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The process development and large scale synthesis for the β-hydroxyamino amide 1 is described. The route evolved from a multistep sequence utilizing a classical resolution to a two-step enantioselective process involving an enzyme-catalyzed aldol reaction and a direct amidation of a carboxylic acid. By utilizing a siliconmediated direct amidation strategy, the route was devoid of protecting and deprotecting steps while retaining the stereochemical integrity of a highly sensitive β-hydroxyamino acid. The two-step strategy employed herein significantly improved the yield, process greenness, cycle time and estimated cost in the production of 1.

TUMMALA, S.; BOTH, D. A.; WANG, C.; DELANEY*, E. J.; Chem. Rev. (Washington, D. C.) 106 (2006) 7, 2794-2810; Process Res. Dev., Bristol-Myers Squibb Pharm. Res. Inst., New Brunswick, NJ 08903, USA; Eng.) -Lindner 41-256

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.