Synthesis of some C-8-modified 3-deoxy-β- d- manno-2-octulosonic acid analogs as inhibitors of CMP-Kdo synthetase

Abstract

Selective C-8 modifications of 2,6-anhydro-3-deoxy- d- glycero- d- talo-octonic acid (“2,3-dideoxy-β- d- manno-2-octulosonic acid”, 1a) were effected via the protected 8-hydroxy derivatives 2d and 2e. Swern oxidation of 2d and 2e gave the aldehydes 3a and 3b, respectively. Compounds 3a and 3b were converted into the oxime 13b and the O-methyloxime 13c derivatives, respectively. Methodology was developed for selective cleavage of the protecting groups of 13b and 13c to give the deprotected oxime 12m and the deprotected O-methyloxime 12n, respectively. Side chain-extended products were prepared from the aldehyde 3a utilizing Wittig methodology. The branched chain allylic amine 12p was prepared from 3a in a sequence the keys steps of which were preparation of the methyl ketone 19a using LiCuMe 2 followed by Swern oxidation, methylenation of 19a using CH 2I 2-Zn-TiCl 4 to give the alkene 19b, followed by Wohl-Ziegler bromination of 19b to give the allylic bromide 19c, and conversion of the latter to the allylic azide 19d. A number of the analogs showed significant activities vs. CMP-Kdo synthetase. The most active of these was the side-chain extended alkene 12d, which proved second in activity only to the 9-amino analog ( 1c).