Asymmetric hydrogenation chiral amine synthesis

Fig. 35.6 Synthesis of chiral amines by an improved procedure for making diphenylphosphinylimines, followed by asymmetric transfer hydrogenation.

The synthesis of amines by the in-situ reductive amination of ketones is termed the Leuckart-Wallach reaction. Recently, an asymmetric transfer hydrogenation version of this reaction has been realized [85]. Whilst many catalysts tested give significant amounts of the alcohol, a few produced almost quantitative levels of the chiral amine, in high enantiomeric excess. 

In contrast to the success in the synthesis of optically active amino acids and related compounds, only limited success has been achieved in the asymmetric synthesis of chiral amines or related compounds. One breakthrough is the asymmetric hydrogenation of arylenamides with Rh catalysts containing... 

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 past 35 years have seen both the asymmetric hydrogenation and asymmetric transfer hydrogenation of imines develop into useful methods for the synthesis of chiral amines. Particularly, focused research over the past 15 years has led to highly enantioselective examples of both reaction types and has added aza aromatics, activated imines, and iminium cations to their purview. In addition, the asymmetric hydrogenation and asymmetric transfer hydrogenation of imines have both been apphed to total syntheses. Because they are necessarily isomeri... 

Monodentate phosphites are another type of prominent monodentate phosphorus ligands applied in asymmetric hydrogenation of enamides for the synthesis of chiral amines. Chiral monodentate phosphites can be easily prepared from a chiral diol and an alcohol. Generally, the chiral diol was first reacted with a phosphorus trichloride to form a phosphorochloridite, followed by the reaction with an appropriate alcohol to yield a chiral monodentate phosphite [35[. The reaction of an alcohol with phos phorus trichoride to yield a phosphorodichloridite, which was then treated with a chiral diol, is also a good procedure for the synthesis of chiral monodentate phosphites [36]. 

Furthermore, secondary monophosphine ligand, (2S,5S) 2,5 diphenylphospho lane, was also used in the rhodium catalyzed asymmetric hydrogenation of P substituted enamide for the synthesis of chiral N acetyl amines, albeit with low enantioselectivity (<28% ee) [46]. 

In contrast to the hydrogenation of N acetyl enamides, there are very few examples of successful asymmetric hydrogenation of N,N dialkyl enamines, which provides a direct approach to the synthesis of chiral tertiary amines. The reason is that an N acetyl group in the enamides is considered indispensable for the substrates to form a chelate complex with the metal of catalyst in transition state, giving good reactivity and enantioselectivity, while there is no N acetyl group in N,N dialkyl enamines. 

The diversity requirement of chiral amines in the synthesis of natural products and chiral drugs is everlasting and the most studies about the catalytic asymmetric hydrogenation of enamines have dealt with simple substrates to date. Hence, it is necessary to explore highly efficient enantioselective protocol to provide more complex and also industrially useful chiral amines. We are confident that the easily accessible and changeable monodentate phosphorus hgands will find a wide appli cation in this field. 

However, the creativity of a large number of synthetic chemists has led to tremendous progress toward addressing these challenges and the development of truly practical methods to prepare chiral amines. Perhaps the best illustration of how an open mind can lead to significant advances toward the asymmetric synthesis of amines is the development of the process to manufacture the blockbuster diabetes drug Januvia by the asymmetric hydrogenation of an unstabilized N H imine. 

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