Asymmetric Total Synthesis of Cytotrienin A: Late‐Stage Installation of C11 Side Chain onto the Macrolactam Scaffold

Abstract

Cytotrienin A, an ansamycin-class antibiotic, exhibits potent apoptosis-inducing activity and has attracted much attention as a lead compound for anticancer drugs. Herein, we report a new asymmetric synthetic route to cytotrienin A, employing an unexplored approach involving the late-stage installation of a C11 side chain onto the macrolactam core. In this strategy, we utilized the redox properties of hydroquinone and installed a side chain on the sterically hindered C11 hydroxy group by the traceless Staudinger reaction. This study also demonstrated that the boron-Wittig/iterative Suzuki-Miyaura cross-coupling sequence was effective for the concise and selective construction of the (E,E,E)-conjugated triene moiety. The developed route opens new opportunities for the structure-activity relationship studies of the side chains of these ansamycin antibiotics and the preparation of other synthetic analogs and chemical probes for further biological studies.

Enantioselective Divergent Syntheses of Diterpenoid Pyrones

“…With vinyltetrahydrofuran-containing DTPs 5 – 7 secured, we turned our attention to the elongation of the side chain (the C11–C16 fragment). As shown in Scheme A, starting from intermediate 11 , we conducted anti-Markovnikov borylation of the terminal alkyne (Scheme , Table 1) . Although initial direct borylation with various boron reagents proved to be ineffective (Table , entry 1), Cu-catalyzed borylation of the terminal alkyne was identified as the method of choice after screening different ligands (Table , entries 2–4).…”