the resulting solution was

added 200 mg of pans-l-chloro-2-iodoethene (1 .O6 mmol) and 1.16 mL of NaOH (2N,

2.32 mmol). The mixture was heated to reflux for 8 h. The reaction was monitored by

TLC, until no starting material was left. Then 248 mg of octenylboronic acid (1 -59

mmol), 6 1 mg of (I?Ph&Pd (0.0053 mmol) catalyst and 1.59 mL of NaOH (2N, 3.1 8

m o l ) were added and the mixture was refluxed for 14 h. The reaction was monitored

by TLC, until al1 of the starting material was consumed. After the completion of the

reaction, it was cooled to r. t., quenched with water and diluted with 20 mL of ether. It

was transferred into a separatory b e l . After shaking the flash, the layers were

separated and the aqueous layer extracted twice with ether (20 mt each). The organic

Iayers were combined and dried over anhydrous MgS04. Following solvent removal in

vmuo, the residue was loaded on the top of a pre-packed silica gel column and

chromatographed (2% pentane: ether) which provided 1 18 mg of (E, E)- 1 -phenyl- 1,3-

decadiene (12) in 52%yield.

Method B (Tandem)

Change in sequence:

Into a 25 mL flame-dried flask was added 107 mg of octenyl boronic acid (0.68 mmol),

1.5 mL of THF and 42 mg (PPh;)4Pd (0.036 mmol). To the resulting solution was added

100 mg of tram- 1 -chloro-2-iodoethene (0.53 mmol) and 1.4 mL of KOH (1 M, 1.3

mmol) and the mixture was heated to reflux for 14 h. The reaction was monitored by

TLC, until no starting matenal was left. Then 97 mg of phenyl boronic acîd (0.79 mmol),

30 mg of (PPh3)8d (0.0025 mmol) and 1.58 mL of KOH (1 M, 1.58 mmol) were added

and the mixture was refluxed at for 24 h. The reaction was monitored by TLC. After the

completion of the reaction, it was cooled to r. t., quenched with water and diluted with 20

mL of ether. It was then transferred into a separatory funnel. After shaking the flask, the

layers were separated and the aqueous layer extracted with ether (2x10 mL). The organic

layers were then combined and dried over anhydrous MgS04. Following solvent removal

in van«>, the residue was loaded on the top of a pre-packed silica gel column and

chromatographed (2% pentane: ether), providing 73 mg of (E, E)-1-phenyl-1,3-decadiene

(12) in 65% yield.

Experimental Section For The Synthesis of Astaxanthin B-D-diglucoside

To a flame-dried 25 mL flask was added 0.103 g of compound 23 (0.58 mmol), 2 mL

THF, 0.1 g of 2 (0.53 mmol), 24 mg of (PPh3)J?d (0.02 mrnol) and 4 mg Cu1 (0.02

mmol). To this mixture was added 49 mg of piperidine (0.58 mmol) followed by the

addition of 1 mL of THF. The solution was heated to reflux for 6 h and monitored by

TLC. After completion of the reaction, it was cooled and quenched with water. The

organic compound was extracted with pentane (3x10 mL) and dried over MgS04. The

solvent was removed in vacuo and then the residue was loaded on the top of a pre-packed

silica colurnn and chromatographed (5% pentane: ether, RF= 0.27), providing yellow

liquid of 1 - ( 5 - c h l o r o p e n t - 4 - e n - 2 - y n y l o x y m e t h y l ) ~ (24) in 79 % yield.

1~NMR(CDCb,400MHz):7.28(d,J=8Hz,2H),6.88(d,J=8Hz,2H),6.56(d,J=

13 Hz, 1 H), 5.99(d, J= 16Hz, 1 H),4.52(s,2H),4.22 (s,2 H),3.81 (s,3 H)pprn.

13 C NMR (CDC13, 100 MHz, APT pulse sequence-evens up (t), odds down (-)): 159.4

(+), 130.9 (-), 129.9 (-), 129.3 (+), 113.8 (-), 113. 2 (-), 88.0 (+), 81.3 (+), 71.4 (+), 57.3

(+), 55.3 (-1 ppm.

IR (neat): 3 100,2924, 1700,1603, 1509, 1243, 1072,900,809,5 10 cm-'.

MS :m/e (hf: 236,235), 201, 171, 135, 121,99, 85, 84, 65,47.

Anal. calcd. for C13H~302Cl: 65.7 C, 5.5 1 W, found 66.5 C, 5.66 H

4-Chloro-1-trimethylsilyl-2-butene-1-yne (13)

To a flarne-dried 25 mL flask was added 0.4 g of compound 2 (1.12 mmol), 98 mg of

(PPh3)ad (0.08 mmol), 10 ml Et20 and 16 mg CUI (0.08 mmol). To this mixture was

added 0.3 mg of TMS-acetylene (3.39 mmol) followed by the addition of 0.289 g of

piperidine (3.39 mmol). The solution was heated to reflux for 6 h and monitored by

TLC. After completion of the reaction, it was cooled and quenched with water. The

organic compound was extracted with pentane (3x10 mL) and dned over MgS04. The

solvent was removed in vacuo and then the residue was loaded on the top of a pre-packed

silica column and chromatographed @entane RF O.9), providing a white solid of I-

chlor0-4-(trimethylsi1anyf)-but- l -en-3 -yne (13) in 70 % yield.

'H NMR (CDC13, 400 MHz): 6.60 (d, J= 16 Hz, 1 H), 5.96 (d, J = 16 Hz, 1 H), 0.18 (s, 9

H) PPm*

13 C NMR (CDC13, 100 MHz, APT pulse sequence-evens up (+), odds down (-)): 132.6

(-1, 113.1 (-), 80.0 (+), 65 (+), 1.8 (-) ppm.

IR (neat): 2959,2063, 1557, 1247,842,643 cm-'.

MS : d e m: 156, 155), 153, 138, 128, 107,99, 86, 77, 69,55,45,41,28.

2,2,6-Trimethylcyclohexanone (15)

To a flame-dried 25 mL fiask was added 0.12 g (1 rnrnol) of diisopropylamine and 5 mL

anhydrous THF. To the resulting solution was added 0.59 mL (1 mmol) of n-butyl-

lithium at O OC and the mixture was stirred for 3 0 minutes at the same temperature. The

reaction mixture was cooled to -78 OC and 0.126 g (1 mmol) of 2,6-

dimethylcyclohexanone was added. M e r stirring for 2 h, during which time the reaction

mixture reached r. t., it was quenched with 0.843 g (5 mmol) of methyl iodide. This

solution was stirred for 30 minutes and then the reaction mixture was quenched with

water and diluted with ether. The organic product was extracted with ether (2x10 mL) in

separatory funnel and dried over magnesium sulfate. The solvent was removed in vacuo

and then the remaining liquid was loaded to the top of a pre-packed silica column and

chrornatographed (pentane), providing 0.15 g (90 % yield) of light yellow oil of 2,2,6-

trimethy lcyclo hexanone (1 3."

'H NMR (CDCb, 400 MHz): 2.62-2.59 (m, 1 H), 2.02-2.0 (m, 1 H), 1.85-1.82 (m, 1 H),

1.73-1.69 (m, 1 H), 1.62-1.57 (m, 1 H), 1.53-1.49 (m, 1 H), 1.28-1.24 (m, 1 H), 1.14 (s, 3

H), 0.98 (s, 3 H), 0.94 (d, 3 H) ppm.

13 C NMR (CDC13, 100 MHz, APT pulse sequence-evens up (+), odds down (-)):

216.0 (+), 45.3 (+), 41.9 (+), 41 (-), 36.8 (+), 26.6 (-), 25.3 (-), 2L.6 (+), 15.0 (-)

MS :m/e @A+: 140), 122, 1 1, 97,82, 69,56,41,28.

2,6,6- Trimet hyl-2-p henylsulfany lcyclo hexanone (26)

To a flame-dried 25 mL flask was added 0.12 g (1 mrnol) of diisopropylarnine and it

was dissolved in 5 mL anhydrous THF. To the solution was added 0.59 mL of n-butyl

lithium in pentane (2.5 M, lmmol) at O OC. After stirring for 30 minutes the reaction

mixture was cooled to -78 OC and 0.14 g (1 rnmol) of 2,6,6-trimethylcyclohexanone was

added. The mixture was stirred for 2 h d u ~ g which time it was warmed to O OC and

0.436 g (2 mmol) of diphenyl-disulfide was added. The solution was stirred for one hour,

quenched with water and diluted with ether. The organic product was extracted with

ether (2x10 mL) in a separatory funne1 and it was dried over magnesium sulfate. The

solvent was removed in vacuo and the residue was loaded to the top of a pre-packed silica

column and chrornatographed (20 % pentane: ether Rf= 0.78 ), providing 0.173 g (70 %

yield) of the 2,6,6-trimethyl-2-phenylsulfanylcyclohexone (26) as a light yellow

'H NMR (CDCls, 400MHz): 7.34 (m, 5 H), 2.20-2.13 (m, 2 El), 1.99-1.92 (rn, 2 H), 1.69-

1.62 (m, 2 H), 1.57 (s, 3 H), 1.25 (s, 3 H), 1.12 (s, 3 H) ppm.

IR (neat): 2926,2859, 1689,1453, 1 127,1013,744 cm-'.

13c NMR: 21 1.1, 137.7, 129.8, 128,55.7,44.4,41.8,40.1,40.0,30.7,29.9,26.5, 18.1

P P -

MS 248), 218, 185, 163, 135, 123, 110,95,69,82,55.

Anal. calcd. for Ci5H200S. H20: 67.62 C, 8.3 1 H, found 68.04 C, 8.46 H

2-Brorno-2,6,6-trimethylcyclohexanone (31)

To a flame-dried 25 mL flask was added 0.1 g (0.7 mmol) of 2,2,6-trimethyl-

cyclohexanone, 3 -5 mL CCL and 0.2 1 5 g (7 mmol) of pure brominated Meidrum' s acid.

The mixture was stirred at 70 OC for 7 h. M e r completion of the reaction (TLC

monitoring) it was cooled and quenched with water. The organic compound was

extracted with ether (3x10 mL) in a separatory funne1 and dried over MgS04. The

solvent was removed in vacuo and the residue was loaded to the top of a pre-packed silica

colurnn and chromatographed (2 % pentane: ether Rf= 0.46) providing 0.14 g of 2-

bromo-2,6,6-trimethylcyclohexanone (89 % yield) as a colorless liq~id.74

1 HNMR (CDC13, 400 MHz): 2.43 (tr, 2 H), 1.92 (tr, 2 H), 1.85 (s, 3 H), 1.71 (m, 2 H),

1.5 1 (s, 3 H), 1.12 (s, 3 H) pprn.

13c NMR(CDC13, 100 MHz): 209.4, 62.7,44.5, 43.7, 39.8, 30.9,30.8,29.9,29.8,28.2,

28.1, 22.5, 18.6, 14.2 pprn.

MS: m/e (Mf: 21 8,220) 1 1 1, 95, 82,69,55,41.

2,6,6-Trimethylcyclohex-2-en-1-one (28)

To a flame, dried 25 mL flask was added 0.1 g (0.45 mol) of 2-bromo-2,6,6-

trimethylcyclohexanone, 0.089 g (1.2 m o l ) of dry lithium carbonate and 0.067 g

(7.7 mol) of anhydrous lithium bromide in 2.5 mL of dry DMSO and the mixture was

stirred at 115 OC for 12 h. The reaction mixture was quenched with water and the organic

compound was extracted with pentane (3x10 mL). In order to remove DMSO, the

organic layer was washed several times with water and dried over MgS04. The solvent

was removed in vacuo and then the residue was loaded on the top of a pre-packed silica

c o l m and separated with pentane, providing yellow liquid of 2,6,6-trimethylcyclo hex-

2-enone (28) in 70-80 % yield. The spectra corresponded to those previously reported.74

'H NMR (CDC13, 400 MHz): 6.62 (broad, s, 1 H), 2.32-2.29 (m, 2 H), 1.82- 1.79 (tr, 2 H),

1.76 (s, 3 H), 1.10 (s, 6H) ppm.

13c NMR (CDC13, LOO M a ) : 204.9, 143.7, 134.0,41.4,37,24.5,23.2, 16.6, 14.2 ppm.

1-[2,6,6-TrimethyIcyclohex-1,3-dienyl] diethyl phosphonate (32)

To a 25 mL flame-dried flask was added 0.072 g (0.7 mmoi) of diisopropylarnine and

3.5 mZ, of TIlF followed by the slow addition of 0.041 mL (2.5 M, 0.64 mrnol) of n-

butyllitium in pentane at O OC. The mixture was stirred for 30 minutes at that

temperature. The solution was cooled to -78 OC and 0.09 g (0.64 mol) of 2,6,6-

trimethylcyclohex-2-enone in 1 rnL HMPA was added. After çtimng for 3 h, during

which tirne the reaction mixture was warmed to -50 OC , O . 122 g ( 0.7 mol) of diethyl

chlorophosphate was added and it was stirred for 1 h. M e r completion (TLC

monitoring), the reaction was quenched with water and the organic compound was

extracted with ether (3x10 mL) in a separatory funnel. The collected organic layers were

dried over MgS04. The solvent was removed in vacuo and the residue was loaded to the

pre-packed silica column and was separated with 70% ether in pentane (Rf= 0.2),

providing yellowish liquid of 1 -[2,6,6-trimethylcyclohex- 13-dienyl] diethy 1 p hosphonate

(32) in 70% yield.

1 H NMR(CDClp, 400 MHz): 5.75 (d, J= 6 Hz,l H), 5.66 (m, 1 H), 4.16 (m, 4 H), 2.19

(s, 2 H), 1.78 (S, 3 H), 1.35 (t, 6H), 1.11 (s, 6H) ppm.

13 C NMR (CDCl3, 100 MHz, APT pulse sequence-evens up (+), odds down (-)):

iSO.1 (+), 128 (-), 122.5 (-), 116.3 (+), 64.05,64.01 (+), 41.3 (+), 25.0 (-), 22.6 (+), 16.5

(-1, 15.0 (-) ppm.

IR (neat): 2979,2928,1666, 1452, 1272,1146, 1036,966,809,774 c d

MS: d e (Mf: 274), 259,245,23 1,203, 185, 155, 120, IO5,9 1,77,53,4 1,28.

Anal. calcd. for Ci3Hu04P: 56.9 C, 8.54 H, found 56.54 C , 9.09 H

2,6,6-(TrimethyIcyclohexyiidene) hydrazone (37)

2,6,6-Trimethylcyclohexanone (0.1 g, 0.7 mmol) was dissolved into 4 mL absolute

ethanol and hydrazine hydrate (10 equivalents) was added to the solution. The reaction

was stirred at 100 OC until the starting material was consumed (2 days) and the solvent

and excess reagents were removed in vacuo. The resulting solid was then loaded to the

pre-packed columo and chromatographed (99: 1 ether: ûiethylamine), providing the 2,6,6-

(trirnethylcyclohexylidene) hydrazone (37) as a white solid in 85% yield.

Melting point: 43-45 OC.

'HNMR(CDC~~, 400 MHz): 5.75 (d, J= ,1 H), 5.60 (m, 1 H), 4.16 (rn, 4 H), 2.19 (s, 2

H), 1-78 (s, 3 H), 1.35(t, 3 H), 1.1 1 (s, 3 H) ppm.

13c NMR (CDC13, 100 MHz): 150.1, 128.7, 122.5, 116.3,64.0,41.3,25.6, 22.6, 16.5,

15.0 ppm.

IR (neat): 3352,3215,2925,2856, 1641, 1455, 1371, 1101,982,~ 16 cm-'.

MS:m/e (M? 154), 139, 122, 109,95, 81,72, 55,41.

HRMS calcd for C9H18N2 154.146, found 154.145.

2-Iodo-1,3,3-trimethylcyclohexene (38)

A solution of 2.05 g of I2 (2.1 equivalents, 8 rnrnol) in ether (1 0 rnL) was added drop-

wise to an ethereal solution of 0.6 g of 2,6,6-(trimethyl-cyclohexylidene) hydrazone (3 7)

(3.8 mmol) and excess of DBN (9.5 g, 60 mmol). As the reaction progressed, the

reaction mixture became turbid and by the end of the addition, a gummy brown layer had

separated. M e r 15 minutes of additional stirring, the reaction was partitioned between

ether and saturated NaHC03. The organic layer was collected over &CO3, filtered, and

concentrated in vacuo. The resulting dark red oil was then dissolved in benzene and

refluxed in the presence of DBN for 2.5 h whereupon, after cooling to room temperature,

the mixture was poured into ether and washed with 1 N sodium thiosulphate. The

organic layer was dried over &CO3, filtered and concentrated in vacuo to give red oil

which was then loaded to a pre-packed column and purifïed (pentane), providing pure 2-

iodo-1,3,3-trimethylcyclohexene (38) as a colorless oil in 70% yield (pentane Rf= 0.6).

1 H NMR (CDC13, 400 MHz): 2.12 (t, 2 H), 1.86 (s, 3 H), 1.67 (m, 2 H), 1.63 (m, 2 H),

1.09 (s, 6 H) ppm.

I3c NMR (CDC13, 100 MHz): 137.7, 117.5,39.6,38.0,33.8, 31.2,29.5, 19.6 ppm.

MS: d e (h.ic: 250), 235, 123, 108,93, 8 1,67,55,41,28.

IR (neat): 2959,2921, 1650, 1455, 1043,920 cm''.

HRMS calcd for Cs HisI 250.02 18, found 250.02 18.

2-(Trans-2-chloro,inyl)-1,3,3-trimethylcyclohexene (42)

To a solution of 50 mg of 2-iodo-1,3,3-trimethylcyclohexene (38) (0.2 mrnol) in ether at

-78 OC was added 0.23 mL of terr-butyllithium (1.7 M in hexane, 0.4 m o l ) drop-wise

and stirred for 20 minutes at that temperature. Triisopropyl borate (0.05 rnL, 0.22 m o l )

was added neat to the solution at -78 OC and stirred for another 20 minutes. It was slowly

warmed to the room temperature and stirred for another hour. To this solution was added

concentrated aqueous NaOH (10 equivalents. 10 M) and stirred for another hour. The

solvent was rernoved and 13 mg of (PPh3)4Pd (0 .O 1 mrnol) and 34 mg of tram- 1 -chlore-

2-iodoethene (0.18 m o l ) were added to this solution following the addition of THE It

was heated to reflux for a few hours until the starting material was al1 consumed. After

completion of the reaction (NMEt monitoring) the reaction was quenched with water and

the organic compound was collected using ether (3x 20 mL). The collected organic layer

was dried over rnagnesiurn sulfate, filtered, and concentrated in vacuo. The resulting

dark oil was loaded to the top of a pre-packed column and chromatographed @entane) (Rf

= 0.56), providing 20 mg of 2-(tram-2-chioroviny1)- 1,3,3-trimethylcyclohexene (42) as

yellow oil in 5560%.

i H NMR (CDCb, 400 MHz): 6.37 (d, J = 12 Hz, 1 H), 5.82 (d, J = 12 Hz, 1 H), 1.99 (t, 2

H), 1.69(s, 3H), 1.63 (m,2H), 1.48(mY2H), 1.07(s76H)ppm.

13 C NMR (CDC13, 100 MHz): 134.8 (+), 131.5 (-), 130.9 (+), 119.7 (-), 39.2 (+), 32.7 (+),

28.0 (-), 22.0 (+), 21.0 (-), 19.0 (+), 14.1(-) ppm.

IR (neat): 2929,2865, 1601, 1457, 1377, 1305,934, 8 1 1 cm

MS: d e (Mf: 186, 184), 169, 151, 133, 109,93,77, 65, 55,41,28.

HRMS calcd for CI ,H17Cl 184.10 1, found 1 84-10 1.

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