THE FURAN APPROACH TO OXYGENATED NATURAL-PRODUCTS - TOTAL SYNTHESIS OF (+)-KDO

A de novo asymmetric synthesis of the higher monosaccharide 3-deoxy-D-manno-2-octulosonic acid, (+)-KDO (1), was completed in 12 steps starting from furan and isopropylidene-D-glyceraldehyde. The synthesis commenced with the conversion of furan (4) into the protected furfuryl carbinol 5 by the highly stereoselective addition of 2-lithiofuran to isopropylidene-D-glyceraldehyde and subsequent trapping of the intermediate alkoxide. Metalation of 5 followed by alkylation with benzyl chloromethyl ether and hydroxyl deprotection then provided 9 in a single operation. The key transformation of the synthesis entailed sequential oxidative processing of 9 with t-BuOOH in the presence of a catalytic amount of VO(acac)2 and O-methylation of the intermediate hemiacetal moiety to furnish the alpha-methyl glycoside 12 as the major product. Stereoselective 1,2-reduction of 12 using K-Selectride (Aldrich) gave the allylic alcohol 15, which was elaborated to 20 by electrophile-induced cyclization of the allylic carbamate 19. Refunctionalization of 20 proceeded in a straightforward fashion by a process involving reductive removal of iodide at C(3) and the benzyl protecting group at C(1) to furnish 23. Oxidation of the intermediate primary alcohol moiety at C(1) of 23 and deprotection of the remaining hydroxyl functions delivered (+)-KDO (1).