抄録
Englerin A (1), a group of guaiane sesquiterpene isolated from the stem bark of Phyllanthus engleri collected in east Africa by Beutler and co-workers, have been shown to be a potent and selective inhibitor of the growth of renal cancer cell lines. Recently we reported that Rh_2(S-TCPTTL)_4 (2) is a highly effective catalyst for enantioselective tandem carbonyl ylide formation-cyclization reactions of α-diazo-β-ketoester with phenylacetylene, ethyl ethynyl ether and styrene dipolarophiles, providing cycloadducts in good to high yields and with enantioselectivities of up to 99% ee as well as with perfect exo diastereoselectibity for styrenes. In conjunction with our continuing interest in the carbonyl ylide cycloaddition strategy for the synthesis of natural products, we embarked on a program aimed at total synthesis of englerins. Herein, we describe our efforts toward a synthesis of (-)-englerin A (1). The 1,3-dipolar cycloadditon of carbonyl ylide derived from α-diazo-β-ketoester 11 with 3 equiv of ethyl vinyl ether (12a) using 1 mol % of Rh_2(S-TCPTTL)_4 afforded the exo-cycloadduct 10a in 75% yield with 95% ee. Ito-Saegusa oxidation of silyl enol ether derived from 10a and subsequent addition of organolithium reagent 18b followed by Red-Al^[R!〇] reduction of tert-butyl ester, tosylation of primary alcohol and oxidative rearrangement furnished enone 24, which was converted to ketone 25 in a stereoselective manner. Intramolecular aldol reaction and subsequent Luche reduction gave allyl alcohol 26 in good yield. Hydrogenation of 26 with Pd/C gave diol 27 as a major product, which was transformed to acetate 28. Oxidation of 28 under the Sharpless conditions followed by reduction of 29 with LiBEt_3H gave diol 5 in high yield. Finally, regioselective acylation of the C9-hydroxy group followed by esterification of the C6-hydroxy group with cinnamic acid using Yamaguchi's procedure and desilylation completed the catalytic asymmetric synthesis of (-)-englerin A (1).
