Carbon-Carbon Bond Forming Reactions

1. Carbon-Carbon Bond Forming Reactions I. Substitution Reaction II. Addition Reaction

2. Carbon-Carbon Bond Forming Reactions II. Addition Reaction : Condensation Reaction Aldol condensation : base catalyzed acid catalyzed Directed Aldol condensation : usually kinetic control

3. Base Catalyzed aldol condensation

4. Acid Catalyzed aldol condensation

5. Mixed aldol condensation Classical : with non-enolizable carbonyls trans : major

6. Base catalyzed v.s. Acid catalyzed Under base catalysis

7. Under acid catalysis

8. Control of regio- and stereochemistry in aldol condensation Directed aldol : regioselective, stereoselective 100% single enolate, generally non-equilibirum

9. Stereocontrol in Aldol Condensation Syn aldol anti aldol

10. Erythro vs. Threo started from sugar chem. Extension (generalization) : following the priority rule for (R, S) configuraiton If priority eclipses --- erythro If priority does not eclipse --- threo syn vs. anti Proposed by Masamune : ACIE 1980, 19, 557

11. Aldol condensation of enolates For syn, anti selectivity i) Enolate geometry is important – usually syn is dominant E,Z-selectivity of enolates depends on substitution, base & additives R= Et 3.3 : 1 R= i-Pr 1.7 : 1 R= t-Bu 1 : >50

12. Aldol condensation of enolates Z-enolate E-enolate

13. Aldol condensation of enolates For syn, anti selectivity • Enolate geometry is important – usually syn is dominant • Cyclic ketones --- anti aldol is major 84 : 16 E-enolate

14. Aldol condensation of enolates For syn, anti selectivity • Enolate geometry is important – usually syn is dominant • Cyclic ketones --- anti aldol is major • Kinetically Z-enolate is preferred • Metal plays an important role – size, ligands • In reality, aggregation state is important -- effect of additives • enolates can equilibrate fast – thermodynamic mixture

15. Aldol condensation of enolates a. Li enolates • Can be easily generated with LDA from ketone, ester, amide, etc. • Can chelate to other functional groups • Regioselective addition

16. Aldol condensation of enolates b. Boron enolate • Cyclic transition state • Transition state is compact – amplify steric factor :better selectivity • Two extra ligand can influence the outcome • Z-enolate dominant • With bulky ligand on boron, E-enolate dominates 97 : 3 (n-Bu)2BOTf 3 : 97 (2-BCO)2BOTf

17. Aldol condensation of enolates c. Ti, Sn, Zr enolate Mostly syn selective !!! • Somewhere between B, and Li enolate • Extra chelation available , could have extra ligands Acyclic T.S.

18. Mukaiyama aldol : acid catalyzed aldol Silyl enol ether + lewis acids + carbonyl (or acetal)

19. Mukaiyama aldol : acid catalyzed aldol Silyl enol ether + lewis acids + carbonyl (or acetal) • Usually acyclic transition state

20. ii) Catalytic aldol condensation !!!

21. Anti – selective aldol condensation Selective formation of E- enolate With 9-BBN-- >97:3 -- syn selective Lewis acid catalyzed aldol 32 : 1 JACS, 2002, 124, 392

22. Evans Chiral Aldol condensation LDA R2BOTf; R3N TiCl4; R3N i) LDA ii) ClTi(Oi-Pr)3

23. Evans Chiral Aldol condensation LDA R2BOTf; R3N TiCl4; R3N

24. Evans Chiral Aldol condensation i) LDA ii) ClTi(Oi-Pr)3

25. Evans Chiral Aldol condensation MgCl2; R3N MgCl2; R3N

26. Evans Chiral Aldol condensation MgCl2; R3N Boat-like T.S.

27. Evans Chiral Aldol condensation MgCl2; R3N Boat-like T.S.

28. Enantio-selective aldol condensation • Chiral center in enolate • Chiral center in aldehyde • Chiral auxiliary • Chiral metal • Chiral Lewis acid

29. Enantio-selective aldol condensation • Chiral center in enolate TL 21, 4678(1980) Through extra chelation

30. Enantio-selective aldol condensation ii) Chiral center in aldehyde Anti aldol products are very minor ** Chiral centers in both aldehyde and enolate ** 85% JOC 46, 2290 (1981) • Kinetic resolution or • Double stereodifferentiation Mutual kinetic resolution

31. Matched v.s. Mismatched

32. Mutual kinetic resolution Product ratio??

33. 97 : 3 (n-Bu)2BOTf 97 : 3 9-BBNOTf 3 : 97 (2-BCO)2BOTf 9-BBNOTf (2-BCO)2BOTf

34. Enantio-selective aldol condensation iii) Chiral auxiliary D.A. Evans W. Oppolzer • Reliable, can predict stereochemistry • stoichiometric, not economic

35. vi) Chiral Metal 1 eq. E.J. Corey, JACS 5493(1989) E.J. Corey, JACS 4977(1990)

36. v) Chiral Lewis acid Catalyst!! S. Masamune E.J. Corey M. Shibasaki E. Carreira

37. Scheme 2.9 Intramolecular Aldol condensation Dieckman condensation

38. Robinson annulation Too reactive Enolate control needed

39. Robinson annulation Stable Vinylketone Enamines for annulation

40. Robinson annulation Asymmetric synthesis

41. Proline catalyzed Asymmetric aldol reaction OL, 3305 (2004) JACS, 123, 5260(2001)

43. Proline catalyzed Asymmetric aldol reaction OL, 3305 (2004) JACS, 123, 5260(2001) JACS, 124, 6798(2002) anti:syn=3:1

44. Application to organic synthesis : “biogenetic type synthesis” Science, 305, 1754(2004) anti:syn=4:1 MgBr2 Et2O glucose MgBr2 CH2Cl2 mannose TiCl4 CH2Cl2 allose

45. Modificaiton of the reaction Electrophile : reactivity Mannich reaction

46. Mannich Reaction

47. Synthesis of tropinone : biogenetic type synthesis Sir. Robinson Decarboxylation

48. Tropinone Roboinson “Mannich reaction” Willstatter

49. Synthesis of tropinone : biogenetic type synthesis Sir. Robinson

50. Amine catalyzed reaction Knoevenagel reaction