ChemInform Abstract: Stereoselective Synthesis of Macrolide and Polyether Antibiotics

Abstract

In order to establish a common methodology for the highly stereoselective and efficient synthesis of macrolide and polyether antibiotics, two macrolide aglycons, 12-membered ring methynolide and 16-membered ring tylonolide, were first synthesized mainly from D-glucose, with the aid of 4-methoxybenzyl (MPM) type protecting groups and construction of three consecutive chiral centers, via the syntheses of respective fragments followed by their coupling (Yamaguchi's esterification) and cyclization (Wittig-Horner reaction). This method was extended to the synthesis of 14-membered ring pikronolide and, together with conformational analysis and control of macrolide rings, some typical 16-membered ring aglycons such as carbonolides, leuconolides, maridonolides, etc. Erythronolide A was also synthesized via an extremely efficient macrolactonization by virtue of conformational control and super activation of a seco-acid. For the synthesis of polyether antibiotics a new synthetic method of substituted tetrahydrofuran and -pyran rings was first established via a cyclization of styryl derivatives by acid catalyzed and/or chelation controlled reactions under kinetic and/or thermodynamic conditions. Highly complex polyether salinomycin was synthesized via coupling of three fragments prepared from D-glucose, D-mannitol, and ethyl L-lactate essentially by the same method developed in the synthesis of macrolides. In this synthesis the MPM type protecting groups acted a crucial role. The synthesis of isolasalocid A was completed via isolasalocid ketone, in which two tetrahydrofuran rings were constructed by the above acid catalyzed and chelation controlled cyclizations. Similarly lasalocid A was synthesized from D-glucose via lasalocid ketone.