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Synfacts 2016; 12(11): 1115
DOI: 10.1055/s-0036-1589290
Synthesis of Natural Products and Potential Drugs
© Georg Thieme Verlag Stuttgart · New York

Synthesis of (R)-Sitagliptin

Contributor(s):
Philip Kocienski
Bae HY, Kim MJ, Sim JH, Song CE * Sungkyunkwan University, Suwon, Republic of Korea and Max-Planck-Institut für Kohlenforschung, Mülheim an der Ruhr, Germany
Direct Catalytic Asymmetric Mannich Reaction with Dithiomalonates as Excellent Mannich Donors: Organocatalytic Synthesis of (R)-Sitagliptin.

Angew. Chem. Int. Ed. 2016;
55: 10825-10829
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Further Information

Publication History

Publication Date:
18 October 2016 (online)

 
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Key words

sitagliptin - DPP-4 inhibitor - asymmetric Mannich reaction - β-amino acids - dithiomalonates - organocatalysis

Significance

The key step in the synthesis of (R)-sitagliptin depicted is an asymmetric Mannich reaction of dithiomalonate B with bench-stable α-amidosulfone A catalyzed by quinidine-derived squaramide catalyst C (2 mol%). The reaction proceeds at 0 °C under aqueous biphasic conditions to give Mannich adduct D in 72% yield and 95% ee. A single recrystallization affords D in >99% ee. Sixteen examples of the reaction demonstrate its broad scope and utility.


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Comment

The superior reactivity of dithio­malonate B compared with monothiomalonates and malonates as Mannich donors is attributed to the higher acidity of its α-hydrogen. Under the reaction conditions, the α-amidosulfone undergoes elimination of sodium benzenesulfinate to an N-Boc-protected imine which reacts before tautomerization to the enamine can occur. Sitagliptin (Januvia) is a DPP-4 inhibitor that is prescribed for the treatment of type 2 diabetes.


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