Jean-Louis Brochu Department of Chemistry University of Ottawa

1. The tandem intramolecular silylformylation-allylsilylation and tandem aldol-allylation: Stereoselective methods for the synthesis of natural product polyol motifs Jean-Louis Brochu Department of Chemistry University of Ottawa Leighton. J. J. Am. Chem. Soc. 2000, 122, 8587-8588 Leighton. J.J. Am. Chem. Soc. 2002, 124, 10672-10673

2. Overview • Introduction • The tandem intramolecular silylformylation-allylsilylation reaction • The tandem aldol-allylation reaction • Application to total synthesis • Summary • Conclusion

3. 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

4. Leighton’s rhodium-catalyzed intramolecular Silylformylation of alkenes First strategy -Efforts in olefin carbonylation reactions -Focus on the homoallylic alcohol class of substrates J. Am. Chem. Soc. 1997, 119, 12416-12417

5. 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

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

7. 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

8. The tandem intramolecular silylformylation-allylsilylation reaction NMR of crude 14 confirms no aldehyde

9. Proposed mechanism of rhodium-catalyzed intramolecular silylformylation

11. Validation of an intramolecular reaction

12. -The diastereoselectivity of the allylation is quite high • Achiral substrate provides a useful benchmark • diastereoselectivity (93:7)

13. 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

14. 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.

15. Proposed model More highly Strained complex Destabilizing steric interaction between the 2-propyl group and the allyl group. Apical position not possible.

16. Substrate study Increasing steric size of propargylic substituent * *

17. 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

18. 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

19. -Focused on catalytic dihydrosilane alcoholysis as an efficient method for the silylation of the substrate alcohols. anti-propionate

20. Tandem silylformylation-crotylsilylation on alkyne substrates 1,5-anti diol anti-propionates syn proprionate Propargylic alcohol Highly diastereoselective

21. 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

22. -All attempts to prepare di-trans-crotylsilanes have failed although trans-crotyl-phenylsilane has been synthesized Achiral alcohol syn-propionate

23. Applying Evans and Brown chemistry Pure & App. 1987, 59, 879 J. Am. Chem. Soc. 1979, 101, 6120-6123

24. Rapid synthesis of a polyketide-like fragment Separated from mixture of acetonides 5 steps from starting alcohol 31% overall yield 8 stereogenic centers

25. The tandem aldol-allylation reaction J. Am. Chem. Soc. 2002, 124, 10672-10673

26. 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.

28. -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.

29. trans syn propionate cis anti propionate < 5% simple aldehyde crotylation Creation of 3 stereocenters.

30. -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.

31. 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

32. 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.

33. 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

34. + <19% direct allylation product syn diols

35. 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

36. 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

37. 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.

38. -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

39. Retrosynthetic analysis

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

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

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

45. Summary The tandem aldol-allylation reaction

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

47. 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

48. 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)