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Proceedings of the 31 st European Peptide SymposiumMichal Lebl, Morten Meldal, Knud J. Jensen, Thomas Hoeg-Jensen (Editors)European Peptide Society, 2010Cryptophycins – Synthesis of Potent FunctionalizedNew Antitumor AgentsBenedikt Sammet and Norbert SewaldBielefeld University, Organic and Bioorganic Chemistry, Bielefeld, 33615, GermanyIntroductionCryptophycins are a family of macrocyclic depsipeptides with high cytotoxicity. Thebioactivity of cryptophycins is based on their ability to interact with tubulin, which leads toa strong suppression of the microtubule dynamics. Cryptophycin-1 was isolated from aculture of Nostoc sp. ATCC 53789 in 1990 and many more synthetic derivatives followed.Cryptophycin-52 (1) has been the pharmacologically most important representative, so far(Figure 1). However, clinical phase I and phase II trials were discontinued due toneurotoxic side-effects and lack of efficacy in vivo [1].Fig. 1. Structure of cryptophycin-52 (1) comprising of four units.Results and DiscussionIn the course of our cryptophycin research a target was to alter the stereochemistry at theepoxide to give rise to the cryptophycin-39 (2) unit A fragment with a cis-epoxide(Figure 2). No total synthetic approach to cryptophycin-39 had been published so far. Thebasis for the synthetic strategy was lactone 4 (Scheme 1). Years ago, a synthesis of rac-4was published in high yields using potassium peroxomonosulfate (Oxone ® ) andtrans-styrylacetic acid (3) [2]. Due to thesimilarity of the Shi-epoxidation reactionconditions to the racemic lactone synthesis itwas possible to apply a Shi-epoxidation toobtain lactone 4 in high enantiomeric excess ona multi-gram scale. The following steps weresimilar to a unit A cryptophycin synthesisrecently published [3]. With only five steps toallyl alcohol 8 it is currently the shortestFig. 2. Structure of cryptophycin-39 (2). synthesis of a cryptophycin unit A buildingblock in literature [4].Scheme 1. Synthesis of cryptophycin-39 unit A building blocks 8 and 9 [4].324