Synthesis of 3'-fluoro-2',3'-dideoxy-2',3'-didehydro-4'-ethynyl-D- and -L-furanosyl nucleosides

An efficient procedure has been developed for the synthesis of 3'-fluoro-2',3'-dideoxy-2',3'-didehydro-4'-ethynyl D- and L-furanosyl nucleosides (1 and 2) starting from 2,3-O-isopropylidene-d-glyceraldehyde. The key intermediate 1-O-benzoyl-3E-fluoro-3,4-unsaturated-5,6-di(tert-butyldimethylsilyloxy)-2-hexanone 8 was obtained in nine steps with the overall yield of 22%. The alpha,beta-unsaturated ketone 8 was then treated with ethynylmagnesium bromide in a typical Grignard reaction procedure to afford the two intermediates 9 and 10, which after deprotection, oxidation, and acetylation gave the corresponding 4-ethynyl-substituted D- and L-sugar moieties 15 and 16, respectively. A series of D- and L-pyrimidine and purine nucleosides were prepared by the coupling of the sugar moieties with various silylprotected bases. The anomeric mixtures were obtained after condensation. After separation, the beta-isomers were further deprotected to yield the target nucleosides. All the newly synthesized 4'-substituted nucleosides were tested for their activities against HIV, among which the D-adenine derivative showed moderate anti-HIV activity (EC(50) = 25.1 microM) without significant cytotoxicity.     

Synthesis of some 3',5'-dideoxy-5'-C-phosphonomethyl nucleosides.

Ammonium [1-(3',5',6'-trideoxy-beta-D-erythro-hexofuranosyl)thymine]-6'- phosphonate (1), ammonium 3',5'-dideoxycytidine-5'-C-methylphosphonate (2) and 3',5'-dideoxyadenosine-5'-C-methyl phosphonic acid (3) have been synthesized and tested for anti-HIV activity. The key steps involved an Arbuzov reaction between triethyl phosphite and 3,5,6-trideoxy-6-iodo-1,2-O-isopropylidene-alpha-D-erythro- hexofuranose (7), followed by condensation with the appropriate nucleoside bases. The substances 1, 2 and 3 have been tested in vitro against HIV.     

Efficient synthesis of 2',3'-dideoxy-2'-amino-3'-thiouridine

[reaction: see text] Metal ion rescue experiments provide a powerful approach to establish the presence and role of divalent metal ions in the biological function of RNA. The utility of this approach depends on the availability of suitable nucleoside analogues. To expand the range of this experimental strategy, we describe the first synthesis of 2',3'-dideoxy-2'-amino-3'-thiouridine (12) in 19.5% overall yield starting from 2,2'-anhydrouridine (1).     

Synthesis of 2',3'-dideoxy-6',6'-difluorocarbocyclic nucleosides

2',3'-Dideoxy-6',6'-difluorouracils, a novel series of gem-difluoromethylenated carbocyclic nucleosides, were synthesized from (Z)-but-2-ene-1,4-diol in 14 steps. A notable step was the construction of the carbocyclic ring via ring-closing metathesis and the incorporation of gem-difluoromethylene group by way of silicon-induced Reformatskii-Claisen reaction of chlorodifluoroacetic ester 3.     

Stereoselective synthesis and conformational study of novel 2',3'-Didehydro-2',3'-dideoxy-4'-selenonucleosides

Stereoselective synthesis of novel 2',3'-didehydro-2',3'-dideoxy-4'-selenonucleosides (4'-seleno-d4Ns) 4a- c was accomplished via 4'-selenoribofuranosyl pyrimidines 11a- c, as key intermediates. 4'-Selenoribofuranosyl pyrimidines 11a- c were efficiently synthesized from d-ribose or d-gulonic gamma-lactone using a Pummerer-type condensation as a key step. Introduction of 2',3'-double bond was achieved by treating cyclic 2',3'-thiocarbonate with 1,3-dimethyl-2-phenyl-1,3,2-diazaphospholidine.