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, 8587-8588 Leighton. J. J. Am. Chem. Soc. 2002, 124, 10672-10673 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 Leighton’s 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, 12416-12417

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, 8587-8588

Second strategy The tandem aldol-allylation reaction Potential variants Crotylsilanes Enolcrotylsilanes J. Am. Chem. Soc. 2002, 124, 10672-10673

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), 3015-3019

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), 2915-2917

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, 7890-7891

-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, 6120-6123

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, 10672-10673

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 we’re 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, 7026-7043

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. <2 % direct allylation of aldehyde cis syn diols trans J. Am. Chem. Soc. 2005, 127, 12806-12807

+ <19% direct allylation product syn diols

Application in total synthesis R = Ac Dolabelide A R = H Dolabelide B Approach to the synthesis of Dolabelide A and B: Fragment synthesis by tandem silylformylation-crotylsilylation Org. Lett. 2003, 5(19), 3535-3537 R = Ac Dolabelide C R = H Dolabelide D Total synthesis of Dolabelide D J. Am. Chem. Soc. 2006, accepted for publication

Divergent synthesis of complex polyketide-like macrolides from a simple polyol fragment 7 chiral centers 8 chiral centers * * * * * * * * * * * * * * * Natural product-like macrolides Org. Lett. 2005, 7(24), 5525-5527

Efficient asymmetric synthesis of (+)-SCH 351448 Stereochemically-enrich with 14 chiral centers 28-membered bis-lactone Natural product Features a new protodesilylative version of the tandem silylformylation-allylsilylation reaction, which provides an efficient synthesis of 1,5-syn-diols.

-Isolated in 2000 by researchers at the Schering-Plough Research institute -Microbial metabolite, Micromonospora sp -Unique ability to specifically activate transcription of a report construct under control of the LDL lipoprotein receptor promoter. -Selective activators of LDL-R transcription may be able to decrease serum LDL levels by increasing LDL uptake by the LDL-R. -Prevention and treatment of coronary heart disease. -ED-50 of 25uM

Retrosynthetic analysis

Org. Lett. 2004, 6(23), 4375-4377

Summary The tandem intramolecular silylformylation-allylsilylation reaction Potential variants Dicrotylsilanes Alkyne substrates 1,3,5-triol

Summary 5 steps from starting alcohol 31% overall yield anti-propionate 5 steps from starting alcohol 31% overall yield 8 stereogenic centers

Summary The tandem aldol-allylation reaction

Summary (Z)-enol-(Z)-crotyl silane (Z)-enol-(E)-crotyl silane

Conclusion These operationally simple tandem reactions provide remarkably efficient access to complex structures with relevance to biologically important polyketide natural products. Leighton and co-workers continue to develop new stereocontrolled strategies and applies them in the synthesis of important natural products. J. Am. Chem. Soc. 2005, 127, 12806-12807

Acknowledgements Group Members Dr. Prabhat Arya Dr. Polepally Reddy Dr. Ayub Reayi Dr. Michaël Prakesch Dr. Stuti Srivastava Dr. Jyoti Nandy Dr. Ravi Naga Prasad Dr. Deogratias Ntirampebura Michael Barnes (TO)