Synthesis of 12-aza analogs of epothilones and (E)-9,10-dehydroepothilones |
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Authors: | Fabian Feyen Kurt Hauenstein |
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Affiliation: | Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology (ETH) Zürich, HCI H405, Wolfgang-Pauli-Str. 10, CH-8093 Zürich, Switzerland |
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Abstract: | N-Boc-12-aza-epothilone analog (azathilone) 1 is a potent inhibitor of human cancer cell growth and represents a structurally new class of natural product-derived microtubule-stabilizing agents. Compound 1 has been prepared employing a convergent strategy that is based on the consecutive assembly of building blocks 3, 4, and 19 into diene 20 and subsequent RCM-mediated macrocycle formation. The aldol reaction between aldehyde 3 and ketone 4 delivered the required 6R,7S diastereoisomer 5 with good selectivity and provided a reliable entry into the stereoselective synthesis of carboxylic acid 12. RCM with diene 20 was highly E-selective, thus giving efficient access to (E)-9,10-dehydro-1 (2). The latter is a key analog in SAR studies with 1. |
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