Available methods for the synthesis of macrolides include the cyclization of long-chain bifunctional precursors,³ depolymerization processes,⁴ ring-enlargement reactions,⁵ and special methods such as the thermal decomposition of tricycloalkylidene peroxides.⁶ The method reported here is essentially that of the submitters.⁷ Its improvements result from a quantitative approach to the cyclization of a series of ω-bromo fatty acids under conditions well defined from the kinetic point of view. A unique feature of this procedure in comparison with other methods involving cyclization of α,ω-bifunctional precursors, which are generally run under Ziegler's high-dilution conditions, is that high rates of feed can be used, so that the special devices usually employed for the slow addition of the reagent into the reaction medium are not required. The synthesis is characterized by relatively mild reaction conditions and simple work-up. Moreover, it is suited for relatively large-scale preparations. Up to 50 g. of 11-bromoundecanoic acid can be cyclized in more than 70% yield in a single run, employing no more than 1 l. of solvent and an addition time of 3–4 hours.

The reaction illustrates a typical preparation of a macrolide. Lactones with more than 12 members can be obtained in even better yields. For example, 15-hydroxypentadecanoic lactone (m.p. 35–37°) and 17-hydroxyheptadecanoic lactone (m.p. 40–41°) were prepared by the submitters in about 95% yield, practically pure, with no trace of the corresponding dilactones.

Recent progress in chemistry and biochemistry of macrolides was recently reviewed.⁸