Dissertation

Novel approaches to medium rings, enantiomerically enriched alcohols and haloalkynes

Rota, F

2012

Overview

Medium rings (8-12 atoms) are present in many naturally occurring molecules which in many cases have potentially useful biological activity. Unfortunately current synthetic methods to synthesise medium rings lack general applicability or require high dilution and/or tedious optimisation procedures. This thesis describes the investigation of a novel strategy in which a suitably functionalised linear precursor undergoes double cyclisation and fragmentation to afford a medium ring. The key to this proposed sequence is the generation of an intramolecular cyclic ylide which can react with a pendant electrophile generating a bicyclic intermediate that subsequently undergoes fragmentation, thus generating a medium ring. The use of sulfur ylides was initially investigated for the synthesis of the 8-membered ring natural product Cephalosporolide-D but all attempts to trigger the proposed sequence of events were unsuccessful leading only to side reactions or decomposition. Alternative metal catalysed approaches to the synthesis of sulfur ylides were also investigated with no success. Nitrogen and phosphorus cyclic ylides were also evaluated and the latter reaction gave small quantities of the target medium ring product. This thesis also describes the discovery that high levels of diastereoselectivity could be achieved by the addition of carbon-nucleophiles to α-sulfenylaldehydes, intermediates in the synthesis of precursors to medium rings. Enantiomerically enriched secondary alcohols could be subsequently obtained from the β-hydroxysulfides after Raney-Ni reduction of the carbon-sulfur bond. In combination with the studies on metal catalysed generation of ylides, this thesis reports a gold(I) catalysed mild procedure for the synthesis of haloalkynes from either terminal alkynes or trimethylsilylacetylenes initially discovered in our laboratories. Interestingly it was found that protic acids were able to catalyse the halogenation of trimethylsilylacetylenes but not of terminal alkynes. The reactions were successfully extended to a series of aromatic and aliphatic alkynes. Procedures were also developed for the conversions of terminal alkynes into α-iodoketones which were also used in situ for the synthesis of heterocycles.

• Publisher: ProQuest Dissertations & Theses
• Subject: Organic chemistry