Concise Diverted Total Synthesis of Amphidinolide T1 and T4 from a (12E)-Cycloalkene by Selective Functionalization of the C12-C13 Double Bond

Abstract

Starting from a 19-membered (12E)-cycloalkene prepared by ring-closing metathesis, amphidinolide T1 and T4 were efficiently synthesized via a short sequence of selective functionalization. The key steps highlighted stereoselective dihydroxylation of the (E)-C12-C13 double bond and highly regioselective silylation/desilylation of the (12S,13S)-diol. In particular, a significant solvent effect was discovered for suppressing 1,4 O→O silyl migration or disilylation during selective mono-silylation of the (12R,13R)-and (12S,13S)-diols in toluene. In combination with our previous synthesis of amphidinolide T3, the same (12E)-cycloalkene serves as an advanced common intermediate for concise diverted total synthesis of amphidinolide T family of marine macrolides.Diverted total synthesis (DTS) has been emerging as a research frontier in chemistry and biology with aiming at decoding the structure-function relationship of natural products through synthesizing libraries of analogues from advanced intermediates and elucidating/optimizing their pharmacophoric space. 1 Efforts in DTS have yielded numerous successful natural product based or inspired drugs such as anticancer agents. 1b In parallel the concept of DTS should be applicable for the synthesis of natural products that share a similar or the same core structural unit from an advanced intermediate of lesser structural complexity. Being isolated from symbiotic marine dinoflagellate Amphidinium sp., 2,3 the amphidinolide T series of marine macrolides highlight such a case that all five congeners (T1-T5) possess a common tetrahydrofuran-containing 19-membered macrolide core. Shown in Scheme 1 are amphidinolide T1 (1), T3 (2), and T4 (3) which are either the regioisomers of the a-hydroxy ketone functionality at C12 and C13 positions (T1 vs. T3) or C12-OH (T3 vs. T4) and C14-Me (T4 vs. T5; structure not shown) epimers, respectively. In addition, amphidinolide T2 differs from T3 only on the side chain by having an extra stereogenic center at C21 position. Cytotoxicity was reported for amphidinolide T1-T4 with IC 50 values of 18, 10, 7.0, and 11 mg/ mL, and 35, 11.5, 10, and 18 mg/mL, respectively, against murine lymphoma L1210 and human epidermoid carcinoma KB cell lines. 3b Total syntheses of amphidinolide T1-T4 have been completed by many research laboratories including ours. 4-8 Among these accomplishments, Fürstner and co-workers took a DTS approach to amphidinolide T1, T3, and T4 by using two acyclic stereochemically and regioselectively differentiated 12,13-diol derivatives. 1d Scheme 1 Structures of amphidinolide T1 (1), T3 (2), and T4 (3) and the common (12E)-cycloalkene intermediate 4In our recent total synthesis of amphidinolide T2 and T3, we envisioned a DTS strategy based on a ring-closing metathesis (RCM) 9 and asymmetric dihydroxylation (AD) 10 sequence. The 19-membered ring (12E)-cycloalkene 4 and an analogue with a different side chain were first assembled via RCM 11 and were then subjected to selective functionalization via AD and post-AD transformations to i...