Synthesis of (S)-Sitagliptin
Catalytic Enantioselective Allylic Amination of Olefins for the Synthesis of ent-Sitagliptin.
20 January 2014 (online)
Key wordssitagliptin - dipeptidyl dipeptidase-4 inhibitor - asymmetric allylic amination - palladium - ene reaction - [2,3]-sigmatropic rearrangement
Sitagliptin is a dipeptidyl dipeptidase-4 inhibitor that is prescribed for the treatment of type II diabetes. The small-scale synthesis depicted features a two-step construction of the allylic amine E involving an ene reaction using the sulfurdiimide B followed by a palladium-catalyzed asymmetric [2,3]-sigmatropic rearrangement of ylid C.
The ylid C does not undergo a [2,3]-sigmatropic rearrangement at 4 °C in the absence of the palladium catalyst. A further five 4-arylbut-1-ene substrates with F, CF3 and OMe substituents gave the allylic amination products in 79–94% yield and 81–94% ee.