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A New Method for the Stereoselective Synthesis of Macrodiolides From TADDOL Derivatives
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1  Instituto de Química del Sur (INQUISUR), Departamento de Química, Universidad Nacional del Sur (UNS)-CONICET, Av. Alem 1253, B8000CPB Bahía Blanca, ARGENTINA

Abstract: Single-enantiomer drug candidates are important to many pharmaceutical companies, and therefore, new methods for the preparation of enantiopure compounds are critical for the development of next-generation pharmaceutical products. The use of microwave (MW) irradiation in organic synthesis has become a popular technique to develop and optimize the libraries of compounds synthesis in short reaction time compare to those obtained with the classical thermal methods in pharmaceutical and academic production. Numerous studies in the past ten years, demonstrated that microwave enhanced chemical reactions and that they are faster than conventional heating methods. In previuos studies, we reported the stereoselective radical addition of organotin hydrides to unsaturated TADDOL diesters. These reactions occurred with intramolecular cyclization under inert atmosphere, radical initiator, toluene and 75°C with high yields and stereoselectivity depending on the reactivity and steric bulk of the organotin hydride employed. Here, we decided to study a new method for the synthesis of these macrocycles through the radical addition of different triorganotin hydrides, R3SnH (R= Me, n-Bu, Ph; Neophyl), to the same insaturated TADDOL diesters, in THF as solvent and under MW conditions. We compared these results with the previous reported method. Under MW conditions, reactions were completed in very short reaction time and neither the products of double hydrostannation nor the products of cyclopolymerization were obtained in both cases. Furthermore, we evaluated the stereoselectivity by 119Sn-NMR spectroscopic analysis in both methods.
Keywords: Cyclohydrostannation; Macrodiolides; TADDOL unsaturated diesters