Domostoj, M.; (2005) Enantiospecific total synthesis of (-)-agelastatin a and evaluation of its biological properties. Doctoral thesis , University of London.

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Abstract

(-)-Agelastatin A (1) is a tetracyclic alkaloid recently isolated from the marine sponge Agelas dendromorpha. It has powerful antitumour properties in vitro and in vivo, and is a selective inhibitor of the ubiquitous enzyme, glycogen synthase kinase 3(3. It also exhibits insecticidal properties. In this thesis, we describe an enantiospecific total synthesis of the cyclopentenone (-)- 175, an advanced intermediate whose racemate had previously been converted into ( )-agelastatin A by Weinreb and co-workers. Our strategy exploited the chiral oxazolidinone 150 as a key intermediate, and commenced from the Hough-Richardson aziridine 234 (which is itself obtainable from D-glucosamine hydrochloride). Noteworthy reactions in the route to 150 include the regioselective trans-diaxial ring-opening of 234 with azide ion to set up the vicinal diamido functionality present in (-)-175, and the Grubbs-Hoveyda ring-closing metathesis reaction that is used to fashion its cyclopentene core. We also describe a new synthetic endgame for converting (-)-150 to (-)-agelastatin A via cyclopentenone 307. This new endgame has so far allowed 223 mg of (-)-agelastatin A to be prepared for detailed toxicological and biological evaluation. Some of the results of these studies are presented in this thesis.

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