Total synthesis of reblastatin: convenient preparation of coupling partners and scaled assembly

Potentially scalable total synthesis of reblastatin was achieved based on Panek's previous study. Novel and convenient synthetic routes were developed for the known C8-C20 and C1-C7 coupling partners. The challenging C8-C20 fragment was prepared from TBS protected (S)-5-(hydroxymethyl)dihydrofuran-2(3H)-one (6) in nine steps (20% overall yield), and the C1-C7 fragment was synthesized from commercially available 3,4,6-tri-O-acetyl-D-glucal (9) in eight steps (35% overall yield). On a larger scale, Panek's eight-step assembly of the target molecule from the two partners was also slightly modified, giving 45 mg reblastatin (19% overall yield) in the first batch synthesis. Notable feature of our study is the settlement of the C14 chirality through a diastereoselective alpha-alkylation of 6 followed by a three-step full reduction of the lactone carboxyl, making vastly available 6 a universally applicable C11-C14 synthon for benzenoid/benzoquinone ansamycins. (C) 2014 Elsevier Ltd. All rights reserved.