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Asymmetric Synthesis

Asymmetric Synthesis. α -Substitution using chiral enolates. Outline. Requirements for stereoselective enolate alkylation Imposing facial bias on alkylation Chiral auxiliaries leading to acids or alcohols Chiral auxiliaries leading to ketones.

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Asymmetric Synthesis

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  1. Asymmetric Synthesis α-Substitution using chiral enolates

  2. Outline • Requirements for stereoselective enolate alkylation • Imposing facial bias on alkylation • Chiral auxiliaries leading to acids or alcohols • Chiral auxiliaries leading to ketones

  3. Requirements for stereoselective enolate alkylation • Only one geometrical isomer must be formed • Base • Solvent • Temperature • Counter-ion • Chiral auxiliary

  4. Stereoelectronic requirements for deprotonation and alkylation • Maximum overlap of orbitals during bond-breaking and formation • Preferred conformation during deprotonation • Electrophile approach is slightly away from perpendicular, towards the auxiliary

  5. Enolate geometry Ireland:

  6. LDA Solution structure

  7. LDA TS in THF Solution

  8. LDA TS with HMPA Sun & Collum, J Amer Chem Soc2000, 122, 2452-2458

  9. Enolate stereochemistry (THF)

  10. Enolate stereochemistry (HMPA)

  11. Other effects • % HMPA • Substituent (R) size • [BuLi]   % hexane • [LiCl] or LiBr] • Other bases

  12. Examples

  13. Effect of chiral auxiliary

  14. Example of facial bias on ring >95:5

  15. Example of facial bias through chelation

  16. Stereoselectivity in alkylation

  17. Evans Oxazolidinone Evans & Gage, Organic Syntheses 1989, 68, 77 Chemical Reviews 1996, 96, 835-875

  18. Stereoselectivity by chelation

  19. Application: Antibiotic X-206

  20. Application: Antibiotic X-206 Evans et al., J Amer Chem Soc 1988, 110, 2506

  21. Other electrophiles • Hydroxylation • Bromination • Amination • Acylation

  22. Hydroxylation

  23. Bromination

  24. Amination

  25. Acylation

  26. Enantioselective ketone synthesis • Acyl converted to imine • Stereochemistry controlled through chelation

  27. Chiral hydrazines SAMP RAMP Enders, In Asymmetric Synthesis (Ed. Morrison), Vol. 3, pp. 275-339.

  28. SAMP Synthesis

  29. RAMP Synthesis

  30. Using RAMP/SAMP

  31. Stereoselectivity in alkylation

  32. Rationalization • Reaction with acyclic and cyclic ketones and aldehydes • Methoxy group is important for high stereoselectivity • Therefore chelation, as in oxazolines • Removal by acid hydrolysis or ozonolysis

  33. Removal of auxiliary

  34. Application Leioburnum vittatum & L. calcar Enders & Baus, Liebigs Ann Chem1983, 1439

  35. Antibiotic X-14547A Nicolaou et al.,J Amer Chem Soc1981, 103, 6967, 6969

  36. Questions ?

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