Monodentate chiral spiro phosphoramidites: efficient ligands for rhodium-catalyzed enantioselective hydrogenation of enamides.

Optically active -arylalkylamines are an important class of compounds that are widely used in organic and pharmaceutical synthesis, and much effort has been made to develop efficient asymmetric synthetic methods for them.[1] Asymmetric catalytic hydrogenation of enamides, initiated by Kagan et al. ,[2] provides a direct and convenient route to chiral amine derivatives. However, many well-known chiral diphosphane ligands, such as DIOP, BINAP, and CHIRAPHOS, which are extremely successful in the asymmetric hydrogenation of dehydroamino acid derivatives, do not give high enantioselectivity in the hydrogenation of enamides.[3, 4] A breakthrough was achieved by Burk et al.[4a] with the introduction of BPE and DuPHOS ligands, which gave excellent enantioselectivity in the Rh-catalyzed asymmetric hydrogenation of enamides. Lately, some other P ligands were also reported to be efficient in the hydrogenation of enamides.[4b, 5] However, all ligands that gave a high degree of enantiocontrol are bidentate. To our knowledge, no efficient chiral monodentate ligand has been reported for the asymmetric hydrogenation of enamides, although some monodentate P ligands were successfully used in the hydrogenation of dehydroamino acid derivatives.[6] Here we describe highly efficient monodentate chiral ligands 1 containing a 1,1 -spirobiindane backbone for the Rh-catalyzed asymmetric hydrogenation of -arylethenylamine derivatives [Eq. (1)] with excellent enantioselectivities (up to 99.7% ee). The chiral monodentate phosphoramidite ligands 1 (abbreviated SIPHOS) were conveniently synthesized in good yields from enantiomerically pure 1,1 -spirobiindane-7,7 -diol, which was easily prepared from 3-methoxybenzaldehyde by using the procedure described by Birman et al.[7] We demonstrated recently that the Rh complex of (S)-1a (R CH3) is a highly efficient catalyst in the asymmetric hydrogenation of dehydroamino acid and itaconic acid derivatives with up to 99.3% ee. Therefore, we were prompted to investigate the utility of this catalyst in the asymmetric hydrogenation of -phenylenamide 4a and an excellent enantioselectivity (up to 98.8% ee) was achieved. This showed, for the first time, that monodentate phosphorus ligands can be effective in the enantiocontrol of asymmetric hydrogenation of enamides. The results in Table 1 show that the enantioselectivity of the reaction was sensitive to the solvent used, and toluene is the solvent of choice. In contrast, the hydrogen pressure has a negligible influence on the enantioselectivity. For example, in the hydrogenation of 4a with Rh/(S)-1a catalyst in toluene, the ee values of product 5a at 25 C under 10 atm and 100 atm H2 were 96% and 96.2%, respectively (Table 1, entries 1 and 2). The investigation of catalyst loading showed that 0.5 mol% catalyst was sufficient to give a high enantioselectivity, while the ee value of the product dropped drastically with 0.1 mol% catalyst.