Highly Enantioselective Rhodium-Catalyzed Hydrogenation of Dehydroamino Acids with New Chiral Bisphosphinites

Asymmetric synthesis based on transition metal catalyzed processes has attracted a great deal of interest because of its high efficiency for the preparation of enantiomerically pure compounds. The development of efficient chiral transition metal complexes has focused mainly on the design and synthesis of new chiral ligands. Many chiral bisphosphines1 have been invented to facilitate enantioselective catalytic reactions, and unique properties of chiral ligands are strongly associated with their ligand frameworks such as biaryl chirality with BINAP and chiral phosphalane with DuPhos. Recently, we have reported a new chiral 1,4-bisphosphine, (2R,2′R)bis(diphenylphosphino)-(1R,1′R)-dicyclopentane (1) [(1R,1′R,2R,2′R)-BICP] (Figure 1) for the effective rhodiumcatalyzed asymmetric hydrogenation of R-(acylamino)acrylic acids.2 This new chiral phosphine has four stereogenic centers, and contains two cyclopentane rings in its backbone which greatly restrict its conformational flexibility. A recent work by Chan et al.3m also concurs with our observation that increasing ligand rigidity is the key for the development of highly enantioselective reactions. In contrast to many chiral phosphines reported in the literature, phosphinites used in metal complexes for asymmetric reactions are generally rather poor ligands with few exceptions.3 While phosphinites are less electron donating than phosphines, they can be excellent ligands for asymmetric hydroformylation4 and hydrocyanation reactions.5 Clearly, it is worthwhile to search for new chiral phosphinites with new chiral scaffolds. Taking advantage of the relatively rigid biscyclopentane backbone of BICP, we made the corresponding chiral bisphosphinite, (2S,2′S)-bis(diphenylphosphinoxy)-(1R,1′R)dicyclopentane (abbreviated (1R,1R′,2S,2′S)-BICPO) (Figure 1), from (1R,1′R)-bicyclopentyl-(2S,2′S)-diol. Highly enantioselective hydrogenation of dehydroamino acids catalyzed by rhodium complexes with this ligand is reported herein. Our goal is not simply to create another asymmetric catalytic system for hydrogenation of dehydroamino acidssa well-studied reactionsthe impact of this study is to enhance fundamental understanding of those factors in chiral ligand design by exploring a variety of chiral ligand motifs. The bisphosphinite ligand (2, (1R,1′R,2S,2′S)-BICPO) is easily made from chiral (1R,1′R)-bicyclopentyl-(2S,2′S)diol 3 in high yield as illustrated in Scheme 1. The cationic Rh(I) complex [Rh(COD)(BICPO)]BF4, prepared in situ by mixing [Rh(COD)2]BF4 with 1.1 molar equiv of (1R,1′R,2S,2′S)-BICPO under an inert atmosphere, is a highly effective catalyst for the hydrogenation of R-acetoamidocinnamic acid at ambient temperature under 1 atm of H2. Table 1 summarizes the results of hydrogenation of R-acetoamidocinnamic acid under a variety of experimental conditions. The reaction medium significantly affects the catalytic activity and enantioselectivity of the product. Unlike our early observation on the additive effect of triethylamine with the BICP system,2 the enantioselectivity and reactivity of the hydrogenation decreased drastically in the presence of a catalytic amount of triethylamine (Rh:2:Et3N ) 1:1.1:50).6 For example, R-acetoamidocinnamic acid was completely reduced with 89.1% ee in THF in the absence of Et3N, while only 30% was reduced with 30.9% ee with a catalytic amount of Et3N under 1 atm of H2 (entry 3 vs 2, entry 5 vs 4). Asymmetric hydrogenation in alcoholic solvents (entries 4, 6, and 8-9), except with CF3CH2OH (entry 7), gave better selectivities than in THF (entry 2) and ClCH2CH2Cl (entry 1). Among several common alcohol solvents, the highest enantioselectivity (94.7% ee, S) for the hydrogenation of R-acetoamidocinnamic acid was achieved in iPrOH under 1 atm of H2 at ambient temperature (entry 9). 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