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The Effect of Additives on the Zinc Carbenoid-Mediated Cyclopropanation of a Dihydropyrrole

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journal contribution
posted on 03.07.2014, 00:00 by Antonio Ramirez, Vu Chi Truc, Michael Lawler, Yun K. Ye, Jianji Wang, Chenchi Wang, Steven Chen, Thomas Laporte, Nian Liu, Sergei Kolotuchin, Scott Jones, Shailendra Bordawekar, Srinivas Tummala, Robert E. Waltermire, David Kronenthal
The synthesis of a key intermediate in the preparation of oral antidiabetic drug Saxagliptin is discussed with an emphasis on the challenges posed by the cyclopropanation of a dihydropyrrole. Kinetic studies on the cyclopropanation show an induction period that is consistent with a change in the structure of the carbenoid reagent during the course of the reaction. This mechanistic transition is associated with an underlying Schlenk equilibrium that favors the formation of monoalkylzinc carbenoid IZnCH2I relative to dialkylzinc carbenoid Zn­(CH2I)2, which is responsible for the initiation of the cyclopropanation. The factors influencing reaction rates and diastereoselectivities are discussed with the aid of DFT computational studies. The rate accelerations observed in the presence of Brønsted acid-type additives correlate with the minimization of the undesired induction period and offer insights for the development of a robust process.