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Enantioselective Pd-Catalyzed α-Arylation of N-Boc-Pyrrolidine: The Key to an Efficient and Practical Synthesis of a Glucokinase Activator

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journal contribution
posted on 04.07.2008 by Artis Klapars, Kevin R. Campos, Jacob H. Waldman, Daniel Zewge, Peter G. Dormer, Cheng-yi Chen
A short and practical synthesis of glucokinase activator 1 was achieved utilizing a convergent strategy involving SNAr coupling of activated aryl fluoride 11 with hydroxypyridine 9. The key to the success of the synthesis was the development of a novel method for enantioselective formation of α-arylpyrrolidines during the course of the project. In this method, (−)-sparteine-mediated enantioselective lithiation of N-Boc-pyrrolidine was followed by in situ transmetalation to zinc and Pd-catalyzed coupling with aryl bromide 3, proceeding in 92% ee. This transformation allowed the preparation of compound 1 in a 31% overall yield over six steps.