Practical, Asymmetric Route to Sitagliptin and Derivatives:
Development and Origin of Diastereoselectivity
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Abstract
The development of a practical and
scalable process for the asymmetric synthesis of sitagliptin is reported.
Density functional theory calculations reveal that two noncovalent
interactions are responsible for the high diastereoselection. The
first is an intramolecular hydrogen bond between the enamide NH and
the boryl mesylate SO, consistent with MsOH being crucial
for high selectivity. The second is a novel C–H···F
interaction between the aryl C5-fluoride and the methyl of the mesylate
ligand