Asymmetric hydrogenation, enamine

The reductive amination of ketones can be carried out under hydrogen pressure in the presence of palladium catalysts. However, if enantiopure Q -aminoketones are used, partial racemization of the intermediate a-amino imine can occur, owing to the equilibration with the corresponding enam-ine [102]. Asymmetric hydrogenation of racemic 2-amidocyclohexanones 218 with Raney nickel in ethanol gave a mixture of cis and trans 1,2-diamino cyclohexane derivatives 219 in unequal amounts, presumably because the enamines are intermediates, but with excellent enantioselectivity. The two diastereomers were easily separated and converted to the mono-protected cis- and trans- 1,2-diaminocyclohexanes 220. The receptor 221 has been also synthesized by this route [103] (Scheme 33). 

Chapter 2 to 6 have introduced a variety of reactions such as asymmetric C-C bond formations (Chapters 2, 3, and 5), asymmetric oxidation reactions (Chapter 4), and asymmetric reduction reactions (Chapter 6). Such asymmetric reactions have been applied in several industrial processes, such as the asymmetric synthesis of l-DOPA, a drug for the treatment of Parkinson s disease, via Rh(DIPAMP)-catalyzed hydrogenation (Monsanto) the asymmetric synthesis of the cyclopropane component of cilastatin using a copper complex-catalyzed asymmetric cyclopropanation reaction (Sumitomo) and the industrial synthesis of menthol and citronellal through asymmetric isomerization of enamines and asymmetric hydrogenation reactions (Takasago). Now, the side chain of taxol can also be synthesized by several asymmetric approaches. 

Reduction of amides without hydride reagents Asymmetric hydrogenation of un functionalized olefins/enamines/imines... 

Fig. 8 Diphosphine ligands 5-8 applied in the Ir-catalyzed asymmetric hydrogenation of exocyclic enamines...

Much like the enol systems discussed in Sect. 6.1, enamines are predictably difficult substrates for most iridium asymmetric hydrogenation catalysts. Both substrate and product contain basic functionahties which may act as inhibitors to the catalyst. Extended aromatic enamines such as indoles may be even more difficult substrates for asymmetric hydrogenation with an additional energetic barrier to overcome. Initial reports by Andersson indicated a very difficult reaction indeed (Table 14) [75]. Higher enantioselectivities were later reported by Baeza and Pfaltz (Table 14) [76]. 

Scheme 15 Asymmetric hydrogenation of cyclic and acyclic enamines...

Kubryk, M. and Hansen, K.B. Apphcation of the Asymmetric Hydrogenation of Enamines to the Preparation of a Amino Acid Pharmacophore. Tetrahedron Asymmetry 2006,17, 205-209. 

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. 

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]. 

One method that shows great promise of being general and scaleable is an asymmetric hydrogenation approach. Although many attempts have been made to reduce enamines, such as 17, to... 

P-amino acid derivatives, the problems associated with obtaining just one isomer of 17 thwarted high ee s. It is now possible to prepare just one isomer of the enamine.94 In addition, the MonoPhos family of ligands have been shown to provide good ee s with either isomer of 17 (Scheme 2.26).95 The ability to prepare ligand libraries and screen them for asymmetric hydrogenations, such as to prepare P-amino acids,96-98 makes this approach a powerful one. For a full discussion on mono-dentate ligands see Chapter 14. 

Like the synthesis of L-DOPA by asymmetric hydrogenation, the manufacture of L-menthol hy Takasago Company is also one of the early examples of an industrial process where asymmetric isomerization is a key step. The desired isomerization reaction is one of the steps of the overall synthetic scheme. The synthesis of L-menthol from diethyl geranylamine is shown by 9.2. The formal electron pair pushing mechanism for the isomerization of the allylic amine to the enamine proceeds according to reaction 9.3. 

The catalysts are Tim hydrides which are generated in situ by reduction of enantio-merically pure L TiCl2 with butyllithium and PhSiH3 they are also highly effective in the asymmetric hydrogenation of imines and enamines.20 The lutetium ansa-metallocene complex (22-XVII) catalyzes the deuteration of 1-pentene (63% e.e.)21 Related samarium compounds hydrogenate imines.22... 

The carbon-carbon double bond of an enamine is also applicable for asymmetric hydrogenation leading to chiral amino acids. For example, hydrogenation of 13 by rhodium catalyst with ferrocenyl diphosphine 15 as a ligand was successful for the synthesis of methyl 3-amino-4-polyfluorophenylbutanoate 14 with excellent stereoselectivity (see Scheme 9.5) [15]. 

Imine hydrogenation produces an N H bond, so the chiral amines produced by this method will necessarily have mono or disubstituted N atoms. Chiral NR-R R amines can, however, be produced by asymmetric hydrogenation, using N,N disubstituted iminium ions or enamines as substrates. Neither of these substrate classes has been studied to the same extent that imines have, but both can be hydrogenated enantioselectively. 

---