The Asymmetric Hydrogenation Route

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]. 

The reactions were carried out using 5 mol% of catalyst, in methanol, at 50 °C under 90 psi of hydrogen. A selection of the results are shown in Table 5.2. 

Astonishingly, the screening results not only showed a trend of enatioselectivi-ties but also gave us a very direct hit. 

In addition to its high enantioselectivity, it is worth emphasizing the robustness of this catalyst. Both the metal precursor [Rh(COD)Cl]2 and the ligand are stable compounds that can be handled in the open air. 

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Although the asymmetric hydrogenation route to 3,3-diphenylalanine via this modified substrate preparation was not developed further, Dowpharma had a requirement to rapidly develop and scale up the manufacture of a related 3,3-diarylalanine product. The work to 3,3-diphenylalanine centred around substrate preparation and removal of impurities leading to high activity associated with the PhanePhos catalyst system allowed for a facile transfer from laboratory scale experiments to the commercial manufacture of the related diphenylalanine derivative by a robust, reproducible and scaleable procedure. 

Asymmetric Hydrogenation of Enol Esters. Prochiral ketones represent an important class of substrates. A broadly effective and highly enantioselective method for the asymmetric hydrogenation of ketones can produce many useful chiral alcohols. Alternatively, the asymmetric hydrogenation of enol esters to yield a-hydroxyl compounds provides another route to these important compounds. 

Chiral organofluorides are increasingly in demand as the pharmaceutical and materials industries seek to take advantage of the special properties these halides impart. A lack of methods to provide chiral monofluorides and trifluoromethyl groups has given the group of Andersson impetus to create new asymmetric hydrogenation routes to these valuable halides [48, 49]. 

Scheme 16.18. The Pfizer/Chirotech asymmetric hydrogenation route to pregabalin (2).

There is no doubt that catalytic asymmetric synthesis has a significant advantage over the traditional diastereomeric resolution technology. However, it is important to note that for the asymmetric hydrogenation technology to be commercially useful, a low-cost route to the precursor olefins is just as crucial. The electrocarboxylation of methyl aryl ketone and the dehydration of the substituted lactic acids in Figures 5 and 6 are highly efficient. Excellent yields of the desired products can be achieved in each reaction. These processes are currently under active development. However, since the subjects of electrochemistry and catalytic dehydration are beyond the scope of this article, these reactions will be published later in a separate paper. 

Dynamic kinetic resolution is well known in pure chemical synthesis, as illustrated by work by Noyori et al. on the asymmetric hydrogenation of a-substituted /f-ketoesters. Noyori et al. [5], Ward [6] and Caddick et al. [7] have reviewed the chemical syntheses, and biocatalytic routes have been discussed by Faber et al. [8]. 

The AHF of 1,1-disubstituted enamides gives access to precursors of -amino acids. Stahl and Landis [43] generated aldehyde precursors, for example, by the AHF of Af-phthaloyl 3-(benzyloxy)prop-l-en-2-amine (Scheme 4.74). Under the applied conditions, the undesired isomerization of the terminal into the nonre-active internal enamide could be suppressed. After oxidation of the formyl group, P -amino acids are obtained, which are usually prepared by an asymmetric hydrogenation route. 

Thus, the delicate process of enantioselection in the asymmetric hydrogenation of p-dehydroamino acids can be roughly described as being determined by the mode of coordination of the double bond of the substrate in octahedral Rh(III) intermediates. The enantioselectivity could be correctly predicted for all studied cases if only the dihyride pathway is considered. The order of enantioselection in each particular case can be affected either by the entropic effect on the activation barrier for the double bond coordination specific for each substrate or by the interference of other catalytic pathways, for example, the unsaturated route, which has been computed to be more energetically demanding and significantly less stereoselective in the case of (Z)-P-dehydroamino acids. 

Enantioselective transfer hydrogenation (from propan-2-ol) of some ketones catalysed by iridium(i) complexes with chiral Schifl-base ligands has been reported, giving product alcohol of up to 33% e.e. with propiophenone as substrate. Other new reductive routes to chiral secondary alcohols involve the asymmetric hydrogenation of enol phosphinates (21) catalysed by chiral ferrocenyl-rhodium... 

Boogers JAF, Felfer U, Kotthaus M, Lefort L, Steinbauer G, de Vries AHM, de Vries JG. A mixed-ligand approach enables the asymmetric hydrogenation of an a-isopropylcin-namic acid en route to the renin inhibitor aliskiren. Org. Process Res. Dev. 2007 11(3) 585-591. 

In contrast to many nonasymmetric hydrogenation reactions, in the asymmetric hydrogenation of a-acetamidocinamic acid (reaction 5.1.2.1), coordination by the alkene is the first step. This step is then followed by the oxidative addition of dihydrogen. This is called the unsaturate route. The contributing factors for this difference are of course the change in the precatalyst as well as the chelating ability of a-acetamidocinamic acid. 

Only a few examples are known in which amino acids are produced by (catalytic) asymmetric synthesis. The asymmetric hydrogenation of dehydroamino acids, previously developed by Monsanto for L-phenylalanine, is today only used for the production of l-DOPA [11]. Many other asymmetric routes for the synthesis of enantiopure amino acids... 

Monsanto s commercial route to the Parkinson s drug, L-DOPA (3,4-dihydroxyphenylalanine), utilizes an Erlenmeyer azlactone prepared from vanillin. The pioneering research in catalytic asymmetric hydrogenation by William Knowles as exemplified by his reduction of 24 to 25 in 95% ee with the DiPAMP diphosphine ligand was recognized with a Nobel Prize in Chemistry in 2001. ... 

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