Synthesis, structural studies, and cytostatic evaluation of 5,6-di-O-modified L-ascorbic acid derivatives

The 5,6-di-O-tosylated derivative Of (L)-ascorbic acid was synthesized by selective protection and deprotection of 2,3- and 5.6-dihydroxy functional groups involving 5,6-ditosylation in the final step, while the novel 6-acetoxy, 6-hydroxy, and 6-chloro derivatives of 4,5-didehydro-L-ascorbic acid were obtained by reaction of ditosylated compound with nucleophilic reagents. The analysis Of (3)J(H-4-H-5) homonuclear coupling constants shows that all L-ascorbic acid derivatives except for epoxy and 4,5-didehydro compounds exist in high population as gauche conformers across C-4-C-5 bonds, while (3)J(C-3-H-5) heteronuclear coupling constants in 4,5-didehydro derivatives indicate cis geometry along C-4-C-5 double bond. The X-ray crystal structure analysis of 2,3-di-O-benzyl-5,6-epoxy- and 5.6-isopropylidene-L-ascorbic acid shows that the oxygen atoms attached at positions 2 and 3 of the lactone ring are disposed in a synperiplanar fashion. Besides that, the dioxolane ring adopts half-chair conformation. The molecules of epoxy derivative are joined into infinite chains by one weak hydrogen bond of C-(HO)-O-center dot center dot center dot type. Two O-(HO)-O-center dot center dot center dot, and C-(HO)-O-center dot center dot center dot hydrogen bonds link the molecules of 5,6-di-O-isopropylidene compound into two-dimensional network. 6-Chloro derivative of 2,3-di-O-benzyl-L-ascorbic acid showed the best cytostatic effects against all tested malignant tumor cells (IC50: similar to 18 mu M) (c) 2006 Elsevier Ltd. All rights reserved.