Acid degradation studies of 6-deoxyerythromycin A.

Erythromycin A (1), a well-established macrolide antibiotic, is unstable under acidic conditions. When administered orally, 1 is in equilibrium with its 8,9-anhydro-6,9-hemiketal and is simultaneously converted directly to the antibacterially inactive 6,9:9,12-spiroketal1}. A number of research groups in recent years have prepared new derivatives of erythromycin A by modification of the functional groups which participate in the degradation reaction, namely the ketone at C-9, the hydroxyl group at C-6, the hydrogen at C-8 and the diol at C-ll,122). Recently a series of erythromycin derivatives lacking the hydroxyl group at C-6, therefore more stable to acid than erythromycin A, were isolated by one ofus3). Nevertheless 2, the most active compound in the series, slowly loses its antibacterial activity in dilute acidic solution. In this paper, we describe the structure and antibacterial activity of the acid degradation products of 2. When 2 was treated with 10% AcOH, a loss of the cladinose moiety was observed to give 3. Treatment of 2 with glacial AcOH at room temperature after four hours gave the conjugated enol ethers 4 and 5 in 83 and 7% isolated yields, respectively. The loss of the cladinose in 3 was indicated by the mass spectrum with mjz 560 (M+H) and by the absence of corresponding resonances in the XHand 13C NMRspectrum. HREI-MS of 4 and 5 are in agreement with the empirical formula C37H63NO1(). The 13C NMR spectra of4 and 5 showed resonances of four olefinic carbons, C-8, C-9, C-10 and C-ll in the range S 105.6 to 153.2. In the NOEdifference spectra, strong NOE's were observed between 8-CH3 and 10-CH3 in 5 and between 8-CH3 and 5-H and a weak NOE between 10-CH3 and one of 7-H,