Fortimicin analogs via glycoside formation.

Fortimicinanalogs have been prepared via glycosylation of suitably protected derivatives of the aminocyclitol fortamine.The analogs contain changes in the sugar portion of the molecule and/or in the manner of its attachment to the cyclitol.Fortimicins A (1) and B (2) are aminoglycosidic aminocyclitol antibiotics discovered in fermentations of Micromonospora olivoasterospora1).These antibiotics are pseudodisaccharides in which 6-epipurpurosamine B ( 19) is attached through an a-glycosidic linkage to O-6 of a novel 1,4-diaminocyclitol (3), fortamine2).Unlike fortimicin B, fortimicin A possesses a 4-N-glycyl substituent and exhibits potent, broad-spectrum antibacterial activity.Also noteworthy is the 1C4 conformation of the cyclitol portion of fortimicin A in which the 4-NCH3COCH2NH2 group is equatorial.In fortimicin B, at and above physiological pH, the cyclitol assumes the 4C1 conformation in which the 4-NHCH3 group is axial.Several fortimicin analogs incorporating changes in the sugar portion of the molecule and/or in the manner of its attachment to the cyclitol have been prepared by glycosylation of suitably blocked fortamines.These analogs are not readily attainable through direct chemical modification and provide some insight into fortimicin structure activity relationships.Fortamine3) (3), derived from fortimicin A or B by acid hydrolysis, was protected for glycosylation in two ways.The intermediate 1-N-benzyloxycarbonylfortamine (4) was prepared directly from 3 by use of N-benzyloxycarbonyloxysuccinimide.Treatment of the latter (4) with the N-hydroxysuccinimide activated ester derivative of N-benzyloxycarbonylglycine provided the desired 1-N-benzyloxycarbonyl-4, N-(N-benzyloxycarbonylglycyl)fortamine (5).Glycosylation of 5 has the advantage of providing 4-Nglycyl or fortimicin A analogs directly provided that the relative reactivity of the various hydroxyl groups directs glycosylation to the C-6 hydroxyl.The second blocked fortamine was prepared by reaction of 4 with N,N'-carbonyldiimidazole in tetrahydrofuran and subsequent treatment with methanol and hydrochloric acid to provide 1-N-benzyloxycarbonyl-4,5-carbamoyl-2-O-methoxycarbonylfortarnine (6).This cyclic carbamate has only the C-6 hydroxyl group free for glycosylation and a flattened 4C 1 conformation as determined by analysis of its pmr spectrum and that of the 2-O-demethoxycarbonyl analog (7) using spin-decoupling experiments.The free hydroxyl group is in a pseudoequatorial orientation in this conformation. Condensation of 6-O-acetyl-2-azido-3,4-di-O-benzyl-2-deoxy-a-D-glucopyranosyl bromide4) (8)with 5 under modified KoENlGs-KNORR conditions with mercuric cyanide in dichloroethane gave, as the only isolable product, 6-0-(6'-0-acetyl-2'-azido-3',4'-di-O-benzyl-2'-deoxy-a-D-glucopyranosyl)-1-Nbenzyloxycarbonyl-4-N-(N-benzyloxycarbonylglycyl)fortamine (9) in 8 % yield.The presence of a nonparticipating azido group at C-2 in Bled to the expected a-glycoside (9) as indicated by a doublet (J1',2' 3 Hz) at 5 5.84 ppm in the pmr spectrum due to the anomeric Cl'H.The failure of 9 to undergo oxidation with lead tetraacetate in acetic acid indicates that the glycoside bond is not at C-2 of fortamine.