Parallel kinetic resolution of methyl (RS)-5-tris(phenylthio)methyl-cyclopent-1-ene-carboxylate for the asymmetric synthesis of (1R,2S,5S)- and (1S,2R,5R)-5-methyl-cispentacin

Parallel kinetic resolution of methyl (RS)-5-tris(phenylthio)methyl-cyclopent-1-ene-carboxylate with a 50:50 pseudoenantiomeric mixture of lithium (S)-N-benzyl-N-(α-methylbenzyl)amide and lithium (R)-N-3,4-dimethoxybenzyl-N-(α-methylbenzyl)amide provides an efficient entry to the corresponding homochiral methyl (1R,2S,5S)- and (1S,2R,5R)-2-amino-5-tris(phenylthio)methyl-cyclopentane-carboxylate derivatives in >98% de, with subsequent, sequential desulfurisation with Raney Nickel, N-debenzylation and ester hydrolysis furnishing (1R,2S,5S)- and (1S,2R,5R)-5-methyl-cispentacin in high yield, >98% de and >98% ee.

Graphical abstractParallel kinetic resolution of methyl (RS)-5-tris(phenylthio)methyl-cyclopent-1-ene-carboxylate with a pseudoenantiomeric mixture of homochiral lithium amides, and subsequent deprotection, gives access to 5-methyl-cispentacin derivatives in >98% de and >98% ee.Figure optionsDownload full-size imageDownload as PowerPoint slide

Methyl (1R,2S,5S,αS)-2-[N-benzyl-N-(α-methylbenzyl)amino]-5-tris(phenylthio)methyl-cyclopentane-carboxylateC41H41NO2S3[α]D23=-81.9 (c 1.0, CHCl3)source of chirality: asymmetric synthesisabsolute configuration: (1R,2S,5S,αS)

Methyl (1R,2S,5S,αS)-2-[N-benzyl-N-(α-methylbenzyl)amino]-5-methyl-cyclopentane-carboxylateC23H29NO2[α]D20=-50.4 (c 1.1, CHCl3)source of chirality: asymmetric synthesisabsolute configuration: (1R,2S,5S,αS)

Methyl (1S,2R,5R,αR)-2-[N-(3,4-dimethoxybenzyl)-N-(α-methylbenzyl)amino]-5-tris(phenylthio)methyl-cyclopentane-carboxylateC43H45NO4S3[α]D23=+72.0 (c 1.0, CHCl3)source of chirality: asymmetric synthesisabsolute configuration: (1S,2R,5R,αR)

Methyl (1S,2R,5R,αR)-2-[N-(3,4-dimethoxybenzyl)-N-(α-methylbenzyl)amino]-5-methyl-cyclopentane-carboxylateC25H33NO4[α]D23=+27.0 (c 0.9, CHCl3)source of chirality: asymmetric synthesisabsolute configuration: (1S,2R,5R,αR)

Methyl (1S,2R,5R,αR)-2-[N-(α-methylbenzyl)amino]-5-methyl-cyclopentane-carboxylateC16H23NO2[α]D20=+126 (c 1.0, CHCl3)source of chirality: asymmetric synthesisabsolute configuration: (1S,2R,5R,αR)

Methyl (1R,2S,5S)-2-ammonio-5-methyl-cyclopentane-carboxylate trifluoroacetateC10H15F3NO3[α]D20=+29.8 (c 1.0, CHCl3)source of chirality: asymmetric synthesisabsolute configuration: (1R,2S,5S)

(1R,2S,5S)-2-Amino-5-methyl-cyclopentane-carboxylic acidC7H13NO2[α]D17=+19.0 (c 1.0, H2O)source of chirality: asymmetric synthesisabsolute configuration: (1R,2S,5S)

Methyl (1S,2R,5R)-2-ammonio-5-methyl-cyclopentane-carboxylate trifluoroacetateC10H15F3NO3[α]D17=-30.0 (c 1.0, CHCl3)source of chirality: asymmetric synthesisabsolute configuration: (1S,2R,5R)

(1S,2R,5R)-2-Amino-5-methyl-cyclopentane-carboxylic acidC7H13NO2[α]D17=-18.8 (c 1.0, H2O)source of chirality: asymmetric synthesisabsolute configuration: (1S,2R,5R)