Enamides, asymmetric amination

Asymmetric catalysis undertook a quantum leap with the discovery of ruthenium and rhodium catalysts based on the atropisomeric bisphosphine, BINAP (3a). These catalysts have displayed remarkable versatility and enantioselectivity in the asymmetric reduction and isomerization of a,P- and y-keto esters functionalized ketones allylic alcohols and amines oc,P-unsaturated carboxylic acids and enamides. Asymmetric transformation with these catalysts has been extensively studied and reviewed.81315 3536 The key feature of BINAP is the rigidity of the ligand during coordination on a transition metal center, which is critical during enantiofacial selection of the substrate by the catalyst. Several industrial processes currently use these technologies, whereas a number of other opportunities show potential for scale up. 

Masson and Zhu et al. applied a calcium phosphate catalyst in asymmetric amination reactions of enamides (Tables 11 and 12) [50] for reviews of asymmetric amination reactions, see [51-58]. The amination products were easily converted to 2-hydrazinoketones and 1,2-diamines by hydrolysis or diastereoselective reduction. 

Asymmetric catalytic reduction reactions represent one of the most efficient and convenient methods to prepare a wide range of enantiomerically pure compounds (i.e. a-amino acids can be prepared from a-enamides, alcohols from ketones and amines from oximes or imines). The chirality transfer can be accomplished by different types of chiral catalysts metallic catalysts are very efficient for the hydrogenation of olefins, some ketones and oximes, while nonmetallic catalysts provide a complementary method for ketone and oxime hydrogenation. 

Chiral monodentate phosphites and phosphoramidites are also effective ligands for Rh-catalyzed asymmetric hydrogenation of enamide substrates. As seen in the structure of MonoPhos illustrated in Figure 1.2, combination of the mod-ihed BINOF backbone and the amine part gives a structural variety to this type of ligand. Combinatorial methods are effective for optimization of the chiral structures.Elucidation of the hydrogenation mechanism catalyzed by the MonoPhos-Rh complex is in progress." ... 

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]. 

Asymmetric hydrogenation offers a useful synthetic route to chiral amines. Although the mechanism is unknown, only the (7%/V-acetyl-1 -arvlalkylamine 21 with 95% ee was obtained by the hydrogenation of a mixture of ( )- and (Z)-enamides 20a and 20b using Rh-Me-DuPHOS (XI). The A-acetvl enamines 20a,b are prepared by the reduction of oximes with Fe powder in acetic anhydride [21]. Also the acetamide 23 was obtained from 22 [22]. 

Several new ligands that possess chirality at the phosphorus center have been developed and shown to be excellent catalysts for the asymmetric reduction of enamides to amino acids and chiral amines and P-enamides to P-amino esters. One ligand that shows great promise to be used at the manufacture scale is Trichickenfootphos, which has demonstrated high activity and enantioselectivity in the production of a chiral intermediate for Pregabalin. 

The asymmetric reduction of enamides to produce chiral amine derivatives has also been examined by the Paris Group (52). Subsequent unpublished studies (53) have shown that the degree of asymmetric synthesis is much higher in benzene than it is in ethanol for such systems up to 92% enantiomeric excess was achieved in one case. 

In a more recent study, the enamide photocyclization with very similar photosubstrates was examined in the presence of chiral amino alcohols and chiral amines as asymmetric inductors [47]. The achieved enantioselectivities are in the same range as the ones reported by Ninomiya and Naito, but in this approach the asymmetric induction was more effective for the cis products. In cyclopentane at — 40°C, 0.1 equivalents of the most effective inductor, (— )-ephedrine (entity, gave the cis cyclization products with up to 37% ee and the trans products with only 2% ee. The role of the chiral inductor as a Br0nsted acid was supported by flash photolysis experiments. The presence of the chiral amino alcohol led to an increase in the rate of disappearance of a transient that was assigned to the primary cyclization intermediate of type 29, i.e., the chiral inductor accelerates the protonation/deprotonation sequence that reestablishes the aromatic ring. 

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]. 

The application of a mixture of a chiral and an achiral monophosphorus ligand for the rhodium catalyzed asymmetric hydrogenation of enamides was tested by Beller and coworkers [45]. By using a mixture of a chiral monophosphine 36a and an achiral ligand tris(4 methoxyphenyl)phosphine [P(4 MeOCf,H4)3] (1 1), the N (1 phenylvi nyl)acetamide (7a) was hydrogenated to amine 8a with 88% ee, but this enantios electivity is inferior to that obtained with single monophosphine 36a (93% ee). 

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 synthesis of N phthaloyl enamides has been reported by a remarkably general method for aerobic oxidative amination of unactivated alkyl olefins as shown in Scheme 9.6 [12]. From a practical synthesis point of view, the phthalimide can not only serve as a directing group for asymmetric hydrogenation but can also be removed under mild conditions. 

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