1. 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

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. 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,

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,

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

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),

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),

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. 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

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,

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,

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,

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

30. 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.

31. Boat-like transition state through tpb orientationZ
favored E
favored
Computational modeling of similar transition states done by:
Denmark, S.E. J. Am. Chem. Soc. 1994, 116,

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,

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),
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),

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),

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

44. Summary 5 steps from starting alcohol 31% overall yield
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,

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)