Enantioselective Metal‐Free Hydrogenation Catalyzed by Chiral Frustrated Lewis Pairs

Abstract

Bulky Lewis acids and Lewis bases do not undergo neutralization to form classical Lewis acid–base adducts because of steric hindrance. The Lewis acids and Lewis bases involved in this phenomenon are termed “frustrated Lewis pairs” (FLPs). The synergy between the unquenched acid and base endows the Lewis pair with the ability to activate small molecules, in particular hydrogen. A milestone discovery in this field was reported by Stephan and co-workers in 2006, in which a phosphine–borane compound was reported to reversibly activate hydrogen under mild conditions. Since then, FLP chemistry has developed into a cutting-edge concept. Most of the reported FLPs, generally based on the strong Lewis acid B(C6F5)3 accompanied by a bulky amine or phosphine, may serve as hydrogenation catalysts. Recently, metal-free hydrogenation using FLP catalysts has been regarded as a promising application of FLP chemistry. FLP catalytic systems are able to hydrogenate a wide range of unsaturated substrates, such as imines, enamines, enol ethers, and heterocycles. Enantioselective hydrogenation, which is still dominated by transition-metal catalysts, plays a pivotal role in organic synthesis. Considering the increasingly stringent limits on the amount of metal impurities found in drug compounds, the development of an effective metal-free catalyst for enantioselective hydrogenation to synthesize chiral molecules is a longterm challenge. FLP-type enantioselective hydrogenation is a rational extension of this hydrogenation chemistry owing to its significant potential for the transition-metal-free synthesis of chiral molecules. However, FLP-type catalytic enantioselective hydrogenation has remained relatively unexplored. This strategy is hampered by the design and synthesis of an effective chiral borane reagent because this class of air-sensitive compound cannot be purified by the usual chromatography techniques. Another issue confronting researchers is that the stereoselectivity of borane connected to the chiral scaffold through a single s bond is difficult to control because two perfluorophenyl groups are necessary to keep enough Lewis acidity for H2 activation. To realize FLP-type catalytic enantioselective hydrogenation, four kinds of chiral FLP catalysts can be considered (Scheme 1), mode I: chiral B moiety, achiral N(P) moiety; mode II : achiral B moiety, chiral N(P) moiety; mode III : intramolecular chiral FLP; mode IV: chiral B moiety, chiral N(P) moiety. Great progress has been made in the rational design of chiral FLP catalysts based on modes I–III in recent years, but mode IV remains to be explored (Figure 1). In mode I, the chiral B H species resulting from H2 activation is expected to undergo an asymmetric hydride transfer to proScheme 1. Enantioselective metal-free hydrogenation by means of an FLP strategy.