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...

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Conformations of the 14-membered macrolide antibiotic oleandomycin and its 8-methylene-9-oxime derivative were determined in various solvents. The experimental NMR data--coupling constants and NOE contacts--were compared with the results of molecular modelling--molecular mechanics calculations and molecular dynamics simulations. The conformational changes, on the right-hand side of the 14-membered ring, affected mostly the 3JH2,H3 values and NOE crosspeaks H3 or H4 to H11. Oleandomycin was found to be present predominantly in the C3-C5 folded-in conformations in DMSO-d6 solution, whereas in buffered D2O, acetone-d6 and CDCl3, there was a mixture of folded-in and folded-out conformational families. The predominant conformation of the 8-methylene-oleandomycin-9-oxime derivative in solution was a folded-out one although different amounts of folded-in conformation were also present depending on the solvent. Oleandrose and desosamine sugar moieties adopted the usual and expected chair conformation. The conformation around the glycosidic bonds, governing the relative orientation of sugars vs. the lactone ring, showed a certain flexibility within two conformationally close families. We believe that by combining the experimental NMR data and the molecular modelling techniques, as reported in this paper, we have made significant progress in understanding the conformational behaviour and properties of macrolides. Our belief is based on our own current studies on oleandomycins as well as on the previously reported results and best practices concerning other macrolides. A rational for macrolide conformational studies and advances in methodology has been suggested accordingly.

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