Origin of the Minor Enantiomeric Product in a Noyori Asymmetric Hydrogenation: Evidence for Pathways Different to the Major Mechanism

Abstract

Hidden pathways: The enantiomeric products of the catalytic hydrogenation of an isotopically labeled substrate were separated. The ratios of the isotopomers revealed that the major and minor enantiomers are formed mostly through different mechanisms. Hence, when analyzing the energy profile of an asymmetric catalytic reaction with the Arrhenius equation, two competing diastereomorphic catalytic cycles should be considered (see scheme). In a typical asymmetric catalytic process, a prochiral substrate (Sub) is converted into a major (ProdS) and a minor (ProdR) enantiomeric product via diastereomeric catalyst–substrate (CatSub) and catalyst–product (CatProd) complexes (Scheme 1). The two cycles are diastereomorphic to each other, but they take place through a single mechanism. As such, the Arrhenius equation can be applied confidently to correlate the ProdS/ProdR ratio to the relative stabilities of the diastereomeric transition states at the first irreversible step from CatSub to CatProd.1 The energy profile thus obtained can be utilized to estimate the structural difference between the two transition states. In most cases, however, this premise of a single mechanism has not been confirmed.2 We have long suspected that in some cases ProdS and ProdR may be generated through entirely different catalytic cycles in which several chain carriers produced in a given reaction system convert the same substrate but with different reactivities and enantioselectivities. In such a catalytic process, various reaction parameters dynamically link the species, and therefore the observed enantioselectivity becomes the average contribution of the mechanistically different cycles.3 Herein, we report for the first time a clear example of asymmetric catalysis that yields ProdS and ProdR from the same substrate but through different mechanisms. Competition between diastereomorphic catalytic cycles. This new case was identified in the hydrogenation of (Z)-3-phenyl-2-butenoic acid ((Z)-2) in the presence of [Ru(CH3CO2)2{(R)-binap}] ((R)-1).4 Under standard conditions ((R)-1 (0.5 mM), (Z)-2 (100 mM), Sub/Cat=200:1, methanol, 30 °C, 1–4 atm), (S)-3-phenylbutanoic acid ((S)-3) was obtained with 94 % ee when a pressure of 1–4 atm was applied. The value decreased to 92 % ee at 50 atm and to 88 % ee at 100 atm,5 whereas the reaction rate was enhanced when the pressure of the hydrogen was increased.6 The substrate (Z)-2 is stable and undergoes neither Z/E geometrical nor α,β/β,γ (C2C3/C3C4) positional isomerization during the course of the hydrogenation.5, 7 To improve the accuracy of the isotope-labeling experiments, the 13C-labeled substrate (Z)-[3-13C]2 was used, and the (R)-1-catalyzed hydrogenations were carried out in CH3OD by changing the hydrogen pressure and the ratio of H2 and D2. All the reactions were stopped at low conversions to minimize complications caused by gas–solvent and gas–gas isotope exchange.2, 5 The enantiomeric products, (S)-3 (major) and (R)-3 (minor), were separated by chiral HPLC (CHIRALCEL OD (20 mm×25 cm); eluent: hexane/2-PrOH/AcOH 1000:1:3),5 and the ratio of the eight isotopomers (3S)-2H,3H-[3-13C]3, (3S)-2H,3D-[3-13C]3, (2R,3S)-2D,3H-[3-13C]3,9 (2R,3S)-2D,3D-[3-13C]3,9 (3R)-2H,3H-[3-13C]3, (3R)-2H,3D-[3-13C]3, (2S,3R)-2D,3H-[3-13C]3,9 and (2S,3R)-2D,3D-[3-13C]39 was determined by 13C{1H,2H} NMR spectroscopic analysis of the S and R products (Scheme 2).5, 10 Structures of the eight possible isotopomers from the reduction of (Z)-[3-13C]2 in CH3OD under H2/D2 mixtures at different pressures. Figure 1 represents the change in the distribution pattern of the major and minor enantiomeric products in going from the H2 to H2/D2 conditions. When the reaction was carried out in CH3OD under a pressure of 4 atm of H2, a mixture of (S)-3 and (R)-3 was obtained in a ratio of 97:3. The major S product consisted of 2H,3H, 2H,3D, 2D,3H, and 2D,3D isotopomers (10:89:0:1). Under an atmosphere of H2/D2 (1:1) in CH3OD, the ratio shifted to 3:46:3:48. This change in distribution can be understood simply in terms of the Ru monohydride mechanism proposed in the Ru–binap-catalyzed hydrogenation of tiglic acid11, 12 or α-(acylamino)acrylic esters.2, 13 In short, a RuH species, generated from (R)-1 and H2, delivers hydride to the Si face at C2 of (Z)-2 to form the (3R)-C3–Ru intermediate. Cleavage of the CRu bond utilizes both H2 gas (the RuH/C3–Ru/H2 route) and CH3OD (the RuH/C3–Ru/H+ route), and leads to a mixture of (3S)-2H,3H and (3S)-2H,3D (10:89).14, 15 Under a 1:1 mixture of H2/D2 gas, the RuH/C3–Ru/H2 route should produce the four isotopomers in a 1:1:1:1 ratio (blue line) and the RuH/C3–Ru/H+ route should produce 2H,3D and 2D,3D in a 1:1 ratio (green line); therefore, a relative proportion of ≈3 each for the (3S)-2H,3H, (3S)-2H,3D, (3S)-2D,3H, and (3S)-2D,3D isotopomers will be derived from the 10 part, and ≈44 for the (3S)-2H,3D and (3S)-2D,3D isotopomers from the 89 part. Simple calculation estimates the ratio to be 3:47:3:47, which is consistent with the observed ratio. Change of the isotopomer ratios in the (R)-binap–Ru-catalyzed hydrogenation of (Z)-[3-13C]2 in CH3OD under 4 atm of H2 or H2/D2 (1:1). Top: (S)-[3-13C]3 obtained as the major product (97 %). Bottom: (R)-[3-13C]3 obtained as the minor product (3 %). The colored arrows indicate the reaction pathways and the estimated distribution of the isotopomers when the conditions are switched from H2 to H2/D2 (1:1). → RuH/C3–Ru/H2 and/or RuH/C2–Ru/H2 (RuH/H2); → RuH/C3–Ru/H+; → RuH2; → RuH/C2–Ru/H+. In contrast, the minor R enantiomer contained largely the (3R)-2H,3H (53 %) together with the (3R)-2H,3D (30 %) and (3R)-2D,3H (17 %) isotopomers. More gaseous hydrogen appears to be consumed in the formation of the minor product than in that of the major S enantiomer, and formation of the 2D,3H isotopomer is characteristic of the minor product. The reaction carried out in CH3OD under a mixture of H2/D2 (1:1) generated a 23:20:13:43 mixture of the four 3R isotopomers. The ambiguous isotope-labeling patterns, which are totally different from those of the major enantiomer, can be explained by assuming that the RuH2 route5 (red line) and the RuH/C2–Ru/H+ route (purple line) are involved as well as the above two reaction pathways (blue and green lines) (Figure 1, minor). The two hydrides on RuH2 are delivered from the same Re,Si face of (Z)-2 to C2 and C3 in a pairwise manner.16 In the RuH/C2–Ru route, a conjugate-type addition of the hydride of a RuH species onto the Si face of C3 generates a (2R,3S)-C2–Ru intermediate,17 which then undergoes hydrogenolysis (RuH/C2–Ru/H2) or protonolysis (RuH/C2–Ru/H+). Thus, the 2H,3H, the 2H,3D, and the 2D,3H isotopomers in the H2/CH3OD reaction are produced through the pathways RuH2 and RuH/H2,18 the RuH/C3–Ru/H+ route, and the RuH/C2–Ru/H+ route, respectively. In light of the 2H,3H:2H,3D:2D,3H:2D,3D distribution coefficients (1:1:1:1 for RuH/C3–Ru/H2 and RuH/C2–Ru/H2 (blue line), 0:1:0:1 for RuH/C3–Ru/H+ (green line), 1:0:0:1 for RuH2 (red line), and 0:0:1:1 for RuH/C2–Ru/H+ (purple line)), the isotopomer ratio obtained by the replacement of H2 with a 1:1 mixture of H2/D2 gas is calculated to be 22:20:13:45. Figure 2 a shows the good agreement between the values estimated from the H2/CH3OD results (colored bars) and the experimental values (gray bars). The colors correspond to those of the reaction pathways shown in Figure 1. Observed (gray) and estimated (colored) isotopomer ratios of the major S and minor R products in the (R)-binap–Ru-catalyzed hydrogenation of (Z)-[3-13C]2 in CH3OD under: a) 4 atm of H2/D2 (1:1), b) 100 atm of H2/D2 (1:1), and c) 50 atm of H2/D2 (44:56). Colored values are estimated from the experimental results of 4, 50, and 100 atm H2/CH3OD conditions. ▪ RuH/C3–Ru/H+; ▪ RuH/C3–Ru/H2 and/or RuH/C2–Ru/H2; ▪ RuH2; ▪ RuH/C2–Ru/H+; ▪ unknown mechanisms; x axis: isotopomers of 3; y axis: yield [%]. This tendency is also seen with changes in the pressure of the hydrogen gas and the H2/D2 ratio (Figure 2 b, c2).19 An increase in hydrogen pressure from 4 to 100 atm in CH3OD approximately tripled the formation of the minor enantiomer (Figure 2 a, minor vs. Figure 2 b, minor), and enhanced the contribution of gaseous hydrogen to both the major and minor product pathways. The amount of major product formed by the RuH/H2 pathway (blue bars) increased approximately five times and was coupled with a significant decrease in the involvement of the RuH/C3–Ru/H+ route (green bars), whereas the contribution of the RuH2 pathway (red bars) to the formation of the minor product doubled. In the case of the reaction carried out in CH3OD under H2/D2 gas (44:56) at 50 atm, the S and R products (96:4) consisted of the eight isotopomers in a 9:31:11:45:1.0:0.6:0.7:1.7 ratio, as indicated by the gray bars in Figure 2 c. A reasonable agreement with the estimation from the results obtained from the reaction in CH3OD under 50 atm of H2 was observed after a 0.44/0.56 correction to the above distribution coefficients. Each asymmetric catalytic cycle proceeding through the RuH/C3–Ru/H2, RuH/C3–Ru/H+, RuH/C2–Ru/H2, RuH/C2–Ru/H+, or RuH2 routes, or other possible reaction pathways, has its own energy diagram, according to which the overall rate as well as the stereochemistry is determined.20 Neither the details of the kinetics nor the structures of the intermediates are known at present, but a series of isotope-labeling experiments indicated that this Ru–binap-catalyzed asymmetric hydrogenation of an α,β-unsaturated carboxylic acid involves several catalytic species and that a significant amount of the minor R enantiomer is formed through the RuH/C2–Ru/H+ and RuH2 pathways, which are hardly involved in the formation of the major product (Scheme 3). Asymmetric catalytic reactions convert a prochiral substrate into an enantiomer-enriched chiral product. The observed enantioselectivity has generally been interpreted to result from competing diastereomorphic catalytic cycles caused by a single chiral catalyst. However, this supposition has not been substantiated. Together with earlier examples,2, 11, 12 our study calls into question such a generalized treatment. Possible catalytic cycles producing the major S and minor R enantiomers from the same (Z)-2 substrate through different chain carriers. C3 substituents of (Z)-2 and products have been omitted for clarity. Supporting information for this article (asymmetric hydrogenation and isotope-labeling experiments) is available on the WWW under http://www.wiley-vch.de/contents/jc_2002/2005/z502463_s.pdf or from the author. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.