Jerry R. Martin

Extension of the erythromycin biosynthetic pathway : Isolation and structure of erythromycin E

Abstract Erythromycin A is slowly metabolized to a new antibiotic, erythromycin E (5), when incubated with fermentations of certain strains of the producing organism Streptomyces erythreus. Erythromycin E contains a novel ortho ester grouping not previously encountered in macrolide antibiotics. The isolation of erythromycin E extends and further delineates the latter stages of the erythromycin biogenetic pathway.

The conformation of erythronolide, the 14-membered aglycone ring of the erythromycin antibiotics☆

Abstract The solution conformation of erythronolide B and derivatives has been deduced from NMR and CD spectral data. The conformation is basically a “diamond lattice” type in which the ring atoms occupy cyclohexane-like positions but slightly modified to incorporate the lactone and ketone groups and to relieve an unfavorable syn -periplanar interaction. Variable temperature experiments revealed that erythronolide B and derivatives do not undergo facile ring inversion or pseudorotation and suggested the presence of a single stable conformation. Several features of the proposed conformation were demonstrated by the NMR and CD spectra of suitable derivatives. These features included the syn -periplanar relationship between the 3- and 5-OH groups, the axial orientation of the 11-OH group, and the proximity of the 6-OH group to the 9-ketone.

Fortimicin B cyclic carbamates

Abstract Preparations are described of fortimicin B 1,2;4,5-biscarbamate and the three possible monocyclic carbamates of fortimicin B that involve the amino and hydroxyl groups of the cyclitol ring. Rearrangement of fortimicin B 1,2-carbamates to fortimicin B 1,5-carbamates has been found to be a convenient route to the latter. Nitrous acid cleavage of fortimicin B 1,2;4,5-biscarbamate gave fortamine 1,2;4,5-biscarbamate, which is an intermediate of potential value for glycosylation at O-6.

8-epi-erythronolide B and its metabolic fate in fermentations of Streptomyces erythreus

Abstract 8-epi-erythronolide B (4) has been isolated as a product formed from the acid treatment of erythronolide B (3). When this compound was fed to a blocked mutant of the erythromycin producing organism, Streptomycetes erythreus (Abbott 2NU153), nearly quantitative yields of 3-O-(α- l -mycarosyl)-8-epi-erythronolide B (10) were obtained. The much desired 8-epi-erythromycins (2) were not realized.

(Ss)-8-hydroxy-5,6-dideoxy-5-oxoerythronolide B, a shunt metabolite of erythromycin biosynthesis—V : Studies on the biosynthesis of the erythromycins—V conformation of macrolide antibiotics—V

Abstract The isolation and structure elucidation of a shunt metabolite of erythromycin biosynthesis, (8S)-8-hydroxy-5,6-dideoxy-5-oxoerythronolide B (1a), is described. NMR and CD data reveal that the title compound and related 5-oxo derivatives (5 and 6) are conformationally homogeneous with erythronolide B (2). Consistent with this observation is the hydroxyketone-hemiacetal equilibrium present in the case of 5. The spectroscopic data further show that 1a, (8S)8)hydroxyerythronolide B (12), and lankolide (13) have identical 8S stereochemistry.

2′-N-acylfortimicins and 2′-N-alkylfortimicins via the isofortimicin rearrangement1

Abstract Fortimicin A and a number of 4-N-acylfortimicins B, although stable as either the fully protonated hydrochloride or sulfate salts, undergo degradation as the free bases in aqueous solution. Detailed studies with fortimicin A and 4-N-acetylfortimicin B have shown that degradation occurs, in part, by simple cleavage of the 4-N-acyl groups with formation of fortimicin B, and, in part, by rearrangement to the 2′-N-acylfortimicins B (the isofortimicin rearrangement). The conversions of the rearrangement products into 2′-N-glycylfortimicin A, 2′-N-acetylfortimicin A, and the 2′-N-(2-aminoethyl)fortimicins A and B are described. The antibacterial activities of the new fortimicin A derivatives are presented.

Preparations of 2-epi-fortimicins A from 2-epi-fortimicin B by intramolecular base-catalyzed 2-O-acylation of 1,2′,6′-tri-N-benzyloxycarbonyl-2-epi-fortimicin B☆

Abstract Preparations of 2- epi -fortimicin A ( 4 ) from 2- epi -fortimicin B ( 3 ) are described. In contrast to the previously reported, selective 4- N -acylation of 1,2′,6′-tri- N -benzyloxycarbonylfortimicin B ( 8 ) with N -( N -benzyloxycarbonylglycyloxy)succinimide, 1,2′,6′-tri- N -benzyloxycarbonyl-2- epi -fortimicin B ( 5 ) underwent predominant 2- O ,4- N -diacylation under similar conditions. Proof of the structure of the diacylated product is presented, with evidence that the diacylated product is formed by initial intramolecular, base-catalyzed 2- O -acylation. The in vitro antibacterial activities of 2- epi -fortimicin A ( 4 ), 2- O -glycyl-2- epi -fortimicin A ( 11 ), 1- N -glycyl-2- epi -fortimicin A ( 12 ), and 5-deoxy-2- epi -fortimicin A ( 13 ) are reported.

3-O-(2″,6″-dideoxy-α-l-ribo-hexopyranosyl)-erythronolide B and 3-O-(2″,6″,dideoxy-α-l-arabino-hexopyranosyl)erythronolide B, aberrant erythromycin biogenetic metabolites with defective sugar moities

Abstract 3-O-(2″,6″-Dideoxy-α- l -ribo-hexopyranosyl)erythronolide B (6) and 3-O-(2″,6″-dideoxy-α- l -arabino-hexopyranosyl)erythronolide B (7), aberrant metabolites of erythromycin biosynthesis, have been isolated from the fermentation broth of a blocked mutant of the erythromycin producing organism Streptomyces erythreus. The defective glycosidesm, when incubated with early blocked mutants of S. erythreus capable of converting authentic erythromycin progenitors to the complete antibiotic, were unmetabolized. The probable origin of the metabolite is discussed.

2-Substituted fortimicins by ring opening of 2-deoxy-1,2-epimino-2-epi-fortimicin B and by nucleophilic displacements of 2-O-(methylsulfonyl)fortimicin derivatives

Abstract Opening of the aziridine ring of 2-deoxy-1,2-epimino-2- epi -fortimicin B ( 10 ) has been effected with both chloride and azide. The reactions are both stereo- and regiospecific and give 2-chloro-2-deoxyfortimicin B ( 2c ) and 2-azido-2-deoxy-fortimicin B ( 2d ). The nucleophilic displacements of the methanesulfonate groups of some 1- N -benzyloxycarbonyl-2- O -(methylsulfonyl)fortimicin derivatives with chloride, azide, and cyanide in N,N -dimethylformamide are dependent both on the nature of the nucleophile and the specific 1- N -benzyloxycarbonyl-2-methanesulfonate employed as the substrate. Striking differences in the stereochemistry of the azide displacements with different 2-methanesulfonates are believed to have a conformational basis. 2-Amino-2-deoxyfortimicin A ( 1c ) and both of the 2-epimeric 2-chloro-2-deoxyfortimicins A ( 1b ) and ( 5 ) were prepared for antibacterial assay and the in vitro results are reported.

2-epi-fortimicin B. Participation of 1-N-benzyloxycarbonylamino and 1-acetamido groups in solvolysis of 2-O-(methylsulfonyl)fortimicin B derivatives☆

Abstract Synthesis of 2- epi -fortimicin B has been accomplished by processes involving solvolyses of both 1- N -benzyloxycarbonyl- and 1- N -acetyl-2- O -(methylsulfonyl)fortimicins B, which occur with participation of the carbonyl oxygen atoms of the 1- N -acyl groups. The results illustrate both the greater effectiveness of acetamido groups in neighboring-group participation relative to benzyloxycarbonylamino groups, and the sensitivity of the nature of the products to the reaction conditions.