The research described in this report covers two areas of investigation:
1) Devolatilisation of Isotopically Labelled Aromatics via Ge-based Phase-tagging:
Isotopically labelled compounds are widely used within the pharmaceutical industry as
trace quantities can be easily detected making them ideal for ADME studies on potential drug substances and their metabolites. Generic protocols for the phase-tagged synthesis of aryl-containing intermediates from [14C]-bromobenzene (PhBr) and [14C]-phenol (PhOH) have been developed. The protocols involve devolatilisation of the above mentioned intermediates during the early stages of synthesis thus avoiding health, environmental, regulatory and cost issues associated with incomplete isotopic
containment. In particular, this chemistry has been developed in the context of the
synthesis of N-Bn-4-acetylamino-4-phenylpiperidine, a key precursor to numerous
neuroexcitatory pharmaceuticals including the Sanofi-Aventis neurokinin antagonist
saredutant (SR-48968). The key elaboration steps are Ir-catalysed borylation, Suzuki
cross-coupling and Mn-catalysed hydration. The approach constitutes a general strategy for the safe preparation of aryl-containing radiolabelled materials.
2) Towards the Total Synthesis of (+)-Lycorine: Work towards the development of a short asymmetric synthesis of the anti-tumour alkaloid (+)-lycorine using 1,4-addition to a cyclic enone and a retro-Cope elimination as key steps has been carried out. As part of this investigation, the diastereoselectivity of 1,4-addition of the lithium enolate of methyldithioacetate (LMDTA) to 4-O-TBScyclohex-2-en-1-one was examined in detail. This study has revealed an intriguing temperature dependent stereodivergency of this process. By controlling the reaction conditions either trans- or cis-selective conjugate addition could be achieved, allowing access to stereochemically defined products previously difficult to access by any other means.