Chemical synthesis of benzamide adenine dinucleotide: inhibition of inosine monophosphate dehydrogenase (types I and II).

Treatment of 3-(2,3-O-isopropylidene-β-d-ribofuranosyl)benzamide (6) with POCl3 in (EtO)3PO afforded only little phosphorylation product (8, 5%), but the major product was 5‘-chlorobenzamide riboside (7, 85%). Reaction of 6 with 2-cyanoethyl N,N-diisopropylchlorophosphoramidite followed by 2-cyanoethanol/tetrazole treatment and oxidation with tert-butyl peroxide gave a 1:1 mixture of the desired 5‘-O-bis(2-cyanoethyl) phosphate 9 and the chloro derivative 7. This mixture was treated with methanolic ammonia and partitioned between CHCl3 and water. The 2‘,3‘-O-isopropylidenebenzamide mononucleotide (8) was obtained in 21.2% overall yield from the aqueous layer. Compound 8 was then converted into the corresponding imidazolide 11b which, upon coupling with 2‘,3‘-O-acetonide of AMP, afforded the acetonide of benzamide adenine dinucleotide (15) in 94% yield together with small amounts of symmetrical pyrophosphates P1,P2-bis(2‘,3‘-O-isopropylideneadenosin-5‘-yl)pyrophosphate (13, 3%) and P1,P2-bis(2‘,3‘-O-isopro...