Enantiomeric syntheses of conformationally restricted D- and L-2', 3'-dideoxy-2',3'-endo-methylene nucleosides from carbohydrate chiral templates.
D- and L-2',3'-dideoxy-2',3'-endo-methylene nucleosides were synthesized as potential antiviral agents. The key intermediates 5-O-tert-butyldiphenylsilyl-D- and L-2,3-dideoxy-2, 3-endo-methylenepentofuranoses (20 and 33, respectively) were obtained by selective protection of the D- and L-2,3-dideoxy-2, 3-endo-methylenepentose derivatives 19 and 32 which were prepared from 1,2:5,6-di-O-isopropylidene-D-mannitol and L-gulonic gamma-lactone, respectively, and converted to 5-O-tert-butyldiphenylsilyl-D- and L-2,3-dideoxy-2, 3-endo-methylenepentofuranosyl acetates (21 and 34, respectively) or the chlorides 22 and 35. The acetates and chlorides were condensed with pyrimidine and purine bases by Vorbrüggen conditions or S(N)2-type condensation. Vorbrüggen conditions using the acetates gave mostly alpha-isomers. In contrast, S(N)2-type condensation using the chlorides greatly improved the beta/alpha ratio. From the synthesis, several D- and L-2',3'-dideoxy-2',3'-endo-methylene nucleoside analogues have been obtained, and their structures have been elucidated by NMR spectroscopy and X-ray crystallography. The synthesized D- and L-adenine derivatives were tested as substrates of adenosine deaminase, which indicated that the D-adenosine derivative 4a was a good substrate of a mammalian adenosine deaminase from calf intestinal mucosa (EC 3.5.4.4) while its L-enantiomer 10a was a poor substrate. Either the D-adenine derivative 4a or its L-enantiomer 10a did not serve as an inhibitor of the enzyme.
Chun
B K
BK
Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, The University of Georgia, Athens, Georgia 30602, USA.
Olgen
S
S
Hong
J H
JH
Newton
M G
MG
Chu
C K
CK
D002241:Carbohydrates / Q000737:chemistry*; D002460:Cell Line; D018360:Crystallography, X-Ray; D006678:HIV / Q000187:drug effects; D006801:Humans; D009690:Nucleic Acid Conformation; D009705:Nucleosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013057:Spectrum Analysis; D013237:Stereoisomerism
D002241:Carbohydrates; D009705:Nucleosides