Recent Advances in the Enantioselective Synthesis of Chiral Amines via Transition Metal-Catalyzed Asymmetric Hydrogenation

Abstract

Chiral amines are key structural motifs present in a wide variety of natural products, drugs, and other biologically active compounds. During the past decade, significant advances have been made with respect to the enantioselective synthesis of chiral amines, many of them based on catalytic asymmetric hydrogenation (AH). The present review covers the use of AH in the synthesis of chiral amines bearing a stereogenic center either in the α, β, or γ position with respect to the nitrogen atom, reported from 2010 to 2020. Therefore, we provide an overview of the recent advances in the AH of imines, enamides, enamines, allyl amines, and N-heteroaromatic compounds.

Figure 1

Selected pharmaceuticals with chiral amine fragments.

Figure 2

Synthesis of chiral amines via AH of unsaturated compounds using transition metal catalysis.

Scheme 1. Iridium- and Ruthenium-Catalyzed AH of N-Phenyl 1-Phenylethanimine

Scheme 2. Iridium-Catalyzed AH of Sterically Hindered N-Aryl Imines

Scheme 3. AH of N-Aryl Dialkyl Imines Using Binary Catalysts of a Metal Complex and a Chiral Phosphoric Acid (HA)

Scheme 4. AH of N-Aryl α-Imino Esters

Scheme 5. AH of Exocyclic N-Aryl Imines

Scheme 6. AH of N-Methyl and N-Alkyl Imines Using Ir(III)-H Complex

Scheme 7. Iridium-Catalyzed AH of N-Alkyl α-Aryl Furan-Containing Imines

Scheme 8. Metal-Catalyzed AH of N-Alkyl Imines

Scheme 9. Iridium-Catalyzed AH of Diaryl N-Alkyl Imines

Scheme 10. Metal-Catalyzed AH of 3H-Indoles

Scheme 11. Metal-Catalyzed AH of Benzodiazepines and Benzodiazepinones

Scheme 12. Access to Chiral Seven-Membered Cyclic Amines via Rhodium-Catalyzed AH

Scheme 13. Metal-Catalyzed AH of Benzoxazines and Benzoxazinones

Scheme 14. Metal-Catalyzed AH of Quinoxalinones

Scheme 15. Enantioselective Synthesis of Chiral Piperazin-2-ones via AH

Scheme 16. Rhodium-Catalyzed AH of Cyclic N-Alkyl Imines

Scheme 17. Iridium-Catalyzed Enantioselective Imine Hydrogenation/Lactamization Cascade

Scheme 18. Synthesis of Chiral 2-Aryl Pyrrolidines and Piperidines via AH

Figure 3

Structures of biologically active compounds and pharmaceutical drugs containing a cyclic 2-aryl amine moiety.

Scheme 19. Iridium-Catalyzed AH of 2-Pyridyl Cyclic Imines

Figure 4

Pharmaceuticals and alkaloids containing chiral 1-substituted THIQs.

Scheme 20. Enantioselective Synthesis of THIQs via Iridium-Catalyzed AH

Scheme 21. Asymmetric Synthesis of Solifenacin via Iridium-Catalyzed AH

Scheme 22. Iridium-Catalyzed AH of Cyclic Iminium Salts

Scheme 23. Palladium-Catalyzed AH of Aryl Alkyl N-Sulfonyl Imines

Scheme 24. Enantioselective Palladium-Catalyzed Hydrogenation of Cyclic N-Sulfonyl Amino Alcohols

Scheme 25. Metal-Catalyzed AH of Different Acyclic α-Substituted N-Sulfonyl Imines

Scheme 26. Nickel-Catalyzed Chemoselective AH of α,β-Unsaturated Ketoimines

Scheme 27. Metal-Catalyzed AH of α-Substituted N-Sulfonyl Imines

Scheme 28. Palladium-Catalyzed AH of Sulfamidites and Sultams Using (S,S)-f-Binaphane as a Chiral Ligand

Scheme 29. Synthesis of MK-3207 via Palladium-Catalyzed AH of Cyclic Sulfamidate Imine S37a

Scheme 30. Iridium- and Nickel-Catalyzed AH of Sulfamidate Imines S37

Scheme 31. AH of Cyclic N-Sulfonyl Ketimino Esters S38 and Enesulfonamides S41

Scheme 32. Metal-Catalyzed AH of N-Phosphinyl Imines

Scheme 33. Iridium-Catalyzed AH of N-Acyl Imines

Scheme 34. Synthesis of Chiral γ-Lactams via Iridium-Catalyzed AH of N-Acyliminium Cations

Scheme 35. Synthesis of Chiral N,O-Acetals via Iridium-Catalyzed AH of Cationic Intermediates

Scheme 36. Nickel-Catalyzed AH of 2-Oxazolones

Scheme 37. Palladium-Catalyzed AH of α-Aryl Hydrazones and α-Alkyl Hydrazones

Scheme 38. Palladium-Catalyzed AH of Fluorinated Aromatic Pyrazol-5-ols via the CH-Tautomer

Scheme 39. Sequential Palladium-Catalyzed AH/Hydrogenolysis of α-Hydrazono Phosphonates

Scheme 40. Rhodium-Catalyzed AH of Allyl and Alkynyl-aryl Hydrazones

Scheme 41. AH of Hydrazones with Ruthenium and Cobalt Complexes

Scheme 42. Enantioselective Synthesis of an Intermediate of BET Inhibitor BAY 1238097 via Iridium-Catalyzed AH

Scheme 43. Metal-Catalyzed AH of Ketoximes

Scheme 44. Iridium-Catalyzed Acid-Assisted AH of Oximes to Hydroxylamines

Scheme 45. Metal-Catalyzed AH of N-Unprotected Imines

Figure 5

P-Stereogenic chiral ligands used in the metal-catalyzed AH of N-acyl enamines.

Scheme 46. Total Synthesis of Conulothiazole A via Rhodium-Catalyzed AH

Scheme 47. Scope of Substrates for Rhodium-Catalyzed AH Using DuanPhos

Scheme 48. Rhodium-Catalyzed AH of Conjugated Enamides

Scheme 49. Rhodium-Catalyzed AH of (Z)- Tetrasubstituted Enamides

Scheme 50. Rhodium-Catalyzed AH of α- and β-Amino Acrylonitriles

Scheme 51. Rhodium-Catalyzed AH of α-Formyl Enamides

Scheme 52. Enantioselective Synthesis of α-Perfluoroalkylated Chiral Amines

Scheme 53. Rhodium-Catalyzed AH of Enamido Phosphonates and β-Phosphorylated Enamides

Scheme 54. Rhodium-Catalyzed AH of α-Boryl Enamides

Scheme 55. Enantioselective Synthesis of β-Stereogenic Amines via AH

Scheme 56. Nickel-Catalyzed AH of 2-Amidoacrylates

Scheme 57. AH of β-Functionalized N-Acyl Enamines Using the Ni/Binapine System

Scheme 58. Co-Catalyzed AH of 2-Functionalized N-Acyl Enamines

Scheme 59. Partial and Total Rhodium-Catalyzed AH of Cyclic α-Dehydroamino Ketones

Scheme 60. Metal-Catalyzed AH of Cyclic Enamides Derived from α- and β-Tetralones

Figure 6

Pharmaceutical drugs containing the chiral 2-aminotetraline structure.

Figure 7

Pharmaceutical drugs containing amines with vicinal chiral centers.

Scheme 61. Metal-Catalyzed AH of Tetrasubstituted Cyclic Enamides

Scheme 62. Metal-Catalyzed AH of α- and β-(Arylsulfonamido)acrylates

Scheme 63. Rhodium-Catalyzed AH of N-Phthaloyl Enamides

Scheme 64. Metal-Catalyzed AH of Lactams

Scheme 65. Ruthenium-Catalyzed AH of 2-Oxazolones

Scheme 66. Metal-Catalyzed AH of Endocyclic and Exocyclic N-Alkyl Enamines

Scheme 67. Catalytic Synthesis of an HIV Integrase Inhibitor

Scheme 68. Metal-Catalyzed AH of N-Aryl Enamines

Scheme 69. Iridium-Catalyzed AH of Exocyclic N-Aryl Enamines

Scheme 70. Rhodium-Catalyzed AH of β-Functionalized Enamines

Scheme 71. Asymmetric Synthesis of Sitagliptin via Rhodium-Catalyzed AH

Scheme 72. Iridium-Catalyzed AH of β-Enamine Hydrochloride Esters

Figure 8

Representative drugs that can be prepared via the AH of allyl amines.

Scheme 73. Rhodium-Catalyzed AH of β- and γ-Phtalimido-Substituted Unsaturated Esters

Scheme 74. Metal-Catalyzed AH of N-Allyl Phthalimides

Scheme 75. Iridium-Catalyzed AH of 2-Aryl N-Sulfonyl Allyl Amines

Scheme 76. Iridium-Catalyzed AH of Cyclic N-Sulfonyl Allyl Amines

Scheme 77. Ruthenium-Catalyzed AH of N-Acyl Allyl Amines

Scheme 78. Iridium-Catalyzed AH of N-Acyl Allyl Amines

Scheme 79. Synthesis of an Agrochemical Building Block via AH

Scheme 80. Iridium-Catalyzed AH of Endocyclic N-Allyl Amines

Scheme 81. Asymmetric Synthesis of a HDAC Inhibitor via AH

Scheme 82. Rhodium-Catalyzed AH of β-Aryl-Substituted α,β-Unsaturated Lactams

Scheme 83. Rhodium-Catalyzed AH of Unprotected Primary Allyl Amine

Scheme 84. Combination of AH and Reductive Amination

Scheme 85. Metal-Catalyzed AH of Unfunctionalized 2-Quinolines and 2,3-Disubstituted Quinolines

Scheme 86. Ruthenium-Catalyzed AH of 2,2′-Bisquinoline Derivatives

Scheme 87. Ruthenium-Catalyzed AH of 2,6-Bis(quinolinyl) Pyridines (PyBQs)

Scheme 88. Mn-Catalyzed AH of Quinolines Enabled by π–π Interaction

Scheme 89. Consecutive Intermolecular Reductive Amination/AH

Scheme 90. Asymmetric Synthesis of THQs through Sequential Processes

Scheme 91. Iridium-Catalyzed AH of Isoquinolines and Pyridines

Scheme 92. Enantioselective Hydrogenation as the Key Step for the Total Synthesis of (−)-Jorunnamycin A and (−)-Jorumycin

Scheme 93. Iridium-Catalyzed AH of Trisubstituted Pyridines

Scheme 94. Iridium-Catalyzed AH of Pyridinium Salts

Scheme 95. Iridium-Catalyzed AH of 2-Aryl-3-phthalimidopyridinium Salts

Scheme 96. Ruthenium-Catalyzed AH of Quinoxalines

Scheme 97. Iridium-Catalyzed AH of Pyrrolo/indolo[1,2-a]quinoxalines and of Pyrrolo[1,2-a]pyrazines

Scheme 98. Iridium-Catalyzed AH of Pyrazinium Salts

Scheme 99. Iridium-Catalyzed AH of N-Protected Indoles

Scheme 100. Metal-Catalyzed AH of N-Protected Indoles Using PhTRAP

Scheme 101. Synthesis of (+)-Duocarmycin SA via Rhodium-Catalyzed AH

Scheme 102. Catalytic Strategies toward the AH of Unprotected Indoles

Scheme 103. One-Pot Synthesis of Chiral Indolines via Palladium-Catalyzed AH

Scheme 104. Metal-Catalyzed AH of Pyrroles

Scheme 105. Ruthenium-Catalyzed AH of Oxazoles, Imidazoles, and Azaindoles Using PhTRAP

Scheme 106. Ruthenium-Catalyzed AH of Indolizines and 1,2,3-Triazolopyridines

Scheme 107. Ruthenium-Catalyzed AH of 2-Pyridones

Scheme 108. Enantioselective Hydrogenation of Quinazolinones Using Pd or Ir Catalysts

Scheme 109. AH of Pyrimidines

Scheme 110. AH of Isoxazolium Salts

Scheme 111. Metal-Catalyzed AH of Phenanthridines

Scheme 112. Ruthenium-Catalyzed AH of 1,5- and 1,8-Naphthyridines