Sintese de peptideos hidroxietilenicos isosteros, inibidores de aspartil proteases

AUTOR(ES)
FONTE

IBICT - Instituto Brasileiro de Informação em Ciência e Tecnologia

DATA DE PUBLICAÇÃO

2002

RESUMO

In the last several years there has been a major research effort towards the development of clinically useful inhibitors of aspartyl proteases. This worldwide search has led to various peptide isosteres, wherein the scissile peptide bond is replace by a hydrolytically more stable isosteric functional group. Atracted by the highly potent inhibition of HIV-1 protease activity of L-682,679 (1) and L-685,434 (2), we initiated a project directed towards their total synthesis. The synthesis began with addition of aldehyde (S)-7 to allylsilane 39 in the presence of SnCl4 at -78°C to give the 1,2-syn aminoalcohol 38 in 82% yeld and 90:10 diastereoselectivity. Treatment of 38 with Me2C(OMe)2 in the presence of catalytic amounts of p-TsOH gave trans-oxazolidine 54 in 91% yeld. Hydroboration of 54 with BH3.DMS gave primary alcohols 37 as a 60:40 mixture in 88% yeld. Dess-Martin oxidation followed by treatment of the intermediate aldehyde under Pinnick conditions led to carboxylic acid 36 in 76% overall yeld. Compounds 1 and 2 are readily prepared from 36 by a simple peptide coupling with the corresponding amines followed by acetonide desprotection with BF3.2AcOH. These diols, prepared also by selective desprotection of acetonide 54 with CF3CO2H were converted to lactones 69 and 70 by treatment with TPAP, NMO at r.t.. As trans-lactones 69 has been converted to inhibitors 1 and 2 earlier by others, at this point we have a formal synthesis of these compounds.

ASSUNTO(S)

peptidios inibidores enzimaticos compostos halogenados

ACESSO AO ARTIGO

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