Chapter 1
Addition of Non-Stabilized Carbon-Based Nucleophilic Reagents to Chiral N-sulfinyl Imines

Melissa A. Herbage Jolaine Savoie Joshua D. Sieber Jean-Nicolas Desrosiers Yongda Zhang Maurice A. Marsini Keith R. Fandrick Daniel Rivalti and Chris H. Senanayake

Boehringer Ingelheim Pharmaceuticals Inc., 900 Ridgebury Rd., Ridgefield, CT 06877, United States

Contents

1. Introduction
2. Mechanism and Stereochemistry
3. Computational and Experimental Studies
4. Stereochemical Models
5. Effect of the Organometallic Reagent
6. Effect of the Solvent
7. Effects of Additives
8. Effect of Coordinating Substituents at the a-Position
9. Effect of a Stereogenic a-Carbon
10. Scope and Limitations
11. Preparation of N-Sulfinyl Imines
12. Preparation of N-Sulfinyl Aldimines
13. Preparation of N-Sulfinyl Ketimines
14. Additions of Alkyl Nucleophiles to N-Sulfinyl Imines
15. Additions of Alkyl Nucleophiles to N-Sulfinyl Aldimines
16. Additions of Alkyl Nucleophiles to N-Sulfinyl Ketimines
17. Additions of Alkenyl Nucleophiles to N-Sulfinyl Imines
18. Additions of Alkenyl Nucleophiles to N-Sulfinyl Aldimines
19. Addition of Alkenyl Nucleophiles to N-Sulfinyl Ketimines
20. Additions of Aryl Nucleophiles to N-Sulfinyl Imines
21. Additions of Aryl Nucleophiles to N-Sulfinyl Aldimines
22. Additions of Aryl Nucleophiles to N-Sulfinyl Ketimines
23. Additions of Allylic Nucleophiles to N-Sulfinyl Imines
24. Additions of Allylic Nucleophiles to N-Sulfinyl Aldimines
25. Additions of Allylic Nucleophiles to N-Sulfinyl Ketimines
26. Additions of Propargylic Nucleophiles to N-Sulfinyl Imines
27. Additions of Propargylic Nucleophiles to N-Sulfinyl Aldimines
28. Additions of Propargylic Nucleophiles to N-Sulfinyl Ketimines
29. Additions of Alkynyl Nucleophiles to N-Sulfinyl Imines
30. Additions of Alkynyl Nucleophiles to N-Sulfinyl Aldimines
31. Additions of Alkynyl Nucleophiles to N-Sulfinyl Ketimines
32. Nucleophilic Additions of Cyanide to N-Sulfinyl Imines
33. Nucleophilic Additions of Cyanide to N-Sulfinyl Aldimines
34. Nucleophilic Additions of Cyanide to N-Sulfinyl Ketimines
35. Removal and Recovery of the N-Sulfinyl Auxiliary
36. Applications to Synthesis
37. Synthesis of Amino Acids
38. Synthesis of Active Pharmaceutical Ingredients
39. Bradykinin B1 Antagonists
40. ß-Secretase-1 (BACE) Inhibitors
41. Plasmodium Dipeptidyl Aminopeptidase (DPAP) Inhibitors
42. Cholesteryl Ester Transfer Protein (CETP) Inhibitors
43. Kinase Inhibitors
44. Melanocortin Type 4 Receptor (MC4R)
45. Cetirizine
46. Synthesis of Natural Products
47. Tubulysins
48. Polyoxins
49. Syomycin A
50. (-)-3-Demethoxyerythratidinone
51. Comparison With Other Methods
52. Chiral Auxiliaries
53. Catalytic Enantioselective Methods
54. Hydrogenation of Imines and Enamides
55. Experimental Conditions
56. General Considerations on Safety
57. Handling Pyrophoric Reagents
58. Handling Cyanide Reagents
59. Experimental Procedures
60. (R)-2-Methyl-N-((S)-1-phenylethyl)propane-2-sulfinamide [Addition of an Alkylmagnesium Nucleophile to an N-Sulfinyl Aldimine].5 ,36
61. (R)-2-Methyl-N-((S)-2-phenylhexan-2-yl)propane-2-sulfinamide [Addition of an Alkylaluminum Nucleophile to an N-Sulfinyl Ketimine].36 ,88
62. (R)-2-Methyl-N-((R)-1-phenylhex-2-en-1-yl)propane-2-sulfinamide [Addition of an Alkenylboron Nucleophile to an N-Sulfinyl Aldimine].43
63. (S)-1-((R)-tert-Butylsulfinyl)-2-phenyl-2-(prop-1-en-2-yl)aziridine [Addition of an Alkenylmagnesium Nucleophile to an N-Sulfinyl Ketimine].187
64. (R)-2-Methyl-N-((R)-1-phenylpropyl)propane-2-sulfinamide [Addition of an Arylmagnesium Nucleophile to an N-Sulfinyl Aldimine].36
65. (R)-2-Methyl-N-((R)-2-methyl-3-phenylpentan-3-yl)propane-2-sulfinamide [Addition of an Arylaluminum Nucleophile to an N-Sulfinyl Ketimine].36
66. (R)-2-Methyl-N-((S)-1-phenylbut-3-en-1-yl)propane-2-sulfinamide [Addition of an Allylindium Nucleophile to an N-Sulfinyl Aldimine].65
67. (R)-2-Methyl-N-((R)-1-phenylbut-3-en-1-yl)propane-2-sulfinamide [Addition of an Allylzinc Nucleophile to an N-Sulfinyl Aldimine].65
68. (R)-2-Methyl-N-((S)-2-(4-(trifluoromethyl)phenyl)pent-4-en-2-yl)propane-2-sulfinamide [Addition of an Allylindium Nucleophile to an N-Sulfinyl Ketimine].65
69. (R)-2-Methyl-N-((S)-1-phenyl-4-(trimethylsilyl)but-3-yn-1-yl)propane-2-sulfinamide [Addition of a Propargylzinc Nucleophile to an N-Sulfinyl Aldimine].244
70. (R)-2-Methyl-N-((R)-3-methyl-6-(trimethylsilyl)hex-5-yn-3-yl)propane-2-sulfinamide [Addition of a Propargylindium Nucleophile to an N-Sulfinyl Ketimine].246
71. (R)-2-Methyl-N-((R)-1-phenyl-3-(trimethylsilyl)prop-2-yn-1-yl)propane-2-sulfinamide [Addition of an Alkynylmagnesium Nucleophile to an N-Sulfinyl Aldimine].200
72. (S)-2-Methyl-N-((S)-2-((1R,4S)-4-methylcyclohexyl)-4-(trimethylsilyl)but-3-yn-2-yl)propane-2-sulfinamide [Addition of an Alkynylaluminum Nucleophile to an N-Sulfinyl Ketimine].250
73. (S)-N-((S)-Cyano(phenyl)methyl)-4-methylbenzenesulfinamide [Nucleophilic Addition of Cyanide to an N-Sulfinyl Aldimine].259
74. (R)-N-((R)-1-Cyano-1-phenylethyl)-2-methylpropane-2-sulfinamide [Nucleophilic Addition of Cyanide to an N-Sulfinyl Ketimine].264
75. Tabular Survey
76. References

Introduction

Chiral branched amines are an extremely important class of molecules that can be found in numerous natural products and marketed pharmaceuticals. Among several general strategies for the asymmetric synthesis of amines, one of the most successful is the addition of carbon-based nucleophiles to imine derivatives bearing a readily cleavable chiral auxiliary to bias the stereoselectivity in the desired direction.1-3 Sulfinamides are one of the most widely used subsets of chiral auxiliaries. The growing number of sulfinamide-based methods and their application to total synthesis, to drug discovery, and to drug development4 is attributed to a number of practical aspects related to this chemistry. A wide range of sulfinamides can be prepared via straightforward synthetic procedures.5-18 Additionally, enantiomerically pure 4-toluene- and tert-butanesulfinamides are commercially available at a reasonable cost. N-Sulfinyl aldimines and ketimines can be synthesized using mild reaction conditions, and the resulting imines are easily handled. The N-sulfinyl group both activates the imines for nucleophilic attack and is a powerful directing group, leading to high diastereomeric ratios and predictable asymmetric induction (Scheme 1). Cleavage of the N-sulfinyl group is achieved using mild acidic conditions. Because of the increasing popularity of sulfinamide chemistry, a number of excellent reviews have been published.19-27 This chapter provides an overview of sulfinamide chemistry through 2017, excluding the patent literature, in which a carbon-carbon bond is formed between the azomethine carbon and the...