Erythromycin series. Part 11. Ring expansion of erythromycin A oxime by the Beckmann rearrangement

Abstract

The synthesis of 10-dihydro-10-deoxo-l l -azaerythromycin A (1 1 ) by the Beckmann rearrangement of erythromycin A oxime (2) and reduction of the imino ether so obtained (5) is described. The structure elucidation of the new ring-expanded semisynthetic erythromycins (5) and (1 1 ) has been established on the basis of their analytical and spectral data and acid-catalysed degradation into the aglycones (7) and (1 3), respectively. Finally, the complete structure of ring-expanded erythronolides (7) and (13) has been determined by X-ray crystallography.Erythromycin A (1) 2-4 is a macrolide antibiotic characterized by a 14-membered lactone ring, erythronolide A,5.6 with a 9-OX0 group. In efforts to modify its biological and/or pharmacodynamic properties numerous derivatives of (1) have been prepared, including 9-imino derivatives7 Of the nucleophiles 0 ( 1 ) E r y t h r o m y c i n A Me Y R2 -L -C l o d i n o s y l H d Me bMewith low steric requirements which were allowed to react at the 9-carbonyl centre of (l), hydroxylamine was the most interesting8v9 in that it yielded erythromycin A oxime, a substrate with potential for further modification of the aglycone ring. On the basis of its configurational analysis it was suggested that the E-isomer (2) predominated in the p r~d u c t .~To develop a method for the efficient introduction of the nitrogen atom into the 14-membered ring we studied the Beckmann rearrangement of 9-oxime (2) and conversion of the product (5) so obtained into a secondary amine (ll)." Such erythromycin derivatives are the first of their kind in the literature. Results and DiscussionIt is well known that 0-arylsulphonyloximes, especially p-tosyl compounds, are very suitable precursors in the Beckmann rearrangement of ketoximes." By the reaction of the 9-oxime (2) with para-substituted arene sulphonyl chlorides in dry acetone in the presence of sodium hydrogen carbonate, a series of new erythromycin A 9-0-arylsulphonyloximes (3a-e) was prepared (Scheme 1).The structure of these compounds was assigned from their spectroscopic properties. In particular, the i.r. spectrum of (3a) ( Table 1) revealed new bands at 1 680 (C=N) and 1 600, 810, and 680 cm-' (p-Ph). The 'H n.m.r. spectrum displayed signals at 6 2.35 (s, 3 H, p-Me), 3.36 (s, 3 H, OMe), and 7.36 (4, 4 H, p-Ph). Apart from a typical chemical shift for dimethylamino protons of (1) (lit.," 2.29 p.p.m.), (3a) showed a signal at 6 2.83 (s, 6 H) which corresponded to the N-methyl hydrogens of the protonated dimethylamine; ' this indicated formation of the hydrochloric salt of (3a). Further characterization of (3a) was achieved by potentiometric titration which showed 4.07% (requires 3.77%) ionic bonded chlorine.Surprisingly, Beckmann rearrangement of 9-0-arylsulphonyloximes (3a-e) carried out by a literature 147' method for related systems gave none of the expected lactam (9). Instead, it afforded the new compound (5) (erythromycin A imino ether) in 70-87% yield. This structure was confirmed by spectroscopic analysis. The i.r. spectrum of (5) showed...

Synthesis and biological properties of 4″-O-acyl derivatives of 8a-Aza-8a-homoerythromycin

“…Starting compounds for the synthesis were 6-O-alkyl-8a-aza-8a-homoerythromycins A 5 (1)(2)(3)(4)(5) having acetyl as 2¢-hydroxy-protecting group. Compounds 6, 13-18, 22, 24, 27 and 29 were prepared by condensation of 2¢-protected compounds 1-5 with the corresponding (hetero)arylalkyl-carboxylic acid using 1-[(3-(dimethyl-amino)propyl]-3-ethyl-carbodiimide hydrochloride (EDC) in the presence of 4-(dimethyl-amino)pyridine (DMAP) in dichloromethane.…”

“…Reduction of the linker double bond and concomitant reduction of the nitro to an amino group (10, 12) diminished potency of compounds compared with their counterparts with unsaturated linker (9, 11), but they are still more active than the starting compounds (1,2).…”

“…Crude product was purified by column chromatography (eluent CH 2 10-H) 1.91 (4-H, 14a-H), 1.68 (7a-H, 4¢a-H …”

“…Crude product was purified by column chromatography (eluent CH 2 Cl 2 /MeOH/NH 4 The same method was followed as for the synthesis of compound 6 starting from 2¢-O-acetyl-6-O-ethyl-8a-aza-8a-homoerythromycin A (0.100 g, 0.12 mmol) and 3-(3-quinolinyl)-2-propenoic acid (0.146 g, 0.73 mmol). Crude product was purified by column chromatography (eluent CH 2 2 00 b-H), 1.78 (d, 4¢a-H), 1.75 (d, 7a-H), 1.40 (m, 14b-H To a solution of compound 16 (0.061 g, 0.065 mmol) in EtOH (8 ml) HOAcAcONa buffer (pH 5) was added dropwise to a pH value of 6.5. Then catalyst 10% Pd/C (0.025 g) was added and the reaction mixture was stirred under hydrogen pressure of 1.4 bar for 4 h. The catalyst was filtered off and the filtrate was evaporated under reduced pressure.…”

Synthesis and Antibacterial Activity of Isomeric 15-Membered Azalides

“…Second-generation macrolide antibiotics such as clarithromycin [1] (6-O-methylerythromycin A) and azithromycin [2,3] (15-membered azalide) have been widely prescribed for upper and lower respiratory tract infections because of their superior antibacterial activity, pharmacokinetic properties and fewer gastrointestinal side effects compared to erythromycin A. However, the therapeutic utility of these macrolides has been severely compromised by the emergence of resistant pathogens [4].…”