Kendomycin

Abstract: Kendomycin, also known as (-)-TAN 2162, is a novel polyketide-derived ansamycin isolated from Streptomyces sp., which exhibits potent antagonist and agonist activities at the endothelin and calcitonin receptors, respectively. This bacterial metabolite also possesses a strong antibiotic activity against a range of gram-positive and -negative bacteria and cytostatic effects on the growth of human cancer cell lines. When a novel macroglycosidation reaction is employed as the key step, the first enantioselective total synthesis of kendomycin has been accomplished. A Friedel-Crafts-type ring closure of the acyclic precursor containing tetrahydropyran and benzofuran moieties produces the macrocycle as a single stereoisomer in good yield, thus establishing the aryl C-glycosidic linkage of the ansa core. This reaction requires a phenolic glycosyl acceptor and appears to proceed through a rapid O-glycosidation followed by a slow rearrangement to an aryl C-glycoside. The requisite secomacrocycle is prepared by the Pd(0)-catalyzed B-alkyl Suzuki-Miyaura cross-coupling of two subunits, which in turn can be expeditiously assembled from readily available building blocks in a modular fashion.

Abstract: Kendomycin [(−)-TAN 2162] 1 was re-isolated from Streptomyces violaceoruber (strain 3844-33C) in the course of our chemical screening programme. The structure with the relative configuration only was confirmed by the X-ray analysis of 1. The absolute configuration of 1 was determined by using the advanced Mosher’s ester method applied to kendomycin acetonide 2. The biosynthesis of 1 was performed using stable isotope labelling experiments. From the results it is assumed that a highly oxygenated benzoic acid, derived from (3,5-dihydroxyphenyl)acetic acid, serves as the starter unit of the aliphatic polyketide chain. The cyclisation generating the 18-membered ansa-bridge by the formation of a C–C bond might follow a new type of aldol condensation. 1 and 2 exhibit antibacterial activity and strong cytotoxicity against different tumor cell lines.

Abstract: The total synthesis of (−)-kendomycin (1), a novel macrocyclic polyketide with antibacterial and antitumor activity, was achieved in 21 steps (longest linear sequence) exploiting an effective Petasis−Ferrier union/rearrangement tactic to construct the tetrahydropyran ring, a ring-closing metathesis to generate the macrocycle, and a biomimetic quinone−methide−lactol assembly.