Cheung, Maxine Lai-Fun; (2003) Studies towards the total synthesis of the naturally-occurring anticancer agent halichomycin. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

This thesis is split into 4 sections, and is concerned with the development of a biomimetic total synthesis of the naturally-occurring antitumour agent, halichomycin. The first section describes a range of biomimetic natural product syntheses that have been devised since 1917, and shows the levels of complexity that have been transcended by various groups in these efforts. The second part of the thesis discusses the discovery and structure elucidation of halichomycin and Wood's synthetic approach to a region of this compound. In addition to earlier ventures, our eventual biosynthetic proposal for tricyclic assembly in halichomycin is described in this thesis. Synthetic efforts towards halichomycin have so far resulted in the synthesis of an advanced AB-carbon backbone intermediate 252. In Chapter 3, our group's original retrosynthetic analysis of halichomycin is described along with our attempts to implement this approach. A biosynthetic proposal for my assembly is then presented, and it will be shown how this served as a source of inspiration for a new synthetic strategy to halichomycin. Our progress towards this objective will then be reviewed. Specifically, the synthesis of an advanced precursor 252 of pre-halichomycin will be discussed. Noteworthy features of our synthesis include the Roush asymmetric crotylboration reaction between 210 and 211, en route to the anti-anti alcohol 212, and the face-selective enolate alkylation of 236 to give 237. Aldehyde 256 was converted to 254 via an Evans aldol reaction, followed by protection, then reduction. A Wittig-Stille sequence on 254 then completed the synthesis of 252.

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