Synthesis of some C-8-modified 3-deoxy-beta-D-manno-2-octulosonic acid analogs as inhibitors of CMP-Kdo synthetase.
Selective C-8 modifications of 2,6-anhydro-3-deoxy-D-glycero-D-talo-octonic acid ("2,3-dideoxy-beta-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 LiCuMe2, followed by Swern oxidation, methylenation of 19a using CH2I2-Zn-TiCl4 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).
Tadanier
J
J
Antiinfective Research Division, Abbott Laboratories, North Chicago, Illinois 60064.
Lee
C M
CM
Whittern
D
D
Wideburg
N
N
D004791:Enzyme Inhibitors / Q000138:chemical synthesis; D004926:Escherichia coli / Q000201:enzymology; D015394:Molecular Structure; D009713:Nucleotidyltransferases / Q000037:antagonists & inhibitors*; D013400:Sugar Acids / Q000138:chemical synthesis* / Q000494:pharmacology
D004791:Enzyme Inhibitors; D013400:Sugar Acids; C002532:2-keto-3-deoxyoctonate; D009713:Nucleotidyltransferases; C028984:3-deoxy-manno-octulosonate cytidyltransferase