Xu F, * Zacuto MJ, * Kohmura Y, Rosen J, Gibb A, Alam M, Scott J, Tschaen D. Merck Research Laboratories, Rahway, USA and Merck Sharp& Dohme Research Laboratories Hoddesdon, UK
Asymmetric Synthesis of Highly Functionalized Tetrahydropyran DPP-4 Inhibitor.
Org. Lett. 2014;
16: 5422-5425
Key words
DPP-4 inhibitors - asymmetric transfer hydrogenation - dynamic kinetic resolution - cycloisomerization - reductive amination
Significance
The target tetrahydropyran DPP-4 inhibitor was of interest for the treatment of type 2 diabetes. The synthesis depicted features three tandem ruthenium-catalyzed reactions: (1) an asymmetric transfer hydrogenation of ketone A with dynamic kinetic resolution (2) a cycloisomerization to form a dihydropyran ring and (3) an oxidation. The overall yield of the synthesis is 25%.
Comment
Extensive optimization of the asymmetric transfer hydrogenation established that significant contributors to the yield, dr and er included the use of the pentafluoro-substituted DAIPEN catalyst B, DABCO as the base and THF as the solvent. The reductive amination of ketone I with NaBH(OAc)3 dramatically improved (dr = 19:1) using DMAc as solvent when the bis(tosylate) salt J was neutralized with Et3N followed by pH buffering with HOAc.
