14 Total Synthesis of Siccanin
Details
Starting from the known keto ester (3), the total synthesis of siccanin (1), a strongly antigerminative mold metabolite produced by Helminthosporium siccans, as well as siccanochromene-E (2), one of biogenetic congeners of the former, has been achieved. The keto ester (3) was submitted to the Robinson annulation with butenone to yield octalone (5), which was then converted into the octaline (8) through the 5-step conventional sequence shown in Scheme 1. After deacetalization of (8), the resultant octalone (10) was isomerized to conjugated enone (11) by treatment with p-toluene-sulfonic acid in methanol, and the latter enone was proven cis-fused by physical and chemical means (Scheme 2). Regioselective hydroxymethylation of the kinetic enolate of 11, followed by methylation with methyl lithium afforded carbinol (25), which was then converted to aldehyde (27) in moderate overall yield (Scheme 3). Diol (28) obtained from 27 in the reaction with lithiated orcinol dimethyl ether yielded, on treatment with pyridinium hydrochloride, tetrahydrofuran derivative (29) in high yield, and the product was then demethylated to monomethyl ether (30) (Scheme 4). While sulfuric acid-induced cyclization of 30 afforded siccanochromene-E methyl ether (31), Lewis acid-catalyzed reaction of 30 gave siccanin methyl ether (32) along with other unidentified products. Demethylation of 32 and 31 were achieved by treatment with sodium ethylthiolate to give 1 and 2 in good yield, respectively (Scheme 5).
