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UBC Theses and Dissertations

Towards a total synthesis of (–)-amphidinolide K : development of new radical cascade methods Campbell, Natalie E.

Abstract

(–)-Amphidinolide K, a novel 19-membered macrolide isolated by Kobayashi and coworkers, possesses cytotoxic activity against L1210 and KB cells in vitro. I have utilized our radical relay cyclization methodology to access the tetrahydrofuran ring in high diastereoselectivity from a readily accessible precursor. N-alkoxyphthalimides, when subjected to radical conditions, are able to generate oxygen radicals, which may undergo a 1,5-hydrogen atom transfer, and subsequently cyclize onto a nearby radical acceptor. I also extended this radical methodology towards the synthesis of a number of 5-membered carbo- and heterocycles. The 1,3-dimethyl stereocenters of our target natural product were accessed by utilizing the inherent C₂ symmetry of a simple diol precursor. Several methods to rapidly access a diene fragment of our target have been explored. A tandem ring-closing metathesis/cycloreversion strategy was originally sought, with a number of approaches towards the synthesis of the requisite sulfur-containing precursors. While this strategy was ultimately unsuccessful, it was the model inspiration for a tandem one-electron/pericyclic cascade approach. Commencing with simple alkyl aldehydes, we are now about to effect the synthesis of substituted 1,3-butadienes in a single step with high yields and diastereoselectivities. Details of this work and progress towards the total synthesis of (–)-amphidinolide K will be discussed herein.

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Attribution-NonCommercial-NoDerivs 2.5 Canada

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