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Title: Rigid analogues of metallopeptidase inhibitors
Author: Podgorski, Tadeusz Antoni
ISNI:       0000 0001 3493 2568
Awarding Body: Sheffield City Polytechnic
Current Institution: Sheffield Hallam University
Date of Award: 1987
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As an introduction the role of angiotensin-converting enzyme (ACE) in the renin-angiotensin system and the design of ACE inhibitors are discussed. The synthesis of azabicyclo [3.3.0.]octane systems was investigated using established and novel methods. The azabicyclo [3.3.0.]octane,8-(hydroxymethyl)-1-azabicyclo [3.3.0]octan-2-one was synthesized from 5-(3-butenyl)-2-pyrrolidinone. Synthetic studies towards the latter system are also presented. Two procedures have been developed for the synthesis of 8-(hydroxymethyl)-1-azabicyclo [3.3.0.]octan-2-one. The first involved epoxidation of 5-(3-butenyl)-2-pyrrolidinone which afforded the expoxy pyrrolidinone and subsequent treatment with sodium hydride gave the 8-(hydroxymethyl)-1-azabicyclo [3.3.0.]octan-2-one. The second relied on cyclisation of 5-(3-butenyl)-2-pyrrolidinone initiated by electrophilic reagents such as iodine and mercuric acetate which resulted in the formation of azabicyclo [3.3.0]octanes. The azabicvclo [3.3.0.]octanes were elaborated to complete the 8-(hydroxy-methyl)-1-azabicylo [3.3.0]octan-2-one syntheses. The synthesis of 3-oxa-1-azabicyclo [3.3.0.]octanes was also investigated. Two procedures have been developed using the key intermediate 5-(3-hydroxymethyl)-2-pyrrolidinone. The first of these involved a deprotection-reprotection technique. The second relied on hydroxy-alkylation using butyl glyoxylate. The latter route has proved more, successful and various 3-oxa-1-azabicyclo [3.3.0.]octanes have been made using this procedure. Finally, synthesis of bicyclo [3.3.0.]octanes, 8-hydroxybicyclo-[3.3.0]octan-2-one and bicyclo [3.3.0]octan-2-one-8-carboxylic acid was investigated. Two approaches to the synthesis of 8-hydroxybicyclo-[3.3.0]octan-2-one were investigated. The first, cyclopentannulation via copper catalysed conjugate addition of Grignard and lithium reagents derived from 2-(2-bromoethyl)-1,3-dioxolane, 2-(2-bromoethyl)-l,3-dioxane and 1-ethoxyethyl 3-bromopropyl ether, respectively, to cyclopenten-2-one was unsuccessful in giving the 8-hydroxybicyclo-[3.3.0.]octan-2-one. The second approach relied on cyclopentannulation via nitrile oxide-olefin cycloaddition. The latter route was successful and the 8-hydroxybicyclo [3.3.0.]octan-2-one was made using this approach. The 8-hydroxybicyclo [3.3.0.]octan-2-one was transformed over four steps to bicyclo [3.3.0.]octan-2-one-8-carboxylic acid. A set of conditions for the transformation are presented.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Organic chemistry