Toward efficient asymmetric hydrogenation: Architectural and functional engineering of chiral molecular catalysts

Abstract

Asymmetric hydrogenation uses inexpensive, clean hydrogen gas and a very small amount of a chiral molecular catalyst, providing the most powerful way to produce a wide array of enantio-enriched compounds in a large quantity without forming any waste. The recent revolutionary advances in this field have entirely changed the synthetic approach to producing performance chemicals that require a high degree of structural precision. The means of developing efficient asymmetric hydrogenations is discussed from a mechanistic point of view.A symmetric catalysis lies outside the realm of traditional organic synthesis. It is a pervasive, global endeavor involving synthetic organic chemistry, catalytic chemistry, structural chemistry, inorganic and coordination chemistry, physical chemistry, and theoretical chemistry, as well as chemical engineering. Chiral Molecular Catalysts:Beyond the Shape Asymmetric catalysis is four-dimensional chemistry (1). High efficiency can be achieved only by using a combination of both an ideal 3D structure (x, y, z) and suitable kinetics (t). Currently, efficient asymmetric catalysis primarily uses a molecular catalyst that consists of a metallic element and chiral organic ligand(s) (2). Fig. 1 illustrates a typical (but not general) catalytic scheme. Under reaction conditions, the initially used precatalyst 1 is converted to the true catalyst 2 (induction process) that activates achiral molecules A and B and transforms them to the chiral product A-B (catalytic cycle). Although the ligand must create a distinct enantio-differentiating environment in transition metal-based complexes, such an architectural design does not suffice to achieve asymmetric catalysis. Some of the steps in the multistep transformation are reversible, whereas the first irreversible step, for example 334, kinetically determines the absolute stereochemistry of A-B. Efficient asymmetric catalysis requires a high turnover number and high turnover frequency, but the best way to generate high catalytic activity is not immediately apparent. First, the induction process of converting 1 to 2 is often not straightforward. Furthermore, to obtain a high turnover frequency, all of the transition metal-based entities 2-4 in this cycle must be neither very unstable nor very stable, avoiding substrate and͞or product inhibition. Instead, 2-4 are required to interconvert one another smoothly by means of a low kinetic barrier, and without any destructive side reactions. The reaction conditions strongly influence the stability and reactivity of 1-4. In general, both suitable architectural and functional engineering are crucial for obtaining sufficient catalytic efficiency. ''Molecular catalysis'' can cope with such requirements, because any molecules, by definition, can be designed and synthesized at will.This perspective deals largely with the intrinsic mechanistic aspects of asymmetric hydrogenation developed in our laboratories (3-5). Although HOH bonds are readily cleaved by transition metal complexes, truly useful asymmetric hydrogena...

Ligand Design for Catalytic Asymmetric Reduction

“…''monohydride/unsaturate mechanism,'' in which the RuH(AcO) species 10B, formed by the heterolytic cleavage of H 2 by the precatalyst 10A, acts as a real catalyst. 21,[49][50][51][52][53] Thus, the Ru hydride species is generated before the substrate coordination forming 10C. The migratory insertion giving 10D, in which the RuÀ ÀC bond is cleaved mainly by H 2 , but also by CH 3 OH solvent to some extent.…”

“…18 14 illustrates a mechanistic model of this hydrogenation. 21,71 The true catalytic RuHCl species 14B is generated by the reaction of the RuCl 2 precatalyst 14A and H 2 by releasing HCl. The catalyst 14B reversibly interacts with the b-keto ester to form the s-type chelate complex 14C.…”

“…Figure 1.15 illustrates two diastereomeric transition states Re-15A and Si-15A in the hydride migration step in the (R)-BINAP-Ru-catalyzed hydrogenation. 21 The protonated carbonyl group, C À À À ÀO þ H, becomes parallel to the H-Ru linkage, bringing the ''R'' group close to the P-phenyl ring of the (R)-BINAP ligand. Thus, transition state Re-15A producing the S alcohol is unfavored because of the R/Ph repulsive interaction in the fourth quadrant.…”

“…18,67,68 However, simple unfunctionalized ketones are totally inert to this catalyst system, because the substrates are unable to stabilize the transition state by forming a chelate structure (Figure 1.15). 21 A combined system of trans-RuCl 2 (binap)(dpen) and alkaline base [84][85][86] or trans-RuH(Z 1 -BH 4 )-(binap)(dpen) 87 with or without a base exhibits excellent catalytic performance in asymmetric hydrogenation of a variety of simple ketones. 21,86 For example, acetophenone is hydrogenated in the presence of an (S)-XylBINAP/(S,S)-DPEN-Ru catalyst (ketone:Ru ¼ 100,000:1) in 2-propanol to give (R)-1-phenylethanol in 99% ee (Figure 1.17).…”

“…22 Figure 1.4 illustrates the chiral template created by an (R)-BINAP-transition metal complex. [18][19][20][21] The naphthalene rings are omitted in the side view for clarity. In this template, the chiral information of binaphthyl backbone is transmitted through the P-phenyl rings to the four coordination sites shown by & and &.…”