1. Groupe Charette, Réunion de littérature, 4 Décembre 2007
Chiral Allylsilanes as Enantioselective Allylation Reagents for Aldehydes
Focusing on work by
James S. Panek and James L. Leighton
James Bull
Groupe Charette, Réunion de littérature, 4 Décembre 2007

2. Outline
Introduction to allylation chemistry Stereocontrol features for allylsilanes Introduce SE2’ reactivity/stereospecificity Hyperconjugation, Open Transition States
James S. Panek
Background/ Concept
Aldehyde Crotylation
Synthesis of chiral allyl silanes
Use in complex molecule synthesis
James L. Leighton
Allylation/Crotylation
Imine electrophiles

3. The importance of allylation/crotylation chemistry

4. Common (Excellent) Enantioselective Methods
Brown
Roush
Well defined cyclic TS’s
(Type I class)
Excellent enantio/diastereocontrol
Unstable to storage
Prepared in situ
Used at low temperature

5. Common (Excellent) Enantioselective Methods
Keck
Lewis Base catalysed enantioselective allylation
Denmark, S. E.; Fu, J. Chem. Rev. 2003, 103, 2763

6. Allylsilanes SE2’ anti Stereospecific Stereocontrol??
New Chiral Centre
Double bond geometry
When E+ = aldehyde, diastereoselectivity

7. What is a stereospecific reaction??
What is SE2’ reactivity??
What is a stereospecific reaction??
Stereospecific ≠ 100% stereoselective
Defined by
mechanism
Determined by
Structure/steric effects
Conformation effects

8. SE2’ reactivity
SN2
Inversion
Stereospecific

9. SE2’ reactivity SN2 SN1 Inversion Non stereospecific Stereospecific
May be stereoselective

10. SE2’ reactivity SN2 SN1 SN2’ Inversion Non stereospecific
May be stereoselective
SN2’
Direct SN2 usually faster
Stereospecifically Syn (depending on nucleophile)
Stork:
Stork, G.; White. W. N. J. Am. Chem. Soc. 1956, 78, 4609.

11. SE2’ reactivity SN2 SE2 Inversion Stereospecific
stereodefined C-M bonds
Inversion
Stereospecific
Grignards: non stereospecific
Li, inversion or retention depending on electrophile
Park, Y. S.; Beak. P. J. Org. Chem. 1997, 62, 1574.

12. SE2’ reactivity SN2 SE2 SN2’ SE2’ Inversion Stereospecific
Stereospecifically SYN
Direct SN2 usually faster
M = Si, B, Mg, Sn, Ti, Cr, Zn, ….
For M = Si Stereospecifically ANTI

13. Stereocontrol for allylsilanes
If there is no clearly prefered ground state conformation
stereoselectivity will be reduced
But reaction still occurs stereospecifically anti
Hyperconjugation: s-conjugation
Parallel bonds
for max interaction

14. Stereocontrol for allyl silanes
Open Transition State
(Type II class)
No preorganisation by Lewis Acid

15. Open TS for crotylsilane reagents
TS may adopt an antiperiplanar or synclinal arrangement
Relative energy differences between antiperiplanar and synclinal TS are negligible
Antiperiplanar Transition States for crotyl silanes
E-silane
SYN diastereoselective
ANTI diastereoselective
Z-silane
SYN diastereoselective
ANTI diastereoselective
SYN product preferred

16. Open TS for crotylsilane reagents
Synclinal Transition States
E-silane
SYN diastereoselective
ANTI diastereoselective
Z-silane
Both antiperiplanar and synclinal TS predict syn selectivity

17. Outline
Introduction to allylation chemistry, Stereocontrol features for allylsilanes Introduce SE2’ reactivity/stereospecificity Hyperconjugation, Open Transition States
James S. Panek
Background/ Concept
Aldehyde Crotylation
Synthesis of chiral allyl silanes
Use in complex molecule synthesis
James L. Leighton
Allylation/Crotylation
Imine electrophiles

18. James S. Panek b. 1956 1979 BSc Chemistry (SUNY Buffalo)
1984 PhD Medicinal Chemistry (Kansas) with Dale Boger
Post Doc (Yale) with Danishefsky
1986 Boston University
Chiral E-crotylsilane:
Well behaved SE2’ Anti addition
Complete transfer of chirality
Provides easily functionalised products
Able to control reaction pathway by control of temperature and Lewis acid

19. Crotylation using syn-selectivity
Complete chirality transfer from silane, no other diastereoisomers observed
Anti SE2’
E double bond
Syn Selective
Panek, J. S.; Yang. M. J. Am. Chem. Soc. 1991, 113, 6594.

20. Crotylation using Syn-selectivity
Panek, J. S.; Yang. M. J. Org Chem. 1991, 56, 5755.

21. Crotylation using Syn-selectivity
Form oxonium in situ
Pd catalysed allylic transposition to form 1,3-diols
complete preservation of chirality
1,3-syn diol
Panek, J. S.; Yang. M.; Solomon J. S. J. Org. Chem. 1993, 58, 1003.

22. Acyclic Diastereoselectivity - Reversing Syn Selectivity
Re face attack
Si face attack
Panek, J. S.; Cirillo, P. F. J. Org. Chem. 1993, 58, 999.

23. Chiral Aldehydes - Double stereodifferentiation
Syn:Anti
R = Me, 64%, 10:1
R = Et, 35%, 15:1
R = Me, 85%, 1:30
R = Et, 69%, 1:10
R = Me,98 %, 1:8
R = Et, 79%, 1:10
R = H, 90%, >30:1
R = Me, 79%, >30:1
R = Et, 74%, 15:1
Chirality of the aldehyde controls the absolute stereochemistry of the oxygen bearing stereogenic centre.
Chelation control with OBn, Felkin control with OTBDPS

24. Chiral Aldehydes - Double stereodifferentiation
Jain, N. F.; Takenaka, N.; Panek, J. S. J. Am. Chem. Soc. 1996, 118,

25. Chiral Aldehydes - 1,3-induction?
Silane reagents override 1,3-induction of the chiral aldehyde
Predisposed to local Felkin induction to determine hydroxy stereochemistry
Jain, N. F.; Takenaka, N.; Panek, J. S. J. Am. Chem. Soc. 1996, 118,

26. Synthesis of chiral silanes
Johnson-
Claisen
Complete preservation
of chirality
Beresis, R. T.; Solomon J. S.; Yang. M.; Jain, N. F.; Panek, J. S.; Org. Synth. 1998, 75, 78.
Panek, J. S.; Yang. M. J. Am. Chem. Soc. 1991, 113, 6594

27. Synthesis of chiral silanes
Ireland-Claisen
Enolate .
Sparks, M. A.; Panek, J. S. Org. Chem. 1991, 56, Panek, J. S.; Yang. M.; Solomon J. S. J. Org. Chem. 1993, 58, 1003
Panek, J. S.; Beresis, R.; Xu, F.; Yang, M. Org. Chem. 1991, 56, 7341.

28. Synthesis of chiral silanes
Huang, H.; Panek, J. S. Org. Lett. 2003, 5, 1991.

29. Synthesis of Oleandolide - Retrosynthesis
Hu, T.; Takenada; N.; Panek, J. S. J. Am. Chem. Soc. 1999, 121, 9229.
Hu, T.; Takenada; N.; Panek, J. S. J. Am. Chem. Soc. 2002, 124,

30. Synthesis of Oleandolide
90%, >30:1 Syn:Anti
Felkin approach
87%, >30:1 Anti:Syn
Felkin approach
Hu, T.; Takenada; N.; Panek, J. S. J. Am. Chem. Soc. 1999, 121, 9229.
Hu, T.; Takenada; N.; Panek, J. S. J. Am. Chem. Soc. 2002, 124,

31. Synthesis of Oleandolide
82%, >20:1 Syn:Anti
82%, >30:1 Anti:Syn
Hu, T.; Takenada; N.; Panek, J. S. J. Am. Chem. Soc. 1999, 121, 9229.
Hu, T.; Takenada; N.; Panek, J. S. J. Am. Chem. Soc. 2002, 124,

32. Synthesis of Oleandolide
Hu, T.; Takenada; N.; Panek, J. S. J. Am. Chem. Soc. 1999, 121, 9229.
Hu, T.; Takenada; N.; Panek, J. S. J. Am. Chem. Soc. 2002, 124,

33. Alternative Reaction Pathways
If allowed to warm..
1,2 silyl migration competes with elimination
Panek, J. S.; Yang, M. J. Am. Chem. Soc. 1991, 113, 9868.

34. Same concepts apply….
Masse, C. E.; Panek. J. S. Chem. Rev. 1995, 95, 1293, Fleming, I.; Barbero, A.; Walter, D. Chem. Rev. 1997, 97, 2063.
Huang, H.; Panek, J. S. J. Am. Chem. Soc. 2000, 122, 9836

35. Outline
Introduction to allylation chemistry, Stereocontrol features for allylsilanes Introduce SE2’ reactivity/stereospecificity Hyperconjugation, Open Transition States
James S. Panek
Background/ Concept
Aldehyde Crotylation
Synthesis of chiral allyl silanes
Use in complex molecule synthesis
James L. Leighton
Allylation/Crotylation
Imine electrophiles

36. James L. Leighton b. 1964 1987 BSc Chemistry (Yale)
1994 PhD Chemistry (Harvard) with David Evans
Post Doc (Harvard) with Eric Jacobsen
1996 Columbia University
Cyclic transition state

37. Concept B reagents - Type I cyclic TS Si Reagents - Type II open TS
Make Si more Lewis-acidic to encourage a cyclic transition state

38. “Strain-Release Lewis Acidity”
Myers and Denmark Utimoto

39. Strained Silacycles: New reagents for allylation
Supports idea that ring strain is important
Ring strain still exists due to long Si-O and short C-O bonds
Proceeds via cyclic TS
Kinnaird, J. W. A.; Ng, P. Y.; Kubota, K.; Wang, X.; Leighton, J. L, J. Am. Chem. Soc. 2002, 124, 7920.
Zhang, X.; Houk, K. N.; Leighton, J. L, Angew. Chem. Int. Ed. 2005, 44, 938.

40. Synthesis of Chiral Allyl Silanes
Screen chiral 1,2-diols, amino-alcohols and diamines
Easily prepared
Stable to storage
Convenient work-up
Mixture of diastereoisomers
Interconvert?
React in same way?
Kinnaird, J. W. A.; Ng, P. Y.; Kubota, K.; Wang, X.; Leighton, J. L, J. Am. Chem. Soc. 2002, 124, 7920.

41. Scope - optimised conditions
Table 1
Kinnaird, J. W. A.; Ng, P. Y.; Kubota, K.; Wang, X.; Leighton, J. L, J. Am. Chem. Soc. 2002, 124, 7920.

42. Diamine ligand Best ee Br confers crystallinity
Stable solid (moderate air sensitivity)
Straightforward synthesis
Single crystallisation to purify
Kubota, K.; Leighton, J. L, Angew. Chem. Int. Ed. 2003, 42, 946.
Zhang, X.; Houk, K. N.; Leighton, J. L, Angew. Chem. Int. Ed. 2005, 44, 938

43. Scope Aliphatic Substrates Aromatic Substrates
Excellent ee“among highest observed for this reaction”
CH2Cl2 best solvent for allylation. Much longer reaction time 20h vs 2h
Kubota, K.; Leighton, J. L, Angew. Chem. Int. Ed. 2003, 42, 946

44. Scope - Chiral substrate
Overrides 1,3 induction of chiral aldehyde
Kubota, K.; Leighton, J. L, Angew. Chem. Int. Ed. 2003, 42, 946

45. Crotylation - Cis reagent
Syn:Anti
dr >15:1
Hackman, B. M.; Lombardi, P. J.; Leighton, J. L, Org. Lett. 2004, 6, 4375

46. Crotylation - Trans reagent
Anti:Syn
dr >25:1
Reagents are crystalline solids but moisture sensitive - storable eg in glove box
High MW diamine. - 90% recoverable
Hackman, B. M.; Lombardi, P. J.; Leighton, J. L, Org. Lett. 2004, 6, 4375

47. Imine electrophiles - Aldimine allylation
Requires NHAc directing group
Single recrystallisation allows
access to enantiopure compounds
Berger, R.; Rabbat, P.M.; Leighton, J. L, J. Am. Chem. Soc. 2003, 125, 9596.

48. Imine electrophiles - Ketimine allylation
Berger, R.; Duff, K.; Leighton, J. L, J. Am. Chem. Soc. 2004, 126, 5686.

49. Imine electrophiles - Aldimine crotylation
Trans reagent
Syn product
89%, 95:5, 97%22
Berger, R.; Rabbat, P.M.; Leighton, J. L, J. Am. Chem. Soc. 2003, 125, 9596.
Berger, R.; Duff, K.; Leighton, J. L, J. Am. Chem. Soc. 2004, 126, 5686.

50. Imine electrophiles - directing groups
Rabbat, P. M.; Valdez, S. C.; Leighton, J. L, Org. Lett. 2006, 8, 6119.
Perl, N. R.; Leighton, J. L, Org. Lett. 2007, 9, 3699.

51. Imine electrophiles - Cinnamylation
Huber, J. D..; Leighton, J. L, J. Am. Chem. Soc. 2007, 129,

52. Imine electrophiles - Cinnamylation
Huber, J. D..; Leighton, J. L, J. Am. Chem. Soc. 2007, 129,

53. Summary Panek: Chiral allyl silanes for acyclic stereocontrol
Leighton: Chiral allyl silanes allowing cyclic stereocontrol