Sitagliptin asymmetric reductive amination

SCHEME 39.21. Synthesis of sitagliptin 83 via direct asymmetric reductive amination. 

A more concise route to chiral amines would be direct synthesis from the ketone via direct asymmetric reductive amination. This has been developed successfully for the conversion of (3-ketoesters to chiral (3-amino acid esters and demonstrated in the manufacture of sitagliptin, a DPP-IV inhibitor for... 

Scheme 14.21 Application of direct asymmetric reductive amination to the synthesis of sitagliptin. ...

The reported asymmetric synthesis of (—)-(R)-sitagliptin was completed in seven steps from commercially available starting materials. Acid-catalyzed hydrolysis of P-dalkylamino ferfbutyl ester 23c, coupling with the triazolopyrazine building block to amide, reduction of amide to tert amine and hydrogenolysis of the N-benzyl and N-phenylethyl unit, afforded (—)-(R)-sitagliptin in 43 % overall yield and 42 % e.e. 

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