Stereocontrol through Synergistic Catalysis in the Enantioselective Î±

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Stereocontrol Through Synergistic Catalysis in the Enantioselective #-Alkenylation of Aldehyde: A Computational Study Mahendra Patil J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02822 • Publication Date (Web): 08 Jan 2018 Downloaded from http://pubs.acs.org on January 8, 2018

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The Journal of Organic Chemistry

Stereocontrol Through Synergistic Catalysis in the Enantioselective α-alkenylation of Aldehyde: A Computational Study Mahendra Patil* UM-DAE Centre for Excellence in Basic Sciences, Health Centre, University of Mumbai, Vidyanagari Campus, Kalina, Santacruz(East), Mumbai 400098, India

Supporting Information Placeholder ABSTRACT: We describe the computational study of an interesting class of reactions involving synergistic action of chiral amine and Cu catalyst. The stereoselectivity-determining step of the enantioselective α-alkenylation of aldehyde has been investigated using the density functional theory (DFT) methods to gain insight into the origin of the product selectivity. We found that the catalytic activation of reactants in the form of enamine and alkenyl Cu(III) intermediate significantly reduces the activation barrier of the addition step through an improved interaction between these two intermediates at the transition state (referred as enamine and Cu catalyst fragments of the transition state in the text). The transition state stabilization through interaction between catalytic fragments, as demonstrated by the interaction/distortion model, clearly outperforms destabilization incurred due to the distortion of catalytic fragments and hence is recognized as a major factor contributing to the high stereoselectivity of reaction. Furthermore, the metal–enamine interaction described through the Cu····C7 distance is identified as a vital non covalent interaction at the transition state. Our calculations show that the catalytic (covalent) activations and metal-enamine interaction can operate in tandem to amplify the net interaction between two catalytic fragments. The cooperative nature of these interactions is also reflected in the trend of interaction energies, which show a large variation with a subtle change in the metal-enamine interaction. Our computational model verified for the different catalytic combinations of chiral amine and Cu catalysts successfully rationalizes the experimentally observed enantioselectivity.

Introduction In recent years, synergistic catalysis involving simultaneous activation of reacting partners using two discrete catalysts has spurred newer avenues to control the stereochemical outcome of chemical reactions.1 A principal feature of synergistic catalysis, that underscores its differences to the other modes of catalysis, is the nature of activation offered by two independent catalysts to the different reactants, allowing bimolecular reactions via HOMO(nucleophile) as well as LUMO(electrophile) activation in the same chemical environment. Owing to unprecedented reactivity achieved by the synergistic combination of catalysts, this catalytic protocol has been successfully applied for the development of new asymmetric transformations.2 While the application of this multi-catalytic approach in chemical synthesis has witnessed explosive growth in recent times, the efforts directed toward elucidating its mechanism using computational methods are rather very limited.3 Herein, we

investigate the selectivity-determining step of the α-alkenylation of aldehydes which involves the synergistic combination of chiral amine and Cu catalyst. The mechanistic details of synergistic functioning of chiral amine and Cu catalyst would be crucial, in particular to understand how two catalysts work together to achieve the enantioselectivity in the reaction. Scheme 1. Enantioselective α-alkenylation of aldehydes with vinyl boronic acids5 or vinyl iodonium salts.6

Asymmetric α-alkenylation of aldehydes, an elaboration of olefin framework adjacent to a carbonyl group represents one of the most desirable, however very challenging processes for the synthesis of optically active α-substituted carbonyl compounds. So far, several novel strategies have been designed to add alkenyl group at the α-position of carbonyl group.4 Very recently, MacMillan and coworkers elegantly demonstrated the scope of dual catalysis for the α-functionalization of aldehydes by combining the copper and chiral amine catalysts in a single process. In these reports, Macmillan and his group has described the enantioselective α-alkenylation of aldehydes using suitable coupling partners such as vinyl boronic acids5 or vinyl iodonium salts.6 Mechanistically, copper catalyst reacts with the alkenyl boronic acid or iodonium salt to generate alkenyl Cu(III) intermediate7 whereas, chiral amine reacts with the aldehyde and forms an enamine intermediate as shown in Scheme 2. The coupling of intermediates i.e. enamine and alkenyl Cu(III) intermediate generated in two discrete catalytic cycles, is most likely to occur in the steric free site of enamine intermediate, avoiding hindrance provided by bulky groups on the chiral amine.8 In such cases, one can speculate that the addition of enamine to the alkenyl Cu(III) intermediate may experience somewhat similar local environment at the competing transition states, resulting into low enantioselectivity. On the contrary, very high enantioselectivity was reported for these reactions. Interestingly enough, changes in the achiral copper catalyst (Cu(OAc)2 vs CuBr) and the chirality of chiral amine catalyst in these reactions provided products with opposite selectivity.5,6 These experimental evidences indicate an active role for the chiral amine as well as achiral copper catalysts, apart from functioning as a HOMO or LUMO activator, in causing differentiation at the diastereomeric transition states. The precise role of

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copper and amine catalysts in the stereoselectivity determining step of these reactions has not yet been delineated. In this article, we present computational insights on the chiral amine–copper synergistic catalysis in the enantioselective α-alkenylation of aldehyde reactions. It is worth mentioning that MacMillan and his group has also employed the synergistic catalysis protocol with considerable success in new asymmetric bond forming transformations such as the enantioselective α-trifluromethylation,9 αarylation,10 α-alkenylation11 and α-oxidation12 of aldehyde. Hence, we anticipate that this study may help to understand the role of catalysts in a wide range of asymmetric reactions involving chiral amine–transition metal synergistic catalysis.

Computational Details All electronic structure calculations were performed using Gaussian 09 quantum chemical program.13 Density functional theory (DFT) was applied using the M06-2X functional14 in combination with the 6-311G** basis set for C, H, O, N and Cu15 and the LANL2DZ effective core potential and the associated double-ζ basis set for Br.16 Solvent effects were incorporated in the calculations using the SMD solvation model17 and ethylethanoate (dielectric constant : 5.98) as solvent. We have also included empirical dispersion corrections in calculations.18 This approach is designated as “M062X” in the text. Since the discussion in this manuscript involves the subtle changes in the structural features and associated energy variations of the diastereomeric transition states, we avoid including energetics obtained for the different basis set (6-311+G**) through single point calculations in the text. The relevant information is provided in Supporting Information. Geometry optimizations were carried out in solvent phase without any constraints. The optimized stationary points were characterized as local minima or transition structures by harmonic force constant analysis. In addition, intrinsic reaction coordinate (IRC) calculations were performed to verify the connection between reactant and product via transition structures.19 The lowest energy conformer of reactants, intermediate and transition structures are reported in the text. Free energies of all stationary points were obtained from calculated thermal and entropic corrections at 298K using unscaled vibrational frequencies. Relative free energies of all stationary points such as reactants, intermediates and transition states were also computed at the following DFT levels, (1) L1: SMD(ethylethanoate)/M06-2X/6311+G**//SMD(ethylethanoate)/M06-2X/6-311G** (2) L2: SMD(ethylethanoate)/B3LYP/6311G**//SMD(ethylethanoate)/M06-2X/6-311G** (3)L3: SMD(ethylethanoate)/wB97XD/6311G**//SMD(ethylethanoate)/M06-2X/6-311G**. The LANL2DZ basis set for Br was used in calculations whenever it was applicable. The empirical dispersion corrections were included throughout the calculations. All these results are documented in the Supporting Information. Natural charges were computed using the natural bond order (NBO) analysis.20 The topological analysis of transition states is performed using Multiwfn program.21

reactions. However, Blackmond and coworkers in recent studies have proposed that the relative stability and reactivity of downstream diastereomeric intermediates formed in the catalytic cycle can dictate the enantioselectivity of chiral amine catalyzed reaction of aldehyde with electrophile rather than the diastereomeric transition states of the addition step in which, a new stereogenic center is created by the attack enamine to electrophile.23 In another interesting study, Pápai and coworkers have suggested that the stereoselectivity and rate of enamine mediated reaction can be determined in two different steps of the catalytic cycle.24 They have also shown that the addition of electrophile to the enamine intermediate (C-C bond forming step) controls the stereoselectivity of reaction, whereas subsequent protonation step determines the rate of enamine mediated reaction. It is worthwhile to note that the catalytic system investigated in this study is completely different from the catalytic system that has been used by Blackmond et al and Pápai et al in their studies. On the contrary to the diarylprolinol ether catalyst investigated in the recent mechanistic studies,23,24 the present study explores the role of imidazolidinone based chiral amine catalyst bearing two bulky substituents on the C-2 and C-5 position of the ring. Such catalytic framework can restrict the formation of downstream intermediates which were proposed by Blackmond et al to explain the stereochemical outcome of α-chlorination of aldehyde catalyzed pyrrolidine-based chiral amine catalyst.23 Moreover, the rate-limiting protonation step discussed by Pápai et al24 is not relevant in the catalytic cycle proposed for α-alkenylation of aldehydes reaction in Scheme 2. Considering all these facts, the step involving the addition of enamine intermediate (5) to the alkenyl Cu(III) intermediate (6) is expected to be the stereoselectivity determining step of reaction. Hereafter, the stereoselective determining step is referred as ‘addition step’. The addition step is investigated using the density functional study (DFT) methods. The five imidazolidinone based catalysts with different α-substituents are employed as chiral amine catalyst in this study (Scheme 2). These catalysts are denoted by letters A, B, C and D which have –methyl (-CH3), -phenyl (C6H5), -phenylmethyl (-CH2C6H5) and –naphthylen-1-ylmethyl (CH2C12H11) groups at the C-5 of imidazolidinone ring, respectively. The tert-butyl substituent at the C-2 of imidazolidinone ring is common to these catalysts. On the other hand, the catalyst E have -phenyl (-C6H5) and tert-butyl group on the C-2 and C-5 position of the ring, respectively. The configuration of chiral centers (C-2 and C-5) of catalysts A, B, C and D are (2S, 5S) whereas, catalyst E has (2R, 5R) configuration on chiral centers. Addition of enamine intermediates (5) formed by the reaction of chiral amines (A – E) with the propanal (1), and the alkenyl Cu(III) intermediate (6a) derived from the reaction of Cu(OAc)2 and boronic acid (2) were considered for the computational investigations (I to V, Table 1).

Results and Discussion The α-alkenylation of aldehydes catalyzed by combination of chiral amine and Cu catalyst may proceeds through pathway shown in Scheme 2. This pathway involves four key steps: formation of enamine intermediate using organocatalysis, formation of Cu(III) intermediate using Cu catalysis, addition of enamine intermediate to Cu(III) intermediate leading to iminium ion intermediate and subsequent hydrolysis to form a final product.22 In general, the step involving addition of enamine intermediate to the electrophile (C–C or C–heteroatom bond formation) is considered as the stereoselectivity-determining step of enamine-mediated


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The Journal of Organic Chemistry Scheme 2. Putative intermediates in enantioselective αalkenylation of aldehydes. The catalysts investigated in this study are shown in the inset.

The addition step with alkenyl Cu(III) intermediate (6b) derived from the reaction of CuBr and iodonium salt (3) is also investigated. The energetics of addition of 5E to 6b which is relevant to the experimental studies is reported in the text (VI, Table 1) and information about addition of other enamines (5A– 5D) to the 6b is provided in Supporting Information. To simplify our work, triflate ion of 6b was replaced by the acetate ion in calculations. Scheme 3. Two faces of enamine intermediate available for the addition to electrophile.

Enamine intermediate (5) have two major isomers arising from the orientation of enamine double bond relative to the bulky substituents (tert-Butyl and R1 substituents) on the imidazolidinone ring. For the sake of convenience, syn and anti notations (as shown in Scheme 3) are used to depict the orientation of enamine double bond relative to the R1 group. A detailed conformational analysis of Syn-(5) and Anti-(5) was performed to identify the conformational possibilities pertaining to different orientations of R1-group. In general, Anti-(5) is found to be slightly unfavorable as compared to Syn-(5) presumably because of the proximity of enamine double bond to the bulky tert-Butyl group at the 2 position of the ring. Since bulky groups placed at the same side of the imidazolidinone ring can effectively hinder one face of enamine olefinic bond, the other face of enamine bond is relatively exposed for the addition step. As a result, for the enamine derived from catalysts A–D, reface of Syn-(5) and si-face of Anti-(5) is preferred for the C–C bond formation with the alkenyl Cu(III) intermediate (6a or 6b). The addition of Syn-(5) to 6a through re face will lead to the (R)enantiomer whereas the si face addition will result in the (S)- enantiomer of 4. In the case of enamine derived from catalyst E, siface of Syn-(5E) and re-face of Anti-(5E) will be relatively exposed in the addition step. Consequently, the addition of 6a (or

6b) to si-face of Syn-(5E) and re-face of Anti-(5E) will lead to (R) and (S)-enantiomer of 4, respectively. The corresponding transition states with different catalyst combinations were located at the M062X level. The free energies of reaction complexes (Rc) and transition states (Ts) for each catalyst computed relative to separated intermediates (5 and 6a or 6b) are provided in Table 1.25 The channel leading to (R)- and (S)-enantiomers of 4 is designated by (R) and (S) letters, respectively. Comparison of relative free energies of TSs involving different catalysts shows a distinct preference for the addition of syn-(5) to 6a. While predicted product selectivity is in agreement with experimentally observed selectivity, calculated enantiomeric excess (ee) varies significantly with the catalyst combinations. Our calculations predict a very low enantioselectivity for the catalyst combination I(5A + 6a) whereas for II(5B + 6a), moderate enantioselectivity is estimated. The best results (high enantioselectivities) are obtained for the catalyst combinations III (5C + 6a), IV(5D + 6a), V(5E + 6a) and VI(5E + 6b). The representative catalyst combinations (IV and VI), for which predicted enantioselectivities are found to be in close agreement with experimental enantioselectivities, discussed succinctly in the following section. In the case of catalyst combination IV, relative to separated intermediates, free energies of reaction complexes Rc-(R)-IV and Rc-(S)-IV are -8.1 and -7.2 kcal/mol, respectively. The transition states Ts-(R)-IV and Ts-(S)-IV are found to be very close to the reacting complexes with activation barriers of 1.6 and 3.3 kcal/mol, respectively, rendering an early transition state for the addition step. The difference in free energies corresponds to enantiomeric excess (ee) of 98% in favor of R–product, which reasonably agrees with the experimentally observed %ee (93%).26 On the other hand, for the catalyst combination VI, >99% ee in favor of S-product is estimated. The change in trend of enantioselectivity from (R)- to (S)-product with a variation in the catalyst combination IV to VI is in agreement with experimental results.5,6 The vital question here is how these catalyst combinations are able to tune asymmetric environment for the addition of 5 to 6a in diastereomeric transition states even though, such additions prefer a less hindered site of the chiral amine catalyst. We next sought to identify the steric as well as electronic factors which govern the stereoselectivity of the reaction by examining lowest energy transition states of the addition step. In general, various factors play crucial role in determining the stereochemical outcome of aminocatalysis.27 These factors include (i) steric interactions offered by α-substituents of chiral amine catalyst (ii) hydrogen bond interactions between catalyst and substrate (iii) geometric distortion of catalyst and substrates at the transition states. In current reaction, bulky α-substituents of the chiral amine catalysts, which are positioned at the same side of imidazolidinone ring, provide an effective shielding to one of the faces of enamine double bond. Such disposition of bulky groups on the catalyst reduces the number of possible approaches of alkenyl Cu(III) intermediate to the enamine 5 and thus, limits the effective interactions of reacting partners. Furthermore, the interaction and the distortion in catalytic fragment namely, enamine fragment and Cu catalyst fragment can also contribute to the energy differentiation in the diastereomeric transition states. The nature and energy costs associated with the distortion of catalytic fragments at the transition states were determined using the distortion/interaction analysis.28 The distortion energies Edis associated with distortion of enamine fragment Edis(5) and Cu catalyst fragment (Edis(6)) at the transition state compared to the ground state geometries of 5 and 6a, respectively were calculated. This analysis also provides interaction energies Eint between enamine fragment and Cu catalyst fragment of the transition states. The energy components for each catalyst combinations (I – VI) and corresponding values are summarized in Table 2. The difference of ∆Eact of diastereomeric transition states in Table 2 show a reasonable correlation with the trend of selectivity (Table 1).29



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Table 1. Relative free energiesa (kcal/mol) of reaction complexes (Rc) and transition states (Ts) computed at the M062X level. Catalyst Combination I : 5A + 6a

Rc-(R)

Ts-(R)

∆G†

Rc-(S)

Ts-(S)

∆G†

%eeb

%eec

-7.5

-4.3

3.2

-7.9

-4.4

3.5

8 (R)

d

II : 5B + 6a

-5.8

-3.2

2.6

-5.8

-2.6

3.2

47 (R)

93 (R)

III : 5C + 6a

-10.2

-8.4

1.8

-5.2

-2.4

2.8

>99 (R)

86 (R)

IV: 5D + 6a

-8.1

-6.5

1.6

-7.2

-3.9

3.3

98 (R)

93 (R)

V : 5E + 6a

-1.7

0.8

2.5

-5.8

-2.5

3.3

99 (S)

̶d

VI: 5E + 6b

-2.3

1.5

3.8

-7.1

-5.0

2.1

>99 (S)

94 (S)

̶

a

The free energies computed relative to separated intermediates (5 and 6a or 6b). bEnantiomeric excess computed using difference in free energies of the diastereomeric transition states. c Experimentally observed enantiomeric excess. d Experimental enantiomeric excess are not available. Table 2. Distortion/Interaction Analysis for the Addition Step with Different Catalyst Combinations (I – VI)a Catalyst Combination

Ts-(R) ∆E

† int

∆E

† dis(5)

∆E

† dis(6)

Ts-(S) ∆E

† dis

∆E

†

∆E

† int

∆E

† dis(5)

∆E†dis(6)

∆E†dis

∆E†

I : 5A + 6a

-69.3

15.2

31.9

47.1

-22.2

-69.5

16.1

30.9

47.0

-22.5

II : 5B + 6a

-65.2

14.0

30.2

44.2

-21.0

-69.7

18.4

30.2

48.6

-21.1

III : 5C + 6a

-74.4

16.6

33.6

50.2

-24.2

-67.3

15.5

30.8

46.3

-21.0

IV: 5D + 6a

-76.9

20.0

31.0

51.0

-25.9

-72.2

17.0

30.8

47.8

-24.4

V: 5E + 6a

-76.3

19.3

40.4

59.7

-16.6

-65.4

14.1

30.3

44.4

-21.0

VI: 5E + 6b

-77.0

23.0

34.0

57.0

-20.0

-82.2

17.7

39.9

57.6

-24.6

a

∆E†int : Interaction energy, ∆E†dis(5) : Distortion energy for enamine fragment, ∆E†dis(6) : Distortion Cu catalyst fragment, ∆E†dis : Total distortion energy, ∆E† : Activation energy. All energies are given in kcal/mol.

Frontier Molecular Orbital (HOMO of Ts-(R)-IV) showing Metal-Enamine Interaction at the transition state

Ts-(R)-IV

Ts-(S)-IV


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The Journal of Organic Chemistry •

Three-centered Cu-C7C8 transition states

•

Cu····C7 interactions (bond distance in the range of 2.10 to 2.16 Å)

•

H-bonding interactions between (acetate) O···H (Cα) of enamine

Distortion in enamine fragment measured using dihedral angles ω1 = C2–N–C6–C7 ω2 = C5–N–C6–C7 ω3 = N–C6–C7–C(Me) Ts-(R)-VI Ts-(S)-VI Figure 1. Optimized transition states for the addition step with catalyst combinations IV and VI. See scheme 3 for the atom-numbering. The values in parentheses indicate geometric distortion of the enamine moiety in the transition state as compared to the parent enamine intermediate. Select bond distances are given in Å and dihedral angles are in degrees. Atom colors: H = white, C = Silver, N= blue, O = red and Br = Brick red.

It is apparent from the data shown in the Table 2 that the distortion energies of alkenyl Cu fragment (30 to 31 kcal/mol) are higher than the distortion energies of enamine fragment. However, the distortion energies of alkenyl Cu fragment remain qualitatively same in the transition states, except for the catalyst combination VI which is discussed separately.(vide infra) Thus, the difference in the total distortion energies of diastereomeric transition states mainly arises from the differential distortion of enamine fragment at the transition states. The optimized geometries of TSs of representative catalyst combination IV (Ts-(R)-IV and Ts-(S)-IV) were considered for a detailed analysis (Figure 1). It is noticed that the coordination of acetate ions to Cu at these transition states shows major deviation when it is compared with the ground state geometry of alkenyl Cu(III) intermediate (6a). The distortion in the coordination of acetate ions to Cu at the transition states presumably occurs to minimize the steric clash with the imdazolidinone ring. However, distortion energies of Cu catalytic fragment in Ts-(R)-IV and Ts-(S)-IV are comparable. Next, we compare geometries of Ts-(R)-IV and Ts-(S)-IV with the geometry of enamine intermediate (5). The C–C bond formation and enamineiminium ion conversion at the transition state is accompanied with the change in conformation of imidazolidinone ring. To account the distortion in enamine fragments, dihedral angles ω1 : C2–N– C6–C7 and ω2 : C5–N–C6–C7 which describe changes in the conformation of imidazolidinone ring relative to enamine double bond C6–C7 were analyzed. We have also noted the dihedral angle ω3: N–C6–C7–C(Me) which exhibits distortion at the C7 during C7–C8 bond formation as shown in the Figure 1. In Ts(R)-IV and Ts-(S)-IV, the ω1 and ω2 show a modest deviation while, ω3 shows a considerable deviation compared to the corresponding angles of the enamine intermediate (5) geometry. The deviation in these dihedral angles is more in Ts-(R)-IV than in Ts-(S)-IV which perfectly correlates with the trend of distortion energies predicted for these transition states.

Scheme 4 : Transition state of Catalyst Free Model reactions. Select bond distances are shown in Å. Similar to catalyzed reactions, the carbon atoms involved in the C–C bond formation are designated as C7 and C8.

Model reaction (M1)

Model reaction (M2)

Similar to the distortion energies, the interaction energies between two catalytic fragments at the transition state also vary with the different catalyst combinations. It is also clear from Table 2 that the stabilization offered by the interaction between enamine fragment and Cu catalyst fragment is much higher than the destabilization incurred due to distortion of these fragments. In order to identify the source of high interaction energies, we have investigated catalyst-free model reactions involving α-alkenylation of aldehydes (Scheme 4).30 In the first model reaction (M1), addition of enolate of propanal to 3-phenyl propene is considered. The free energy of activation for this reaction is found to be as high as 27.7 kcal/mol while, the energy of interaction between two reactants at the transition state is 11.7 kcal/mol. In another model reaction, we have considered addition of enol form of propanal to the alkenyl Cu intermediate. In this case, free energy of activation and interaction energy at the transition state are 14.0 and 33.8 kcal/mol, respectively. These results clearly demonstrate that high interaction energies stemming from the augmented interaction between catalytic fragments can be attributed to the catalytic (HOMO and LUMO) activation of reactants achieved in the synergistic catalysis. Such dual catalytic activation of reactants, ultimately, helps to reduce the activation barrier of addition step. It is worthwhile to note that free energies of activation predicted for the addition step (C–C bond formations) in present work are significantly lower as compared to the free energies of activation reported for the C–C bond forming step in various enamine mediated reactions.31 How-


The Journal of Organic Chemistry 65 Distortion Energy

ever, the effect of HOMO-raising and LUMO-lowering activation achieved through synergistic catalysis is expected to remain same in the diastereomeric transition states, and likely to contribute equally to the interaction energies. Interestingly, interaction energies computed for the diastereomeric transition states of various catalytic combinations are not in the same range. For instance, the interaction energy in Ts-(R)-IV is 4 kcal/mol higher than that of Ts-(S)-IV which suggests, that the stabilizing non-covalent interactions between two catalytic fragments may also add to the net interaction energy. The comparison of transition state geometries reveals the possibility of two stabilizing non covalent interactions at the transition state. First one includes the interaction between Cu and the enamine moiety (referred as metal – enamine interaction). In Ts-(R)-IV, Cu is located at 2.12 and 2.48 Å from C7 and C6, respectively (Figure 1). Natural population analysis of the transitions state shows Cu bears a partial positive charge (1.24 e) while C7 and C6 of enamine bond have -0.44 e and 0.21 e, respectively. This charge distribution suggests that Cu may interact with the C7 of enamine moiety which is also involved in the C–C bond formation process at the transition state. The corresponding frontier molecular orbital showing Cu····C7 orbital interaction is shown in the Figure 1. Along with the Cu···C7 interaction, hydrogen bonding interaction between oxygen of acetate and hydrogen on the C2 or C5 of imidazolidinone ring is also identified in the transition state. The (acetate) O···H distance at the Ts-(R)-IV is 2.14 Å. These two interactions Cu···C7 and (acetate) O···H(Cα) are relatively weak in Ts-(S)-IV which is evident from the slightly longer Cu···C7 and (acetate) O···H distances in Ts-(S)-IV (2.14 and 2.24 Å, respectively). We have also analyzed topological features of electron density distribution at the transition state to quantify the extent of non covalent interactions using multiwfn program. The electron densities of bond critical points (BCP) for the the Cu···C7 and (acetate) O···H interactions in Ts-(R)-IV are 0.073 and 0.016 au, respectively. On the other hand, in Ts-(S)-IV, the electron density values of BCP for these interactions are found to be lower by 0.004 to 0.005 au as compared to Ts-(R)-IV. It is clear from topological analysis of transition states that Cu···C7 interaction is more prominent than the (acetate) O···H (Cα) hydrogen bonding interaction and could be a major contributing factor that leads to the differences in interaction energies at the diastereomeric transition states. To obtain further support to our hypothesis, we have also examined transition state geometries (Figure 1) of the catalyst combination VI in which, (S)-product selectivity is predicted. In this catalyst combination, one of the acetate ions of 6a is replaced by bromide ion to model the alkenyl Cu(III) intermediate (6b) derived from the reaction of iodonium salt and CuBr. Even with this catalyst combination, the Cu···C7 distance in the lower energy Ts-(S)-VI is shorter by 0.03 Å compared to Ts-(R)-VI (2.10 vs. 2.13 Å). Accordingly, interaction energy of the catalytic fragments in the preferred Ts-(S)-VI is found to be 5 kcal/mol higher than that of Ts-(R)-VI. The distortion energies of Cu catalyst fragment, however, follow a different trend in comparison to other catalyst combinations. The distortion energies of Cu catalyst fragment in Ts-(R)-VI, and Ts-(S)-VI and net distortion energies of these transition states are higher than that of other transition states. This is mainly because of the large displacement of bromide ion in the transition states relative to the original position in the ground state geometry of 6b. Interestingly, the net distortion energies in Ts-(R)-VI and Ts-(S)-VI qualitatively remained the same and therefore, we reasoned that the difference in interaction energies which primarily arises from the Cu···C7 interaction might be responsible for the energy difference in these transition states.

R² = 0.7827

60 55 50 45 40 65

Cu---C7 Bond Distance

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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70

75 80 Interaction Energy

85

R² = 0.774

2.17 2.16 2.15 2.14 2.13 2.12 2.11 2.1 65

70

75 80 Interaction Energy

85

Figure 2. Correlation plot of (a) distortion energy vs. interaction energy (b) Cu···C7 bond distance vs. interaction energy. Energies are given in kcal/mol and bond distances in Å. After having analyzed stabilizing and destabilizing factors at the transition states, we further discussed the salient features of computational model of synergistic catalysis presented in this study. It is noticed that the interaction and distortion energies computed for the transition states of various catalyst combinations (Table 2) exhibit interesting variations. A plot of distortion vs. interaction energies of transition states of catalyst combinations (I – VI) display a reasonable correlation with R2=0.782 (Figure 2a).32 This trend in the distortion and interaction energies conveys that catalytic fragments may experience a sizable distortion to maximize the interaction between these fragments at the transition states. However, sufficiently strong stabilizing interaction between two catalytic fragments undertakes destabilization caused by the distortion in catalytic fragments, resulting into low activation energy for the transition state. Our computational model also suggests that a subtle change in the metal–enamine interaction described through the Cu···C7 distance may determine the variation in the interaction energies of diastereomeric transition states. Consistent with this hypothesis, a linear relationship between the Cu···C7 distance (at the transition state) and interaction energies computed for the transition states of catalyst combinations (I –VI) is obtained (Figure 2b).33 The plot shows that the deviation of 0.06Å in Cu···C7 distance may cause approximately 15 kcal/mol variation in the interaction energy. Such a large variation in the interaction energy is possible only if the metal-enamine interaction operate in tandem with catalytic (covalent) activation. Careful examination of the metal-enamine interaction allows envisaging a threecentered transition state for the addition step wherein, the metal activates both reacting centers, C7(nucleophilic) and C8(electrophilic). Thus, the enamine fragment may experience additional nucleophilic activation through metal – enamine interaction. The cooperative nature of these interactions may facilitate C7···C8 bond formation, rendering additional stabilization to the transition state. A further support for the co-action of catalytic activations and metal-enamine interaction comes from the com-


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The Journal of Organic Chemistry parison of Cu···C7 distance in the transition state of catalyzed vs. catalyst-free model (M2) reaction. In catalyst-free transition state of model reaction (M2), the Cu···C7 distance is increased by about 0.14–0.19Å relative to that in the transition state of catalyzed reactions (Scheme 4). The weakening of Cu···C7 interaction without an enamine activation of aldehyde manifests the cooperation between the catalytic activations and metal-enamine interaction at the transition state. Besides, a topology analysis of Cu···C7 interaction, which recognized it as a relatively strong non-covalent interaction than the hydrogen bonding interaction, justifies the large fluctuation in interaction energies with a delicate change in the Cu···C7 distance. In summary, the differential metal-enamine interaction at the diastereomeric transition states within a synergistic catalytic framework primarily dictates the enantioselectivity of reaction.

Conclusions

Taken together, our computational results demonstrate that the basis for enantioselectivity in this reaction may be ascribed to the different degrees of interaction among catalytic fragments at the competing transition states, and the interaction energies are mainly determined by the cooperation of catalytic (covalent) activations and the metal-enamine interaction at the transition state. We speculate that the computational model presented in this paper may provide a guideline to a rational design of catalyst combinations for other asymmetric reactions that rely on the synergistic action of organo- and metal catalysis.

Supporting Information

AUTHOR INFORMATION Corresponding Author *[email protected]

Notes The authors declare no competing financial interests.

ACKNOWLEDGMENT I thank Department of Science and Technology (DST), India (SB/FT/CS-086/2012) for the partial funding.

REFERENCES

Computational investigations of the stereoselectivity-determining step of the enantioselective α-alkenylation of aldehyde reveal interesting aspects of the synergistic catalysis in the asymmetric reaction. We have examined different combinations of chiral amines (A – E) and Cu catalysts in the computational model to provide a comprehensive view on the origin of the high enantioselectivity in the reaction. In general, bulky substituents on the chiral amine, as demonstrated in the various activation modes of aminocatalysis such as iminium, enamine and SOMO activation catalysis, play a crucial role in the asymmetric induction, providing a differential steric environment for the addition of nucleophile/electrophile.34 However, in the present reaction, the addition of the enamine intermediate derived from the chiral amines (A – E) to alkenyl Cu(III) intermediate (electrophile) prefers a face opposite to bulky groups and thus, minimizes the contribution of steric factor in the chiral induction. In the absence of steric discrimination at the competing transition states, our calculations show that the interaction between catalytic fragments (enamine and alkenyl Cu catalyst fragments) in the synergistic catalytic framework can be decisive for the stereoinduction in reaction. The high interaction energies, in the range of 65 to 80 kcal/mol, are predicted using distortion/interaction analysis. Furthermore, at the transition state, the Cu is seen to activate the enamine fragment through the Cu···C7 interaction. The typical Cu···C7 distance at the transition state is found to be in the range of 2.10 to 2.16 Å. This interaction allows Cu catalyst to engage in nucleophilic (at C7) and electrophilic (at C8) activation simultaneously, via a three-centered transition state. Owing to cooperative nature of these interactions, a subtle change in the Cu···C7 interaction leads to a substantial variation in the interaction energies of diastereomeric transition states.

ASSOCIATED CONTENT

Optimized Cartesian coordinates and total energies of all computed stationary points are provided. This material is available free of charge via the Internet at http://pubs.acs.org.

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Stereocontrol through Synergistic Catalysis in the Enantioselective Î±

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