Jean-Louis Brochu Department of Chemistry University of
Ottawa
The tandem intramolecular silylformylation-allylsilylation and
tandem aldol-allylation: Stereoselective methods for the synthesis
of natural product polyol motifs Leighton. J. J. Am. Chem. Soc.
2000, 122, Leighton. J. J. Am. Chem. Soc. 2002, 124, Jean-Louis
Brochu Department of Chemistry University of Ottawa Overview
Introduction
The tandem intramolecular silylformylation-allylsilylation reaction
The tandem aldol-allylation reaction Application to total synthesis
Summary Conclusion Introduction Interest in polyketide
macrolide-derived natural products with the skipped polyol
structural motif and the development of efficient stereocontrolled
strategies for their synthesis Dolabelide A First strategy
Leightons rhodium-catalyzed intramolecular Silylformylation of
alkenes -Efforts in olefin carbonylation reactions -Focus on the
homoallylic alcohol class of substrates J. Am. Chem. Soc. 1997,
119, Allylsilanes are well-known aldehyde allylation agents
Is a tandem carbonylation-aldehyde allylation possible? Potential
variants Dicrotylsilanes Alkyne substrates 1,3,5-triol J. Am. Chem.
Soc. 2000, 122, Second strategy The tandem aldol-allylation
reaction
Potential variants Crotylsilanes Enolcrotylsilanes J. Am. Chem.
Soc. 2002, 124, Strain release Lewis acidity
Responsible for spontaneous allylation Concept first described by
Denmark`s group -Distortion of the tetrahedral geometry imparts a
strain energy which is released upon coordination of a Lewis base,
narrowing the internal angles to a trigonal-bipyramidal geometry.
Internal C-Si-O angle 95o Internal C-Si-O angle 90o
Organometallics, 1990, 9(12), The tandem intramolecular
silylformylation-allylsilylation reaction
NMR of crude 14 confirms no aldehyde Proposed mechanism of
rhodium-catalyzed intramolecular silylformylation Validation of an
intramolecular reaction -The diastereoselectivity of the allylation
is quite high
Achiral substrate provides a useful benchmark diastereoselectivity
(93:7) Alkyne substrates Alkynes are also well known substrates for
silylformylation The silicon-substituted carbon is no longer
stereogenic -Diastereoselectivity in the allylation would have to
derive from the original propargylic stereocenter. -Thus leading to
remote 1,5-stereoinduction Angew. Chem. Int. Ed. 2001, 40(15),
First Alkyne study 0.1 mol% -Upon tandem formylation-allylation,
product was submitted to protodesilylation and the peracetylation.
- Major product is the 1,5-anti product, which is opposite to
alkene substrates. Proposed model More highly Strained complex
Destabilizing steric interaction between the 2-propyl group and the
allyl group. Apical position not possible. Substrate study
Increasing steric size of propargylic substituent * * Selective
replacement of either allyl group with a nontransferable
A key feature Both diastereotopic allyl groups can transfer and
each lead to a different product diastereomer. Selective
replacement of either allyl group with a nontransferable group
would lead to a stereospecific reaction. 1,5 syn 1,5 anti
Crotylsilylation -Investigation of the spontaneous allylation with
dicrotylsilanes Propionate unit -Synthesis of di-cis-crotylsilane
and di-trans-crotylsilane were required. J. Am. Chem. Soc. 2002,
124, -Focused on catalytic dihydrosilane alcoholysis as an
efficient method for the silylation of the substrate alcohols.
anti-propionate Tandem silylformylation-crotylsilylation on alkyne
substrates
1,5-anti diol anti-propionates syn proprionate Propargylic alcohol
Highly diastereoselective Transition state of the crotylsilylation
on alkene substrates
di-cis-crotylsilane The alkyl chain of the aldehyde occupy a
pseudoaxial position Transition state of the crotylsilylation on
alkyne substrates di-cis-crotylsilane -All attempts to prepare
di-trans-crotylsilanes have failed
although trans-crotyl-phenylsilane has been synthesized Achiral
alcohol syn-propionate Applying Evans and Brown chemistry
Pure & App. 1987, 59, 879 J. Am. Chem. Soc. 1979, 101, Rapid
synthesis of a polyketide-like fragment
Separated from mixture of acetonides 5 steps from starting alcohol
31% overall yield 8 stereogenic centers The tandem aldol-allylation
reaction
J. Am. Chem. Soc. 2002, 124, Polyketide chains Envisioned the metal
(MLn) would bear the desired number of enolate fragments as well as
an allyl group. Upon completion of the aldol cascade,
intramolecular allylation of the terminal aldehyde would halt the
chain propagation. The silicon, constrained in a five-membered
ring, possesses Lewis acidity to distort tetrahedral geometry to
tbp. -The strain induced in the silacycle by the 1,2-diol is
essential for the reaction.
-To expand the scope of the process, cis and trans-crotylsilanes
were prepared, 55 and 56. Creation of 3 stereocenters.
trans syn propionate cis anti propionate < 5% simple aldehyde
crotylation Creation of 3 stereocenters. Creation of 3
stereocenters.
-To further expand the scope of the process, (E) and
(Z)-crotylenolsilanes were prepared, 59 and 60. 61 38% yield Z + ~
15% simple aldehyde crotylation + ~ 30% simple aldehyde crotylation
E Aldol reaction of 59 and 60 proceed through boat-like transition
states. Creation of 3 stereocenters. Boat-like transition state
through tpb orientation
Z favored E favored Computational modeling of similar transition
states done by: Denmark, S.E. J. Am. Chem. Soc. 1994, 116,
Possibility of creating 4 stereocenters in one reaction
(Z)-enol-(Z)-crotyl silane (Z)-enol-(E)-crotyl silane Improved
stereoselectivity - Focus on (Z)-enol silanes due to poor results
with 60. Propenol units can lead to tertiary carbinols, found in
important natural product.
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