Catalytic bromination for organic synthesis

Abstract

On the instigation of Dr. C.S.P. McErlean I have investigated an enduring problem in synthetic organic chemistry: the lack of general methodologies for enantioselective halogenation. This omission in our otherwise broad capacity for introducing p-block elements asymetrically hampers the synthesis of naturally-occuring organohalogens, a large and growing class of known natural products possessing broad biological activity. We used rational design to envisage a chiral, nucleophilic catalyst with secondary binding sites upon catalyst. We synthesised a family of triazole-bearing BINOL-derived phosphoramidites and addressed issues related to the stability of these novel ligands. We showed that our catalytic system could be used to access the principle brominated substructures found in natural products. Our catalysts promoted rapid, chemoselective and diastereoselective bromocyclisation reactions, although enantioselectivity proved to be an enduring challenge. The delivery of a chloronium ion was also shown to be possible. Our success prompted us to embark on the synthesis of the snyderane natural products. We began with a one-step total synthesis of 3β-bromo-8-epicaparrapi oxide. Following this we synthesised the snyderols – the parent natural products of this family of sesquiterpenes. Our snyderol synthesis also required only a single step. We then targeted luzofuran, a recently isolated snyderane which had not previously been made. We synthesised luzofuran in a racemic fashion in two steps. We then completed a four-step asymmetric total synthesis, includeding the first report of a successful Noyori reduction of an allyl aryl ketone. An alternative reagent system based on the use of phosphine oxides as strong halogen bond acceptors was explored as a means to promote electrophilic halogenation reactions of prochiral biarylmethanes – substructures of interest in medicinal chemistry. We demonstrated that bifunctional catalysts were uniquely capable reagents in performing these reactions as compared to monovalent systems. The difficulty entailed in controlling the steric environment around the monovalent, reactive halonium equivalent meant that enantioselectivity was an enduring challenge.