Asymmetric synthesis of α-mercapto-β-amino acid derivatives: application to the synthesis of polysubstituted thiomorpholines

Tandem conjugate addition of homochiral lithium N-benzyl-N-(α-methyl-p-methoxybenzyl)amide to tert-butyl cinnamate and enolate trapping with TsStBu proceeds with high diastereoselectivity to give a homochiral anti-α-tert-butylthio-β-amino ester. Stepwise deprotection gives the corresponding free α-tert-butylthio-β-amino acid without epimerisation. Tandem conjugate addition of homochiral lithium N-allyl-N-(α-methylbenzyl)amide to tert-butyl cinnamate and enolate trapping with TsStBu followed by conversion of the S-tert-butyl group to a disulphide, and reduction with Lalancette’s reagent generates polysubstituted thiomorpholine derivatives.

Graphical abstractTandem conjugate addition of a homochiral lithium amide to tert-butyl cinnamate and quenching with TsStBu gives access to homochiral anti-α-mercapto-β-amino acid and polysubstituted thiomorpholine derivatives.Figure optionsDownload full-size imageDownload as PowerPoint slide

tert-Butyl (2R,3R,αR)-2-phenylthio-3-[N-benzyl-N-(α-methylbenzyl)amino]-3-phenylpropanoateC34H37NO2S[α]D25 = +31.6 (c 1.0, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (2R,3R,αR)

tert-Butyl (2R,3R,αR)-2-tert-butylthio-3-[N-benzyl-N-(α-methylbenzyl)amino]-3-phenylpropanoateC32H41NO2S[α]D25 = −8.5 (c 1.0, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (2R,3R,αR)

tert-Butyl (2R,3R,αR)-2-mercapto-3-[N-benzyl-N-(α-methylbenzyl)amino]-3-phenylpropanoateC32H41NO2S[α]D25 = −749.2 (c 0.6, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (2R,3R,αR)

tert-Butyl (2R,3R,αR)-2-tert-butylthio-3-[N-allyl-N-(α-methylbenzyl)amino]-3-phenylpropanoateC28H39NO2S[α]D25 = −10.0 (c 0.9, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (2R,3R,αR)

tert-Butyl (2R,3R,αR)-2-tert-butylthio-3-[N-(α-methylbenzyl)amino]-3-phenylpropanoateC25H35NO2S[α]D25 = +11.2 (c 1.0, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (2R,3R,αR)

tert-Butyl (2R,3R,αR)-2-tert-butylthio-3-[N-allyl-N-(α-methyl-p-methoxybenzyl)amino]-3-phenylpropanoateC29H41NO3S[α]D23 = −6.4(c 1.7, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (2R,3R,αR)

tert-Butyl (2R,3R,αR)-2-tert-butylthio-3-[N-benzyl-N-(α-methyl-p-methoxybenzyl)amino]-3-phenylpropanoateC33H43NO3S[α]D23 = −13.5 (c 0.5, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (2R,3R,αR)

tert-Butyl (2R,3R,αR)-2-tert-butylthio-3-[N-(α-methyl-p-methoxybenzyl)amino]-3-phenylpropanoateC26H37NO3S[α]D23 = +24.0 (c 1.6, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (2R,3R,αR)

(2R,3R)-2-tert-Butylthio-3-amino-3-phenylpropanoic acidC13H19NO2S[α]D23 = +23.7 (c 0.4, MeOH)Source of chirality: asymmetric synthesisAbsolute configuration: (2R,3R)

tert-Butyl (2R,3R,6S,αR)-3-phenyl-4-(N-α-methylbenzyl)-6-methylthiomorpholine-2-carboxylateC24H31NO2S[α]D25 = −70.3 (c 1.0, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (2R,3R,6S,αR)

tert-Butyl (2S,3R,6R,αR)-3-phenyl-4-(N-α-methylbenzyl)-6-methylthiomorpholine-2-carboxylateC24H31NO2S[α]D25 = +106.4 (c 1.0, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (2S,3R,6R,αR)

tert-Butyl (2S,3R,6S,αR)-3-phenyl-4-(N-α-methylbenzyl)-6-methylthiomorpholine-2-carboxylateC24H31NO2S[α]D25 = +92.0 (c 1.0, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (2S,3R,6S,αR)