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The total synthesis of a new platelet aggregation-inhibiting gamma-lactam PI-091 (1) gave a 1:1 diastereomeric mixture at the gamma-ketal carbon. The high-yielding aldol reaction of an appropriately protected 1,3,4-trihydroxy-4-methyldecan-2-one 42, prepared from D-glucose, with the kinetically generated enolate of 3-methyl-2-butanone provided 43. The resulting diastereomeric mixture of the aldol adduct 43 was converted to a 2,4-alkylated furan 45 via an intramolecular ketalization followed by dehydration. The addition of a singlet oxygen to the alpha-trimethylsilylated furan 48derived from 45 under photochemical conditions efficiently provided an alpha,gamma-dialkylated gamma-hydroxy gamma-lactone 47. The transformation of methyl ketal 52 prepared from 47 into gamma-hydroxy gamma-lactam 53 was achieved by exposure to liquid ammonia in MeOH. The total synthesis of 1 was achieved from 52 through the Dess-Martin periodinane oxidation of the secondary hydroxy group in the side chain. The present total synthesis revealed that the stereogenic carbon center in the side chain in natural 1 is S.

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The inhibitory properties of a series of synthetic epimers and analogues of swainsonine towards the multiple forms of human alpha-mannosidases were studied in vitro and in cells in culture. Of the five epimers tested, only the 8a-epimer and 8,8a-diepimer of swainsonine were specific and competitive inhibitors (Ki values of 7.5 x 10(-5) and 2 x 10(-6) M respectively) of lysosomal alpha-mannosidases in vitro and induced storage of mannose-rich oligosaccharides in human fibroblasts in culture. The structures of these storage products indicated that processing alpha-mannosidases had also been inhibited. This was consistent with the observed inhibition in vitro of these enzymes by these compounds. In contrast, the 8-epimer, 1,8-diepimer and 2,8a-diepimer of swainsonine had no appreciable effect on any alpha-mannosidases. The corresponding open-chain analogues of swainsonine, namely 1,4-dideoxy-1,4-imino-D-mannitol, of the 8a-epimer, namely 1,4-dideoxy-1,4-imino-D-talitol, and of the 8,8a-diepimer, namely 1,4-dideoxy-1,4-imino-L-allitol, were weaker competitive inhibitors of lysosomal alpha-mannosidase, with Ki values of 1.3 x 10(-5), 1.2 x 10(-4) and 1.2 x 10(-4) M respectively. These analogues also proved less effective at inducing oligosaccharide accumulation and in disturbing glycoprotein processing. These compounds offer the opportunity to determine which alterations in the chirality of the swainsonine molecule affect its inhibitory specificity. A comparison of their biological activities has identified reagents that will be useful for studying steps in the biosynthesis and catabolism of glycoproteins and that may be of potential value in chemotherapy.