Asymmetric Synthesis

1. Asymmetric Synthesis Additions to carbonyl compounds

2. Outline • Addition of non-chiral nucleophiles to chiral aldehydes or ketones • Cram’s rule • Felkin-Anh model • Chelation control • Chiral auxiliaries • Chiral acetals • Chiral reagents • Chiral catalysts • ‘Chiral amplification’

3. Achiral Nu + prochiral C=O

4. Addition to Cram Karabatsos Cram & Elhafez, J Amer Chem Soc 1952, 74, 5828.

5. Addition to Cram & Elhafez, J Amer Chem Soc 1952, 74, 5828.

6. Faulty Assumptions • Ground state and reactive conformation are wrong. • Ground state and reactive conformation (TS) cannot be assumed to be the same. • The directing influence of substituents does not only derive from their steric effects. Electronic interactions are crucial. • The C=O group assumes pyramidal state early, therefore Cram model is unfavourable.

7. Felkin-Anh Model

8. Nucleophile Approach Anh, Bürgi-Dunitz

9. Chelation Control J Amer Chem Soc1990, 112, 6130.

10. Examples

11. Chiral auxiliaries • Attached to the carbonyl compound • Attached to the nucleophile • Chiral acetals and a-ketoaldehydes • Sulfoxides • Organometallics • Allylboranes, -silanes, -stannanes

12. Auxiliary attached to carbonyl Tetrah Lett 1991, 32, 2919

13. 1,3-Oxathianes

14. Transition state model

15. Auxiliary attached to nucleophile J C S Perkin I 1981, 1278

16. Organometallic: Chiral ligand Tetrah Lett 1986, 27, 5711

17. Allylic nucleophiles • Alternative route to aldol-type products • Two new chiral centres introduced • Complication: reaction at C-1 • Achiral reactants: syn and anti racemates • Chiral reactants: in principle one major stereoisomer

18. Chiral boron reagents

19. Examples (1) R anti:syn e.e. % n-C9H19 > 99:1 88 TBSOCH2CH2 > 97:3 85 tBu 95:5 73 n-C7H15CH=CH > 99:1 74

20. Examples (2) R anti:syn e.e. % n-C9H19 3:97 86 TBSOCH2CH2 > 3:97 72 tBu > 1:99 70 n-C7H15CH=CH 3:97 62

21. Examples (3) R e.e. % n-C4H9 95 Ph 90 tBu 98 C6H11 99 Chen, Eur J Org Chem2005, 1665-1668

22. Transition state

23. Selectivity: E→ anti

24. Double asymmetric synthesis

25. Iterative Asymmetric Synthesis J Amer Chem Soc 1990, 112, 6348

26. Diisopinocampheylborane

27. Addition to aldehydes R e.e. % Yield % Me 93 74 Et 86 71 iPr 90 86 nBu 87 72 tBu 83 88 Ph 96 81

28. Other allylic boranes • High diastereoselectivity and enantioselectivity • Reagent enantioselectivity overrides intrinsic chiral aldehyde facial selectivity • Consistent and predictable • Also with -chiral aldehydes • Diamine-based ligands

29. Allylsilanes and Allylstannanes • Promoted by Lewis acids • High diastereoselectivity • ‘Cram controlled’ • “Chelation controlled’

30. Chiral Catalysts • Organozinc catalysts • Chiral amplification

31. Chiral ligand as catalyst • Organometallic reagent must be relatively unreactive towards C=O unless combined with the catalyst – ligand acceleration. • Catalyst must have suitable 3D structure to provide high e.e.

32. Dialkylzinc addition to aldehydes R Nu e.e., % Ph Me 91 Ph Et 99 Ph Bu 98 p-Cl-Ph Et 93 p-MeO-Ph Et 93 2-Furyl C5H11 >95 (E)-C6H5-CH=CH Et 96 (E)-Bu3SnCH=CH C5H11 85 PhCH2CH2 Et 90 J Amer Chem Soc 1986, 108, 6071

33. Transition state model

34. Aminothiocyanate derivatives R Yield, % e.e., % Ph 98 96 p-Cl-Ph 97 95 o-MeO-Ph 96 90 p-MeO-Ph 95 91 2-Naphthyl 95 93 C6H13 82 75 Tetrahedron Letters 2005, 46(15), 2695-2696

35. Transition state? Tetrahedron Letters2005, 46, 2695-2696

36. Chiral amplification • High catalyst optical purity is not needed! J Amer Chem Soc 1989, 111, 4028

37. Why amplification? (50%) (50%)

38. Summary • Addition of non-chiral nucleophiles to chiral aldehydes or ketones • Cram’s rule • Felkin-Anh model • Chelation control • Chiral auxiliaries • Chiral acetals • Chiral reagents • Chiral catalysts • ‘Chiral amplification’

39. Questions ?