Total Synthesis of Ionophore Antibiotic X-14547A

A highly stereocontrolled and convergent total synthesis of optically active ionophore antibiotic X-14547A (1) was designed and carried out. Degradative reactions led to the key intermediates 3 and 6, which served as convenient comparison stages. The tetrahydropyran building block 3 was totally synthesized in its natural form from (-)-diethyl D-tartrate by a series of highly efficient steps and an epoxide opening-ring closure reaction accompanied by clean inversion, whereas the requisite tetrahydroindan block 4 was synthesized in its racemic (from δ-valerolactone) and optically active form (from the SAMP hydrazone 25) employing an Enders-type stereoselective alkylation and an intramolecular Diels-Alder reaction as the key steps. Coupling of the two fragments by a two-carbon link using Grignard and sulfone anion chemistry followed by stereoselective construction of the trans-butadienyl system and functional group elaboration afforded the advanced intermediate 42. Finally attachment of the 2-ketopyrrole system by new technology involving the 2-pyridinethiol ester functionality and a magnesium-pyrrole reagent proceeded smoothly and after base hydrolysis completed the total synthesis of X-14547A.