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 aldolanti aldol

10. Erythro vs. Threo syn vs. anti started from sugar chem. Extension (generalization) : following the priority rule for (R, S) configuraiton If priority eclipses --- erythro If priority does not eclipse --- threo 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 i)Enolate geometry is important – usually syn is dominant ii)Cyclic ketones --- anti aldol is major E-enolate 84 : 16

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

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

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

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

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

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

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 R 2 BOTf; R 3 N TiCl 4 ; R 3 N i) LDA ii) ClTi(Oi-Pr) 3

23. Evans Chiral Aldol condensation LDA R 2 BOTf; R 3 N TiCl 4 ; R 3 N

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

25. Evans Chiral Aldol condensation MgCl 2 ; R 3 N

26. Evans Chiral Aldol condensation MgCl 2 ; R 3 N Boat-like T.S.

27. Evans Chiral Aldol condensation MgCl 2 ; R 3 N Boat-like T.S.

28. Enantio-selective aldol condensation i)Chiral center in enolate ii)Chiral center in aldehyde iii)Chiral auxiliary iv)Chiral metal v)Chiral Lewis acid

29. Enantio-selective aldol condensation i)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% Kinetic resolution or Double stereodifferentiation JOC 46, 2290 (1981) Mutual kinetic resolution

31. Matched v.s. Mismatched

32. Mutual kinetic resolution Product ratio??

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

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

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

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

37. Intramolecular Aldol condensation Dieckman condensation Scheme 2.9

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 JACS, 123, 5260(2001) OL, 3305 (2004)

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

44. Application to organic synthesis : “biogenetic type synthesis” Science, 305, 1754(2004) anti:syn=4:1 MgBr 2 Et 2 O MgBr 2 CH 2 Cl 2 TiCl 4 CH 2 Cl 2 glucose mannose allose

45. Modificaiton of the reaction Mannich reaction Electrophile : reactivity

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

51. 81% 80%

52. Amine catalyzed reaction Baylis-Hillman reaction Org. Rxn. 51, 201 (1997) Chem. Rev. 103, 811 (2003)

53. The Baylis-Hillman Reaction

54. Asymmetric Baylis Hillman Reactions: Chiral Auxiliary Leahy, JACS. 1997, 119, 4317

55. Asymmetric Baylis Hillman Reactions: Chiral Catalyst Hatakeyama : JACS 1999, 121, 10219 R = Alkyl, Aryl Yield: 31-58% ee: R (>91%) Yield: 82-96% ee: (S) 79-92% Shi : Chem. Commun. 2003, 1310

56. Application of the Baylis-Hillman reaction M. Krische, JACS, 2003, 124, 2404 H. Tae, Ph.D.Thesis, KAIST

57. Claisen condensation Michael addition

58. Acylation Forming the enolate Drives equilibrium. Electrophile Mg enolate prevents O-acylation

59. Acylation Weinreb amide Stile’s reagent

60. Homework Chapter 2 : 1, 2, 13, 15 Due : April, 27