Efficient synthesis of (1R,2S) and (1S,2R)-2-aminocyclopentanecarboxylic acid ethyl ester derivatives in enantiomerically pure form

A 4-step synthesis of an optically active synthetic intermediate [(1R,2S)-2-(4′-fluorobenzylamino)cyclopentanecarboxylic acid ethyl ester complex with (S)-(+)-mandelic acid; compound 12, >99% de] required for the preparation of a promising HCV NS5B polymerase inhibitor is reported. This process utilizes mandelic acid as a resolving agent, which can be recovered in good yield by a simple extraction. An optimized version of the chemistry described avoids the use of chromatographic purifications making it suitable for large-scale applications. In addition, the straightforward conversion of compound 12 to enantiomerically pure (1R,2S)-2-aminocyclopentanecarboxylic acid ethyl ester and the corresponding Boc and Cbz derivatives is reported. The preparation of the enantiomer of 12 (compound 15) in enantiomerically pure form and the conversion of this entity to (1S,2R)-2-aminocyclopentanecarboxylic acid ethyl ester and the corresponding Boc and Cbz derivatives is also described.

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(1R,2S)-2-(4′-Fluorobenzylamino)cyclopentanecarboxylic acid ethyl ester complex with (S)-(+)-mandelic acidC23H28FNO5De = >99%[α]D23=+20.1 (c 0.76, CH3OH)Source of chirality: (S)-(+)-mandelic acidAbsolute configuration (amino-ester): (1R,2S)

(1R,2S)-2-Benzyloxycarbonylaminocyclopentanecarboxylic acid ethyl esterC16H21NO4Ee = >99%[α]D23=-71.9 (c 1.0, CH3OH)Source of chirality: (S)-(+)-mandelic acidAbsolute configuration: (1R,2S)

(1R,2S)-2-tert-Butoxycarbonylaminocyclopentanecarboxylic acid ethyl esterC13H23NO4Ee = >99%[α]D23=-93.9 (c 1.0, CH3OH)Source of chirality: (S)-(+)-mandelic acidAbsolute configuration: (1R,2S)