Asymmetric synthesis of α,α-disubstituted α-amino alcohol derivatives

Herein we report the asymmetric synthesis of α,α-disubstituted α-amino alcohol derivatives 22, 25 and 26, key intermediates of a novel immunomodulator, using Seebach’s method. This synthetic method can be applied to the large scale synthesis of chiral sphingosine 1-phosphate-1 (S1P1) receptor agonists, with significant improvements to the previously reported method with regard to the reaction temperature.

Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slide

Methyl (2R,4R)-2-tert-butyl-4-methyl-4-[2-(1-methyl-1H-pyrrol-2-yl)ethyl]-1,3-oxazolidine-3-carboxylateC17H28N2O3Ee = >99%[α]D27=-12.6 (c 1.00, MeOH)Source of chirality: asymmetric synthesisAbsolute configuration: (2R,4R)

Methyl (2R,4R)-2-tert-butyl-4-methyl-4-[2-(thiophen-2-yl)ethyl]-1,3-oxazolidine-3-carboxylateC16H25NO3SEe = >99%[α]D25=-13.6 (c 2.31, MeOH)Source of chirality: asymmetric synthesisAbsolute configuration: (2R,4R)

Methyl (2R,4R)-2-tert-butyl-4-methyl-4-[2-(furan-2-yl)ethyl]-1,3-oxazolidine-3-carboxylateC16H25NO4Ee = >99%[α]D25=-7.7 (c 2.33, MeOH)Source of chirality: asymmetric synthesisAbsolute configuration: (2R,4R)