Infoscience

Thesis

Access to long-chain polyketides by double-elongation reactions: the AB and CD spiroacetals of the spongistatins

Due to the spongistatins' fascinating and complex molecular architectures, and their important biological activities, these marine macrolides have been the subject of intensive efforts directed towards their total synthesis. As an attractive alternative to isolation from marine microorganisms, which usually provides only minuscule quantities of this family of macrolides, total synthesis aims to deliver sizable amounts of the natural product, along with enabling access to novel structural analogues, for further biological evaluation. These factors, combined with the impressive molecular architectures themselves, present compelling and formidable challenges to contemporary organic synthesis with regard both to strategy and methodology for their total synthesis in the laboratory. To this end, efforts targeting such complex macrolides provide an arena in which the synthetic chemist can develop new and more efficient methodologies and display such advances to the ultimate task of complex target synthesis. Through this process, new levels of stereocontrol and novel strategies to streamline the entire synthetic route help evolve the field as a whole. The synthetic efforts directed at the AB and CD spiroacetals of the northern fragment are herein disclosed. In conjunction with the synthesis of the southern fragment within our group, this renders itself as an original and efficient formal total synthesis of spongistatin 1. The synthesis of these key fragments has been optimized to reduce protections, set up chirality in an efficient and absolute manner and avoid fluctuations in oxidation states. Achievements in these aspects, that are often used to define the art of modern day total synthesis, have resulted in a rapid synthesis of these key fragments. The synthesis of the AB and CD spiroacetals was completed in 7 and 11 steps, respectively, rendering the process competitive with the most rapid previous synthesis to date. The sequences are based around the use of 1,3-bis(trimethylsilyl)-2-methylidenepropane in double elongation Sakurai reactions with both aldehydes and ketones to form advanced functionalized polyketides.

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