Total Syntheses of (+)-Altholactone [(+)-Goniothalenol] and Three Stereocongeners and Their Cytotoxicity against Several Tumor Cell Lines

Abstract

Abstract Enantiospecific total synthesis of (+)-altholactone [(+)-goniothalenol] (1), a novel tetrahydrofuropyran-5-one possessing significant cytotoxicity against several tumor cell lines, has been achieved by using l-arabinose as the redundant starting material. The pivotal tetrahydrofuran formation was realized by treatment of the diastereomeric mixture of (2S,3R)-4,5-epoxy-5-phenyl-1,2,3-pentanetriol 1,3-benzylidene acetals 8 and 8′ with silica gel. Simultaneous stereochemical inversion at C-4 and C-5 of the major cyclization product, O,O′-benzylidene derivative of (2S,3R,4S,5S)-2-(hydroxymethyl)-5-phenyltetrahydrofuran-3,4-diol (11), to the 2S,3R,4R,5R diastereomer 10 was achieved by hydroboration of (2S,3S)-3-hydroxy-2-(hydroxymethyl)-5-phenyl-2,3-dihydrofuran O,O′-benzylidene derivative (18) which derived from 11. Pfitzner-Moffatt oxidation of 10 followed by NaBH4 reduction gave the 2S,3R,4S,5R diastereomer 20 exclusively. Displacement of the triflate group in (2S,3R,4S,5S)-2-(hydroxymethyl)-5-phenyl-4-[(trifluoromethylsulfonyl)oxy]tetrahydrofuran-3-ol O,O′-benzylidene derivative (21) by acetate, which was prepared from 11, furnished the 2S,3R,4R,5S diastereomer 22. The total synthesis of 1 was completed by Collins oxidation of (2S,3R,4R,5R)-2-(hydroxymethyl)-3,4-bis(methoxy-methoxy)-5-phenyltetrahydrofuran (34), which was prepared from 10, and subsequent Witting olefination with (ethoxycarbonylmethylene)triphenylphosphorane followed by hydrolysis. By employing the analogous reaction sequence, compounds 11, 20, and 22 were efficiently converted into (+)-7,8-di-epi- (2), (+)-7-epi- (3), and (+)-8-epi-altholactone (4), respectively. The cytotoxicity of 1–4 against several tumor cell lines was examined.