Russian Chemical Reviews 71 (1) 33 ± 48 (2002) Mechanisms of asymmetric induction in catalytic hydrogenation, hydrosilylation and cross-coupling on metal complexes V A Pavlov Contents I. Introduction II. Asymmetric induction prior to the catalytic reaction III. Asymmetric induction in the stage of substrate coordination by catalytic complexes IV. Asymmetric induction in the course of transformations of the first or subsequent intermediates of the catalytic reaction V. Asymmetric induction caused by nonbonded diastereomeric interactions VI. Conclusion Abstract. of mechanisms the on studies of state current The The current state of studies on the mechanisms of asymmetric and hydrosilylation hydrogenation, asymmetric hydrogenation, hydrosilylation and cross-coupling cross-coupling induced by metal complexes is considered.The possibilities for the induced by metal complexes is considered. The possibilities for the identification involving reactions catalytic of stages of identification of stages of catalytic reactions involving asymmetric asymmetric induction of types the of classification The analysed. are induction are analysed. The classification of the types of asym- asym- metric stages these in differences the to according induction metric induction according to the differences in these stages is is proposed. the in occurs induction asymmetric cases, most In proposed. In most cases, asymmetric induction occurs in the stage stage of ± key (the complexes catalytic by coordination substrate of substrate coordination by catalytic complexes (the key ± lock lock interaction).the of favour in presented is Evidence interaction). Evidence is presented in favour of the assumption assumption that in product the in formed is atom carbon asymmetric the that the asymmetric carbon atom is formed in the product in the the stages intermediate, asymmetric the of transformations of stages of transformations of the asymmetric intermediate, even even though the starting chiral catalytic complex is The though the starting chiral catalytic complex is C2-symmetric. -symmetric. The bibliography includes 118 references bibliography includes 118 references. I. Introduction Asymmetric catalytic reactions involving prochiral substrates on chiral metal-complex catalysts proceed through the interaction of these species to form diastereomeric intermediate complexes.The rational description of the phenomenon of asymmetric induction (or diastereoselectivity) { in asymmetric synthesis can be given using empirical stereochemical rules and models 1 analogous to those proposed by Prelog, Cram, Cornforth, et al. Asymmetric induction can take place either in the stage of interaction (coor- dination) of a metal-complex catalyst with a substrate to form an intermediate complex or in the course of subsequent transforma- tions of the resulting complex. The first alternative is sometimes called the steric control or the `key ± lock' interaction (the terms `chiral recognition' and `chiral discrimination' are also used).For the reaction product, [AB]2... [AB]1 A+B where A is the substrate and B is the reagent (catalyst), the following general classification of the types of asymmetric induc- tion is proposed: (1) prior to the reaction (due to a chiral medium); V A Pavlov N D Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Leninsky prosp. 47, 119991 Moscow, Russian Federation. Fax (7-095) 135 53 28. Tel. (7-095) 938 35 02. E-mail: pvlv@cacr.ioc.ac.ru Received 25 April 2001 Uspekhi Khimii 71 (1) 39 ± 56 (2002); translated by T N Safonova #2002 Russian Academy of Sciences and Turpion Ltd DOI 10.1070/RC2002v071n01ABEH000677 33 33 35 40 44 46 (2) the stage involving the interaction of A with B (coordina- tion of the substrate by the catalyst); (3) transformations of the first ([AB]1), second ([AB]2) and subsequent intermediates already involving the coordinated sub- strate; (4) nonbonded diastereomeric interactions analogous to those existing between enantiomers in racemates.Asymmetric induction of the first type is observed in reactions performed in a chiral matrix [for example, in cholesteric liquid crystals (CLC) in the mesophase temperature range, where a chiral helical structure is formed] or in a chiral solvent and, probably, under the combined action of the electric and magnetic fields.2, 3 Asymmetric induction of the second type takes place in asymmet- ric metal-complex catalysis, in particular, on hydrogenation and hydrosilylation of aromatic ketones.Asymmetric induction occurring in the course of transformations of the first and second intermediates (the third type) has been examined in detail for catalytic allylic alkylation.4 The nature of asymmetric induction, which is caused by interactions between enantiomers in racemates (the fourth type) and due to which the racemates differ from the constituent individual enantiomers in some chemical and physical properties, is poorly known. Asymmetric induction, if considered as a way of communicat- ing stereochemical information, involves two components, viz., static discrimination due to steric hindrance and dynamic dis- crimination resulting from kinetic or thermodynamic factors.5 Hydrogenation, hydrosilylation and cross-coupling are of importance from the practical standpoint because they comprise a minimal set of reactions, which provide the preparation of chiral products bearing many functional groups involved in pharma- ceuticals.6 Because of this, the present review deals with the mechanisms of asymmetric induction occurring in these three reactions.II. Asymmetric induction prior to the catalytic reaction Asymmetric induction prior to the reaction should be considered as a manifestation of the chiral action of a medium both on the catalyst, which in this case can be achiral, and the prochiral substrate. Asymmetric reactions can proceed in a CLC medium { The enantioselectivity can be considered as a measure of asymmetric induction in asymmetric catalysis where the enantiomeric product is isolated from a diastereomeric intermediate complex.34 in the mesophase temperature range where a chiral helical structure is formed (for more detailed arguments in favour of asymmetric induction prior to the reaction, see below).However, the published data on asymmetric synthesis in a CLC medium as a chiral matrix are contradictory. The enantioselective Claisen rearrangement performed in a CLC mesophase has been reported:7 OH O * CNB 200 8C, 6 h CNB is cholesteryl p-nitrobenzoate. The authors judged the enantioselectivity of the reaction from the CD spectra of the product. Ethyl(phenyl)malonic acid was decarboxylated in a CLC mesophase in an optical yield (p) of 18%:8H CO2H Et CO2H Et CO2H cholesteryl benzoate 160 8C, 2 h (R) In the photochemical synthesis of hexahelicene performed in CLC within the mesophase temperature range of 20 ± 25 8C, the enantioselectivity of the process was 1%, which was confirmed by the presence of a CD maximum in the absorption band of the hexahelicene obtained.9cholesteryl nonanoate ± cholesteryl chloride (3:1), I2, hn 23 8C, 1.5 h [a]D=+40 (CHCl3) However, photocyclisation of a-(N-methylanilino)styrene into N-methyl-2-phenylindoline in various CLC mesophases afforded a racemic product.10 When studying thermochemical interconversions of sulfoxides in a cholesteryl p-nitrobenzoate mesophase, a small enantiomeric excess (ee) of the product was observed.11 O O CNB, 150 ± 200 8C S S Me Me (S) (R) ee=9.2% O O S S CNB, 150 ± 200 8C Me Me (S) (R) ee=2.4% It was concluded 10, 11 that asymmetric transformations in cholesteric mesophases, like those in standard chiral solvents, proceed in low optical yields.However, the authors of the cited papers noted that exceptions are possible in the case of strong specific interactions between the dissolved compound and CLC. In another study,12 even the theoretical possibility of the manifestation of the asymmetric effect in a CLC mesophase was V A Pavlov denied because the helical step of CLC (300 ± 400 nm) is incom- patible with the molecular sizes of standard reagents. These molecules do not `notice' the helical structure of CLC, much as people do not notice the curvature of the earth's surface.Never- theless, CLC, owing to the chirality of their molecules, can exert a slight asymmetric effect on chemical reactions, if only as optically active solvents. The asymmetric influence of the magnetic field is poorly known.{ Pasteur was the first to take an interest in this problem. He believed that if the magnetic field can induce rotation of the polarisation plane of light in the case of achiral compounds (the Faraday effect), it can generate the disymmetry analogous to that possessed by chiral molecules. Kelvin reasoned that this idea is in error because the magnetic rotation does not possess the right- or left-handed quality, i.e., it is not chiral. However, P Curie noted that the magnetic field parallel to the electric field can induce chirality because the mirror operation (which provides interchan- geability of components) is applicable to the parallel and antipar- allel molecular arrangements in this combined field.14 The above- considered enantiomorphism and the enantiomorphism of chiral molecules are distinguished as the `false' and 'true' chirality, respectively.2, 3 This raises the question of whether the `false' chiral effect can cause asymmetric induction.It is known that the symmetry is broken at the level of elementary particles. It is assumed that the `false' chiral effect can induce analogous symmetry distortions in chemical reactions. Changes in the symmetric (in the absence of this effect) energy barriers in the path of formation of enantiomers of the product can lead to differences between the rate constants of formation of enantio- mers in the chemical reaction away from the equilibrium.2, 3 This theoretical reasoning has been supported experimentally.Thus Gerike 15 discovered the enantiomeric enrichment (although small and irregular) of the product (ee<1%) in alkylation of prochiral ketones with Grignard reagents, the addition of bromine at the double bond and some other reactions using various combinations (parallel, antiparallel and orthogonal mutual arrangements) of the electric (15 ± 8100 V cm71) and magnetic (constant and alternating, 86103 ± 1.176105 A m71, 0 ± 50 Hz) fields. It was reported that reduction of ketones with Grignard reagents and lithium aluminium hydride in a constant magnetic field proceeded with high enantioselectivity.16 However, this conclusion was disproved by one of the authors.17 It is agreed 2, 3 that the concept of the asymmetric influence of the constant magnetic field is reasonable, but this influence can serve only as a `starter' and must be combined with a chiral autocatalytic process. Apparently, this problem calls for further careful exper- imental investigation. We also examined asymmetric induction in catalytic reactions proceeding in a liquid-crystal chiral matrix 18, 19 by studying hydrogenation of a-acetamidocinnamic acid (ACA) in the pres- ence of achiral Wilkinson's catalyst RhCl(PPh3)3 possessing a substantial molecular volume (this fact is of importance in imparting the helical ordering of the CLC molecules to the molecules of the catalyst).Since RhCl(PPh3)3 and ACA are insoluble in a CLC melt, viz., in cholesteryl tridecanoate (CTD), the reaction was carried out in a CTD±BunOH±C6H6 mixture. In this solution, the molecules of CTD, the substrate (ACA) and the catalyst RhCl(PPh3)3 have helical ordering at the mesophase temperature of 60 ± 70 8C. This is evidenced by the fact that the CD spectra show maxima of induced circular dichroism of the same sign in the absorption bands of the substrate and the catalyst. Probably, the same sense of helical ordering of the substrate and catalyst molecules facilitates discrimination between the Re- and Si-sides of the C=C bond in the substrate coordinated to the catalyst in an intermediate complex.Actually, a moderate temperature-dependent enantioselectivity was observed in the reaction under consideration (Fig. 1). { The non-asymmetric influence of the magnetic field on chemical reac- tions has long been known (see, for example, the review 13).Mechanisms of asymmetric induction in catalytic hydrogenation, hydrosilylation and cross-coupling on metal complexes p (%) 15 105 58 60 62 T /8C Figure 1. Temperature dependence of the optical yield of N-acetylphe- nylalanine in hydrogenation of ACA. The dependence has a maximum in the middle of the temper- ature range of the CTD mesophase where the cholesteric liquid crystal is helically ordered. This effect could also be attributed to the effect of CLC as a chiral solvent.However, the fact that the maximum of enantioselectivity coincides with the middle of the temperature range of the liquid crystal mesophase counts in favour of the former explanation. With the aim of investigating the effect of a combination of the electric and constant magnetic fields on chemical reactions, we } used a solenoid.20 Acid- and base-catalysed mutarotation of D-glucose in water was examined. In the mutarotation of mono- saccharides, the equilibrium was established between the a and b forms, which are diastereomers. In the initial stage, the reaction was far from the equilibrium (this is a necessary condition for the magnetic field to exert the asymmetric effect 2, 3).The reaction was carried out in a temperature-controlled polarimetric tube placed in a solenoid and its course was followed from the change in the optical rotation. The rate constant of mutarotation k was calcu- lated according to the first-order equation. The magnetic field strength (H) was calculated from the magnetic rotation of the polarisation plane of light under the action of water at l=589 nm. The direction of magnetic field was judged from the direction of the observed rotation of the plane of polarisation induced by water. To obtain a more accurate estimate of the dispersion of the rate constants, some experiments were repeated several times at the same temperature. The results are given in Table 1. Presently, one cannot give an unambiguous answer to the question of how the rate constant is changed depending on the direction of magnetic field.However, the reaction at low temper- atures in the field with (+)-aD H2O proceeds somewhat more rapidly than that in the field with (7)-aD H2O. At the same time, Table 1. Rate constants of mutarotation of D-glucose at different temper- atures depending on the direction of magnetic field in a solenoid.20 H /G 103 k /min71 103Dk /min71 T /8C (+)-aD H2O (7)-aD H2O 1266 6.2 1265 10.2 3.69 0.02 3.42 0.08 5.65 0.03 5.59 0.02 3.73 0.04 3.74 0.03 6.01 0.02 5.81 0.04 1262 20 1259 30 5.50 0.04 16.72 0.05 16.82 0.06 41.57 0.08 6.02 0.01 16.68 0.05 16.80 0.03 43.57 0.29 +0.04 +0.32 +0.36 +0.22 +0.52 70.04 70.02 +2.00 71.60 +7.29 1256 38.3 43.10 0.20 83.58 0.62 42.50 0.39 90.87 0.49 } The experiment was carried out in collaboration with E I Klabunovskii.35 it can be said with reasonable confidence that the effect of a constant magnetic field (without combining with the electric field) is absent. The results of the investigation of D-glucose mutarota- tion in water in a constant magnetic field demonstrated that the changes in the rate constants depending on the direction of the magnetic field are comparable in value to the errors of the measurements (Table 2). Table 2. Rate constants of mutarotation of D-glucose at 200.1 8C depending on the direction of constant magnetic field (H=7490 G).103 k /min71 103Dk /min71 (+)-aD H2O (7)-aD H2O 70.94 0.85 70.19 0.26 71.02 0.41 +0.29 0.56 70.07 0.42 14.67 0.29 15.03 0.07 15.19 0.23 14.85 0.11 15.07 0.11 13.73 0.85 14.84 0.26 14.17 0.41 15.14 0.56 15.00 0.42 III. Asymmetric induction in the stage of substrate coordination by catalytic complexes The elucidation of the nature of asymmetric induction and the identification of the stage where it takes place are closely related to the investigation of the general mechanism of asymmetric reac- tions. For the latter problem to be solved, it is necessary to reveal individual elementary stages, determine their rates, detect and characterise intermediates (including the establishment of their absolute configurations) and, finally, identify the key stage of asymmetric induction.If asymmetric induction occurs in the stage of substrate coordination by a chiral catalytic complex, this fact can be established using rather simple logical approaches consid- ered below. The mechanism of hydrogenation of the C=C bond in substrates was studied using rhodium phosphine catalysts, involv- ing such ligands as dipamp,21 ± 25 chiraphos,26 ± 29 diop,21, 29 bppm,30, 31 dioxop 32, 33 and BisP*.34 Me Me OMe Ph O O P P Me Me Ph PPh2 Ph2P MeO PPh2 Ph2P (S,S)-( ± )-chiraphos (R,R)-( ± )-dipamp (R,R)-( ± )-diop Me P R Ph2P R P O Me PPh2 BisP* O N Ph2P PPh2 CO2But dioxop bppm R=But, Et3C, cyclo-C5H9, cyclo-C9H11, 1-adamantyl In studies on hydrogenation of itaconic, citraconic and mesaconic acids in the presence of [Rh(bppm)]+ giving rise to 2-methylsuccinic acid, an attempt was made to reveal the stage involving asymmetric induction (the optical yields of the products are given below the formulae of the acids).35 CO2H HO2C HO2C HO2C CH2CO2H CO2 Me Me CH2 50.9% (S ) 22.0%(S ) 85.3% (S )36 In the event that the enantioselectivity of the reaction is controlled by intermediate 1 common to all the three substrates (which follows from Halpern's theory discussed below), the optical yields must be close, which is contradictory to the experimental data considered above.Hence, it was concluded that asymmetric induction occurred in the stage of substrate coordination (the `key ± lock' interaction).OHO S P Rh HO2C H P Me 1 S is the solvent It should be noted that the chiral catalytic complex with the bppm ligand does not possess symmetry elements (except for C1) and, hence, asymmetric induction in the stage of substrate coordination is performed by the asymmetric complex. The hydrogen pressure influences the enantioselectivity of hydrogenation of acetyl- and benzoylaminocinnamic acids and their esters in the presence of rhodium complexes with the bppm, diop or dipamp ligands (with NEt3 and without it). To explain this fact, Ojima et al.35 offered the hypothesis that two reaction pathways compete with each other: Path A H2 * Rh+(C=C) * Rh(C=C) * Rh(C=C)H2 Path B (C=C) * RhH2 * Rh+H2 * RhH2(C=C) Paths A and B are favourable at low and high hydrogen pressures, respectively.Path B has been found previously in the studies of hydrogenation of alkenes on Wilkinson's catalyst. The authors of the cited study postulated 35 that paths A and B afforded different enantiomers. Hence, an elevation of the pres- sure, which facilitates path B, would be expected to decrease the enantioselectivity up to the inversion of the configuration. It is this situation that was experimentally observed. Interestingly, the addition of triethylamine weakened the influence of the hydrogen pressure on the enantioselectivity. The anion, which is generated upon the addition of NEt3 to acid (the substrate), has a much higher tendency to form an adduct with the rhodium phosphine complex than the corresponding acid.Consequently, the contri- a p (%) p (%) 60 60 40 40 20 200 0 pH /atm 25 2 H Figure 2. The optical yield of the product (S)-AcPhe in hydrogenation of ACA vs. the hydrogen pressure (a), the reaction temperature (b), the ratio of the concentrations of ACA and the catalytic complex (c) and the dielectric constant of the solvent (d ). The reaction conditions: (a) � T=20 8C, [ACA] : [Ph]=100 : 1, C6H6 ±MeOH (1 : 1); (b) � p 2 =1 atm, [ACA] : [Ph]=100 : 1, C6H6 ±MeOH (1 : 1); (c) � T=50 8C, p 2 =1 atm, PriOH; (d) � T=25 8C, pH2 =1 atm, [ACA] : [Ph]=100 :1, the solvent: (1 ) DMF; (2) dioxane; (3) THF (4) EtOH ± C6H6; (5) MeOH±C6H6 ; (6) EtOH; (7 ) MeOH.(S/R)-product (R/S)-product b 50 25 T /8C V A Pavlov bution of path B in the presence of a base is insignificant, which agrees with the experimental evidence that the enantioselectivity remained virtually unchanged at different hydrogen pressures. Hence, the hypothesis under consideration provides an adequate explanation for the effect of the hydrogen pressure and the influence of the addition of a base on the enantioselectivity. However, this scheme, as applied to the hydrogenation of derivatives of amidocinnamic acid, does not allow one to reveal the stage responsible for asymmetric induction due to a lack of detailed stereochemical information on two competitive reaction pathways. Nevertheless, the hypothesis for two competitive reaction pathways is fruitful.It was found 36 ± 39 that the enantio- selectivity of hydrogenation of ACA in the presence of the [Rh((R)-PheNOP)(cod)]ClO4 complex H CH2Ph OPPh2 N Ph2P Me (R)-PheNOP depends on the hydrogen pressure, the temperature, the ratio of the concentrations of ACA and the complex and the dielectric constant of the solvent (Fig. 2). These dependences can readily be explained within the framework of the above-considered concept. The contribution of the reaction path B becomes more significant and, correspondingly, the higher enantiomeric excess of the product adopting a certain configuration, viz., (S )-AcPhe, is achieved as the hydrogen pressure is elevated, the concentration of the substrate with respect to the catalyst is decreased, the temperature is lowered and the dielectric constant of the solvent decreases.The role of the first two factors follows directly from the schemes of the reaction paths A and B. The influence of the two last-mentioned factors is in agreement with the observations made in the study.35 The proposed explanation is also confirmed by the fact that rhodium hydride was observed in the reaction mixture at low temperature (720 8C).37 Upon hydrogenation of the enamide substrate on complexes with bppm and PheNOP, asymmetric induction occurs during the transformation of an asymmetric intermediate. The pure dihydride mechanism (path B), which is realised even at low temperature and hydrogen pressure, was considered in the study 34 devoted to hydrogenation of methyl a-acetamidocinna- mate (AcDPheOMe) on a rhodium complex containing (S,S )-1,2- bis(tert-butylmethylphosphino)ethane (Scheme 1).Asymmetric induction takes place during substrate coordina- tion by the dihydride complex (major intermediate) present in an p (%) c d p (%) 30 60 1 20 3 40 2 4 10 20 5 7 6 0 0 300 [ACA] : [Rh] 20 10 e 710 HMechanisms of asymmetric induction in catalytic hydrogenation, hydrosilylation and cross-coupling on metal complexes But Me P +Rh But P Me H2, MeOH(S) But Me S (R)-AcPheOMe P +Rh But S P Me 2 But Me P +Rh But P NHCOMe Me CH2CH CO2Me (R)-AcPheOMe 2 Me ButH Me O P Rh + NH But P O CH2Ph Me OMe Me S P + ButHRh CH2Ph But P O X Me NH Me excess.As can be seen from Scheme 1, this intermediate is devoid of symmetry elements, i.e., the asymmetric carbon atom is generated in the product in the stage of the transformation of the asymmetric intermediate although the starting chiral catalytic complex 2 possessed the symmetry C2. The mechanism of asymmetric induction was investigated for hydrogen-transfer hydrogenation of aromatic ketones R1COR2 O O In all cases, the configuration of the product was determined by the configuration of the ligand and was independent of the nature of the metal atom. If ketones as substrates of this reaction are arranged in order of decreasing difference between the molecular volumes of two substituents (Fig. 3), it can be seen that ee tends to decrease in the series FlCOMe>2-NpCOMe> PhCOMe> PhCOEt>PhCOPri.In the case of rhodium com- plexes with the ligand 3a, the corresponding series is as follows: FlCOMe>2-NpCOMe&PhCOMe&PhCOEt&PhCOPri. Me Me The most pronounced difference in ee is observed for FlCOMe and PhCOMe. This fact can be interpreted using the quadrant rule. 2-NpCOMe FlCOMe O O O Pri Et Me Ar on rhodium and iridium complexes, which were generated in situ and contained Schiff bases, viz., derivatives of (S,S)- (3a ± c) and (R,R)-1,2-diaminocyclohexane (4).40 N N N N Ar Ar Ph Ph 3a ± c (S,S ) 4 (R,R) 3: Ar=Ph (a), C6H4OMe-o (b), Np-2 (cetal atom in the C2-symmetric chelate chiral complex (the catalyst) is oriented toward the intersection point of the Me Me ButH S P P + ButHRh Rh + But But H P P S Me Me 1 : 10 AcDPheOMe Me P + ButH H Rh But H P X O Ph Me NH Me X=CO2Me N C N C M Ar 37 Scheme 1 H + S S Blocked quadrants M R2 R1 C R2 >R1 O38 ee, % 60 40 60 40 60 40 60 40 70 50 II I Figure 3.Influence of the difference between the molecular volumes of the substituents R1 and R2 in ketone R2COR1 (R2>R1) on the enantio- selectivity of hydrogenation. (The catalytic system: (a) Rh/3a, Rh/4; (b) Rh/3b; (c) Rh/3c; (d ) Ir/4; (e) Ir/3b. Ketone: (I) FlCOMe; (II) 2-NpCOMe; (III) PhCOMe; (IV) PhCOEt; (V) PhCOPri.quadrants and the C2-symmetrically arranged aryl substituents fall in the quadrants related by the symmetry C2 (left upper and right lower), thus `blocking' them. The larger the difference between the molecular volumes of the substituents in the ketone involved in the intermediate complex (the average of two possible positions, which can occupy the ketone in the intermediate, is indicated by an empty arrow), the higher the probability of the bulky substituent of the carbonyl group of the ketone being located in the free quadrant and, correspondingly, the larger the chiral discrimination and, consequently, the higher the enantiose- lectivity. It is this situation that was experimentally observed and, hence, the data obtained can be considered as an argument in favour of the fact that asymmetric induction (chiral recognition) takes place in the stage of substrate coordination in an intermedi- ate complex.Other authors also support the idea that asymmetric induction in hydrogenation with the hydrogen transfer catalysed by rho- dium and iridium complexes occurs in the stage of ketone coordination. Thus the following catalytic cycle (Scheme 2) was proposed 41 for hydrogen-transfer hydrogenation of acetophe- none catalysed by (S)-(+)-3-sec-butyl-, (S)-(7)-3-(1,2,2)-trime- thylpropyl- or (S,S)-(+)-3,8-di-sec-butyl-1,10-phenanthroline complexes of rhodium(I) in a PriOH±KOH medium. a (R) product (S) product bcde IV III V MeCHOH Me Me Ph O H N Rh N N N 9 As can be seen from Scheme 2, asymmetric induction occurs upon substrate coordination by asymmetric intermediate 7.How- ever, this mechanism of hydrogenation needs additional evidence. For the reactions catalysed by iridium complexes with Schiff bases, which were prepared from pyridine-2-carbaldehyde and a-phenylethylamine, a mechanism was proposed according to which asymmetric induction takes place in the stage of the hydro- gen transfer from the donor (isopropyl) group to the acceptor molecule (ketone subjected to hydrogenation) in the cyclic tran- sition state (Scheme 3).42, 43 Products DH2 N N Ir O X O H C OH7 Ph H2O N N Ir O X O CPh DH2 is propan-2-ol; X=DH2, OH7; R=Me, Et, Prn, Pri. H Me N Me N Rh O N H N 5 Ph Me HO7 HO H H2O N N N Rh NH O Me 6 Me Me Ph H O N Rh N N N 8N N Ir DH2 X DH2 Me Me C HR Me Me C HR N C N Ir O X O C H R Ph V A Pavlov Scheme 2 + O Me Me H N Rh N N N 7O Ph Me Scheme 3 PhCOR DH2 N H Me C N Ir O X Me O C Ph H ROH7 H2O N Me C N Ir O X Me O C H R Ph Me MeMechanisms of asymmetric induction in catalytic hydrogenation, hydrosilylation and cross-coupling on metal complexes Me Me O N P Me Ir P H H MeN P Ir O P Me Me OH H Me H MeN Me P HO Ir O P Me H P=PPh2. The catalytic cycle proposed 44 for hydrogenation of benzylideneacetone in the presence of the HIr[(R)-Ph..CH(Me)N(CH2CH2PPh2)2] complex is shown in Scheme 4. The structure of the intermediate was established by X-ray diffraction analysis. According to this scheme, asymmetric induction occurs in the stage of coordination of the ketone by the asymmetric complex. Scheme 3 involves direct hydrogen transfer, whereas Scheme 4 implies that the transfer proceeds with the participation of metal hydride.44 Both schemes are to a large extent conven- tional, but the latter scheme seems to be better justified } because the hydride intermediate was found experimentally.44 Therefore, there is some evidence that asymmetric induction takes place in the stage of ketone coordination by an asymmetric intermediate complex, which lost the symmetry C2 (if it was present in the starting catalytic complex). The complex, which is formed in situ based on CoCl2, semi- corrin ligand 10 and NaBH4 in alcohol, serves as an efficient catalytic system for asymmetric reduction.46, 47 CNN N H OSiMe2But ButMe2SiO 10 Amides and esters of a,b-unsaturated acids are reduced by this system with high enantiomeric excess (ee=90% ± 99%).O O NaBH4 (1 equiv.), CoCl2 (0.1 mol.%),Me Me 10 (0.12 mol.%) Me Me R R EtOH ± diglyme, 23 8C HN HN ee=98.7% (R=(CH2)2Ph), 98.9% (R=C6H11), 92.4% (R=Ph); O Me Me O Me Me OEt Me OEt Me ee=96% } At the same time, Scheme 4 ignores the reversibility of the reaction involving the hydrogen transfer from isopropanol 45 and, hence, Scheme 3 seems to be preferable.H O Me MeN PP H Me The investigation of the reaction mechanism followed with the use of NaBH4 in an EtOD ±DMF medium or using NaBD4 in an EtOH ±DMFmedium demonstrated that borohydride and EtOH serve as sources of hydrogen atoms at the b- and a-carbon atoms of the product, respectively.47 Hydrogenation of substrates bear- ing a prochiral carbon atom in the a-position proceeds non- enantioselectively with respect to this atom.47, 48 The assumed structure of the intermediate complex is shown in Fig. 4. R4 EtOOCN N R1 R3 R2 A Figure 4. Possible structures of the intermediate complex in reduction reactions on a cobalt-containing catalyst (the cobalt ± hydride bond is omitted for clarity).47 The involvement of the coordinated alkene in structure B is sterically hindered so that the transition state A is more favour- able.Unfortunately, the authors did not indicate the Co7H bond, whereas the latter, probably, provides an explanation for the fact that the asymmetric carbon atom is generated only in the b-position of the alkene and hydrogen is generated from NaBH4. Actually, the experimental observations mentioned above can readily be explained by assuming that the alkene containing the non-equivalent a- and b-carbon atoms is coordinated to the cobalt atom (whose hydride ion is, undoubtedly, generated from NaBH4) as shown belowHOEt EtOH a N C Co N H Cb 39 Scheme 4 H Ir OMe R1 R4 COOEt R1 N N R1 R2 R3 B40 H C O * Si Rh(P2)Cl Si H * Si Rh(P2)Cl * Rh(P2)(S)Cl+ ±S *Pis chiral phosphine, S is the solvent.Reduction of the C=C bond in substrates of the types O Me Me O Me Me or OEt Me Ph NH Me Me involves the enantioselective addition of the hydride ion at the Cb atom, which is controlled by an asymmetric Co hydride complex, whereupon the intact chiral C2-symmetric metal complex frag- ment, apparently, cannot ensure the enantioselective attack on the a-carbon atom. This explanation agrees well with the conclusion made previously that asymmetric induction is realised in the stage of the transformation of an asymmetric intermediate. Hence, turning back to Fig. 4, it can be said that asymmetric induction takes place in the stage of coordination of alkene by the asym- metric monohydride complex of cobalt.The mechanism of asymmetric hydrosilylation has been studied less thoroughly than the mechanism of asymmetric hydro- genation. It was suggested 49 that the enantioselectivity results from the competition between diastereomeric silyloxyalkyl(aryl)- rhodium intermediates (Scheme 5). According to another assumption, asymmetric induction takes place in the stage of the addition of ketone to an intermedi- ate complex 50, 51 (Scheme 6). Scheme 6 O O H H H R1 R2 R1 R2 L* Rh Si L* Rh Si L* Rh Si R1 R2 O O R2 R1 HSi H H L* L* L* Rh Rh Rh Si Si R1 R2 O O H H R2 R1 Si Si R2 R1 O O R1 R2 L* is (S,S)-(+)-2,3-O-isopropylidene-2,3-dihydroxy-1,4-bis(diphenyl- phosphino)butane [(S,S)-(+)-diop].This scheme is similar to that proposed in the study 52 where the following structure of the five-membered transition state was assumed d7 d+ O Si Rh d7 d+ H C R1 R2 V A Pavlov H Scheme 5 S C *C ** H+Rh(P2)(S)Cl * Rh(P2)Cl H SiO SiO H O C * Si Rh(P2)Cl O *CH In all the above-considered cases, asymmetric induction is realised in the stage of substrate coordination by an asymmetric intermediate. IV. Asymmetric induction in the course of transformations of the first or subsequent intermediates of the catalytic reaction Research on the mechanism of catalytic hydrogenation of sub- strates like (Z)-a-acetamidocinnamic acid in the presence of rhodium phosphine complexes was started with the detailed investigation of the kinetics of hydrogenation of methyl (Z)-a- acetamidocinnamate catalysed by a rhodium complex containing achiral diphosphine, viz., 1,2-bis(diphenylphosphino)ethane (diphos).27, 53 ± 55 The catalytic cycle of this reaction is shown in Scheme 7.The precursor of the catalytic complex, viz., an ionic adduct of diene with a catalyst (11), is involved in the catalytic cycle after reduction of the diene. The structure of complex 12 was determined by 31P NMR spectroscopy 53 and the structure of complex 13 was established by 31P, 13C and 1H NMR spectro- scopy and X-ray diffraction analysis.24 At room temperature, the oxidative addition of hydrogen to the complex 13 is the rate- limiting step of the reaction, whereas reductive elimination of the product becomes the rate-limiting step at 740 8C.As a result, alkyl hydride complex 15 at 775 8C was accumulated in a concentration sufficiently high for analysis by 31P, 13C and 1H NMR spectroscopy.29, 54 Of compounds presented in Scheme 7, only intermediate 14 was not identified and its structure was proposed `by anal- ogy'.56, 57 Later on, the dihydride intermediate was found exper- imentally.58 The intermediates 13, 14 and 15 as well as the reaction product are racemates (both enantiomers of these intermediates are shown in Scheme 7). 2 2 2 2 2 2 The catalytic cycle of hydrogenation of the same substrate catalysed by {Rh[(R,R)-dipamp]}+ is shown in Scheme 8.In this catalytic cycle, the corresponding intermediates are diastereomers and it is reasonable that the reactions involving these intermedi- ates proceed at different rates.59 An analogous catalytic cycle was proposed 26, 27 for hydrogenation in the presence of {Rh[(S,S)- chiraphos]}+. In both cases, 31P NMR spectroscopic studies demonstrated 26, 29, 55, 59 that one of the diastereomers (16maj) was present in a high excess with respect to the other diastereomer (16min). The structure of the major diastereomer (16maj) obtained in the reaction in the presence of {Rh[(S,S)-chiraphos]}+ was established by X-ray diffraction analysis 26 and circular dichroism spectroscopy.27 However, the configuration of the resulting product was opposite to that, which would be expected to be realised if the reaction proceeds through this intermedi- ate.23, 26, 60, 61 Hence, it was suggested 26, 55 that the enantioselec- tivity is associated with the difference between the constants kmin and kmaj (kmin kmaj, see Scheme 8) due to which the reaction proceeded predominantly through the intermediate 16min whose concentration was small compared with that of 16maj.In the case of hydrogenation of methyl (Z)-a-acetamidocinnamate in the presence of {Rh[(R,R)-dipamp]}+ at 0 8C, the ratio of the constants kmin : kmaj&1000.59 Halpern 55 assumed that this sit- uation follows the Curtin ± Hammet principle according to whichMechanisms of asymmetric induction in catalytic hydrogenation, hydrosilylation and cross-coupling on metal complexes (R,S)-PhCH2CH(NHAc)CO2Me Me O P RhIII H P Me HN S MeO2C Ph 15MeO2C * H2 kmaj 2 + NH HMeO2C P * Rh Me P Ph O H17maj S kmaj 3 H + NHSCO2Me Ph + O H P RhIII P HMe + NH P Rh Me P Ph O 16maj major cycle + Me O P Rh NHSCO2Me P * Ph 18maj Me H H N O minor product, (R) + P RhI P 11 2H2, MeOH(S) + S P k1 RhI P S k71 12 + NH MeO2C PRhIII Me P Ph O H + HN H CO2Me PRhIIIP PhO H 14 H CO2Me Ph NHCOMe Me kmin 1 kmaj 1 P * S Rh(I)S P kmin 4 kmaj 4 HN S MeO2C Ph H HN CO2Me MeO2C O Ph Ph major product, (S) CO2Me NHAc Ph + NH MeO2C P RhI Me P Ph O + HN CO2Me P RhI Me P PhO 13 H2 + HN CO2Me P Rh * P PhO 16min HN minor cycle Me PhO + Me kmin 3 O P Rh H P * 18min Me 41 Scheme 7 Scheme 8 H2 kmin 2 + CO2Me P H Rh * P H 17min S42 1 1 1 1 the ratio of the products depends only on the difference between the free energies of the transition states and is independent of the ratio of the conformers (intermediates).According to Halpern's theory, the chiral recognition (asymmetric induction) takes place in the transformation 16!17 involved in the catalytic cycle. Unfortunately, no explanation was offered for the differences in stability and reactivity of the intermediates 16maj and 16min, which could allow an understanding of the reason for the substantial difference in the rates of their transformations.Halpern's theory provides an explanation for the effects of hydrogen pressure and temperature on the enantioselectivity of the reaction. It was demonstrated 35 that the enantioselectivity decreased and even the configuration of the product was changed as the hydrogen pressure was increased. According to Halpern's mechanism (see Scheme 8), the formation of the intermediates 17 is accelerated as the hydrogen pressure is increased. At some time, this step ceases to be rate-limiting and the process is controlled by the reversible formation of the diastereomeric adduct 16, i.e., the enantioselectivity is determined by the ratio kmin : kmaj.Since kmaj>kmin, another catalytic cycle, which affords an opposite isomer of the product, becomes more favourable and the enantio- selectivity is decreased. It is this situation that was experimentally observed. The formation step of adduct 16 is characterised by a substantially higher enthalpy of activation than the next step of the addition of hydrogen (in the presence of [Rh-dipamp]+ as the catalyst, 18.3 and 6.3 kcal mol71, respectively). What this means is the rate of the first step is decreased much more rapidly than that of the second step as the temperature is decreased and, conse- quently, the first step can become rate-limiting. Hence, the enantioselectivity would be expected to decrease with decreasing temperature. This situation was observed in reactions involving some phosphine catalysts.32, 35 Since Halpern's theory provides an explanation for many experimental observations, it was commonly accepted in the 1980s.62 ± 65 However, this theory has a number of drawbacks.1. According to Scheme 8, the coordination mode of enamide is not changed (Re ± Si ) and, consequently, the balance between the major and minor catalytic cycles remains unchanged on going from the planar-square complex 16 containing the C2-symmetric chiral (diphosphine)Rh(I) fragment to the octahedral complex 17 containing the asymmetric (diphosphine)Rh(III)H2 fragment. S +Rh X X P *P S R R X +Rh X R Rh + P *P P *P R However, the real situation may be different.Moreover, intra- molecular interconversions of the complex 16 are quite possible and even (see Ref. 66) the energy barrier for these interconver- sions is low. It is conceivable that the interconversion Re ± Si occurs in the step 16!17, in which case the major enantiomer is formed in the major catalytic cycle. 2. Most likely, Halpern's theory is inapplicable in the case of rhodium complexes serving as catalysts of hydrogenation of enamides with ee=99.0% ± 99.9%. In this case, with the gener- ally observed ratio between the major and minor intermediates (10 : 1), the ratio of the rate constants kmin : kmaj must be even several orders of magnitude larger than that in the case of the rhodium complex with the chiraphos ligand (ee=88%, V A Pavlov kmin : kmaj&1000).This difference in the rate constants of the transformations of diastereomeric intermediates seems to be unlikely. For the reaction involving the rhodium complex with the BisP* ligand, another mechanism was proposed 34 (see above). 3. Halpern's scheme provides no explanation for some exper- imental evidence, for example, for the difference in enantioselec- tivity of hydrogenation of the E and Z isomers.67, 68 The enantioselectivities of hydrogenation of (Z)- and (E )-a-benzoyl- aminocinnamic acids using the Rh/(S,S)-diop system differ not only in magnitude but also in sign.69 This may be associated with the different modes of coordination of the above-mentioned substrates by the rhodium atom (the E isomer is coordinated through the carboxy carbonyl group, whereas the Z isomer is coordinated through the amide carbonyl fragment).70 Appa- rently, the Re- or Si-side of the coordinated double bond of the substrate may also be changed. Halpern's theory provides no explanation for the influence of bases on the value of ee in the reactions performed in the presence of catalysts for which this theory has been initially proposed.35 Thus according to Halpern's hypothesis, the enantioselectivity of hydrogenation in the pres- ence of diphosphine catalysts decreases as the temperature is decreased; however, this is not necessarily the case.Thus in hydrogenation of dehydroamino acids in the presence of rhodium complexes with the prophos, cycphos or diop ligands, the optical yields decreased as the temperature was raised.42, 71 Apparently, Halpern's mechanism is only a special case.The mechanism of hydrogenation of substrates, such as tiglic acid, catalysed by the Ru(OAc)2[binap] complex has been studied in sufficient detail. It was demonstrated that hydrogenation proceeded through the formation of a ruthenium monohydride complex.72 The mechanism of hydrogenation of tiglic acid on this catalyst was detailed in the study.73 Me Me H+ H2 O O P P O O Ru Ru O O *P *P O H O CO2H * CO2H Me Me O O P P O O Ru Ru O O *P *P O O H+ * * The bis(carboxylato)ruthenium complex involving a substrate performs the heterolytic splitting of H2 giving rise to a hydride.The hydride ion reduces the C=C bond in the coordinated substrate to form the chelate which contains the chiral product in the half-hydrogenated state. Protonolysis of the newly formed Ru7Cbond affords the target product. According to this scheme, asymmetric induction takes place in the formation of the chelate complex with the substrate hydrogenated, i.e., in the step of the transformation of the intermediate devoid of symmetry elements (except for C1). An analogous mechanism for hydrogenation of tiglic acid on the catalytic methallyl complex [binap]Ru. .[Z3-(CH2)2CHMe]2 was proposed in the study. 74 In the cited study, it was also assumed that asymmetric induction occurs in the step of the transformation of the asymmetric intermediate, which already involves the substrate in the coordination sphere.Asymmetric cross-coupling of Grignard reagents with alkenes has been less well studied. According to the presently accepted mechanism, the reaction proceeds through the formation of the intermediate p-allyl(aryl)ML2 (Scheme 9).75 ± 79Mechanisms of asymmetric induction in catalytic hydrogenation, hydrosilylation and cross-coupling on metal complexes Scheme 9 Y Me Y 2ArMgX R=H, Ph, CO2Et, SiMe3; X2ML2 Ar2ML2 A Ar2 2MgX2 Cat= ArMgX MgXY + Ar Y L L L Y7 M M M L L L C Y Ar B Y Ar Among the intermediates which confirmed the general reac- tion mechanism proposed previously, species involving p-coordi- nated alkene (the substrate) were identified by 31P NMR and CD spectroscopy.Probably, these intermediates, which exist in the equilibrium with intermediates 20, are involved in the overall reaction (Scheme 10). X=Hal;M=Ni, Pd; L2=P2, P P; Y=Br, OH, OPh, COMe, OSiMe3, CO2Me. The stages A!B, B!C or C!products may be responsible for asymmetric induction. With the aim of elucidating this problem, we studied the reaction of arylmagnesium bromides with derivatives of crotyl alcohol under the action of a nickel catalyst by increasing successively the molecular volume of the leaving group (OR):80 The chiral arrangement of the phosphine phenyl groups of the coordinated dpcp ligand presented in Scheme 10 is based on the results of X-ray diffraction analysis of the complex 81 (the cyclo- pentane ring of the dpcp ligand is omitted). The crotyl ligands in the intermediates 20a ± 20d involve the stereogenic 82 carbon atom whose configurations are symbolised as (R) and (S ).The p-co- ordinated crotyl ligand of this type can be subjected both to the (R) ± (S )-inversion of the p-allylic chirality and the syn ± anti transformation according to the p ± d ± p mechanism.83 ± 85 Hence, it can be assumed that all possible forms of the intermedi- ate 20 (a ± d) exist in the equilibrium. In turn, each intermediate can exist in equilibrium with the intermediates 21a ± 21d. The interconversion 20d NiBr2[(R,R)-dpcp] 2 PhMgBr 2 MgBr2 Ph2Ni[(R,R)-dpcp] 19 Ph7Ph Ni0[(R,R)-dpcp] Y Y Me Ph Ph Ph Ph Ph P P P P Ni P Ni Ph (R) (S) (R) Ph Ph Ph Me MePh 20a 20b Me Ph Ph Ph Ph Ph P Ni P P Ni P P Me Ph Ph Y Ph Me Y Ph Ph 21a 21b Me Ph H Y (S) [(R,R)-dpcp]Ni0 Cat Me OR+ArMgBr THF PPh2 NiBr2 {( ± )-NiBr2[(R,R)-dpcp]}.PPh2 21d experiences the smallest of steric Y Y Ph Ph P Ni P Ph Ph 20c Ph Ph P Ni P Y Ph Ph Y 21c (allyl)NiY[(R,R)-dpcp] Ph Me Ph Ph Ni P P Ph (S ) Ph 43 Ar* Ar + Me Scheme 10 Y Me Ph P Ni Ph (S ) 20d Me Ph P Ni Ph 21d PhMgBr MgBrY44 hindrances. The reaction proceeding through these intermediates affords a product whose configuration is identical with that observed experimentally. The larger the molecular volume of the leaving group, the more favourable this path and the higher the expected enantioselectivity. This fact was confirmed experimen- tally.Hence, asymmetric induction in the reaction under consid- eration takes place in the stage of the interconversion of the asymmetric intermediates 20(a ± d) This mechanism allows one to explain rather readily the characteristic features of the reaction observed experimentally, viz., the dependence of the enantioselectivity on the molecular volume of the leaving group (the larger the molecular volume, the more favourable the path through the intermediate 21d and the higher the enantioselectivity) and the fact that the enantiomeric excess of the product is independent of the temperature (because the equilibrium can be established even at low temperatures).Both intermediates responsible for asymmetric induction already involve the coordinated substrate and are asymmetric. Another type of cross-coupling, for example, the reaction of a racemic mixture of 1-phenylethylmagnesium chloride with (Z)-b- bromostyrene catalysed by nickel complexes (the dynamic kinetic resolution) can be represented by Scheme 11.86 MgCl Ph H Me MgBrCl AS L Ni L2BrNi L Ph Ph H Me BR Ph Br Ph (R) Ph H Me Asymmetric induction can take place both in steps A and B (in both cases, the intermediates are asymmetric). V. Asymmetric induction caused by nonbonded diastereomeric interactions Solutions containing one enantiomer or a mixture of enantiomers (a racemate) may differ in physical properties.Thus the NMR spectra of the racemate differ from those of the optically active compounds comprising this racemate.87, 88 Analogous effects were also observed in calorimetric studies. These effects are attributable to diastereomeric interactions between enantiomers in solu- tions.89, 90 The enthalpies of interactions of amide derivatives of L- and D-alanine as well as of dipeptides containing the terminal L- and D-alanine residues in aqueous solutions are given in Table 3. R2 R1 C MeC(O)HN CONH2 (S )-22: R1=Me, R2=H; (R)-22: R1=H,R2=Me. 21(a ± d). Scheme 11 MgCl Me Ph H MgBrCl AR L Ni L Ph Ph Me Ph H BS Ph Br Ph (S) Me Ph H HNCONH2 C N R2 R1 O C O Me (S,S )-23: R1=Me, R2=H; (S,R)-23: R1=H,R2=Me.V A Pavlov Table 3. Enthalpies of interactions of peptide fragments containing the terminal L- and D-alanine residues.91 Solution B Solution A HAB /J kg mol72 (see a) (S )-22 (R)-22 (S )-22 (S )-22 (R)-22 (S )-22 (R)-22 (S )-22 (S,S )-23 (S,R)-23 (S,R)-23 (S )-22 (R)-22 (R)-22 (S,S )-24 (S,S )-24 (S,S )-23 (S,S )-23 (S,R)-23 (S,S )-23 (S,R)-23 (S,S )-23 2695 2775 33710 48817 5789 76949 74816 80322 162924 13998 151543 a This dimension was used by the authors of the cited study.91 Me H HN CONH2 C MeC(O)HN H Me O (S,S )-24 The observed differences in H are indicative of the presence of nonbonded interactions between enantiomers in solutions, such as monomer ± monomer, monomer ± dimer and dimer ± dimer con- taining the terminal L- and D-alanine residues.91 An impressive example of the separation of an enantiomer and a racemate by fractional distillation was reported.92 It appeared that the boiling point of the racemate of trifluorolactic acid differs from that of its enantiomers.This is indicative of the presence of strong nonbonded diastereomeric interactions. However, this effect was not observed for the ester of lactic acid. The differences in the physical properties of enantiomers and the racemate in solutions are generally rather small,{ but they are sufficiently large for these substrates to exhibit different chemical activities.94 The following general principle was stated: the reaction rate for a chiral compound and the ratio of the resulting products depend, among other things, on the enantiomeric composition of the starting compound.95 The following reactions can be distin- guished: R+R RR(enantiomeric recognition), S+S SS(enantiomeric recognition), R+S RS(antipode interaction).Below examples are given of reactions where one of the nonbonded interactions (or all these interactions taken together) leads to different compositions of the products. K (1 equiv.) 1. NH4Cl + NH3 (liq.) 2. H2O OH OH O (R)-borneol (R)-camphor (R)-isoborneol 1. NH4Cl K (1 equiv.) OH O NH3 (liq.) 2. H2O + OH (S)-isoborneol (S)-camphor (S)-borneol { Differences in the physical properties of the enantiomers and the race- mate in crystals have long been known and were described in handbooks (for example, see Ref.93). These differences are due primarily to the differences in the molecular packings in the crystals.Mechanisms of asymmetric induction in catalytic hydrogenation, hydrosilylation and cross-coupling on metal complexes If (R)- or (S )-camphor was used as the starting substrate, the excess of borneol in the resulting mixture was insignificant. However, the reaction starting from racemic camphor afforded borneol as the major product.96 In contrast, reduction of (R)-cam- phor with LiAlH4 gave rise predominantly to isoborneol, whereas borneol was obtained as the minor product (90.2% and 9.8%, respectively).95, 97 A somewhat different composition of the mix- ture was obtained in the reaction starting from (R,S)-camphor (88.7% and 11.3%, respectively).Reductive dimerisation of camphor LiAlH4 TiCl3, THF O afforded a mixture of isomers (R,R)-cis (R,R)-trans The reaction involving the (R)-monomers of camphor gave rise to the (R,R)-cis and (R,R)-trans dimers in a ratio of 34.8 : 65.2. In the product obtained from the racemate of camphor, (R,S)-cis [(R,R,S,S)-cis] and (R,S)-trans [(R,R,S,S)-trans] isomers were present in a ratio of 37.4 : 62.6.95 Oxidative dimerisation of the (S)-monomer of a phenol derivative Me * K3[Fe(CN)6] MeMe OH afforded the (P,S,S) and (M,S,S) diastereomers in a yield greater than 97.5%.95 The racemic monomer can, in principle, give eight diastereomers: Me Me Me MeMe OH Me HO (P,S,S) Me Me Me MeMe OH Me HO (P,R,R) + (R,S)-cis (R,S)-trans * * Me Me Me MeMe OH Me HO Me Me Me MeMe OH Me HO (M,S,S)Me Me Me MeMe OH Me HO (M,R,R) 45 Me Me Me Me Me Me Me Me Me Me OH Me OH Me HO HO (M,R,S) (P,R,S) Me Me Me Me Me Me Me Me Me Me OH Me HO OH Me HO (M,S,R) (P,S,R) However, dimerisation of this monomer produced a mixture of the (P,S,S ), (M,S,S), (P,R,R) and (M,R,R) diastereomers (trans dimers) in 66% yield, whereas the theoretically possible yield is 50%.This inconsistency can be considered as an argument in favour of active interactions between the enantiomers. The reaction CHO ZnPri2 20% DBNE, C7H8, 0 8C AcO OH * AcO HO NBu2 , ( ± )-DBNE = Me Ph catalysed by chiral aminoalcohol yielded a chiral compound bearing an asymmetric centre in the terminal fragment.98 (7)-Aminoalcohol catalysed the formation of (R)-alcohol with the diastereomeric excess de=97% independently of its enantio- meric purity (100% and 21%), whereas the (S) product with de=87% was obtained in the presence of (+)-aminoalcohol (ee=100%).This result is attributable to nonbonded diastereo- meric interactions between the chiral substrate and the amino- alcohol. The non-linearity of the changes in the optical and enantio- meric purities, which was observed in some cases, is accounted for by similar reasons. The effect of the non-linear dependence of the enantiomeric excess of the product on the enantiomeric (or diastereomeric in the case of a diastereomer) purity of the catalyst (the reagent) can be manifested in asymmetric catalysis 99 (in asymmetric synthesis and in stereoselective reactions 100) if a chiral catalyst (or a reagent) can form a dimeric diastereomeric complex with one of the reagents of the catalytic (or non-catalytic) reaction.Possible dependences of the enantiomeric excess of the product on the enantiomeric excess of the catalyst (the reagent) are shown in Fig. 5. A wide range of such reactions is presently known.99, 100 These effects are attributed to the differences in the reactivity of homochiral and heterochiral dimeric complexes.46 ee (of the product) (%) 100 2 80 60 1 40 200 60 40 20ee (of the catalyst) (%) Figure 5. Possible deviations from the linear dependence of ee of the product on ee of the catalyst.(1) the linear dependence, (2) the positive non-linear effect, (3 ) the negative non-linear effect. For example, in the reaction O R2Zn H NMe2 OH the homochiral (7) . (7) dimer R N Zn O O Zn N R ( ± ) . ( ± ) homochiral Table 4. Ligands involved in catalytic complexes, which are used in various reactions. ee (%) Ligand, complex Hydrogenation of enamides catalysed by rhodium complexes 98 ± 100 Ph2P PPh2 Bz N 99 Ph2P PPh2 100 Ph2P PPh2 Me But P P CH2 >99.9 But Me 3 100 80 OH * R R N Zn O O Zn N R (+) .(+) Ref. 20, 81 104 105 106 is 1200 times more active than the heterochiral dimer, R N Zn O O Zn N R(+) . ( ± ) heterochiral which gives rise to the positive non-linear effect.101 ± 103 VI. Conclusion Recent investigations demonstrated that the enantioselectivity of some metal-complex catalysts approaches 100%. Ligands for complexes, which ensure the record-breaking enantiomeric purity of the products in various reactions, are given in Table 4. All the listed ligands are conformationally rigid and possess a pro- nounced helical component bearing bulky groups at the ends of an incomplete helical turn.6 The investigation into the mechanism of hydrogenation of enamides in the presence of one of such complexes (the octahedral asymmetric rhodium dihydride complex containing the BisP* ligand) demonstrated that asymmetric induction takes place in the stage of substrate coordination by the complex. The high enantioselectivity of this catalytic reaction (99.9%) is determined by the 99.95% probability of the coordination of enamide by one side {the Re-side in the case of the Rh[(S,S)-BisP*] complex}.106 This is indicative of a large difference between the free activation energies of substrate coordination through the favourable and unfavourable sides.The probability of the substrate being coor- dinated through a particular side is, evidently, determined by the helical component of the conformationally rigid ligand of the complex bearing bulky groups at the ends of the incomplete turn of the helix.As an alternative mechanism for improving the diastereomeric purity of an adduct of a dihydride complex with enamide, intra- molecular isomerisation is less probable due to the high reactivity (short lifetime) of this intermediate (such an isomerisation is more likely in the case of an adduct of the starting complex with the substrate,66 which is not involved in the catalytic cycle 34). Ligand, complex Hydrogenation of enamides catalysed by rhodium complexes Me 1-Adamantyl P P Me Adamantyl-1 Et Et P P Et Et Pr Pr P P Pr Pr V A Pavlov Ref. ee (%) 107 99.9 108 98.1 108 99.8Mechanisms of asymmetric induction in catalytic hydrogenation, hydrosilylation and cross-coupling on metal complexes Table 4 (continued).ee (%) Ligand, complex Hydrogenation of ketones, ketoesters and aminoketones catalysed by ruthenium complexes 99 ± 100 Ph2P PPh2 MeO OMe 98 Ph2P PPh2 MeO OMe 97.8 2,4-But2H3C6 C6H3But2-2,4 Reduction of enamides and imines catalysed by cobalt complexes CN 98.9 N N Co ButMe2SiO OSiMe2But 98 N N Co O O O O The relationship between the sense of the helical component of a ligand in a rhodium complex involved in hydrogenation of enamides and the configuration of the product 6 either results from asymmetric induction taking place in the stage of substrate coordination or is a consequence of an alternative mechanism, which is most likely common to the overall series of reactions in which this regularity is observed.The available experimental data indicate that the reactions proceeding under the action of chiral C2-symmetric metal-com- plex catalysts generate the asymmetric carbon atom in the product in a step involving an asymmetric intermediate. 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