The Transannular Diels-Alder Reaction:Background and Applications

William MorrisLiterature PresentationSeptember 23 ,2003

What is a Transannular Diels-Alder Reaction? How does it compare with an Intramolecular Diels-Alder Reaction?

General Outline

Triene (or Diene) Geometry:TTT trienes: Application to (–)-oblongolideTCC trienes: Application to (+)-maritimolFuran Dienes: Application to chatancinTTC trienes: Application to Aphidicolin

Total Synthesis of (–)-Longithorone A (Shair)

Total Synthesis of (–)-FR182877 (Evans)

Total Synthesis of (+)-FR182877 (Sorensen)

I.

II.

III.

IV.

V.

The Transannular Diels-Alder Reaction

m

n TADA

A.B.C. [m.6.n]

Chemo-, regio-, and diastereoselectivities based on conformational restrictions

Applicable to tetrasubstituted dienophiles, alkyne dienophiles, and terminally substituted dienes

m

n*

**

*

Intramolecular DA is the acyclic version of the TADA

TADA Reactions of trans-trans-trans (TTT) trienes

Synthesizing macrocyles with 3 trans unsaturations is very difficultLow activation energy required for TADA step (rt to120 oC)

Me

R1

(TTT)

Me

R1 Me

H

HR1

MeR1

Me

H

HR1

H

Me

R1

R1

Me

H

Me

R1Me

R1

Application to (–)-oblongolide

OO

Me

H

HMe

(-) - oblongolide

TADAMe O

OMe

(TTT)

Me O

OMe

PhMe

refluxO

O

MeMe(-) - oblongolide

O

O

MeMe

OO

Me

Me

X

Begley, M.J.; Grove, J.F. J. Chem. Soc., Perkin Trans. 1 1985, 861-863

TADA Reactions of trans-cis-cis (TCC) Trienes

MeO

OMe

Me

E CN

CNOHCMe

HMe Me

E

O

Steps

OHMe

Me

HMeMe

HO

DMSO, H2O155 oC

Model studies reveal stereochemistry is governed by the nitrile substituent

MeO

TIPSO

Me

CN

MeO

TIPSO

Me

CN

Me CHO

NC

H

H

Me

OTIPS

Me

NC H

CHO

MeTIPSO

TIPSOMe

CNOHCMe

H

TIPSOMe

CNOHCMe

H

H

Toro, A.; Lemelin, C.-A.; Preville, P.; Belanger, G.; Deslongchamps, P. Tetrahedron 1999, 55, 4655-4684

(+)-Maritimol

TADA Reactions of Furan DienesTowards the Synthesis of Chatancin:

Me O

EHO

E

E

O

Me

HO

E

EE

O

MeHO E

EEDMSO:H2O

105 oC

E

EH

O

OH E

Me

E

EH

O

OH E

Me

90% 10%

Toro, A.; Wang, Y.; Deslongchamps, P. Tetrahedron Lett. 1999, 40, 2765-2768

TADA Reactions of trans-trans-cis (TTC) Trienes

Aphidicolin

Steps

Me CHO O

Me

TIPSO

NEt3, PhMe230 oC

Me CHOO

MeTIPSO

X

(81%)

Me

MeOH

HO

OH OH

Me

MeTIPSO

H

H

HOO

Me

MeTIPSO

CHO

H

H

O

+

(8%)

Me

MeTIPSO

CHO

H

O

Me

Me

CHO

O

TIPSO

Belanger, G.; Deslongchamps, P.; Org. Lett. 2000, 2, 285-287

O

H

MeO

Me

O

O

Me

O

O

Me

Me

OO

H

O

Me

(–)-Longithorone A

Intermolecular Diels-Alder followed by Transannular Diels-Alder

O H

M.E. Layton, C.A. Morales, M.D. Shair, J. Am. Chem. Soc. 2002, 124, 773

Ene-yne Metathesis Macrocyclization

OPOPMe

MeO

Me OP

OMeOP

Me

Me

Removable Atropisomer Control Element

MeO OP

POH

OP

Me

POH

OP

MeOMe

PO

A(1,3) Strain Disfavors These Rotamers

ene-yne metathesis

ene-yne metathesis

Synthesis of Paracyclophanes

BrMeO

Br OMe

TIPS I

Me

+

Zn0 THF0oC

Pd(PPh3)498%

MeO

OMe

MeTIPS

nBuLi, Et2O, -780CDMF, -780C - 350C

94%

1.

2. O

H

BBr3, CH2Cl2-78 - 23 0C

1.

TBSOTfiPr2Et, CH2Cl2

0 0C

2.

88% 2 steps

TBSO

OMe

MeTIPS

O

H

Common Intermediate for both Paracyclophanes

Paracyclophane Synthesis Continued...

TBSO

OMe

MeTIPS

O

H

MeI

TMSITBSO

tBuLi, 1 or 2, Et2O, -78 0C, ZnBr2, Et2O, 0 0C

premixed nBuLi/ (1S,2R)-N-methylephedrine 3, PhMe, 0 0C

TBAF, THF, 0 0C

1.

2.

HO

OMe

MeTIPS

OHMe

HO

OMe

MeTIPS

OH

OH

1 2

Model for Diastereoselectivity:

ZnA

R

O

O

N

Me Me

H

Ph

Me

ZnB

RR

H

Ar

PhNMe2

Me

OH3

H

91% ee

95% ee

Oppolzer, W.; Radinov, R. N. Tetrahedron Lett. 1991, 32, 5777-5780

HO

OMe

MeTIPS

OHMe

Paracyclophane synthesis continued...

5% Pd / BaSO4, quinoline1 atm H2 (1:1)

1-hexene: MeOH, RTHO

OMe

MeTIPS

OHMe

TBAF, THF0 0C - RT

HO

OMe

Me

OHMe

TBSClimidazole

DMF0 0C

63% over 3 steps

TBSO

OMe

Me

OTBSMe

TBSO

OMe

Me

OTBSMe

Macrocyclization

0.5 eq. (Cy3P)2Cl2RuCHPhethylene (1atm)

CH2Cl2, high dilution OMe

RO

Me

Me

OMe

RO

OR

OR

Me

0.5 eq. (Cy3P)2Cl2RuCHPhethylene (1atm)

CH2Cl2, high dilution

OTBSMeO

HTBSO

OTBS

Me

> 20:1

2.8:13.9:1 (E:Z)

LnRuPh

LnRuPh

LnRu CH2

H2C CH2

LnRu

LnRu

H2C

LnRu

CH2H2C

H

CH2CH2

catalyst

OTBSMeO

O

Me

H

Test of Biosynthetic Model

OMe

TBSO

Me

Me

+Me2AlClCH2Cl2-20 0C70%

OMe

TBSO

Me

Me

OTBSMeO

Me

H

O

OO

Me

Me

O

O

MeO

H

MeO

Me

O

O

Me

(–)-Longithorone A

RT

40 hours

H

O HOH

(–)-FR182877Evans

HO

OH

MeH

MeH

OMe O

O

Me

HBr

OR

H

H

MeOR

H

CO2Et

Me

O

H

Me

endo

TBSO

MeTBSO

CO2Et

OMe

OTBS

MeBr

TBSO

MeTBSO

B(OH)2

CO2Et

OMe

OTBS

Me

Br

Br

+

Alkylation

SuzukiCoupling

FR182877

I

Evans, D.A.; Starr, J.T. Angew. Chem., Int. Ed. 2002, 41, 1787-1790

Comparison to Hexacyclinic Acid

AcO

OH

MeH

HO2C

H

O

Me O

O

Me

H

OH

Hexacyclinic Acid

Common Relative and absolute configurations of the C6-C8 substituents as well as lower DEF ring system

Only stereochemical difference is ring fusion associated withe rings ABC

HO

OH

MeH

Me

H

O

Me O

O

Me

H

FR182877

A

C

D

E F

B

Synthesis of Fragments 1 & 2

H

OMe

OTBS

O N

O

Bn

O

Me

Bu2BOTf, TEA88%

OHMe

OTBSMe

O

NO

O

Bn

1. MeNHOMe/HCl, Me3Al, THF 96%2. TBSCl, im. 96%3. TsOH:nBu4NHSO4 (1:4), MeOH 89%

OTBSMe

OHMe

O

NMeO

Me

1. DMP

2. CBr4, PPh3, 74%

OTBSMe

Me

O

NMeO

Me Br

Br

H

OOTBDPS

O

N

(Bu)2BOMe

O

Bn

89%

O N

O

Bn

O

Me

OH

OTBDPS1. MeNHOMe/HCl, Me3Al, THF 97%2. HCCMgBr, THF 77%

H

OTBDPSOH

Me

OH1. TBSCl, im. 94%2. cat. Cy2BH, catecholborane then 1N NaOH 97% crude

BOTBDPS

OTBS

Me

OTBSHO

OH

3. DIBAl, THF dr > 20:1 98%

Diastereoselective syn reduction

1

2

O

Me

OH

OTBDPS

H

OTBDPSOH

Me

OH

DIBAL-H, THF dr > 20:1 98%

Model for syn reduction

H

Al

O

O

H

Me

H

R

RPO

Conformational Analysis:

R'

P = TBDPSR = isobutylR' = H

-H

Favored Disfavored

P = TBDPSR = isobutylR' = H

Al

O

O

R

R

HMe

H

OP

R'-H

Coupling of Fragments 1 & 2OTBS

Me

Me

O

NMeO

Me Br

Br

BOTBDPS

OTBS

Me

OTBSHO

OH

Pd(PPh3)4, Tl2CO3, 84%+

OTBSMe

Me

O

NMeO

Me

Br

OTBSTBDPSO

Me

OTBS

1. DIBAL, THF2. EDA, cat. SnCl2 3. TBAF, AcOH 64% 3 steps

OTBSMe

Me

O

Br

OTBSHO

Me

OTBS

EtO

O

1. I2, PPh32. Cs2CO377%, dr 1:1

CO2EtH

OMe

OTBS

TBSO

TBSO

Me

Me

Br

2

1

2 Carbon Homologation: Roskamp

OTBSMe

Me

O

H

Br

OTBSTBDPSO

Me

OTBS

EDA, cat. SnCl2

OTBSMe

Me

O

Br

OTBSTBDPSO

Me

OTBS

EtO

O

DCM

H

NN

O

OEt

NN

O

OEt

R H

OSnCl2

1,2 hydrogen shift

EDA

R

OSnCl2

OEt

OH

C.R. Holmquist, E.J. Roskamp, J. Org. Chem. 1989, 54, 3258

Mechanism:

NN

CO2EtH

OMe

OTBS

TBSO

TBSO

Me

Me

Br

CO2Et

OMe

OTBS

TBSO

TBSO

Me

Me

Br

MeTBSO

OTBSBr

O CO2Et

MeOTBS

Me

TBSO

OTBS

MeH

BrH

OMe TBSO

CO2Et

Me

H

Initiation of Cycloadditions

Ph2Se2O3TEATHF

RT to 50o

Initiation of Cycloadditions

CO2Et

OMe

OTBS

TBSO

TBSO

Me

Me

Br

CO2EtSe

OMe

OTBS

TBSO

TBSO

Me

Me

Br

PhO

SePhO

CO2EtH

R

CO2Et

OMe

OTBS

TBSO

TBSO

Me

Me

Br

PhSe

O

OSe

Ph

O

TBSO

OTBS

MeH

BrH

OMe TBSO

CO2Et

Me

H

Conclusion of the SynthesisHO

OH

MeH

MeH

OMe HO

CO2Et

Me

H

HF/MeCN, 89%Me3B3O3

[Pd(dppf)Cl2]Cs2CO3, DMF 80oC 71%

1.2.

TMSOK, THF

Mukaiyama's Reagent, NaHCO362% (2 steps)

1.

2.

HO

OH

MeH

MeH

OMe O

O

Me

H

FR182877NMe

ClI

Mukaiyama's Reagent

HO

OH

MeH

BrH

OMe HO

CO2Et

Me

H

Suzuki Methylation

Me3B3O3, [Pd(dppf)Cl2]Cs2CO3, DMF, 80 oC 71%

HO

OH

MeH

MeH

OMe HO

CO2Et

Me

H

LPd0 OxidativeAddition

PdBr

OB

OBO

B-

Me

MeMe

P(C6H5)2

P(C6H5)2

dppf

Base

transmetallation PdMe

+ OB

OBO

BBr

MeMe

ReductiveElimination

LPd0Me

+L =

L L

Fe

M. Gray, I.P. Andrews, D.F. Hook, J. Kitteringham, M. Voyle, Tetrahedron Lett. 2000, 41, 6237

Sorensen's Approach to (+)-FR182877

Me

MeHO

O

OO

Me

MeOHH

H

H

HH

(+)-FR182877

Me

MePO

O

Me

MeOPH

H

H

HH

RO O

PO

Me

MeTESO OP

OMe

OTMS

O

Ot-Bu

Me

Me

MeTESO OP

OMe

OTMS

O

Ot-Bu

Me

X

D.A. Vosburg, C.D. Vanderwal, E.J. Sorensen, J. Am.Chem.Soc. 2003, 5393-5407

Synthesis of MacrocycleTESO OTES

Me

MeSnMe3

OTES

OAc

MeOTMS

MeN

OOMe

Me

TESO OTESMe

Me OTES

MeN

OOMe

MeMe

OP

+

TESO OTESMe

Me OH

MeO

Me

OH

Ot-Bu

O

TESO OTESMe

Me O

MeO

Me

OTMS

Ot-Bu

O

O

OMe

Pd2dba3, LiCl, i-Pr2NEtNMP, 40 oC, 85%

LDA, t-BuOAc, THF, -78 oC-0 oC, 81%

TBAF, THF, -30 oC - -10 oC, 86%

1.

2.

MeOCOCl, py., DCM, 93%

TMSCl, imidazole, DCM, 95%

TESO OTESMe

Me O

MeO

Me

OTMS

Ot-Bu

O

O

OMe

Pd2dba3, THF (0.005M)40 oC, 80%

Double Transannular Diels-Alder Reaction

Me

MeTESO OP

OMe

OTMS

O

Ot-Bu

Me

KHMDS, PhSeBr, THF-10 oC, 91%

PhSe

mCPBA, DCM, -78 oC

Me

MePO

O

Me

MeOP

H

H

RO O

PO

Me

MePO

O

Me

MeOP

H

H

RO O

PO

1.

2.

NaHCO3, CHCl3, 40 oC, 40% over 2 steps

Me

MePO

O

Me

MeOPH

H

H

HH

RO O

PO

Completion of the Synthesis

PPTS, MeOH, 23 oCTFA/CH2Cl2 (1:9) 0-23 oC

EDC, DMAP, CH2Cl2, 23 oC62% over 3 steps

1.2.3.

Me

MeHO

O

OO

Me

MeOHH

H

H

HH

(+)-FR182877

Summary

The transannular Diels-Alder reaction is a powerful approach to the synthesis of complex polycyclic molecules

One limitation is the difficulty in predicting the outcome of the [4+2]

Macrocycle preparation can also be a limitation

Streocontrol is dicdated by the conformation of the macrocyle