Synthesis Of 3-C-Branched Kdo Analogs

In the family of 2-keto-3-deoxy sugar acids,3-deoxy-D-manno-oct-2-ulsonic acid(Kdo)is often found as an essential component of the inner core structures of lipopolysaccharides(LPS)in the outer membrane of gram-negative bacteria.Kdo analogues can serve as potential therapeutic agents of combating antibiotic-resistant bacteria,so the assembly of new types of Kdo analogues for glycobiological research is very attractive.The stereoselective construction of C-C bonds at the C-3 position of Kdo residue has not been reported,since the reactivity of the acidic keto-sugars could be greatly affected by the electron-withdrawing effect of the C-l carboxylic group and the absence of a hydroxyl group at the C-3 position.In this paper,we report a highly efficient method to access the 3-C-branched mono-and di-Kdo enyne analogues based on Sonogashira coupling of 3-iodo Kdo glycal with a range of terminal alkynes and dialkynes.The 3-iodo Kdo glycal can be obtained by NIS/TMSOTf promoted one-step reaction from peracetylated Kdo ethyl ester.Moreover,asymmetric hydrogenation of the resulting Kdo enyne analogs over Pearlman's catalyst followed by saponification can be effectively carried out to provide the 2-deoxy-a-Kdo analogues in a stereospecific manner.It lays the foundation for inhibitory activities against CMP-Kdo synthetase.