Since 1996, he has been a full professor at the University of Vienna. His main research interests lie in the total synthesis of structurally and physiologically interesting natural products. Scheme 1. Early Fragmentation of Carbocation Observed Scheme 2. Fragmentation of Carbocation into Olefin and Ketone Scheme 3. Eschenmoser's Pioneering Work on Fragmentations Scheme 4. Spontaneous Fragmentation of β-Bromo Acid 19
Discriminating elimination: A new method for the synthesis of methyl-branched trisubstituted Z olefins, a structural motif in many polyketides with anticancer activity, relies on an (-)OH-induced decarboxylative Grob-type fragmentation (see scheme; Ms = mesyl). The starting materials are beta-mesyloxy lactones with a quaternary alpha center, which are prepared by aldol reactions in a diastereo- and enantioselective manner.
Methyl-branched (Z)-trisubstituted olefins are found in many polyketides with interesting biological activity, such as epothilone D (1), discodermolide (3), and peloruside A (2). Despite the employment of numerous different strategies, this motif has often been the weak point in total synthesis. Thus, we present a novel hydroxide- induced Grob-type fragmentation as an easy access to trisubstituted olefins. In our case, beta-mesyloxy delta-lactones with three stereogenic centers were chosen whose fragmentation underlies a high stereoelectronic control. Major challenges in the syntheses were the installation of quaternary stereocenters, achieved by enzymatic desymmetrization of meso-diesters and by aluminium-promoted stereoselective rearrangement of chiral epoxides, respectively. Different aldol strategies were developed for the formation of the fragmentation precursors. Additionally a short survey about nucleophilic additions to aldehydes with quaternary alpha-centers is presented.
In October 2007 the first epothilone derivative has received FDA approval for the treatment of metastatic breast cancer. This event forms the background of this review which tries to highlight the historical development of the epothilones, namely their discovery, biosynthesis, fermentation, total synthesis, semisynthetic derivatives and clinical trials.
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