New Approaches to the Synthesis of Alkyl-Substituted Enol Lactone Systems, Inhibitors of the Serine Protease Elastase

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We have synthesized a series of alkyl-substituted enol lactones designed to act as mechanism-based inhibitors of human neutrophil elastase (HLE). General methods were developed for the preparation of α- and β-alkyl-substituted 5-hexynoic acids by the bromoform reaction on the corresponding alkynoic methyl ketone, prepared by an Eschenmoser-Tanabe fragmentation sequence from a suitably substituted cyclohexenone. By this method, β-methyl- and β,β-dimethyl-5-hexynoic acids were synthesized from commercially available isophorone and 3,5-dimethyl-2-cyclohexen-1-one, respectively. α-Substituted 5-hexynoic acids were prepared from 3-ethoxy-2-cyclohexen-1-one, using a novel ZnCl2-mediated alkylation that we developed; this method gives high yields of α′-alkylation products, even with secondary halides. The most efficient method for the preparation of α-substituted 5-hexynoic acids involved a four-reaction sequence—alkylation of the α-substituted ester with 1,4-dibromobutane, elimination, bromination and bisdehydrobromination—that proceeded in high overall yield. Protio enol lactonizations were performed with mercury(II) catalysis in CH2Cl2 or CH2Cl2-H2O. Stereoselective Z-bromo enol lactonization was carried out by Br+-induced lactonization in the presence of Ag+. E-Bromo enol lactonization with N-bromosuccinimide in CH2Cl2 in the presence of a small amount of water gave better yields and shorter reaction times than the traditional anhydrous conditions. In studies of the inhibitory activity of these lactones toward several proteases (reported in full elsewhere), we found that the α-alkyl-substituted protio and bromo enol lactones 1–3 were very good inhibitors of HLE, with ka/Ki values ranging from 14 500 to 37 500 M−1 s−1; the β-alkyl-substituted enol lactones 5–8 showed only moderate inhibition of HLE.

Original languageEnglish (US)
Pages (from-to)1900-1908
Number of pages9
JournalJournal of Organic Chemistry
Issue number7
StatePublished - 1993

ASJC Scopus subject areas

  • Organic Chemistry

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