Synthesis of (3R,4S)-5,5-dihydroxymethyl-4-hydroxy-3-methylpyrrolidone

Abstract

For the synthesis of (+)-lactacystin 1, the key intermediate,(3R,4S)-5,5- dihydroxymethyl-4-hydroxy-3-methylpyrrolidone 48, has been synthesized effectively via aminomercuration of allylic trichloroacetimidate 65. Epoxide 64 was prepared by the known procedure from methyl (s)-(+)-3- hydroxy-2-methylpropionate over 6 steps in 48% overall yield. Allylic diol 60 was readily obtained by the opening of the epoxide ring in 64 in 75% yield. Mercurals 85 was elaborated via aminomercuration of allylic trichloro- acetimidate 65 derived from allylic diol 60 in 85% yield. Treatment of 85 with TEMPO in the presence of lithium borohydride introduced the hydroxy group successfully to furnish oxazolines 87 in 85% yield. Amides 94 were obtained from 87 by deprotection,acetylation and diol protection in sequence in 67\% yield. Amides 94 were debenzylated and the resulting primary alcohols were oxidized to provide carboxylic acids 97. γ-Lactam 98 and 99 were prepared by deprotection of amide group of 97 and the cyclization of γ-aminoacids. The reductive cleavage of N-O bonds and the concomitant hydrolysis of acetonide groups in 98 and 99 provided the triol γ-lactam 48 in 82% yield.