1. Lecture 14 APPLICATIONS IN ORGANIC SYNTHESIS Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display.

2. I. Enantioselective functional group interconversions ORGANOMET CHEM IN ORGANIC SYNTHESIS

3. II. Carbon-carbon bond formation via nucleophilic attack on a  ligand. ORGANOMET CHEM IN ORGANIC SYNTHESIS

4. III.Carbon-carbon bond formation via carbonyl or alkene insertion. ORGANOMET CHEM IN ORGANIC SYNTHESIS

5. IV. Carbon-carbon bond formation via transmetallation reactions. ORGANOMET CHEM IN ORGANIC SYNTHESIS

6. V. Carbon-carbon bond formation through cyclization reactions. ORGANOMET CHEM IN ORGANIC SYNTHESIS

7. The C=C and C=O undergoes transformations to variety of organic compounds (alcohols, alkyl halides, alkanes). The C=C and C=O are planar and achiral but in their reactions creates one or more stereogenic centers in the reaction product. Assymetric Hydrogenations

8. Methods of producing an enantiomer of a chiral compound: Chemical resolution of a racemate Chiral chromatography Use of a chiral natural products as starting material Stoichiometric use of chiral auxilliaries Asymmetric catalysis Asymmetric Hydrogenations

9. Chiral chromatography: - Use of chiral, enantioenriched groups to the solid support - In the chiral environment, the two enantiomers will have diastereomerically different interactions with the columns ORGANOMET CHEM IN ORGANIC SYNTHESIS

10. Synthesis of biotin (involved in enzymatic transfer of CO 2 ): ORGANOMET CHEM IN ORGANIC SYNTHESIS

11. Use of chiral auxiliaries: ORGANOMET CHEM IN ORGANIC SYNTHESIS

12. Asymmetric Catalysis: same approach as the use of chiral auxilliary except that the selectivity occurs catalytically The most environmentally benign approach to enantioselectivity. ORGANOMET CHEM IN ORGANIC SYNTHESIS

13. Wilkinson’s catalyst: L n M + (M = Rh or Ir) Assymetric Hydrogenations

14. Chiral Diphosphine Ligands: Asymetric Hydrogenation using Rh Catalysts

15. Mechanism: Assymetric Hydrogenation using Rh-CHIRAPHOS

16. Assymetric Hydrogenation

19. Assymetric Hydrogenation of C=C bonds using Ru(II)

20. Noyori pioneered the development of Ru(II) catalysts showing enantioselective hydrogenation. ASYMMETRIC HYDROGENATION OF C=C BONDS

23. Asymmetric Hydrogenation of C=O

24. ASYMMETRIC HYDROGENATION OF C=O

26. ORGANOMET CHEM IN ORGANIC SYNTHESIS

28. Transfer hydrogenation (TH) Asymmetric TH ASYMMETRIC HYDROGENATION OF C=O

30. Assymetric Hydrogenation Using Ir(I) Catalysts

31. ORGANOMET CHEM IN ORGANIC SYNTHESIS

33. ASYMMETRIC OXIDATION

34. ORGANOMET CHEM IN ORGANIC SYNTHESIS

35. Pd-Catalyzed Oxidation of Secondary Alcohols

36. OXIDATION OF SECONDARY ALCOHOLS

37. ORGANOMET CHEM IN ORGANIC SYNTHESIS

38. CARBON – CARBON BOND FORMATION VIA NUCLEOPHILIC ATTACK ON AN  3 - ligand: THE TSUJI-TROST REACTION ORGANOMET CHEM IN ORGANIC SYNTHESIS

40. TSUJI – TROST REACTION Organic synthesis using allylic substrates: unpredictable stereochemistry poor control of regioselectivity possible carbon- skeleton rearrangement. Leaving groups for Tsuji-Trost Reaction

41. Tsuji-Trost Reaction: With hard nucleophiles (pKa of conjugate acid >25) results in an overall inversion of configuration at the allylic site. With soft nucleophile (pKa of conjugate acid < 25) react to give retention of configuaration.

42. TSUJI – TROST REACTION

44. TSUJI – TROST REACTION - EXAMPLE

45. TSUJI – TROST REACTION

46. Several points in catalytic cycle where asymmetric reaction could occur: a) enantiomeric faces of the alkene b) enantiomeric leaving groups c) enantioface exchange in the  3 allyl complex d) attack at enantiotopic termini of the  3 ally ligand e) Attack by different enantifaces of prochiral nucleophiles. ASSYMETRIC TSUJI – TROST REACTION

47. TSUJI-TROST REACTION

48. TSUJI_TROST REACTION Assymetric Quat center

49. Tsuji-Trost Reaction – Quat Center

50. EXAMPLE: Tsuji-Trost Reaction

51. ORGANOMET CHEM IN ORGANIC SYNTHESIS

52. Tsuji Trost Reaction:

53. C-C Bond formation via CO and alkene insertion CARBONYLATION INSERTIONS

54. CARBONYL INSERTIONS EXAMPLE

55. CARBONYL INSERTIONS

56. C-C Double bond Insertion: The Heck Reaction

57. Heck Reaction – migratory C=C insertion Step a ) OA b) alkene coordination c) migratory insertion of C=C d)  -elimination Insertion is key step R = aryl, alkyl, benzyl or allyl X = Cl, Br, I, OTf

58. Rate of reaction and regioselectivity are sensitive to steric hindrance about the C=C bond. Rate of reaction varies according to: Heck Reaction:

59. Example: Heck Reaction

62. Also know as Cross Coupling Reaction: C-C Bond Bond formation via Transmetallation Reactions

63. Transmetallation Reaction Transmetallation Reaction – a method for introducing a  -bonded hydrocarbon ligands Into the coordination sphere transition metals. The equilibrium is thermodynamically favorable from left to right if the electronegativity of M is greater than that of M’.

64. TRANSMETALLATION REACTIONS

65. Via a concerted -bond metathesis --------transfer of R to M with retention of configuration. TRANSMETALLATION REACTION MECHANISM

66. TRANSMETALLATION REACTIONS 4-TYPES

67. GENERAL REACTION MECHANISM

68. CROSS-COUPLING REACTION - GENERAL

69. CROSS-COUPLING REACTION

70. The use of organotin compound have the advantage that one group will preferentially transfer over the other: CROSS-COUPLING REACTION

71. Example: Propose a catalytic cycle for the cross coupling plus carbonylation reaction below CROSS-COUPLING REACTION

72. Mechanism: CROSS-COUPLING REACTION - STILLE

73. Synthesis Application Example: CROSS-COUPLING REACTION - STILLE

74. Sample Problem: CROSS-COUPLING REACTION - STILLE

75. Transmetalating Agent is R-B(R’) 2 but similar in scope as the Stille. CROSS-COUPLING REACTION - SUZUKI

76. Reaction Pathway: CROSS-COUPLING REACTION - SUZUKI

77. Synthesis Application: The chemo-, regio-, and stereoselectivity similar to those with Stille. Suzuki more widely used for aryl-aryl coupling. CROSS-COUPLING REACTION - SUZUKI

78. Cross coupling between alkynyl and aryl : CROSS-COUPLING REACTION - Sonogashira -Requires high loadings of Cu and Pd catalysts, relativelly hight temperatures -Cu-alkynes are formed in situ and then the alkyne is transferred to Pd.

79. Mechanism: CROSS-COUPLING REACTION -

80. Mechanism: CROSS-COUPLING REACTION - Sonogashira

81. Synthesis Applications: CROSS-COUPLING REACTION - Sonogashira

82. Method of choice for syhthesis of acrylic, di- and tri- terpenoid systems. Organozinc are often used. CROSS-COUPLING REACTION - Negishi

83. Reaction mechanism: CROSS-COUPLING REACTION - Negishi

84. Synthesis Applications: CROSS-COUPLING REACTION – Negishi

85. Mechanism: Dotz Arene Synthesis C-C Bond formation: Cyclizations

86. Cyclization involving Palladium

87. Mechanism: CYCLIZATION Pd

88. Cyclization – Oppolzer’s

89. Cyclization – Pauson - Kand

90. CROSS-COUPLING REACTION