Nucleosides from Carbohydrate Adducts of Diaminomaleonitrile. A Novel Synthesis of 5-Amino-1-(β-D-ribofuranosyl)imidazole-4-carboxamide and 5-Amino-1-(β-D-ribopyranosyl)imidazole-4-carboxamide

Article abstract of DOI:10.1021/jo00206a004

The stereospecific and regiospecific synthesis of 5-amino-1-(β-D-ribofuranosyl)imidazole-4-carboxamide (16) was achieved in six steps.A key intermediate in the synthesis, N-(2',3',5'-tri-O-benzoyl-β-D-ribofuranosyl)diaminomaleonitrile (3), was prepared by two routes: the reaction of diaminomaleonitrile (1) with 1-bromo-2,3,5-tri-O-benzoyl-β-D-ribofuranose (2) and the reaction of the bis(trimethylsilyl) derivative of diaminomaleonitrile (4) with 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose (5).Reaction of 3 triethyl orthoformate yielded 4,5-dicyano-1-(2',3',5'-tri-O-benzoyl-β-D-ribofuranosyl)imidazole (10).Alternatively 10 was synthesized by the acid-catalyzed cyclization of the N-formyl derivative 12 which was prepared by the reaction of the trimethylsilyl derivative of N-formyldiaminomaleonitrile 11 with 5.Deblocking 10 with 1 equiv of sodium methoxide at room temperature resulted in the regiospecific formation of the 5-imidate 14.Reaction of 14 with alkaline hypochlorite yielded 5-amino-1-(β-D-ribofuranosyl)imidazole-4-carbonitrile (15) by a Hofmann rearrangement.Alkaline hydrolysis of the nitrile function yielded the corresponding amide 16. 5-Amino-1-(β-D-ribopyranosyl)imidazole-4-carboxamide (28) was prepared by a similar synthetic sequence.Reaction of diaminomaleonitrile (1) with ribose gave a mixture of the α- and β-anomers of D-ribopyranosyldiaminomaleonitrile (17).Compound 17 was converted to a mixture of the anomeric tri-O-acetates which on heating with triethyl orthoformate gave a separable mixture of the α- and β-anomers of 4,5-dicyano-1-(2',3',4'-tri-O-acetyl-D-ribopyranosyl)imidazole (19 and 20, respectively).Reaction of 19 with NH3/CH3OH at room temperature cleaved the three acetyl groups and regiospecifically converted the 5-cyano to the 5-imidate (26).The regiospecificity is due to the attack of the 2'-oxy anion on the 5-cyano group as shown by the isolation of the cyclic imidate 25 when the reaction is carried out at 0 deg C.The Hofmann rearrangement of imidate 26 followed by alkaline hydrolysis gave 5-amino-1-(β-D-ribopyranosyl)imidazole-4-carbonitrile 27 and 28, respectively.The 1H and 13C NMR spectra of imidates 14 and 26 have multiple peaks for the protons and carbons, respectively.Restricted rotation of the 5-imidate (energy of activation 18 kcal) results in isomers of 14 and 26 with different NMR spectra.The C-2, H-1' coupling constants of 2.5-3.1 Hz of the isomeric species comprising imidates 14 and 26 are consistent with a H-2, H-1' dihedral angle of 135 deg and an anti orientation of the imidazole with respect to the ribose ring; a conclusion confirmed by NOE measurements.