Enantioselectivity Model for Pd-Catalyzed C–H Functionalization

May 19, 2017 - ... Emory University, 1515 Dickey Drive, Atlanta, Georgia 30322, United ...... Examination of the transition state structures responsib...
0 downloads 0 Views 2MB Size
Download PDF
Research Article pubs.acs.org/acscatalysis

Enantioselectivity Model for Pd-Catalyzed C−H Functionalization Mediated by the Mono-N-protected Amino Acid (MPAA) Family of Ligands Brandon E. Haines,† Jin-Quan Yu,‡ and Djamaladdin G. Musaev*,† †

Cherry L. Emerson Center for Scientific Computation, Emory University, 1515 Dickey Drive, Atlanta, Georgia 30322, United States Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037

‡

S Supporting Information *

ABSTRACT: The mono-N-protected amino acid (MPAA) family of ligands is arguably the most prolific scaffold for enabling enantioselective C−H activation via metal insertion. However, its mechanism for asymmetric induction is not fully understood. Here, we developed a practical model for asymmetric induction from the viewpoint of rationalizing chiral, bidentate ligands for C− H activation via metal insertion. The model is validated against Pd(II)-catalyzed C−H activation in 2-benzhydrylpyridine mediated by the [(cyclohexyloxy)carbonyl]-L-leucine (MPAA) ligand. We found that full control elements of enantioselectivity are (a) inherent strain in the bidentate coordination of substrate and the ability of the ligand to enhance it, (b) the gearing effect that restricts the C−H bond activation to one face of the Pd catalyst, (c) potential interactions between the ligand and substrate, and (d) chelate inversion which is controlled by the ligand-anchored base that restricts the C−H bond activation to one side of the Pd catalyst. We also identified two pathways for loss of enantioselectivity: (1) equilibration of the ligand half-chair conformations and (2) loss of bidentate coordination through partial dissociation of the ligand. We applied this general enantioselectivity model to explain the observed increase in enantioselectivity of the Pd(II)-catalyzed asymmetric C−H activation of 1,1-disubstituted cyclobutanes upon replacing Boc-protected L-leucine (MPAA) ligand by the chiral mono-N-protected α-amino-Omethylhydroxamic acid (MPAHA) ligand. We found that the observed trend in enantioselectivity upon replacing MPAA and MPAHA is due to increased interactions between the ligand and substrate. We proposed a strategy for the use of such a model to design highly selective chiral ligands for C−H functionalization. KEYWORDS: C−H functionalization, enantioselectivity, predictive models, MPAA ligands, ligand design, DFT

■

INTRODUCTION

One of the pressing challenges for transition metal (M) catalyzed C−H functionalization is the development of chiral ligands and catalysts capable of producing highly enantioenriched products.1,2 Current broadly utilized strategies include (a) carbene and nitrene insertion in the presence of bulky and chiral carboxylate ligands3,4 and (b) directed C−H activation via metal insertion facilitated by a metal chelating or directing group (DG) in the presence of a chiral ligand (L*, Figure 1).5,6 Despite numerous advances, the identification and optimization of chiral ligands to implement these strategies with high levels of enantioselectivity remains a highly active research area. Among the latest breakthroughs in the field of directed C−H activation via metal insertion, we wish to emphasize the development of the prolific mono-N-protected amino acid (MPAA) family of ligands7 developed by the Yu group, which notably includes the mono-N-protected α-amino-O-methylhydroxamic acid (MPAHA) variants.8,9 These ligands have been extensively used to desymmetrize a wide range of prochiral © 2017 American Chemical Society

Figure 1. Asymmetric transition metal (M) insertion into prochiral C−H bonds utilizing a chiral ligand (L*) and directing group (DG).

substrates through selective C−H arylation,10−14 alkenylation,15−24 alkylation,25−28 halogenation,29,30 and others. These Received: April 20, 2017 Revised: May 17, 2017 Published: May 19, 2017 4344

DOI: 10.1021/acscatal.7b01281 ACS Catal. 2017, 7, 4344−4354

Research Article

ACS Catalysis

active species has been studied in detail, here we focus on the development of a reliable enantioselectivity model for the monomer active species. We will report further studies on the mechanism and enantioselectivity for C−H activation by the dimeric Pd(II)/MPAA complexes in the near future. Since the initial step for developing a general enantioselectivity model, on the basis of the roadmap presented above, is elucidation of the reaction mechanism, here we take advantage of previous findings on the mechanism of the MPAA-mediated Pd(II)-catalyzed enantioselective C−H functionalization33,34,43−46 to build the foundations of the model. In 2012, we proposed the “N−H bond cleavage and subsequent C−H bond activation” mechanism (Figure 2) for the Boc-Val-OH

successes have triggered the further design of novel chiral ligands that enable differentiation of especially challenging prochiral C−H bonds. For example, it is found that the aminoethylquinoline (APAQ) ligand scaffold enables enantioselective arylation of a β-methylene center 31 and the monoprotected aminomethyl oxazoline (MPAO) scaffold allows for versatile desymmetrization of an isopropyl group through C−C bond formation32 (Figure 1). While these findings have received broad attention from the synthetic and mechanistic communities, a deep understanding of the fundamental role of these chiral ligands in enantioselective C−H functionalization remains an aspirational goal. Extensive mechanistic studies of MPAA-mediated Pd(II)catalyzed enantioselective C−H functionalization have revealed that the apparent simplicity of the MPAA scaffold belies the complexity of its role in asymmetric induction.7,33,34 The “chiral relay” model33 proposed in the literature for asymmetric induction is based on (a) a gearing effect arising from steric interactions between the MPAA protecting group (PG) and side chain substituent (R) and (b) conformational strain in the substrate.34 However, this model has limitations in the design of new ligand scaffolds because it lacks a few important factors (see below). For example, this model often overestimates the enantioselectivity and cannot explain observed trends in the enantioselectivity due to small changes within the ligand scaffold, such as the MPAA side chain35 or modification of a donor group (i.e, MPAA → MPAHA).9 As such, there is a need for a more general and practical model for asymmetric induction in enantioselective C−H insertion for the MPAA family of ligands. Success in this endeavor is expected to enable the design of chiral catalysts with increased enantioselectivity and will open avenues to design new C−H functionalization reactions. Detailed analysis reveals that in order to build a more general enantioselectivity model, it is vital to (a) elucidate the detailed mechanism of the reaction, (b) identify the stereodetermining transition states (TSs) and all geometric transformations that characterize these TSs, (c) elucidate all specific elements (i.e., conformations, nonbonding interaction, etc.) that influence the relative stability of the diastereomeric TSs, and (d) determine pathways that lead to loss of enantioselectivity. To utilize this roadmap, herein, we (i) present a general model for asymmetric induction with bidentate (see below for reasoning), point-chiral ligands for selective metal insertion into the C−H bond of a prochiral center and (ii) use density functional theory (DFT) calculations to validate and refine the model by examining the enantioselectivity for the MPAA family of ligand mediated Pd(II)-catalyzed C−H functionalization reactions. This new model (a) identifies specific factors controlling the stability of the diastereomeric C−H activation TSs involving the MPAA ligand and (b) defines a pathway through which enantioselectivity is lost, in order to explain the peculiar enantioselectivity trend observed for the MPAA side chain (where R = t-Bu, i-Bu, i-Pr, Me) in the desymmetrization of 2-benzhydrylpyridines.35 It also provides insights into the major reasons MPAHA ligands are more selective than MPAA ligands in desymmetrization of 1,1-disubstituted cyclobutane substrates.9 An increasingly recognized factor in Pd-catalyzed C−H functionalization is the nuclearity of the active catalyst and intermediate species.36−41 However, the relevance of monomeric and dimeric species for a given reaction is still largely up for debate.42 Since the general mechanism for the monomer

Figure 2. “N−H bond cleavage and subsequent C−H bond activation” mechanism for MPAA ligand mediated and Pd catalyzed C−H activation.

mediated and monomeric Pd(II) species catalyzed enantioselective C−H bond activation of 2-benzhydrylpyridine.46 We also demonstrated that the MPAA ligand plays multiple roles during the reaction.45 At first, in order to initiate the reaction, a singly deprotonated MPAA ligand weakly coordinates as a monoanionic ligand to the Pd center and stabilizes the {[κ2(NH,O)]-MPAA}-Pd(II)-[DG-SUB] precatalyst (where DGSUB = C−H functionalization substrate, Figure 2). Then, the coordinated amide group is deprotonated and acts as a soft electron donor (from the N-terminus) that leads to generation of the catalytically active {[κ2-(N,O)]-MPAA}-Pd(II)-[DGSUB] intermediate with a bidentately coordinated dianionic [κ2-(N,O)]-MPAA ligand. Thus, a key factor in designing the general enantioselectivity model for the MPAA family of ligand mediated Pd(II)-catalyzed C−H f unctionalization reactions is bidentate coordination of the ligand to a monomeric metal center. From the resulting catalytically active intermediate with bidentately coordinated ligand, arene C−H bond activation may occur via either the “internal base (i.e. MPAA) assisted” or “external base assisted” concerted metalation−deprotonation (CMD) mechanisms (denoted below as IN and EX mechanisms, respectively), as illustrated in Figure 2. We previously showed34,45,46 that operation of the EX pathway relies heavily on the reaction conditions such as base concentration, solvent, counterion, etc., whereas the IN pathway depends mostly on the electronic and steric properties of the MPAA ligand (i.e, the PG) and substrate, including Pd− DG interaction. The general enantioselectivity model should be capable of making predictions regardless of mechanism: i.e., it should be able to handle the electronic and steric features of the diastereomeric C−H activation transition states occurring through both IN and EX pathways. 4345

DOI: 10.1021/acscatal.7b01281 ACS Catal. 2017, 7, 4344−4354

Research Article

ACS Catalysis We have previously shown34,45,46 that the Pd center acts as a coordinatively and conformationally flexible metal center during the C−H activation. The weak coordination of the substrate and ligand to the metal center allows them the freedom to dissociate or adopt several conformations. Therefore, coordinative and conformational f lexibility of the coordinated ligand and substrate are also important characteristics of the successf ul complete enantioselectivity model. Complete Enantioselectivity Model. Herein, we present a complete enantioselectivity model that is designed to explain and predict the enantioselectivity arising from point-to-point asymmetric induction from the MPAA family of ligands and their derivatives in transition metal catalyzed C−H functionalization. The proposed model incorporates mechanistic knowledge on the MPAA ligand mediated Pd(II)-catalyzed enantioselective C−H functionalization presented above.33,34,43−46 Namely, it represents the active species for C−H activation that (i) is monomeric by nature, (ii) has one doubly deprotonated and bidentately coordinated MPAA ligand, and (iii) allows the coordinative and conformational flexibility of the ligand and substrate. Therefore, the model, as presented in Figure 3, is built to have the following geometric features.

C−H groups, C1 and C2. The basis of chelate inversion is exchanging the positions of the C1 and DG centers of the substrate to form III (i.e., isomerization). This may also be defined as a choice between coordination of DG either trans or cis to a chosen ligand donor group, A. To summarize, in the model proposed here, the ligand produces high levels of enantioselectivity in the reaction via control of the (a) substituent inversion (e.g., I vs II) and (b) chelate inversion (e.g., I vs III) transformations. Importantly, in investigations of these transformations and factors affecting them for a specific system, it is critical to carefully account for the structural and coordination flexibility of the ligand and substrate, which may significantly contribute to the relative energies of the identified transformations but will not alone alter the stereochemical outcome of the reaction.

■

COMPUTATIONAL METHODS The Gaussian 09 suite of programs47 was used for all described calculations. Geometry optimizations and frequency calculations for all reported structures were performed at the B3LYPD3BJ/[6-31G(d,p)+Lanl2dz(Pd)] level of theory (B3LYPD3BJ/BS1) with the corresponding Hay−Wadt effective core potential for Pd and Grimme’s empirical dispersion correction with Becke−Johnson damping for B3LYP.48 Each reported minimum has zero imaginary frequencies and each transition state (TS) structure has only one imaginary frequency. Intrinsic reaction coordinate (IRC) calculations were performed for selected transition state structures to confirm their identity. Bulk solvent effects are incorporated for all calculations using the self-consistent reaction field polarizable continuum model (IEF-PCM)49−51 with either tetrahydrofuran or methanol as the solvent, and the calculated Gibbs free energies are corrected to a solution standard state of 1 M at 358.15 or 343.15 K,52,53 as determined by the reported experimental conditions for each reaction. Final reported energies include (a) electronic energies of each structure computed at the B3LYP-D3BJ/[6-311+G(2d,p)+SDD(Pd)] level of theory (B3LYP-D3BJ/BS2) and the B3LYP-D3/BS1 calculated geometries and (b) thermal corrections for the free energy and enthalpy calculated at the B3LYP-D3/BS1 level of theory. Counterpoise calculations54,55 were performed for selected structures to ensure that basis set superposition error is not a major factor in the reported energies (see the Supporting Information for more details.) We compute the enantiomeric excess (ee) value by using all of the identified conformational and configurational isomers of the diastereomeric TSs. It is increasingly recognized that determination of the selectivity from one pair of diastereomeric TSs may not be an effective approach for systems with conformational flexibility.56 Here, we calculate the enantiomeric ratio (er) using the Boltzmann distributions from each diastereomeric TSs using eq 1

Figure 3. Analysis of the general transformations that lead to diastereomeric transition states in directed C−H activation via M insertion.

(1) A generalized ligand is present with a tetrahedral chiral center that bidentately coordinates to a square-planar transition metal catalyst (M) to form a ring chelate of unspecified size. The chiral center has two substituents (R1 and R2) and two chelating groups (A and B). In Figure 3, the stereochemistry of the ligand is arbitrarily defined as S. (2) A generalized substrate with a prochiral and tetrahedral center (C*) is present. This substrate coordinates to the M center via a donor/directing group (DG). Insertion into a diastereotopic C−H bond, C1−H (presented as C1), creates a bidentately coordinated substrate, where the other diastereotopic C−H bond, C2−H (presented as C2), and R3 are substituents on the chiral center. In Figure 3, the initial stereochemistry of the activated substrate is arbitrarily defined as R to form diastereomer I. With the core geometric features of the general enantioselectivity model defined, we examined the transformations leading to conformational and configurational isomers of the diastereomeric C−H activation transition states that will collectively contribute to the enantioselectivity of the reaction. We start our analysis with diastereomer I, as defined in Figure 3. From I, the opposite stereochemistry of the substrate, i.e. its S stereoisomer, can be obtained through (a) substituent inversion or (b) chelate inversion, as illustrated in Figure 3. The basis of substituent inversion is exchanging the positions of the C2 and R3 centers of the substrate to form II. This may also be defined as a choice between activating either of the prochiral

er =

∑i(R) e−ΔΔ Gi ∑j(S) e−ΔΔ Gj

⧧

⧧

/ RT

/ RT

ΔΔGi⧧

(1) ⧧

where and ΔΔGj are the free energy differences for the R and S diastereomeric TSs with conformations summed over i and j, respectively, R is the gas constant, and T is the temperature in kelvin.57 Then, er is converted to ee using eq 2:

ee = 4346

er − 1 × 100 er + 1

(2) DOI: 10.1021/acscatal.7b01281 ACS Catal. 2017, 7, 4344−4354

Research Article

ACS Catalysis This approach is valid under Curtin-Hammett conditions, where the reactants associated with the diastereomeric transition states are in rapid equilibrium.58 Application of the Proposed Enantioselectivity Model to MPAA/Pd(II) Systems. Next, we validate the proposed enantioselectivity model by applying it to the MPAA/Pd(II)catalyzed C−H activation of 2-benzhydrylpyridine (1; Figure 4). This reaction is well studied experimentally and gives

Figure 4. Substrate and ligands examined for validation of enantioselectivity model.

suboptimal enantioselectivity for substrate 1 with the MPAA ligand N-[(−)-menthoxylcarbonyl]-L-leucine (2) at elevated temperature (79% ee in favor of the R isomer at 80 °C).35 Since experiments have demonstrated that the substituent of the ester PG does not have a pronounced effect on the observed enantioselectivity,35 herein we modeled the menthol group of ligand 2 as cyclohexane. Thus, in the present model studies, we utilize [(cyclohexyloxy)carbonyl]-L-leucine (3) as the ligand with R1 = i-Bu, R2 = H, A = CyOCON− (Cy = cyclohexyl), and B = CO2− and 1 as the substrate, where C1 and C2 = Ph, R3 = H, and DG = pyridine. In order to properly assess the factors affecting the enantioselectivity of the reaction via the proposed substituent inversion and chelate inversion, we identify all conformations that will contribute to the formation of diastereomeric C−H activation transition states. For simplicity, at first, we focus on analysis of diastereomeric C−H activation transition states of the IN (i.e., the “internal base assisted”) pathway. As shown in Figure 5, in these transition states the six-membered-ring chelate of the substrate adopts a pseudoboat conformation, where (i) one of its Ph substituents (C2) is either pseudoaxial or pseudoequatorial and determines the R or S stereoisomer and (ii) the chiral center (C*) is either above (u) or below (d) the coordination plane of the Pd. A similar structural motif is present for the MPAA ligand (i.e., left-hand-side ligand motif of the model presented in Figures 3 and 5).59 To describe these structural features of the diastereomeric C−H activation transition states, we developed a notation as follows: L(R/S,u/d):Sub(R/S,u/d), where L = ligand, Sub = substrate, R/S indicates the R and S stereoisomers, and u/d indicates the “up” and “down” position (relative to the coordination plane of the Pd) of the ligand and substrate chiral centers. If we fix the S stereochemistry of the ligand and vary only the location (up or down) of its chiral-center (C*), then the substituent inversion will lead to the following eight diastereomeric transition states: L(S,u):Sub(R,d), L(S,u):Sub(S,d), L(S,u):Sub(R,u), L(S,u):Sub(S,u), L(S,d):Sub(R,d), L(S,d):Sub(S,d), L(S,d):Sub(R,u), and L(S,d):Sub(S,u) (see Figure 5 for representative examples). The proposed chelate inversion concept further differentiates these eight diastereomers by location of the DG of the substrate either trans or cis relative to the N-protected amide center (i.e., PG) of the chelated MPAA ligand. To signify this, the final label for each transition state structure also includes a trans or

Figure 5. Representative examples of the diastereomeric C−H activation transition states of the IN pathway identified to elucidate the enantioselectivity model.

cis prefix (see Figure 5). Thus, there are 16 total diastereomeric C−H activation transition states in the IN pathway for [3]Pd(II)-[1] that we use to calculate the enantioselectivity of the reaction. The calculated relative free energies of these transition state structures are given in Table 1, and their geometrical parameters are presented in the Supporting Information. Using the relative free energies of the calculated R and S TS structures presented in Table 1 and eqs 1 and 2 gives the Table 1. Computed Free Energy for Each TS Structure for C−H Activation through the IN Pathway C−H activation transition state structures of the IN pathway, isomer leading to R product

relative free energy ΔΔG⧧(i) (kcal/mol)

trans-[L(S,u):Sub(R,d)] trans-[L(S,u):Sub(R,u)] trans-[L(S,d):Sub(R,d)] trans-[L(S,d):Sub(R,u)] cis-[L(S,u):Sub(R,d)] cis-[L(S,u):Sub(R,u)] cis-[L(S,d):Sub(R,d)] cis-[L(S,d):Sub(R,u)] C−H activation transition state structures of the IN pathway, isomer leading to S product

0.0 9.3 21.8 12.9 37.6 32.8 44.3 40.9 relative free energy ΔΔG⧧(j) (kcal/mol)

trans-[L(S,u):Sub(S,d)] trans-[L(S,u):Sub(S,u)] trans-[L(S,d):Sub(S,d)] trans-[L(S,d):Sub(S,u)] cis-[L(S,u):Sub(S,d)] cis-[L(S,u):Sub(S,u)] cis-[L(S,d):Sub(S,d)] cis-[L(S,d):Sub(S,u)]

5.4 3.1 a 7.6 32.5 38.7 38.1 43.9

a Every attempt to locate the trans-[L(S,d):Sub(S,d)] TS converged to the trans-[L(S,d):Sub(S,u)] TS through a half-chair flip of the substrate, indicating that it is not a stable structure.

4347

DOI: 10.1021/acscatal.7b01281 ACS Catal. 2017, 7, 4344−4354

Research Article

ACS Catalysis

conformational flexibility within the core geometric features of the proposed general enantioselectivity model. One such factor affecting the conformation of the substrate via the ligand−substrate interaction is the nature (electronic and steric) of the entire MPAA ligand scaffold. In order to demonstrate this factor, we replaced the MPAA ligand with two acetates, where one of them acts as an internal base for the C− H activation via an IN-type transition state. The absolute energy differences between the pairs of “d” isomers, trans[L(S,u):Sub(R,d)] and trans-[L(S,u):Sub(S,d)], and “u” isomers, trans-[L(S,u):Sub(R,u)] and trans-[L(S,u):Sub(S,u)], for the two-acetate system is quite large: 4.3 and 4.2 kcal/mol, respectively (Figure 6, red). Comparison of these values with those for ligand 3 (5.4 and 6.2 kcal/mol, respectively) shows the effect of the MPAA ligand scaffold on the substrate conformation is only 1.1 and 2.0 kcal/mol for the pairs of “d” and “u” isomers, respectively. The substrate conformation is conserved both with and without the MPAA ligand, which is consistent with the observed relative energies (see the Supporting Information for structures). Further analysis of the geometry of the transition states with MPAA and two acetate ligands shows that their energy difference may arise from the positioning of the reactive center of the ligand. Indeed, the MPAA ligand restricts the O−Pd− N−C dihedral angle to values of 141 and 143° for trans[L(R,u):Sub(R,d)] and trans-[L(R,u):Sub(S,d)], respectively. However, the O−Pd−O−C dihedral angles with acetate (analogous to the O−Pd−N−C dihedral angle with MPAA) are 136 and 134°, respectively (see the Supporting Information for more details). Thus, acetate is much more flexible to ideally position itself to activate the substrate C−H bond in the transition state in comparison to the MPAA ligand. Another important factor affecting the substrate conformational flexibility via the ligand−substrate interaction is the steric bulkiness of the R1 substituent of the MPAA ligand. In order to assess its effect on the relative stability of the four “d” and “u” transition states, we compared their energy difference with ligand 4 (where R1 = H, see Figure 4) to the acquired results for ligand 3 (where R1 = i-Bu). In this case, we find that the absolute free energy difference between the pairs of the “d” isomers is on the order of that calculated for ligand 3 (Figure 6, blue). In other words, the bulkiness of the R1 group is not a major contributor to the substrate conformations of the “d” isomers. This can be partially explained by the fact that the “d” isomers position the R1 group and the chiral center of the substrate on different faces of the coordination plane of the Pd. In contrast, the “u” isomers position the R1 group and the chiral center of the substrate on the same face of the coordination plane of the Pd, which is reflected in the resulting energy difference for ligands 3 and 4: 0.9 kcal/mol (6.2 and 5.3 kcal/ mol, respectively). These results show the existence of a tangible effect of the R1 group of the MPAA ligand on the substrate “u” conformations and, consequently, the enantioselectivity of the reaction (see also Figure 7). Thus, the findings presented above demonstrate that the conformational flexibility of the substrate is an important factor to consider when developing a highly selective reaction, even it is achiral. In addition, the interaction between the substrate and the chiral, bidentately coordinated MPAA ligand with a bulky R1 substituent is vital for controlling the selectivity of the reaction. The MPAA ligand and its R1 group can also affect the substituent inversion transformation via direct perturbations of

computed enantioselectivity as 97% ee in favor of the R product at 80 °C for IN pathway C−H activation of 1 by [3]-Pd(II). Thus, the calculated ee is 28% higher than its experimental value of 79%. The error in the calculated enantioselectivity suggests that the model needs to be improved. Therefore, below we carefully examine the contributions of each conformer to the computed enantioselectivity of these transition state structures in order to understand the limitations of the model, improve it, and expand its scope.

■

RESULTS AND DISCUSSION Substituent Inversion. We start our discussion by analyzing the transformations leading to substituent inversion (i.e., exchange of the Ph and H substituents attached to the chiral center C*). For simplicity in our analysis, we use two pairs of diastereomeric TSs associated with the conformational flexibility of the substrate (i.e., substrate inversion): “d” isomers, trans-[L(S,u):Sub(R,d)] and trans-[L(S,u):Sub(S,d)], and “u” isomers, trans-[L(S,u):Sub(R,u)] and trans-[L(S,u):Sub(S,u)] (Table 1, Figure 5, and Figure S1 in the Supporting Information).60 As shown in Table 1 and illustrated in Figure 6, the absolute free energy differences between the pairs of “d” and “u” isomers

Figure 6. Comparison of conformational isomers for the substituent inversion transformation under different ligand environments (3, black; 4, blue; OAc, red).

are 5.4 and 6.2 kcal/mol, respectively. Within these pairs of diastereomeric TSs, the direct substituent inversion (associated with the torsional strain in the C* substituents (i.e., Ph vs H)34) differentiates the substrate conformers (R and S) and therefore the stereoisomers. However, this factor, denoted below as the substrate conformation effect, alone cannot control enantioselectivity, as evidenced by each of the “d” and “u” pairs favoring the R and S stereoproducts, respectively (Figure 6). In addition, the fact that the magnitude of the energy difference between the pairs of “d” and “u” isomers is not equal suggests that interactions between the chiral ligand and the d and u conformers of the achiral substrate play a crucial role in determining the enantioselectivity of the reaction. Below, we analyze in detail the ligand−substrate interaction with the aim of identifying the factors affecting the substrate 4348

DOI: 10.1021/acscatal.7b01281 ACS Catal. 2017, 7, 4344−4354

Research Article

ACS Catalysis

(R,d)] and trans-[L(S,u):Sub(S,u)] isomers by 0.8 kcal/mol (in comparison to that between the trans-[L(S,u):Sub(S,d)] and trans-[L(S,u):Sub(R,u)] isomers) can be explained by the formation of a stabilizing interaction between the R1 group of MPAA and Ph substituent of the substrate, which in this specific case partially mitigates the substrate conformation and gearing effects. One should note that repulsive interactions with the opposite effect (i.e., enhancing the substrate conformation and gearing effects) could also form depending on the nature of the R1 group of the ligand and the substituent of the substrate. With ligand 4, where there is no direct interaction between the R1 substituent and PG of amide and, consequently, no gearing effect, the energy differences between the trans[L(S,u):Sub(R,d)], trans-[L(S,u):Sub(S,u)] isomers and the trans-[L(S,u):Sub(R,d)], trans-[L(S,u):Sub(S,u)] isomers is calculated to be almost zero (i.e., only 0.2 and 0.1 kcal/mol, respectively) (Figure 6, diagonal arrows). Interestingly, as shown in Figure 7, without a bulky R1 group, the PG can extend to either side of the Pd coordination plane in order to accommodate the substrate conformation for C−H bond activation: the calculated C−N−Pd−O dihedral angles for the trans-[L(S,u):Sub(R,d)] and trans-[L(S,u):Sub(S,u)] structures are 146 and −147°, respectively, and for the trans-[L(S,u):Sub(S,d)] and trans-[L(S,u):Sub(R,u)] structures are 147 and −147°, respectively (see the Supporting Information). Thus, direct interaction between the R1 group of MPAA and protecting group of amide is another major contributor to the substrate conformational f lexibility and enantioselectivity of the overall reaction via the gearing mechanism. One should mention that in all of the analyses presented up to this point, the chiral center of the ligand is positioned above (i.e., “u”) the coordination plane of the Pd. However, we also analyzed transition state conformers with the chiral center of the ligand positioned below (i.e., “d”) the coordination plane of the Pd (the trans-[L(S,d):Sub(R,d)] structure is schematically shown in Figure 5; for more details see the Supporting Information). As shown in Table 1, all of the ligand “d” isomers are higher in free energy than the corresponding “u” isomers. Furthermore, the lowest energy “d” isomer, trans-[L(S,d):Sub(S,u)], leads to the S stereoisomer because the change in ligand conformation induces a switch in the gearing effect, where C− N−Pd−O = −133° for trans-[L(S,d):Sub(S,u)]. As such, changing the ligand conformation (i.e., “d” → “u”) is generally a potential mechanism for loss of enantioselectivity. However, while the ligand conformation is a general contributing factor to the enantioselectivity, the energies of the alternative ligand conformations for the studied model system are too high (>7.6 kcal/mol) to produce a tangible effect on the calculated ee. Therefore, in order to ensure the desired gearing effect and ef fectively control the face of the Pd catalyst where the C−H bond activation occurs, the ligand conformation must be f ixed. In summary, above we explicitly demonstrated that the conformational flexibility of the substrate and the interaction between the substrate and the bidentately coordinated MPAA ligand with a bulky R1 substituent, both by direct means and via the gearing mechanism, are vital for controlling the substituent inversion transformation and, consequently, the overall enantioselectivity of the reaction. As illustrated in Figure 8, we show here that (a) the bidentately coordinated MPAA ligand slightly enhances the substrate conformational effect, (b) the interaction between the R1 group and the substrate tunes the conformational flexibility of the substrate, and (c) the interaction between the R1 group and the protecting group of

Figure 7. Important geometric features of the Pd-mediated C−H activation transition state structures illustrating the gearing effect of the MPAA ligand. Energies are reported in kcal/mol, distances in Å, and angles in deg.

the C−H activation transition states. Indeed, as shown by previous mechanistic analysis of the MPAA systems, the most favorable geometrical motif for the C−H activation TSs via the IN pathway is for the activated C−H bond of the substrate to be positioned downward to the basic carbonyl oxygen of the PG of the MPAA ligand.33 Steric repulsion between the R1 group and PG of MPAA ligands pushes the PG below the Pd coordination plane and toward the activated C−H bond for better positioning of the internal base to react with the substrate C−H bond in the TS (i.e., chiral relay).33 In order to further examine the importance of the steric interaction between the R1 substituent and PG of amide, we analyzed the geometry and relative energies of the trans-[L(S,u):Sub(R,d)], trans-[L(S,u):Sub(S,u)] and trans-[L(S,u):Sub(S,d)], trans-[L(S,u):Sub(R,u)] transition state isomers for ligands 3 (R1 = i-Bu) and 4 (R1 = H). As consistent with the previous mechanistic analysis, when the ligand 3 has a bulkier substituent, the C−N−Pd−O dihedral angleswhich are characteristic parameters for the gearing effect33are 141 and −174° for trans-[L(S,u):Sub(R,d)] and trans-[L(S,u):Sub(S,u)], respectively. Likewise, these values are 143 and −171° for the trans-[L(S,u):Sub(S,d)] and trans-[L(S,u):Sub(R,u)] isomers, respectively (see the Supporting Information). These geometries clearly show that the “d” isomers adopt the ideal position for the activated ortho C−H bond of the prochiral carbon (C*) of the substrate and the carbonyl of the internal base on opposite faces of the Pd coordination plane. Similar to the results above, the trans-[L(S,u):Sub(S,d)] and trans-[L(S,u):Sub(R,u)] isomers do not have a direct interaction between the R1 group and the Ph substituent of the substrate (Figure 6). Therefore, we can confidently assign the calculated 3.9 kcal/mol energy difference between these transition states to the gearing effect. In contrast, trans[L(S,u):Sub(S,u)] has a direct interaction between these groups (as discussed above and illustrated in Figure 7). Therefore, both the gearing effect and ligand−substrate interactions contribute to the calculated 3.1 kcal/mol energy between the trans[L(S,u):Sub(R,d)] and trans-[L(S,u):Sub(S,u)] isomers. Lowering of the energy difference between the trans-[L(S,u):Sub4349

DOI: 10.1021/acscatal.7b01281 ACS Catal. 2017, 7, 4344−4354

Research Article

ACS Catalysis

through a stable six-membered cyclic TS. Conversely, in the cis isomers, the Pd-coordinated carboxylate group is not competent in this role because it must dissociate from the Pd and forms a highly strained four-membered cyclic TS. Therefore, for the IN mechanism, the nature and positioning of the internal base are more important for the relative energy of the trans and cis isomers than the trans influence. Interestingly, the lowest energy cis transition structure, cis[L(S,u):Sub(S,d)], leads to the S product and the enantioselectivity calculated from only the cis transition state structures slightly favors the S isomer (−22% ee) (Table 1), Thus, the opposite stereoisomeric form of the product would result from chelate inversion (initiated by the trans to cis isomerization). These f indings allow us to conclude that the MPAA ligand controls enantioselectivity of the reaction via the chelate inversion by f ixing the position of the internal base on only one side of the catalyst in the catalytically active intermediate [MPAA]-Pd(II)-[1] (see Figure 9). EX Pathway. Above we identified and analyzed the diastereomeric TSs that contribute to the enantioselectivity of the C−H activation via the IN pathway. In this section, we briefly discuss analogous structures for C−H activation via the EX pathway. As mentioned above, the EX pathway of the reaction is a tremendously complex process and is heavily dependent on the “external” conditions such as base concentration, solvent, counterion, etc.34,45,46 Furthermore, here, a free acetate acts as a base for C−H activation and does not have the same geometric constraints as the base in the IN mechanism. In other words, for the EX mechanism the C−H activation does not have to occur on a particular face or side of the catalyst as dictated by the ligand. We identified and examined eight transition state structures that contribute to the C−H activation via the EX pathway (excluding ligand “d” isomers for simplicity). The relative energies of these TSs are presented in Table 2, and their

Figure 8. Important factors contributing to the substituent inversion transformations.

amide of the MPAA ligand controls the face of the Pd coordination plane where the C−H activation occurs. We also identified equilibration of the ligand “u” and “d” conformations as a potential mechanism for loss of enantioselectivity. Chelate Inversion. Next, we discuss the IN pathway C−H activation transition state structures that contribute to the enantioselectivity of the reaction via the chelate inversion. As defined in Figures 3 and 5, chelate inversion takes into account exchange of the coordination sites of the substrate chelating centers C1 and DG (i.e., isomerization). Above we identified this transformation on the basis of the position of the DG of the substrate trans or cis to the protected amide center (i.e., PG) of MPAA.61 As shown in Table 1, all trans structures are significantly lower in free energy than their cis counterparts (ΔΔG⧧ = 32.5−44.3 kcal/mol), which is consistent with a previous study.44 We initially expected that the relative energy of the trans and cis isomers would be governed by the common inorganic concept of trans influence, where the thermodynamic stability of a coordinated ligand is affected by the ligand with a trans relationship to it. However, the large magnitude of the relative energies of the trans and cis isomers and close examination of the geometries of these isomers also reveal the importance of the geometry and coordination of the internal base: the carbonyl of the N-protecting group (−N(RCO)) and Pdcoordinated carboxylate group (−OCO), respectively, as shown in Figure 9 (see the Supporting Information for structural analysis). In the trans isomers, the carbonyl of the PG is an excellent base to activate the C−H bond of substrate

Table 2. Computed Free Energy for Each Transition State Structure for C−H Activation through the EX Pathway C−H activation transition state structures of the EX pathway, isomer leading to R product

relative free energy ΔΔG⧧(i) (kcal/mol)

trans-[L(S,u):Sub(R,d)] trans-[L(S,u):Sub(R,u)] cis-[L(S,u):Sub(R,u)] cis-[L(S,u):Sub(R,d)] C−H activation transition state structures of the EX pathway, isomer leading to S product

1.1 4.6 5.0 1.9 relative free energy ΔΔG⧧(j) (kcal/mol)

trans-[L(S,u):Sub(S,u)] trans-[L(S,u):Sub(S,d)] cis-[L(S,u):Sub(S,d)] cis-[L(S,u):Sub(S,u)]

1.3 4.1 0.0 5.8

geometrical parameters are given in the Supporting Information. We again used eqs 1 and 2 with the energy values in Table 2 to calculate the enantioselectivity of the reaction. We find that the EX pathway leads to the S isomer (−61.4% ee), while the calculations based on the transition state structures of the IN pathway, as well as experiment,35 favor the R isomer with 97% and 79% ee, respectively. Thus, if the C−H activation proceeds via the EX pathway, it would produce the opposite stereoproduct in comparison to the IN pathway and experiment. These findings indicate that MPAA ligand 3 mediated Pd(II)-

Figure 9. Summary of the factors controlling the chelate inversion transformations. 4350

DOI: 10.1021/acscatal.7b01281 ACS Catal. 2017, 7, 4344−4354

Research Article

ACS Catalysis catalyzed C−H activation of substrate 1 proceeds via the IN mechanism. One should note that the lowest energy EX pathway TSs that control stereoselectivity of the reaction are cis-[L(S,u):Sub(S,d)] and trans-[L(S,u):Sub(R,d)]. This indicates that the trans influence is a major factor for determining the enantioselectivity in the absence of geometrical constraints imposed by the ligand in the TS. Thus, as summarized in Figures 8 and 9, we have defined several channels, through which the MPAA ligand controls the enantioselectivity (such as substituent inversion including substrate conformation, ligand conformation, gearing effects, and direct ligand−substrate interactions, as well as chelate inversion). However, we have not yet identified the source of the overestimation (i.e., 97% calculated vs 79% experimental) of the calculated enantioselectivity by the designed enantioselectivity model. In order to improve the predictive power of the proposed model, other factors that could lead to loss of enantioselectivity have to be explored. Partial Ligand Dissociation. Our extensive analyses show that one such factor could be partial dissociation of the MPAA ligand in the course of the reaction. This expectation is also supported by previous experiments of Yu and co-workers showing that alkylation of 2-benzhydrylpyridines proceeds in the absence of MPAA ligand and gives a racemic mixture.35 This indicates that, if partial ligand dissociation were to occur, the nonselective reaction would still be able to proceed. To obtain further support for this element of the model, we set out to explain a peculiar trend in the experimentally reported enantioselectivity of the sterically different ligands, R1 = t-Bu, i-Bu, i-Pr, Me (PG = Boc was used to maintain consistency with the experimental ee data35): as was reported by Yu and co-workers and shown in Table 3, the bulkiest ligand

Figure 10. Schematic presentation of the proposed partial dissociation mechanism of bidentately coordinated MPAA ligand from the {[κ2(N,O)]-MPAA}-Pd(II)-[DG-SUB] active catalyst.

us to conclude that, indeed, partial dissociation of the MPAA ligand is a potential mechanism for loss of enantioselectivity. In our analysis, we hypothesized that bulkiness at the βposition of the MPAA increases congestion at the metal center and lowers its propensity for bidentate coordination. When R1 = Me is changed to R1 = i-Bu, the increase in both ΔGPG and ee suggests that bulkiness farther from the metal center (i.e., γ position) is advantageous to bidentate coordination of the ligand and also presumably the gearing effect in the C−H activation transition state. Complete Enantioselectivity Model for MPAA Family of Ligands. After elucidating the major mechanisms for enantioselectivity loss, we are positioned to present the complete enantioselectivity model for the MPAA family of ligand mediated Pd(II)-catalyzed C−H functionalization (Figure 11). As mentioned above, the substituent inversion

Table 3. Comparison of Experimental ee Values5 and Calculated Ligand Dissociation Energies for MPAA Ligands with Varying R1 Substituents R1 (PG = Boc)

exptl ee (%)

ΔGPG (kcal/mol)

i-Bu (Leu) Me (Ala) i-Pr t-Bu

90 80 70 52

−7.4 −6.2 −5.2 −4.7

(R1 = t-Bu) gives the lowest ee,35 which contradicts the mechanism presented above and the previously proposed gearing (or chiral relay) mechanism that is based on steric interactions between R1 and PG.33 In order to explain this trend, we calculated the energy difference (ΔGPG) between the [κ2-(NH,O)-MPAA] bidentate and [κ1-(O)-MPAA] monodentate coordination motifs of MPAA ligand from the {[κ2-(N,O)]-MPAA}-Pd(II)-[DGSUB] active catalyst (see Figure 10). We find that the trend in the calculated ΔGPG values correlates well with the reported trend in ee (Table 3). Loss of bidentate coordination of the ligand leads to removal of the chiral center of the ligand from the vicinity of the Pd center and the substrate, which lowers its effectiveness for transferring chiral information. In addition, it was shown experimentally that increasing the temperature significantly lowers the enantioselectivity of the reaction.35 This experimental finding supports the partial ligand dissociation mechanism but is not by itself conclusive. These f indings allow

Figure 11. Complete enantioselectivity model for [MPAA]Pd(II) mediated C−H activation. Representative structures shown for the “internal-base-assisted” (IN) pathway.

controls enantioselectivity by (a) conformational flexibility in the bidentate coordination of substrate at the C−H activation TSs and the ability of the ligand to enhance it, (b) the gearing effect that restricts the C−H bond activation to one face of the Pd catalyst, and (c) potential interactions between the ligand and substrate that may modulate the magnitude of the substrate and gearing effects. Other transformations contributing to the enantioselectivity of this class of reactions are the chelate 4351

DOI: 10.1021/acscatal.7b01281 ACS Catal. 2017, 7, 4344−4354

Research Article

ACS Catalysis

We next consider the chelate inversion transformation on the observed enantioselectivity of the C−H activation mediated by ligands 6 and 7. Since both Pd coordinated CO2 (6) and CONOMe (7) groups would form highly strained fourmembered TSs to achieve C−H activation through the IN pathway, we expect the cis isomers to be much higher in energy than the trans isomers (e.g., the relative energies of the cis isomers are ΔΔG⧧ = 32.5−44.3 kcal/mol with ligand 3). We next consider the pathways for loss of enantioselectivity defined in the complete enantioselectivity model in turn. First, for the role of the ligand conformational flexibility, it is reasonable to assume that ligands 6 and 7 are not conformationally flexible and their “u” conformation will be fixed due to the steric bulkiness of the R1 group (i-Bu) and PG (Boc). Second, for the partial ligand dissociation mechanism, ΔGPG values for 6 and 7 are −6.3 and −14.2 kcal/mol, respectively. The increased stability of bidentate coordination of the MPAHA ligand (7) relative to the MPAA ligand (6) could be playing a role in determining the difference in enantioselectivity, but further assessment after obtaining calculated ee values is required. Therefore, from systematic application of the newly developed enantioselectivity model, we identified the lowest energy transition state structures contributing to the enantioselectivity for C−H activation of 5 as mediated by the MPAA (6) and MPAHA (7) ligands to be trans-[L(S,u):Sub(R)] and trans-[L(S,u):Sub(S)] (see Figure 13). The calculated

inversion, which is controlled by the ligand-anchored base that restricts the C−H bond activation to one side of the Pd catalyst. In addition to these enantioselectivity-enhancing transformations, we also identified two pathways for loss of enantioselectivity: (1) equilibration of the ligand half-chair conformations (i.e., fixing the ligand conformation) and (2) loss of bidentate coordination through partial dissociation of the ligand. Highly selective ligands must thoroughly control all of these factors. Comparison of Enantioselectivity of the MPAA and MPAHA Ligand Mediated Pd(II)-Catalyzed C−H Functionalization. In order to demonstrate the predictive and exploratory power of the newly developed enantioselectivity model, here we applied it to elucidate the factors leading to the increased enantioselectivity upon replacing MPAA by MPAHA in the desymmetrization of 1,1-substituted cyclobutanes through C−H arylation, as shown in Figure 12.9 With the

Figure 12. Pd catalyzed desymmetrization of 1,1-substituted cyclobutanes through C−H arylation with MPAA and MPAHA ligands.

ethyl-substituted substrate 5, experiments give 37% and 79% ee (in favor of the R product) with the Boc-protected L-leucine (6) ligand and its MPAHA analogue (7), respectively. However, it is not immediately clear why the substitution of carboxylic acid (in MPAA) with O-methylhydroxamic acid (in MPAHA) would have such a marked effect on the enantioselectivity. In our analyses, we systematically follow the roadmap designed above and use the previously described mechanistic information for the MPAA ligand mediated Pd(II)catalyzed C−H activation.33,34,43−46 Here we study the C−H activation of substrate 5 (where DG = CO(Ar)N− (Ar = 4CN(C6F4)) in the presence of each of the ligands 6 and 7 (with R1 = i-Bu, R2 = H, A = t-BuOCON−, and B = CO2−, CONOMe−, respectively).9 Since our previous calculations and the enantioselectivity model show that Pd(II) catalyzed C−H activation mediated by the MPAA family of ligands proceeds via the IN pathway (the EX mechanism leads to the incorrect stereochemistry), here we start our analyses by determining a set of relevant diastereomeric TSs for the substituent inversion through the IN pathway. The 1,1-substituted cyclobutane substrates such as 5 do not have a single prochiral center; instead, the prochiral C−H bonds are on opposite sides of the cyclobutane ring and so there are no “u” and “d” isomers or torsional strain analogous to those for 1. Therefore, for this system, we were able to locate only limited conformational isomers based on rotations of the (i) substrate ethyl group, (ii) DG phenyl ring, and (iii) ligand CONOMe group (MPAHA only) that will contribute to the substrate conformational effect. The calculated energies and geometry parameters of the identified TS structures affecting the enantioselectivity via the substrate inversion transformation are presented in the Supporting Information.

Figure 13. Important geometric features of the Pd-mediated IN pathway C−H activation transition state structures of 5 in the presence of 6 (top) and 7 (bottom). Energies are reported in kcal/mol, and distances are in Å.

ee values for 6 and 7, by utilizing these transition states, are found to be 29% and 71%, respectively, showing that the enantioselectivity model does an adequate job in reproducing the experimental ee values of 37% and 79%, respectively. In this case, we do not need to invoke the partial ligand dissociation mechanism because the calculated ee values are not overestimated. The analyses presented above (i.e., ruling out TSs on the basis of ligand conformation, chelate inversion, and partial ligand dissociation) and the accuracy of the calculated ee values suggest that the source of the increase in enantioselectivity upon replacing MPAA by MPAHA can be determined from the substituent inversion transformation (i.e., gearing effect, 4352

DOI: 10.1021/acscatal.7b01281 ACS Catal. 2017, 7, 4344−4354

Research Article

ACS Catalysis

(i) inherent strain in the bidentate coordination of substrate and the ability of the ligand to enhance it, (ii) the gearing effect that restricts the C−H bond activation to one face of the Pd catalyst, (iii) potential interactions between the ligand and substrate, and (iv) chelate inversion which is controlled by the ligand-anchored base that restricts the C−H bond activation to one side of the Pd catalyst. (4) Two pathways for loss of enantioselectivity were identified. They are (a) equilibration of the ligand half-chair conformations (i.e., fixing the ligand conformation) and (b) loss of bidentate coordination through partial dissociation of the ligand. (5) The developed enantioselectivity model was used to explain the observed increase in enantioselectivity for Pd(II) catalyzed asymmetric C−H activation of 1,1-disubstituted cyclobutanes upon replacing Boc-protected L-leucine (MPAA) ligand with Boc-protected α-amino-O-methylhydroxamic acid (MPAHA) ligand. It is shown that the observed trend in enantioselectivity is due to increased interactions between the ligand and substrate upon replacing MPAA and MPAHA: the greater the difference of this interaction in the R and S isomers, the higher the enantioselectivity of the reaction. Overall, this study suggests that there is still potential to optimize the enantioselectivity in C−H activation reactions with MPAA ligands. Therefore, we expect that the strategy presented above will aid the design of novel, highly selective chiral ligands for C−H functionalization.

substrate−ligand interactions, and substrate conformational flexibility). Examination of the transition state structures responsible for these transformations (see Figure 13) suggests that the substrate does not experience a significant gearing effect for either ligand. Indeed, in the trans-[L(S,u):Sub(R)] and trans-[L(S,u):Sub(S)] transition states, the calculated C− N−Pd−O dihedral angles are 148 and 150° for 6 and the analogous C−N−Pd−N dihedral angles are 146 and 150° with 7, respectively. Furthermore, we do not observe any significant interactions between the ligand R1 group and the substrate: the closest distances between the R1 group of 6 and 7 and the substrate ethyl group are 3.42 and 3.24 Å, respectively. After these analyses, we turned to inspection of the substrate conformational flexibility and identification of the source of the increased enantioselectivity upon replacing MPAA by MPAHA. Gratifyingly, we found that an interaction between a C−H bond of the substrate ethyl group and a C−F bond of the DG (called here the H1−F1 distance) correlates with the relative free energy of the diastereomeric TSs (see Figure 13). For 6, where the calculated enantioselectivity is 29%, the H1−F1 distances are 2.54 and 2.68 Å for the R and S isomers, respectively. For 7, where the calculated enantioselectivity is 71%, the H1−F1 distances are increased to 2.59 and 2.84 Å for the R and S isomers, respectively. This interaction itself may be stabilizing for the TS, but it is also indicative of the influence of interactions between the NOMe group of the ligand and the large arene DG on conformation of the substrate. Therefore, a strategy to design ligands with increased enantioselectivity in the C−H activation mediated by MPAHA ligand scaffolds is careful tuning of the interaction between the CONOMe and DG on the periphery of the catalyst. In summary, we have demonstrated the predictive and exploratory power of the newly developed general enantioselectivity model for Pd(II) catalyzed C−H functionalization mediated by the MPAA family of ligands. We show that the observed increase in enantioselectivity of the Pd(II) catalyzed C−H activation of substrate 5 in the presence of each of the ligands 6 and 7 is due to substrate−ligand interaction, which is stronger for MPAHA than for MPAA. We demonstrated that the gearing effect is only a single component of the mechanism for asymmetric induction and that the ligand must employ a multifaceted approach to effectively control the enantioselectivity of a given reaction.

■

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acscatal.7b01281. Additional analysis and geometrical information for computed diastereomeric transition state structures and computed energies in hartree (PDF) Cartesian coordinates for all reported structures (XYZ)

■

AUTHOR INFORMATION

Corresponding Author

*E-mail for D.G.M.: [email protected]. ORCID

Jin-Quan Yu: 0000-0003-3560-5774 Djamaladdin G. Musaev: 0000-0003-1160-6131

■

CONCLUSIONS In summary, (1) A roadmap for designing a more general enantioselectivity model is presented. It includes: (a) elucidation of the detailed mechanism of the reaction, (b) identification of the stereodetermining transition states (TSs) and all geometric transformations that characterize these TSs, (c) elucidation of all specific elements that influence the relative stability of the diastereomeric TSs, and (d) determination of pathways that lead to loss of enantioselectivity. (2) A general and practical model for asymmetric induction from point chiral, bidentate ligands for C−H activation via metal insertion is disclosed. (3) The developed general enantioselectivity model was validated with Pd(II)-catalyzed C−H activation in 2-benzhydrylpyridine (1) mediated by the [(cyclohexyloxy)carbonyl]-Lleucine (MPAA) ligand (3). It is found that (a) the gearing effect alone is not enough to explain enantioselectivity of the reaction and (b) the control elements for enantioselectivity are

Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS This work was supported by the National Science Foundation under the CCI Center for Selective C−H Functionalization (CHE-1205646). We gratefully acknowledge NSF MRI-R2 grant (CHE-0958205 for D.G.M.) and the use of the resources of the Cherry Emerson Center for Scientific Computation. We also thank Mrs. Pritha Verma for reading preliminary drafts and providing helpful comments.

■

REFERENCES

(1) Engle, K. M.; Yu, J. Q. J. Org. Chem. 2013, 78, 8927−8955. (2) Newton, C. G.; Wang, S. G.; Oliveira, C. C.; Cramer, N. Chem. Rev. 2017, DOI: 10.1021/acs.chemrev.6b00692. (3) Davies, H. M. L.; Manning, J. R. Nature 2008, 451, 417−424. (4) Doyle, M. P.; Duffy, R.; Ratnikov, M.; Zhou, L. Chem. Rev. 2010, 110, 704−724. 4353

DOI: 10.1021/acscatal.7b01281 ACS Catal. 2017, 7, 4344−4354

Research Article

ACS Catalysis (5) Giri, R.; Shi, B. F.; Engle, K. M.; Maugel, N.; Yu, J. Q. Chem. Soc. Rev. 2009, 38, 3242−3272. (6) He, J.; Wasa, M.; Chan, K. S. L.; Shao, Q.; Yu, J. Q. Chem. Rev. 2016, DOI: 10.1021/acs.chemrev.6b00622. (7) Engle, K. M. Pure Appl. Chem. 2016, 88, 119−138. (8) Xiao, K. J.; Chu, L.; Chen, G.; Yu, J. Q. J. Am. Chem. Soc. 2016, 138, 7796−7800. (9) Xiao, K. J.; Lin, D. W.; Miura, M.; Zhu, R. Y.; Gong, W.; Wasa, M.; Yu, J. Q. J. Am. Chem. Soc. 2014, 136, 8138−8142. (10) Laforteza, B. N.; Chan, K. S. L.; Yu, J. Q. Angew. Chem., Int. Ed. 2015, 54, 11143−11146. (11) Chan, K. S. L.; Fu, H. Y.; Yu, J. Q. J. Am. Chem. Soc. 2015, 137, 2042−2046. (12) Chan, K. S. L.; Wasa, M.; Chu, L.; Laforteza, B. N.; Miura, M.; Yu, J. Q. Nat. Chem. 2014, 6, 146−150. (13) Wan, L.; Dastbaravardeh, N.; Li, G.; Yu, J. Q. J. Am. Chem. Soc. 2013, 135, 18056−18059. (14) Engle, K. M.; Thuy-Boun, P. S.; Dang, M.; Yu, J. Q. J. Am. Chem. Soc. 2011, 133, 18183−18193. (15) Yang, W.; Ye, S.; Schmidt, Y.; Stamos, D.; Yu, J. Q. Chem. - Eur. J. 2016, 22, 7059−7062. (16) Xiao, K. J.; Chu, L.; Yu, J. Q. Angew. Chem., Int. Ed. 2016, 55, 2856−2860. (17) Dastbaravardeh, N.; Toba, T.; Farmer, M. E.; Yu, J. Q. J. Am. Chem. Soc. 2015, 137, 9877−9884. (18) Li, G.; Leow, D.; Wan, L.; Yu, J. Q. Angew. Chem., Int. Ed. 2013, 52, 1245−1247. (19) Shi, B. F.; Zhang, Y. H.; Lam, J. K.; Wang, D. H.; Yu, J. Q. J. Am. Chem. Soc. 2010, 132, 460−461. (20) Wang, D. H.; Engle, K. M.; Shi, B. F.; Yu, J. Q. Science 2010, 327, 315−319. (21) Zhong, X. M.; Cheng, G. J.; Chen, P.; Zhang, X. H.; Wu, Y. D. Org. Lett. 2016, 18, 5240−5243. (22) Bera, M.; Sahoo, S. K.; Maiti, D. ACS Catal. 2016, 6, 3575− 3579. (23) Patra, T.; Bag, S.; Kancherla, R.; Mondal, A.; Dey, A.; Pimparkar, S.; Agasti, S.; Modak, A.; Maiti, D. Angew. Chem., Int. Ed. 2016, 55, 7751−7755. (24) Li, S. D.; Cai, L.; Ji, H. F.; Yang, L.; Li, G. Nat. Commun. 2016, 7, 10443. (25) Cheng, G. L.; Li, T. J.; Yu, J. Q. J. Am. Chem. Soc. 2015, 137, 10950−10953. (26) Thuy-Boun, P. S.; Villa, G.; Dang, D. V.; Richardson, P.; Su, S.; Yu, J. Q. J. Am. Chem. Soc. 2013, 135, 17508−17513. (27) Wasa, M.; Engle, K. M.; Lin, D. W.; Yoo, E. J.; Yu, J. Q. J. Am. Chem. Soc. 2011, 133, 19598−19601. (28) Li, J.; Warratz, S.; Zell, D.; De Sarkar, S.; Ishikawa, E. E.; Ackermann, L. J. Am. Chem. Soc. 2015, 137, 13894−13901. (29) Chu, L.; Wang, X. C.; Moore, C. E.; Rheingold, A. L.; Yu, J. Q. J. Am. Chem. Soc. 2013, 135, 16344−16347. (30) Chu, L.; Xiao, K. J.; Yu, J. Q. Science 2014, 346, 451−455. (31) Chen, G.; Gong, W.; Zhuang, Z.; Andra, M. S.; Chen, Y. Q.; Hong, X.; Yang, Y. F.; Liu, T.; Houk, K. N.; Yu, J. Q. Science 2016, 353, 1023−1027. (32) Wu, Q. F.; Shen, P. X.; He, J.; Wang, X. B.; Zhang, F.; Shao, Q.; Zhu, R. Y.; Mapelli, C.; Qiao, J. X.; Poss, M. A.; Yu, J. Q. Science 2017, 355, 499−503. (33) Cheng, G. J.; Chen, P.; Sun, T. Y.; Zhang, X. H.; Yu, J. Q.; Wu, Y. D. Chem. - Eur. J. 2015, 21, 11180−11188. (34) Haines, B. E.; Musaev, D. G. ACS Catal. 2015, 5, 830−840. (35) Shi, B. F.; Maugel, N.; Zhang, Y. H.; Yu, J. Q. Angew. Chem., Int. Ed. 2008, 47, 4882−4886. (36) Haines, B. E.; Berry, J. F.; Yu, J. Q.; Musaev, D. G. ACS Catal. 2016, 6, 829−839. (37) Cook, A. K.; Sanford, M. S. J. Am. Chem. Soc. 2015, 137, 3109− 3118. (38) Powers, D. C.; Ritter, T. Acc. Chem. Res. 2012, 45, 840−850. (39) Deprez, N. R.; Sanford, M. S. J. Am. Chem. Soc. 2009, 131, 11234−11241.

(40) Nielsen, M. C.; Lyngvi, E.; Schoenebeck, F. J. Am. Chem. Soc. 2013, 135, 1978−1985. (41) Sanhueza, I. A.; Wagner, A. M.; Sanford, M. S.; Schoenebeck, F. Chem. Sci. 2013, 4, 2767−2775. (42) Eremin, D. B.; Ananikov, V. P. Coord. Chem. Rev. 2017, DOI: 10.1016/j.ccr.2016.12.021. (43) Baxter, R. D.; Sale, D.; Engle, K. M.; Yu, J. Q.; Blackmond, D. G. J. Am. Chem. Soc. 2012, 134, 4600−4606. (44) Cheng, G. J.; Yang, Y. F.; Liu, P.; Chen, P.; Sun, T. Y.; Li, G.; Zhang, X. H.; Houk, K. N.; Yu, J. Q.; Wu, Y. D. J. Am. Chem. Soc. 2014, 136, 894−897. (45) Musaev, D. G.; Figg, T. M.; Kaledin, A. L. Chem. Soc. Rev. 2014, 43, 5009−5031. (46) Musaev, D. G.; Kaledin, A.; Shi, B. F.; Yu, J. Q. J. Am. Chem. Soc. 2012, 134, 1690−1698. (47) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, J. A., Jr.; Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin, K. N.; Staroverov, V. N.; Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam, M. J.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas, Ö .; Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J. Gaussian 09, Revision D.01; Gaussian, Inc., Wallingford, CT, 2009. (48) Grimme, S.; Antony, J.; Ehrlich, S.; Krieg, H. J. Chem. Phys. 2010, 132, 154104−154119. (49) Cances, E.; Mennucci, B.; Tomasi, J. J. Chem. Phys. 1997, 107, 3032−3041. (50) Mennucci, B.; Tomasi, J. J. Chem. Phys. 1997, 106, 5151−5158. (51) Scalmani, G.; Frisch, M. J. J. Chem. Phys. 2010, 132, 114110− 114124. (52) Essafi, S.; Tomasi, S.; Aggarwal, V. K.; Harvey, J. N. J. Org. Chem. 2014, 79, 12148−12158. (53) Plata, R. E.; Singleton, D. A. J. Am. Chem. Soc. 2015, 137, 3811− 3826. (54) Boys, S. F.; Bernardi, F. Mol. Phys. 1970, 19, 553−566. (55) Simon, S.; Duran, M.; Dannenberg, J. J. J. Chem. Phys. 1996, 105, 11024−11031. (56) Hatanaka, M.; Maeda, S.; Morokuma, K. J. Chem. Theory Comput. 2013, 9, 2882−2886. (57) Hansen, E.; Rosales, A. R.; Tutkowski, B.; Norrby, P. O.; Wiest, O. Acc. Chem. Res. 2016, 49, 996−1005. (58) Peng, Q.; Duarte, F.; Paton, R. S. Chem. Soc. Rev. 2016, 45, 6093−6107. (59) We also examined several rotational isomers of the R1 (i-Bu) and PG (CyOCON) groups of the ligand, but to simplify the analysis, we only include the lowest energy isomers to calculate the enantioselectivity. (60) Below we only discuss in detail the energetically most stable trans isomers, but all findings for the substituent inversion based on the trans isomers also apply to the cis isomers. (61) The conclusions from the substituent inversion transformation above were performed for the trans isomers but these are also valid for the cis isomers, and so we are not repeating this analysis here.

4354

DOI: 10.1021/acscatal.7b01281 ACS Catal. 2017, 7, 4344−4354