Stereoselective methodology for syntheses of biologically active compounds
Doctor of Philosophy
The lipase from Pseudomonas sp. K-10 catalyzes enantioselective hydrolyses of methyl sulfinylacetates. These are used in the asymmetric SPAC (Sulfoxide Piperidine And Carbonyl) transformation, a multistep reaction of a sulfinylacetate, an $\alpha$-methylene aldehyde and piperidine, to produce a $\gamma$-hydroxy-$\alpha$,$\beta$-unsaturated ester. Superior asymmetric induction is obtained using methyl sulfinylacetates which incorporate aromatic electron-withdrawing groups. Diastereomerically and optically pure sulfinylacetates incorporating chiral auxiliaries in the ester functionality are also synthesized. Double diastereoselection occurs when these are used in the SPAC reaction, with the chirality of the sulfoxide always assuming the dominant stereochemical role. The lipase from Pseudomonas sp. K-10 is also used to resolve $\gamma$-hydroxy-$\alpha$,$\beta$-unsaturated esters via irreversible acylations in hexane. The substrates which incorporate a relatively small or large side chain are resolved efficiently, but with opposite selectivity, while those of intermediate size are acylated with poor induction. When used in tandem with the asymmetric SPAC reaction, $\gamma$-hydroxy-$\alpha$,$\beta$-unsaturated esters are obtained in good yield and high optical purity. One such chiron is used in the synthesis of (3S,4S)-4-amino-S-cyclohexyl-3-hydroxypentanoic acid, an analogue of the unusual amino acid statine. Monoacylations of pentitol-derived diols catalyzed by lipase from Candida cylindracea are described, wherein the symmetry of the product is reduced with respect to the staring material; chirons containing three asymmetric centers are generated by these biocatalytic desymmetrization processes. Some of these monoacylations are accomplished with high stereoselectivity, depending on the structure of the diol. Changing the protecting groups on the diols has little effect on the stereoselectivity. An extensive review of the syntheses of the stereoisomers and analogues of castanospermine is given. Methodology based on an asymmetric allylation reaction is then described which allows access to eight previously unreported stereoisomers. Three of these are synthesized; 1,6,8-triepicastanospermine via desymmetrization of an adonitol-derived meso diol, and 1,7,8-triepicastanospermine and 1,6,7,8-tetraepicastanospermine from L-arabinose and D-xylose respectively. (1S,2R,7R,7aR)-1,2,7-Trihydroxypyrrolizidine, the ring-contracted analogue of swainsonine, was also synthesized from D-isoascorbic acid as a model study.