Syntheses of derivatives of 4'-deoxymycaminosyl tylonolide and mycaminosyl tylonolide modified AT C-23.

Sir: In the foregoing communications' we reported the synthesis of 4'-deoxymycaminosyl tylonolide (1a) which showed fairly strong antibacterial activity. This paper describes the syntheses of derivatives of la and of mycaminosyl tylonolide (Ib) modified at C-23. Treatment of the diethylacetal (2a) of la with acetic anhydride in acetonitrile as described previously" gave the 2'-O-acetyl derivative (3) (93%), m.p. 187-190'C, [a]2 +28° (c 1, chloroform). Acylation of 3 with acetyl chloride, propanoyl chloride, n-or isobutanoyl chloride and benzoyl chloride in pyridine (20°C, ^-1 hour) followed by treatment of the acyl derivatives with methanol (50°C, overnight')) to remove the 2'O-acetyl group, gave 23-O-acetyl (4), 23-0propanoyl (5), 23-0-n-butanoyl (6), 23-0-isobutanoyl (7) and 23-O-benzoyl (8) derivatives in higher than 90% yields (after purification) in all cases; the values of [a]p (c 1, chloroform) were: 4, +10'; 5, +13°; 6, +13°; 7, +17°; 8, +11°. The acylated positions (the 23-hydroxyl group) were confirmed, in their 1H NMR spectra (4-8), by the appearance of two proton signals assignable to 23-CH0O-acyl at 8 4.2-4.4 (cf. the shift values of H-3 and -23 of 3,23-di-0-acetylmycaminosyl tylonolide diethylacetal2)). Deacetalation of the acyl derivatives with 0.1 M aqueous hydrochloric acid in acetonitrile (3: 2 v/v, 25°C, 1 hour) gave the desired 23-0-acetyl(9a, m.p. 106108'C, [a]W-12' (c, 1, chloroform)), 23-0-propanoyl(10a, 6°), 23-0-n-butanoyl(11a, -9°), 23-0-isobutanoyl(12a, -6°) and 23-0-benzoyl4'-deoxymycaminosyl tylonolides (13a, -19°) in higher than 90% yields (after purification). As the reference compounds, 23-0-acetyl(9b), 23-0-propanoyl(10b), 23-0-n-butanoyl(11b), 23-O-isobutanoyl(12b) and 23-O-benzoylmycaminosyl tylonolides (13b) were also prepared similarly from mycaminosyl tylonolide diethylacetal21 (2b) by way of 2',4'-O-acetylation, selective 23-0-acylation, de(2',4'-di-O-acetyl)ation and deacetalation. C-23-halo derivatives of la were next prepared. Treatment of 2a with triphenylphosphine and carbon tetrachloride (molar ratio of 1 : 2.2: 1.1) in pyridine under nitrogen (room temperature, 20 hours) according to the method of ANISUZZAMAN and WHISTLERS) gave 23-chloro-23,4'dideoxymycaminosyl tylonolide diethylacetal (14a) (99 %), ni.p. 164 ' 167°C, [a]ll +12° (c 1, chloroform); Found (Calcd. for C3JH80NO9Cl): C, 62.19 (62.34); H, 8.71 (8.97); N, 2.32 (2.08); Cl, 5.16 (5.26) %. The structure was confirmed by the 1H NMR spectrum of the 3-0-acetyl derivative of 14a (H-3: 6 5.17; H-3'; 0 2.47, dt, J 11.5x2 and 4 Hz). Similarly, 23-bromo-23deoxy (15a) (95%) and 23-deoxy-23-iodo (16a) (87%) derivatives of 2a were prepared by treating 2a with triphenylphosphine and carbon tetrabromide (room temperature, 1 hour) or triphenylphosphine and carbon tetraiodide (room temperature, 1 hour); 15a: [a]' D'+31' (c 1, chloroform), 16a: [a]21+78° (c 1, chloroform); Found (Calcd. for C3,H80NO1I): C, 54.88 (54.90); H, 7.75 (7.90); N, 1.77 (1.83); 1, 16.28 (16.57%). Deacetalation of the halo derivatives gave the corresponding 23-chloro-23,4'-dideoxy[17a, [a]L; -8° (c 1, chloroform)], 23-bromo-23,4'-dideoxy(18a, +11°), and 23,4'-dideoxy-23-iodo-mycaminosyl tylonolides (19a, +56°), in high yields. As the reference compounds, 23-chloro-23-deoxy(17b), 23-brom o-23-deoxy(18b) and 23-deoxyla lb 9a 9b 10a 10b 11a 11b 12a 12b 13a R1