Asymmetric sitagliptin synthesis

Prior to the beginning of our work on sitagliptin, there had been some reports in the literature of catalytic asymmetric hydrogenation of enamines to access chiral secondary amines [19]. The synthesis of P-amino acids had also been established by catalytic asymmetric hydrogenation of enamides [20]. All these reports relied on N-acylenamines as substrates, since it was believed that the N-acyl group was required in order to achieve good reactivity and selectivity [21]. 

The requirement for an acyl protecting group represented a major drawback for an asymmetric hydrogenation approach in the synthesis of sitagliptin, since it would likely introduce additional chemical steps in the sequence for protection and deprotection. The ideal situation would be to perform the asymmetric hydrogenation on an unprotected enamine. Unfortunately, this transformation was unprecedented when we started the development work on sitagliptin [22]. 

I 5 Synthesis of Sitagliptin, the Active Ingredient in Januvia " and Janumet" Table 5.2 Asymmetric hydrogenation of unprotected enamine-amide 27. 

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. 

G., and Hughes, G. (2010) Biocatalytic asymmetric synthesis of chiral amines from ketones applied to sitagliptin manufacture. Science, 329, 305-309,... 

C.K. Savile, l.M. laney, E.C. MundorlF, J.C. Moore, S. Tam, W.R. larvis, l.C. Colbeck, A. Kreb-ber, F.l. Fleitz, 1. Brands, P.N. Devine, G.W. Huisman, G.J. Hughes, Biocatalytic asymmetric synthesis of chiral amines from ketones applied to sitagliptin manufacture. Science 329 (2010)... 

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. ...

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