A new efficient synthesis of enantiopure diastereomeric 3′-aminocyclopentylglycines

A new synthesis of enantiopure (1′S,3′R,2R)- and (1′R,3′S,2R)-3′-aminocyclopentylglycines (−)-12a and (−)-12b was performed by taking advantage of (±)-2-amino-3-oxo-norbornane-2-carboxylic acid derivative exo-2 as the starting material. The use of an acylase from Aspergillus melleus in phosphate buffer allowed the ‘one-pot’ transformation of the β-ketoester (±)-exo-2 into 3′-carboxycyclopentylglycine (±)-3a and (±)-3b, via a retro-Dieckman reaction, which, by direct kinetic resolution, were isolated as compounds (−)-3a and (−)-3b.Starting from a mixture of (−)-3a and (−)-3b, enantiopure 3′-aminocyclopentylglycines (−)-12a and (−)-12b as well as differently substituted 3-amino derivatives were prepared efficiently using a very simple synthetic protocol that requires a single chromatographic purification.

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Ethyl (1′S,3′R,2R)-2-benzoylamino-(3′-ethoxycarbonylamino-cyclopentyl)-acetateC19H26N2O5[α]D25=-5.3 (c 0.3, CHCl3)Source of chirality: enzymatic resolutionAbsolute configuration: (1′S,3′R,2R)

Ethyl (1′R,3′S,2R)-2-benzoylamino-(3′-ethoxycarbonylamino-cyclopentyl)-acetateC19H26N2O5[α]D25=-21.2 (c 0.3, CHCl3)Source of chirality: enzymatic resolutionAbsolute configuration: (1′R,3′S,2R)

(1′S,3′R,2R)-2,3′-Diamino-cyclopentyl-acetic acid dihydrochlorideC7H16Cl2N2O2[α]D25=-17.7 (c 1, MeOH)Source of chirality: enzymatic resolutionAbsolute configuration: (1′S,3′R,2R)

(1′R,3′S,2R)-2,3′-Diamino-cyclopentyl-acetic acid dihydrochlorideC7H16Cl2N2O2[α]D25=-15.2 (c 1, MeOH)Source of chirality: enzymatic resolutionAbsolute configuration: (1′R,3′S,2R)

Ethyl (1′S,3′R,2R)-2-benzoylamino-(3′-t-butoxycarbonylamino-cyclopentyl)-acetateC21H30N2O5[α]D25=-10.3 (c 1, CHCl3)Source of chirality: enzymatic resolutionAbsolute configuration: (1′S,3′R,2R)

Ethyl (1′S,3′R,2R)-2-benzoylamino-[3′-(N′-pmethoxybenzyl)ureydo-cyclopentyl]-acetateC25H31N3O5[α]D25=-6.9 (c 0.4, DMSO)Source of chirality: enzymatic resolutionAbsolute configuration: (1′S,3′R,2R)

Ethyl (1′S,3′R,2R)-2-benzoylamino-(3′-amino-cyclopentyl)-acetate p-toluensulfonateC23H30N2O6S[α]D25=+8.9 (c 0.4, DMSO)Source of chirality: enzymatic resolutionAbsolute configuration: (1′S,3′R,2R)

Ethyl (1′R,3′S,2R)-benzoylamino-(3′-carbamoyl-cyclopentyl)-acetateC17H21N5O4[α]D25=+3.0 (c 1, CHCl3)Source of chirality: enzymatic resolutionAbsolute configuration: (1′R,3′S,2R)

Ethyl (1′R,3′S,2R)-benzoylamino-(3′-ureydo-cyclopentyl)-acetateC17H23N3O4[α]D25=-10.2 (c 1, MeOH)Source of chirality: enzymatic resolutionAbsolute configuration: (1′R,3′S,2R)