Synthesis of (3S)-(tert-butyldimethylsilyloxy)methylcyclopentan-1-one as a key intermediate of sphingosine 1-phosphate-1 receptor agonists

Herein we report the asymmetric synthesis of (3S)-(tert-butyldimethylsilyloxy)methylcyclopentan-1-one (S)-3 as a practical chiral synthon for a wide range of pharmaceutical and/or natural products, using Lipshutz’s asymmetric copper-catalyzed conjugate reduction. This method makes it feasible to prepare a conformationally constrained cyclopentane analogue 12, which is one of the key intermediates for the synthesis of novel sphingosine 1-phosphate-1 receptor agonists.

Figure optionsDownload as PowerPoint slide

(3S)-3-(tert-Butyldimethylsilyloxy)methylcyclopentan-1-oneC12H24O2Siee = 95%[α]D25=−37.3 (c 1.06, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3S)

tert-Butyl (5R,7S)-2,2-dimethyl-7-(1-methyl-1H-pyrrol-2-yl)-3-oxa-1-azaspiro[4.4]nonane-1-carboxylateC19H30N2O3[α]D25=−52.2 (c 1.05, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (5R,7S)

1-{5-[(1S,3R)-3-Amino-3-(hydroxymethyl)cyclopentyl]-1-methyl-1H-pyrrol-2-yl}-5-(4-methylphenyl)pentan-1-one hemifumarateC25H34N2O4[α]D25=−36.1 (c 1.07, AcOH)Source of chirality: asymmetric synthesisAbsolute configuration: (1S,3R)