An enantioselective synthesis of (+)-azimic acid

Herein we report a concise enantioselective synthesis of (+)-azimic acid starting from (5S,6S)-6-methyl-5-benzyloxy-2-piperidinone 8a, which was prepared from protected (S)-3-hydroxyglutarimide 6 according to a method recently disclosed in our laboratory. The key step is a stepwise regioselective reductive alkylation of the imide 10, which established the 2,6-cis-stereochemistry in excellent diastereoselectivity.

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(5S,6S)-5-Benzyloxy-6-methyl-2-piperidinoneC13H17NO2[α]D20=+9.4 (c 0.5, CHCl3)Source of chirality: (S)-glutamic acidAbsolute configuration: (5S,6S)

(5S,6S)-5-Benzyloxy-1-(tert-butyloxycarbonyl)-6-methyl-2-piperidinoneC18H25NO4[α]D20=+8.9 (c 1.1, CHCl3)Source of chirality: (S)-glutamic acidAbsolute configuration: (5S,6S)

tert-Butyl [(2S,3S)-3-benzyloxy-12-(tert-butyldimethylsilyloxy)-6-oxododecan]-2-yl carbamateC30H53NO5Si[α]D20=-13.5 (c 0.9, CHCl3)Source of chirality: (S)-glutamic acidAbsolute configuration: (2S,3S)

tert-Butyl [(2S,3S)-3-benzyloxy-12-hydroxy-6-oxododecan]-2-yl carbamateC24H39NO5[α]D20=-24.6 (c 0.8, CHCl3)Source of chirality: (S)-glutamic acidAbsolute configuration: (2S,3S)

(10S,11S)-10-Benzyloxy-11-(tert-butoxycarbonylamino)-7-oxododecanoic acidC24H37NO6[α]D20=-15.9 (c 1.0, CHCl3)Source of chirality: (S)-glutamic acidAbsolute configuration: (10S,11S)

(+)-(2S,3S,6R)-Azimic acidC12H23NO3[α]D20=+7.7 (c 0.5, MeOH)Source of chirality: (S)-glutamic acidAbsolute configuration: (2S,3S,6R)