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.