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374ChemInform Abstract An efficient method of protecting the 10,11-double bond in 16-membered macrolides such as (Ia) (rosaramicin) involves Michael addition of thioacetic acid (II) to the 10,11-ene (→ e.g. (Ic)). Subsequent reaction with a diazoalkane such as (III) (→ e.g. (Id)) and deprotection with fluoride ion provides corresponding 20-C-alkyl derivatives (so-called "oxo analogues") such as (Ib). Usingthis method, the derivatives (IVd), (IVe), (IVf) of 12,13-de-epoxy-12,13-dehydrorosaramicin (IVa), tylosin (IVb), and desmycosin (IVc) are likewise prepared. The reactions of diazomethane (III) with unprotected macrolides are also studied including the synthesis of the leucomycin A5 derivative (Vb) from (Va). Derivatives in which the 20-formyl group is replaced by methyl and by halogeno groups, as well as derivatives having a 2,3-ene are described. A number of base-catalyzed rearrangement products are also described; for example, desmycosin (IVc) gives the 8β,20α-aldol (VIa) which can be isomerized to the 8α,20β-aldol (VIb). -In general, the 20-C-alkyl and 20-deoxy-20-dihydro macrolides described exhibit an antibacterial spectrum similar to that of the mycinamicins.

Selective acytation techniques have been developed that enable the synthesis of 3-0-acetyl-4"-0isovaleryltylosin and 3-0-acetyl-23-0-demycinosyl-4"-0-isovaleryltylosin to be carried out in an efficient manner starting from tylosin. The syntheses of the 2'-O-acetyl, 23-0-acetyl, and 2',23-di-0acetyl derivatives of the latter are also described. The synthesis of key hydrazones is also described. The regio-and stereo-selective epoxidation of tylosin and its acyl derivatives afforded the 12,13-epoxy analogues, which were used t o synthesize novel acylated 12,13-epoxy derivatives of 2 3 -0demycinosyltylosi n.The methodology used to synthesize 23-O-demycinosyltylosin (1) (23-DMT) in the preceding paper was not compatible with the presence of 3-O-acyl groups in the molecule. We therefore set out to develop alternative, selective acylation strategies that could be used to synthesize certain key target derivatives of tylosin (8) and 23-O-demycinosyltylosin (l), namely 3-O-acetyl-4"-O-iso-valeryltylosin (9) and 3-O-acetyl-23-O-demycinosyl-4"-O-isovaleryltylosin (2) respectively. n ~4 0 Me (

23‐O‐Demycinosyltylosin (23‐DMT) derivatives of type (IIIa) are more potent than their tylosin analogues.