CMP-Kdo synthetase' catalyzes a key step in the biosynthesis of bacterial lipopolysaccharide'. Recently, the 2-deoxy derivative of/LKdo (7) was reported to be a potent inhibitor of CMP-Kdo synthetase3. Two different syntheses of 7 have been reported4v5, the first involving hydrogenolysis of the glycosyl chloride of Kdo tetraacetate methyl ester, ant thus requiring Kdo as a starting materia14. Although Kdo can be prepared in practically useful yield by the Conforth condensation of D-arabinose and oxalacetic acid', the preparation is tedious and one of the starting materials, oxalacetic acid, is rather expensive. The second synthesis started with much less expensive D-mannose, but the method gave an ~1, fl mixture of 2-deoxy-Kdo derivatives, together with C-4 epimerized byproducts'. In this Note we describe a new, stereospecific synthesis of 2-deoxy+Kdo which also starts from D-mannose.
RESULTS AND DISCUSSION
Our synthetic plan was to construct the tetrahydropyran ring of 2-deoxy+Kdo by intramolecular C-C bond formation. We selected a 2,3-O-isopropylidene-COalkoxycarbonylmethyl-D-mannitol derivative having a leaving group at C-l as the key intermediate, expecting that the 2,3-O-isopropylidene group would assist the intramolecular cyclization by forcing the two relevant functional groups into close proximity (they would be cis on the five-membered acetal ring).
In order to introduce an ethoxycarbonylmethyl group at O-4, the reaction of 1-O-tert-butyldimethylsilyl-2,3:5,~i-O-isopropylidene-~-mannitol (24) with ethyl bromoacetate in the presence of sodium hydride in oxolane was first attempted. However, the reaction did not give the expected ether but instead resulted in extensive O-desilylation. This result indicated that a base-stable protecting group is necessary at O-l, and the benzyl group was chosen for the purpose. Thus, the primary alcohol function of 1,2:4,5-di-U-isopropylidene-D-mannito16
(1) was selectively benzylated by treatment with benzyl bromide and sodium hydride in Me,NCHO at 0" to give I-Obenzyl-2,3:5,6-di-O-isopropylidene-D-mannitol(2b) in 85% yield. Treatment of 2b with