A practical synthesis of optically active δ-nitro-α-ketoesters and 4-cyclohexyl-proline catalyzed by chiral squamides

Inexpensive and readily available squamides derived from 9-amino-9-deoxyepiquinine or 9-amino-9-deoxyepiquinidine were found to be superior catalysts for the asymmetric conjugate additions of t-butyl nitroacetate to β,γ-unsaturated-α-ketoesters. After the subsequent decarboxylation with silica gel, a variety of δ-nitro-α-ketoesters were obtained in good yields and with excellent enantioselectivities. The products were further transformed into ethyl 4-aryl-prolinate via a cascade nitro reduction and amination. A new synthesis of (2S,4S)-4-cyclohexyl-proline was also developed. A practical synthesis of optically active δ-nitro-α-ketoesters and 4-aryl-proline derivatives is described.

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(2R,4S)-Ethyl 5-nitro-4-phenyl-2-(tosyloxy)pentanoateC20H23NO7S[α]D20 = +24.0 (c 0.7, CH2Cl2)Absolute configuration: (2R,4S)

(2S,4S)-4-Cyclohexylpyrrolidine-2-carboxylic acidC11H19NO2[α]D20 = −31.8 (c 0.2, AcOH)Absolute configuration: (2S,4S)