Exploitation of symmetry in organic synthesis.

摘要

Two-directional synthesis by simultaneous chain homologation and terminus differentiation has been one of our favorite strategies in the synthesis of complex natural products. The efficiency of this strategy has been exemplified by the synthesis of two target molecules: uvaricin, and the F-ring of halichondrin B.; Annonaceous acetogenins constitute a new class of more than 300 compounds that have shown extremely diverse biological activities. Their novel mechanism of action and the high potency against tumor cells render them attractive as synthetic targets. A C2-symmetric 1,2-diol bis-(allylic acetate) (1) was synthesized in seven steps from D-tartrate via two directional chain synthesis. Bis-(allylic acetate) 1 was subjected to palladium-mediated, ligand-controlled double cyclization reaction to afford the bis-THF core, where two new stereogenic centers were selectively introduced, followed by subsequent desymmetrization via Sharpless asymmetric dihydroxylation to set one carbinol center. Further functional group manipulation gave a key intermediate in a known total synthesis of uvaricin.; Both C2 and sigma-symmetric 1,3-diol diacetates were synthesized from cyclopentenediol in 5 steps via two-directional chain synthesis. The palladium-mediated, ligand-controlled C 2-diol desymmetrization provided the desired stereocenters on the newly formed furan ring. Protection and selective hydroboration of the terminal alkene provided a functionalized C22 end of halichondrin B. Deprotection, oxidation and methylenation with the concomitant removal of the acetate furnished the allylic alcohol 2 with the exo-methylene in place. Isomerization of the alcohol to aldehyde by a cationic iridium catalyst provided the F-ring module of halichondrin B as well as the right functionality for future segment coupling. The desymmetrization of the meso substrate enantioselectively provided the diastereomer, leading to a refined understanding of the transition state model.; An alternative, more practical route to the halichondrin B F-ring was also pursued. It involved the ozonolytic desymmetrization of a C 2-symmetric 4-cyclohexen-1,2-diol yielding an acyloxy acetal-lactone, and the subsequent convex face C-glycosidation provided the desired carbon skeleton with the correct stereochemistry. Further functional group manipulations provided the F-ring of halichondrin B in 9 steps overall.