The synthesis and evaluation of valine mimic protio and halo enol lactones as human neutrophil elastase inhibitors

Human neutrophil elastase (HNE) has been found to be responsible for the destruction of lung tissue in emphysema. Based on the primary substrate selectivity of HNE, a series of valine mimic protio and bromo enol lactones were designed as HNE inhibitors. General methods were developed for the preparation of α- and β-alkyl-substituted 5-alkynoic acids by the bromoform reaction of the corresponding alkynoic methyl ketone, prepared by the Eschenmoser-Tanabe fragmentation. β-Methyl- and β,β-dimethyl-5-hexynoic acids were synthesized from commercially available isophorone and 3,5-dimethyl-2-cyclohexen-2-one, respectively. α-Substituted 5-hexynoic acids were prepared from 3-ethoxy-2-cyclohexen-1-one, using a novel ZnCl$\sb2$-mediated alkylation of 3-ethoxy-2-cyclohexen-1-one. The most efficient method for preparation of α-substituted-5-hexynoic acids involved a four reaction sequence--alkylation of the corresponding α-substituted ester with 1,4-dibromobutane, elimination, bromination and bis-dehydrobromination--with an overall yield of 40%. Protio enol lactonizations were performed with mercury(II) catalysis in CH$\sb2$Cl$\sb2$ or CH$\sb2$Cl$\sb2$-H$\sb2$O. Stereoselective Z-bromo enol lactonization was carried out by Br$\sp+$-induced lactonization in the presence of Ag$\sp+$. E-Bromo enol lactones were stereoselectively prepared by an improved method with NBS in CH$\sb2$Cl$\sb2$-H$\sb2$O.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Chemistry

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2011

Author dc:creator

• Dai, Wei

• Chemistry, Biochemistry

Statement dc:rights

• Copyright 1991 Dai, Wei

Language dc:language

eng

Identifier

AAI9210777
(UMI)AAI9210777

OAI identifier oai:identifier

oai:www.ideals.illinois.edu:2142/19894