A highly efficient synthesis of sitagliptin, a potent and selective DPP-4 inhibitor for the treatment of type 2 diabetes mellitus (T2DM), has been developed. The key dehydrositagliptin intermediate 9 is prepared in three steps in one pot and directly isolated in 82% yield and >99.6 wt % purity. Highly enantioselective hydrogenation of dehydrositagliptin 9, with as low as 0.15 mol % of Rh(I)/(t)Bu JOSIPHOS, affords sitagliptin, which is finally isolated as its phosphate salt with nearly perfect optical and chemical purity. This environmentally friendly, 'green' synthesis significantly reduces the total waste generated per kilogram of sitagliptin produced in comparison with the first-generation route and completely eliminates aqueous waste streams. The efficiency of this cost-effective process, which has been implemented on manufacturing scale, results in up to 65% overall isolated yield.

We demonstrate that Pd/C without added ligands catalyzes the Suzuki cross-coupling reaction with aryl chlorides. The ability of heterogeneous Pd to activate the C−Cl bond is explained in terms of a synergistic anchimeric and electronic effect that occurs between the Pd surface and the aryl chloride. Furthermore, the importance of selectivity control following C−Cl bond activation is illustrated by the striking role that solvents play in determining homo- vs cross-coupling pathways of the aryl chlorides.

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Marked shifts in enantioselectivity in the asymmetric hydrogenation of several prochiral substrates were observed as a function of the availability of hydrogen to the catalyst in both heterogeneous and homogeneous catalytic reactions. The key kinetic parameter affecting enantioselectivity was found to be concentration of molecular hydrogen in the liquid phase, [H2], rather than hydrogen pressure in the gas phase, and it was observed that under typical reaction conditions, [H2] could differ widely from its equilibrium saturation value. It was demonstrated that the reported pressure dependence on enantioselectivity may in fact be reproduced at constant pressure for several systems by varying the rate of gas−liquid mass transfer. The general significance of the conclusions suggest that considerations of hydrogen diffusion limitations might be important in other asymmetric hydrogenation studies reported in the literature. For systems where enantioselectivity depends positively on hydrogen pressure, the intrinsic ability of a catalyst to effect asymmetric hydrogenation may be masked in a reaction carried out under conditions where gas−liquid diffusion is the rate-limiting step.