Asymmetric synthesis of (−)-(R)-sitagliptin

The asymmetric synthesis of (−)-(R)-sitagliptin was achieved in seven steps from commercially available starting materials using the highly diastereoselective conjugate additions of either lithium (R)-N-benzyl-N-(α-methylbenzyl)amide or lithium (R)-N-benzyl-N-(α-methyl-p-methoxybenzyl)amide to tert-butyl 4-(2′,4′,5′-trifluorophenyl)but-2-enoate to install the correct stereochemistry. Subsequent sequential acid-catalysed hydrolysis of the resultant β-amino esters, HOBt/EDC mediated coupling with the triazolopyrazine fragment, and hydrogenolysis gave (−)-(R)-sitagliptin in 43% and 42% overall yields, respectively.

Graphical abstractThe asymmetric synthesis of (−)-(R)-sitagliptin was achieved in seven steps from commercially available starting materials and in 43% overall yield using the highly diastereoselective conjugate addition of an enantiopure lithium amide reagent to tert-butyl 4-(2′,4′,5′-trifluorophenyl)but-2-enoate as the key step.Download full-size image