Studies on the Total Synthesis of Amphidinolide O (III): A Stereoselective Synthesis of C1-C11 Fragment

Abstract

The amphidinolides were isolated from the marine dinoflagellate Amphidinium sp., which produces a host of secondary metabolites endowed with potent cytotoxicity against various cancer cell lines. Amphidinolide O (1) displayed potent in vitro cytotoxicity against L1210 marine leukemia cells and human epidermoid carcinoma KB cells with 1.7 and 3.6 μg/mL of IC50s, respectively. In addition to our recent reports regarding to the synthesis of C12-C17 and C3-C11 fragments of amphidinolide O (1), we describe herein a new route to diastereoselective synthesis of C1-C11 fragment of 1. The retrosynthetic analysis of 1 led to the C1-C11 fragment 2 and C12-C17 fragment 3 (Scheme 1). The hemiketal 2 was expected from acyclic precursor 4 which, in turn, would be derived by diastereoselective aldol reaction between ketone 5 and aldehyde 6. The C1-C6 fragment 8 (equivalent to 5 in scheme 1) was prepared as summarized below (Scheme 2). Enolization of carboximide 7 with Bu2BOTf and EtN(i-Pr)2 was followed by reaction with aldehyde to provide the syn-aldol product in 86% yield (ds = > 97 : 3 by H NMR analysis) (Scheme 2). The aldol product was treated with N,O-dimethylhydroxylamine hydrochloride and Al(Me)3 to provide the Weinreb amide in 91% yield. The free hydroxyl group was protected as PMB ether, and finally Weinreb amide was converted to ketone 8 in 85% yield by reaction with MeMgCl. Synthesis of C7-C11 fragment 10 (equivalent to 6 in scheme 1) was completed via 5-step sequences (Scheme 3). Monoprotection of propane-1,3-diol (9), Swern oxidation of the remaining alcohol to aldehyde, and Wittig-olefination was undertaken to give α,β-unsaturated ester, which was subsequently reduced by DIBAL and oxidized to provide the C7-C11 fragment 10, another key intermediate in the next aldol reaction. Aldol-reactions of fragments 8 and 10 were investigated with four chiral boron reagents in ether at −78 C (Scheme 4), and the use of chlorodicyclohexylborane provided the desired product with the best diastereoselectivity (11a : 11b = 67 : 33) in 61% (11a) and 30% (11b) yield, respectively. Hydroxyl group-directed 1,3-anti reduction of either 11a or 11b with NaBH(OAc)3 provided the 5,7-anti diol 12a or 12b in 91% yield. The (5R,7S)-isomer 12a was treated with 2,2-dimethoxypropane in the presence of PPTS (Scheme 5). The PMB-