Deciphering the Origin of Enantioselectivity on the Cis

Article Cite This: J. Org. Chem. 2019, 84, 7664−7673

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Deciphering the Origin of Enantioselectivity on the CisCyclopropanation of Styrene with Enantiopure Di-chloro,Di-gold(I)SEGPHOS Carbenoids Generated from Propargylic Esters Pedro Villar, Adán B. González-Pérez,* and Angel R. de Lera* Departamento de Química Orgánica, Facultade de Química and Centro de Investigacións Biomédicas (CINBIO), Universidade de Vigo, Lagoas-Marcosende, 36310 Vigo, Spain Downloaded via UNIV AUTONOMA DE COAHUILA on July 17, 2019 at 10:48:27 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.

S Supporting Information *

ABSTRACT: The stereoselective synthesis of cis-disubstituted cyclopropanes by the Au(I)/PPh3-catalyzed cycloaddition of propargylic esters and styrene has been studied using density functional theory calculations. The computed mechanistic scheme involves the rate-limiting 1,2-rearrangement of the propargylic ester with the π-coordinated gold complex, followed by the (2 + 1)-cheletropic reaction of styrene with the alkenyl−Au(I) carbene intermediate to afford the cis-disubstituted cyclopropane derivative in a high cis/ trans diastereomeric ratio. With a (R)-di-chloro,di-goldDTBM-SEGPHOS complex as the catalyst, computations are consistent with a rate-determining (2 + 1)-cheletropic reaction, in which facial discrimination is proposed to result from a combination of subtle steric and electronic effects in the SiRe facial approach transition structure, which favor the formation of the cis-cyclopropane diastereomer of 1R,2S absolute configuration, as experimentally observed.

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internal alkynes.21−25 Allenes can undergo further activation by the gold catalyst, which promotes their subsequent reactivity.26−31 Computational studies support the carbenoid nature of the Au−C bond in different intermediates and more comprehensively as a continuum between carbene and carbocation depending upon the substituents and ligands attached to the metal center.12−14,19,20 The bond length between gold and the carbene carbon was found to decrease with stronger σdonating metal ligands (NHC ligands, phosphines...).6,10−14 The reluctance of these ligands to undergo back-donation appears to enhance that of the π-nature from the gold center to the carbon atoms, thus increasing its carbene character.11,32 Being considered as singlet Fischer-type species, gold carbenes can therefore be engaged in the concerted cyclopropanation of olefins as they fulfill the orbital symmetry requirements for 1,2-cheletropic reactions. Compared to other transition metals, the gold-catalyzed cyclopropanation of olefins takes place under milder reaction conditions and exhibits greater selectivity.6,33,34 Gold carbenes are commonly generated from the corresponding propargylic ester precursors by selective 1,2-acyloxy migrations. In general, Au(I)complexed propargylic esters A (Scheme 1) derived from terminal alkynes (R1 = H) or electronically biased internal alkynes (R1 = EWG) favor the 1,2-rearrangement (a 5-exo-dig

INTRODUCTION Homogeneous Au(I) and Au(III) catalysts are components of modern synthetic protocols because they promote a wide variety of transformations that significantly increase molecular complexity and structural diversity with high efficiency.1,2 The alkynophilic character of gold complexes allow the π-acid activation of unsaturated precursors to generate carbenoid intermediates at one of the two unsaturated carbon positions and promote the addition of appropriate nucleophiles,3 thus becoming an atom-economical methodology to create a variety of cyclic and acyclic scaffolds depending upon the overall molecular structure of the reactants.1,2,4−9 Recent developments have exploited these catalysts as components of useful methodologies6,10−15 for the total synthesis of complex skeletons, including those of a wide variety of natural products.2,9 In the case of propargylic esters, the ability of the carboxyl group, in competition with other nucleophiles, to undergo intramolecular 1,2- or 1,3-rearrangements from the so-formed alkyne−gold complexes to any of the two alkyne carbons can afford intermediates that exhibit a diverse and rich reactivity.16−18 1,2-Ester migration, which is favored for terminal alkynes, affords vinyl gold carbenoids, that is, gold carbenes or gold-stabilized carbocations,12−14,19,20 as the key reactive intermediates,13,14 which can then be trapped by a variety of nucleophiles.21−24 The alternative 1,3-rearrangement of the Au(I)-activated propargylic esters to generate allene structures becomes a competing or even the leading path for © 2019 American Chemical Society

Received: February 15, 2019 Published: May 16, 2019 7664

DOI: 10.1021/acs.joc.9b00250 J. Org. Chem. 2019, 84, 7664−7673

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The Journal of Organic Chemistry

enantioselective cyclopropanation of olefins using chiral enantiopure Au(I) ligands described above (Scheme 2B).21 Prior computational studies by Soriano and Marco-Contelles on the nonenantioselective version (Scheme 2A) of the Au(I)promoted stereoselective cyclopropanation of olefins starting from propargylic acetates21 were carried out at the B3LYP/631G(d)_LANL2DZ level of theory using the PCM model to account for solvent effects and LANL2DZ as ECP for gold.23 A three-step mechanism was proposed (Scheme 3): a stepwise 1,2-migration of the acetate group in the π-activated Au(I) complex 1 to afford the cyclic intermediate 2, followed by its ring-opening to a vinyl carbenoid intermediate 3,21 and the rate-limiting-concerted cyclopropanation of styrene. Following alternative motions, transition states leading to the E- or Zvinyl carbene isomers of gold carbenoids were localized.23 The computational analysis of the competing approaches of these intermediates to the olefin to afford the 1,2-disubstituted cyclopropanes indicated a transition-state stabilization for the favored cis diastereomer, resulting from a combination of πstacking interactions and diminished steric effects. The computational results were found to be fully consistent with the experimental cis/trans isomer ratio of the cyclopropanation products (only the cis diastereomer is shown in Scheme 3).21 The enantioselective version of the cyclopropanation reaction using chiral enantiopure ligands is the focus of the present study. The following objectives were addressed: (a) to evaluate the effect of advanced computational methodology (choice of functional, inclusion of dispersion,41−44 solvent,45 the use of triphenylphosphine as the metal ligand46) and determine their relevance for the description of the enantioselective version of the reaction (Scheme 3);21 (b) to get a deeper insight into the role of π−π interactions in these diastereoselective cyclopropanation reactions;15,47−51 and (c) to compile these effects and thus provide a rationale for the enantiocontrol on the cyclopropanation reaction when (R)DTBM-SEGPHOS was used as the Au(I) ligand.21 Further insights into the effect that small structural changes on the substrates and the enantiopure Au(I) ligands could have on the stereoselectivity of the cyclopropanation reaction were also expected. Given the complex structure of the (R)-DTBM-SEGPHOS(AuCl)2 catalyst experimentally used, we decided to first address the process with the reactants used in the nonenantioselective version having a pivalate ester, two methyl substituents, and PPh3 as the Au(I) ligand (system 1A, Scheme 3; system 1B was also studied to allow comparison with the

Scheme 1. Alternative Migrations of Au(I)-Activated Propargylic Esters Depending upon Their Substitution Pattern

cyclization) and provide vinylcarbenoid intermediates. The rationale for the selective 1,2- versus 1,3-acyloxy migration (the latter, a 6-exo-dig cyclization)18,23,35,36 has recently been proposed based on computational studies at the B3LYP-D3/ 6-311++G(d,p)_SDD/IEF-PCM//B3LYP/6-31+G(d,p) _SDD/IEF-PCM level of theory on model systems with PMe3 as the Au(I) ligand.37 The electronic effects of the terminal substituents and therefore the contribution of the alternative resonance structures were considered to be the main factors affecting the selectivity of this rearrangement.37 Toste et al. first reported the stereoselective intermolecular cyclopropanation of olefins with propargylic esters catalyzed by cationic gold complexes (Scheme 2), a process presumably taking place through the intermediacy of a carbene species (B in Scheme 1) generated upon 1,2-migration of the ester to the Au(I)−activated alkyne.21 The reaction showed substratedependent cis/trans diastereoselectivities when PPh3 was used as the Au(I) ligand, and the major cis-configured cyclopropanation products were proposed to arise from the most favored syn approach transition state for carbene transfer to the olefin. Steric interactions between the Au(I)−ligand complex and the phenyl group were considered to be the most relevant structural factors that are responsible for the high diastereoselectivity of the cyclopropanation reaction. Moreover, enantioenriched substrates were found to afford racemates, which are consistent with the intermediacy of vinylAu(I)−carbene species (B in Scheme 1). Interestingly, when the propargylic pivalate reactant was treated with styrene in the presence of catalytic amounts of enantiopure (R)-DTBMSEGPHOS(AuCl)2 and AgSbF6, the disubstituted cyclopropane was obtained in a highly diastereo- and enantioselective manner (Scheme 2B).21 As a follow-up of our previously reported studies on the computational analysis of diastereo- and enantioselective Au(I)-catalyzed reactions,38−40 we became interested in the

Scheme 2. Highly Diastereoselective (A) and Enantioselective (B) Au(I)-Catalyzed Olefin Cyclopropanation of Styrene and Propargylic Esters Reported by Toste et al.21

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Scheme 3. Mechanistic Proposal for the Gold(I)-Catalyzed Rearrangement of Propargylic Esters to Au(I)−Carbene 3 Followed by Cyclopropanation of Styrene 5 To Afford Cis-Disubstituted Cyclopropane Diastereomer 423

more simplified system already reported;23 see Supporting Information). All calculations were carried out using the Gaussian 09 program package.52 The general method employed was density functional theory with ωB97XD as the functional.53 For geometry optimizations, a mixed basis set (def2svpp for nonmetals and SDD for Au) was used. Single-point energy calculations were carried out with a triple ζ basis for the nonmetal atoms (6-311+G*). The SMD model was used to include the solvent (the experimentally used nitromethane) in the single-point calculations (a comparison between solvent and gas-phase optimizations is shown in the Supporting Information).45 The nature of the different saddle points was determined by the number of imaginary frequencies and these structures were connected via IRC. When this level of theory was employed for the most complex system (with (R)-DTBMSEGPHOS as the ligand), several problems were found. The structural convergence using the mixed basis set def2svpp was poor for this large system and we were forced to switch to a 631+G* basis set for geometry optimizations. The NCI plot program54 has been used to estimate the steric effects on the structures combined with the VMD visualization program.55 The aromaticity of transition structures was evaluated by the isotropic NICS value.56,57

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RESULTS AND DISCUSSION The most stable conformations of the starting alkyne−gold complexes 1 were found to depend upon the substitution pattern of the propargylic esters (1A and 1B, see Supporting Information). Structure 1A, shown in Figure 1, features the ester in a syn conformation with respect to the gold complex, which is likely due to the destabilizing steric interactions between the methyl groups observed in the alternative anticonformation. The most salient structural feature of 1A is the deformation of the alkyne bond angle (161°; shown in blue color in Figure 1), which is likely due to the greater steric interactions that are now present in the gold complex. The coordination of the cationic gold complex to the alkyne takes

Figure 1. Optimized geometries of structures 1A, TS1A, 2A, TS2A, 3A, and TS3A−ReSi computed at the ωB97XD/def2svpp_SDD level of theory. The most relevant structural parameters (bond distances in angstroms and bond angles in degrees) are shown.

place with bond distances that can be considered as those of typical π−M interactions.37 7666


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The Journal of Organic Chemistry The [1,2]-ester migration that generates the Au-carbene 3A, which has already been described as a stepwise process,58 can proceed in an anti or syn manner, and eventually enter into competition with the alternative [1,3]-rearrangement. After locating the transition states for these transformations, the computed activation energy values allowed to discard the syn[1,2]- and both [1,3]-migrations because of their higher energy values relative to that of the most favored anti-[1,2]rearrangement (see Supporting Information). The transition state for the anti-[1,2]-rearrangement was found to be very late, as judged from the Au−C2 bond distance of ca. 2.67 Å, which is 0.41 Å longer than in the reactant complex (1A) and from the C2−O bond-forming distance of 2.22 Å (Figure 1). The structure of the so-generated intermediate 2A indicates the presence of a dioxolane carbocation with a local planar geometry. The [1,2]-ester rearrangement was further corroborated by APT charge analysis (1.58e partial charges for 2A) and a Au−C1 bond length of σ character (2.05 Å).12−14,19,20 The five-membered cyclic alkenyldioxolane cation is nonsymmetrical, with a C2−O bond length that is 0.04 Å longer than that of C3−O (Figure 1). Intermediate 2A evolves through ring opening of the alternative dioxolane bond via transition-state TS2A (Figure 1), in which the C3−O bond distance increases to ca. 2.22 Å. A combined carbonyl-group rotation and shortening of the C2−C3 bond length favor the formation of the CC bond, whereas the Au−C1 distance remains virtually unaltered despite its formal evolution to a carbene intermediate. On the other hand, the C1−C2 bond length of 1.35 Å indicates its partial double bond character. These structural data suggest that the major electron rearrangements of acyl migration take place after reaching the transition state. The so-formed Au(I)−carbene species (3A) shows similar lengths (ca. 1.39 Å) for the C1−C2 and C2−C3 bonds, whereas the carbene nature of the Au−C1 bond is noted in its bond length of 2.03 Å (Figure 1). The structural data suggest that the charge is being delocalized along the Au−C1−C2−C3 fragment.19 Au(I)−carbene species 3A then reacts with the styrene double bond to form a 1,2-disubstituted cyclopropane. The cyclopropanation can occur through four alternative facial approaches via transition states leading to the corresponding cis and trans cyclopropane diastereoisomers. Because the two pairs of enantiomers are formed through isoenergetic transition states, only two facial approaches of styrene and the gold(I)− carbene intermediate, termed ReRe and ReSi, are required in order to justify the diastereoselectivity of the cyclopropanation reaction. The transition states for the two alternative facial approaches (ReRe and ReSi of the Au(I) carbene and styrene, respectively) were characterized as corresponding to formal (2 + 1)-cheletropic reactions. Intermediate 3A, a Fischer-type gold carbene structure (namely, a singlet species with the electron pair in a C sp2 orbital, and an empty p orbital) reacts with the olefin in an asynchronous manner. The most advanced bond reorganization involves the interaction of the styrene highest occupied molecular orbital with the carbene empty p orbital and is then followed by trapping of the styrene π* orbital with the carbene C sp2 orbital (Figure 2). The characterization of this step as a pericyclic (2 + 1)-cheletropic reaction was supported by the NICS(0) values (ca. −30 ppm in all these TSs, as measured at the center of the ring). The strong diamagnetic shielding of the ring critical points is a

Figure 2. Representation of the orbitals involved in the (2 + 1)cheletropic cyclopropanation transition state TS3B (see Supporting Information). A, the carbene C sp2 orbital; B, the carbene p orbital; C, the olefin π orbital; and D, the olefin π* antibonding orbital.

magnetic indication of aromaticity of these transition structures.57,59 Fourteen transition states, which differ in the geometry of the facial approach and the relative spatial orientation of the reactants, were characterized for the cyclopropanation reaction. Eight of these are predicted to afford the trans-disubstituted cyclopropanes whereas six would lead to the cis diastereomer. Application of the Curtin−Hammett principle60 to this cyclopropanation reaction via different transition states predicts the formation of a ca. 72:28 cis/trans diastereomeric ratio of cyclopropane diastereomers (see Supporting Information). A 86:14 cis/trans cyclopropane product ratio was experimentally obtained starting from the same reactants.21 The relative stabilization of these alternative approaches could reasonably justify the cis/trans ratio of the cyclopropane derivatives experimentally observed.21 A weak interaction between the olefin that is vicinal to the Au(I)−carbene and the aryl group of the styrene (which shows a distance between the centroids of the aryl ring and the olefin of 3.69 Å61) was noted in the most stable transition structure TS3A−ReSi (Figure 1). This interaction might be relevant for the analysis of the structural effects that promote the enantioselective cyclopropanation reaction21 because they could rationally be considered varying depending upon the competing facial approaches between the reactants. The cyclopropanation transition state was noted to be highly asynchronous because both forming C−C bonds exhibit substantially different bond lengths (2.58 and 2.17 Å for C1’−C1 and C2’−C1, respectively, Figure 1). On the other hand, the transition state TS3A−ReSi retains the carbene nature of precursor 3A (AuC1 bond length of 2.06 Å). In the ul (ReSi or SiRe) facial approaches leading to the ciscyclopropane diastereomers (Figure 3), an extra π−π interaction of the aryl rings of the reactant and the Au(I)/ phosphine group was noted because styrene was found to be placed facing the gold carbenoid.41 In the alternative lk approaches (ReRe or SiSi), the phenyl groups of the styrene and the phosphine were found to be closer (Figure 3) and, as a consequence, the reacting styrene underwent an upward displacement relative to the carbene, leading to a reduced 7667


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complex 1A, which indicates the exergonic nature of the Au(I)−carbene intermediate formation. The stabilization of the positive charge by the tert-butyl substituent could explain the relatively low activation energy value required for the formation of this species. The ring opening of 2A through transition-state TS2A can be considered, both in the gas phase and in solution, as the rate-limiting step. In this transition structure, the ring opening of the dioxolane with the formation of a carbene and a C2−C3 double bond is concurrently taking place. These electronic motions and bond formation/breaking events appear to occur in a concerted manner, which could justify the relatively high-energy barriers computed. The formation of the gold−carbene species 3A from precursor 2A, both in the gas phase and in the presence of the solvent, is an endergonic step. As previously mentioned, different transition states for the cyclopropanation reaction of styrene and 3A were located. Their activation energies vary between 15.6 and 21.5 kcal/mol, which indicates the relevance of small geometrical changes of the approaching reactants in the transition-state energy values. The final Au(I)-bound product 4A is then easily formed because the whole process is highly exergonic (Figure 4). The enantioselective version of the Au-catalyzed cyclopropanation of propargylic esters reported by Toste et al. (system C)21 relies on the use of enantiopure (R)-DTBMSEGPHOS with connected o-benzodioxole rings bearing two 3,5-di-tert-butyl-4-methoxyphenylphosphine ligands for each of the two gold metal centers (Figure 5). The complex structure contains an improper second-order rotational axis. In order to successfully perform computations on the enantioselective cyclopropanation reaction experimentally carried out using the enantiopure (R)-DTBM-SEGPHOS ligand21 with such a large amount of electrons, the level of theory for the geometry optimizations had to be lowered to ωB97XD/6-31G*_SDD. The use of double ζ Ahlrichs basis sets (def2svpp) originated unsurmountable troubles to reach structural convergence. Therefore, we first optimized the structure of the enantiopure digold complex of axial aR absolute configuration,21 which is shown in Figure 5. This

Figure 3. Schematic representation (with additional steric interactions in red color) of the facial approaches of styrene and Au(I)−carbene, termed ReSi or ReRe (or enantiomorphic SiRe or SiSi) together with the optimized structure of their corresponding transition states (TS3A−ReSi and TS3A−ReRe). The bond lengths for the forming bonds (in Å) and the angles (in degrees) are also shown.

orbital overlapping. The angles corresponding to the Au−C1− center of the olefin fragment in the lower-energy transition structures of these alternative facial approaches, namely 96.4° for ReSi (TS3A−ReSi) and 114.3° for ReRe (TS3A−ReRe), are in agreement with the aforementioned skeletal distortions (Figure 3). The computed free energy difference between these transition states is 1.0 kcal/mol. In order to better understand the kinetics and thermodynamics of the cyclopropanation of styrene by the alkyne−gold complex, the minimum energy path (MEP) for the process is shown in Figure 4. In order to allow for a side-by-side comparison of all saddle points, the styrene reactant has been included as a spectator in the rearrangement steps prior to the cyclopropanation, even if not shown in some steps of Figure 4. A first endergonic step leads to the formation of the reacting complex 1A, which is 5.1 kcal/mol less stable than the noninteracting styrene and Au(I)/PPh3 reactants. The first step of the propargylic ester 1,2-rearrangement of 1A leading to the five-membered dioxolane cation ring-formation takes place through TS2A with a barrier of ca. 12.1 kcal/mol, and therefore it can be predicted to easily occur at ambient temperature. The relative energy of intermediate 2A was computed to be 1.4 kcal/mol, ca. 3.7 kcal/mol lower than that of reacting

Figure 4. MEP for the cyclopropanation of styrene with Au(I)-activated reactant 1A to afford the Au(I)-coordinated cis-disubstituted cyclopropane 4A. The styrene structure was included in all calculations, but it is not shown for clarity, with the exception of the energy reference. Free energy values (in kcal/mol) refer to the sum of all reacting species (the alkyne bound to the gold complex on one hand and styrene on the other) computed separately in the presence of solvent at the ωB97XD/def2svpp_SDD//ωB97XD/6-311+G*_SDD (SMD, solvent = nitromethane) level of theory. 7668


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carbene Re face, the reacting alternative Si face was found to be blocked by one of the 3,5-di-tert-butyl-4-methoxyphenyl substituents of the Au(I)−ligand complex. In contrast, compared to the carbene Si face, the reactivity of the alternative Re counterpart was noted to be hindered by the benzodioxole group as shown in Figure 6.

Figure 5. Optimized structure of the (R)-DTBM-SEGPHOS(AuCl)2 complex at the ωB97XD/6-31G*_SDD level of theory.

structure was optimized using the first X-ray structure of the complex (R)-MeO-DTBM-biphep as the starting point.62,63 The structure obtained is in agreement with the X-ray structure of DTBM-SEGPHOS(AuBF4)2 and the DFT-optimized structure of (R)-DTBM-SEGPHOSAu2BF4Cl reported by Abadie et al.64 As relevant structural features, the Au−P and Au−Cl bond lengths (2.30 and 2.34 Å, respectively) are longer than those usually found in typical phosphines (i.e., 0.07 and 0.06 Å longer, respectively, than in the chloro-(triphenylphosphine)-Au(I) complex).65 The additional π−π interaction established between the biaryl group and Au(I), which reduces the extra π-retrodonation and decreases the strength of these bonds, might explain the contrasting values for bond distances in these complexes relative to structural analogues with simple phosphines. We hypothesized that the key transition state (TS3) likely responsible for the enantioselectivity of the process should be the one corresponding to the cyclopropanation step. Because a chiral Au(I)−ligand is present in the catalytic species, the transition structures for the alternative facial approaches to styrene are no longer enantiotopic but diastereotopic. Thus, the transition structure leading to the experimentally formed enantiomer of the cyclopropane product should correspond to the most favorable of those diastereofacial approaches of enantiopure gold carbene and styrene. As anticipated, the structural and energetic features corresponding to the steps of the formation of the precursor intermediates and their connecting transition structures are similar to those already discussed for the nonenantioselective version and will not be described in detail (see Supporting Information). Instead, we focused our attention on the cyclopropanation step and analyzed the lowest energy structures for each of the possible transition states corresponding to the ReRe, ReSi, SiSi, and SiRe diastereo- and enantioselective facial combinations of the Au(I)L*-carbene intermediate and styrene. From the comparative structural analysis of these transition states, we expected to be able to identify the structural and electronic factors acting on the cyclopropanation step that may allow to justify the experimental findings.41,49,50 Dispersion interactions between Au(I)−L* and the benzodioxole moieties of the catalyst were noticed in all optimized structures containing the (R)-DTBM-SEGPHOS(AuCl)2 complexes. The orientation toward styrene of the carbene when is part of the SEGPHOS-bis-metallic complex was expected to differ depending upon the selected reacting face, and therefore diastereomeric faces of these metal carbene species should exhibit different destabilizations because of the ensuing steric interactions. For example, when compared to the

Figure 6. Optimized geometries at the ωB97XD/6-31G*_SDD level of theory for carbenoid species 3C−Re (left) and 3C−Si (right), with the styrene structure being hidden for clarification.

It was anticipated that the greater steric hindrance observed when the bulky 3,5-di-tert-butyl-4-methoxyphenyl substituent blocks the approach of the reacting fragments along the Si face would result in extra destabilization and therefore in higher relative energy values for this approach. However, the lowest energy complex in which the styrene approaches the Re face of the carbene is 1.4 kcal/mol more stable than the diastereomeric complex along the Si face. The planarity of the carbene appears to diminish the expected extra destabilizing steric effects. On the other hand, analysis of the geometrical distortions of the reacting species in TS3 further supports the hypothesis that steric effects likewise play a crucial role in the diastereo- and enantioselective cyclopropanation of styrene. Several structures corresponding to the alternative facial approaches were characterized and only those of lower energy values for each series were taken into consideration as relevant for the discussion. For structural comparison, these transition structures are shown in Figure 7. In agreement with the experimental results, upon bond formation the lowest energy TS3C−SiRe leads to the experimentally observed major cyclopropane enantiomer. Subtle differences in steric and electronic features between TS3C−SiRe and alternative diastereomeric transition structures should allow to justify the diastereo-(and enantio)selectivity of the cyclopropanation step. First, TS3C−ReRe and TS3C−ReSi are destabilized because of additional steric interactions, in particular those induced by the bulky pivalate substituent, which hinders the adoption of a fully extended anticonformation by the reacting metal center. Second, contrasting orientations of the styrene phenyl group were noted in TS3C−SiRe and the closest energy diastereomeric transition structure TS3C−SiSi, which might rationalize their energy difference. Third, in TS3C−SiRe, the aromatic ring faces the double bond following a downside displacement (relative to the orientation depicted in Figure 7), which induces a weak although stabilizing π−π interaction among the unsaturated fragments (the distance between the phenyl ring and the center of the double bond is 3.72 Å).61 As mentioned above, the orientation of the styrene olefin in system A does 7669


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Figure 7. Optimized structures computed at the ωB97XD/6-31G*_SDD level of theory for the different cyclopropanation transition structures TS3C, including all facial approaches. The bond lengths for the forming bond (in Å), the angles (in degrees), and their relative energies (in kcal/ mol) relative to the lowest-energy transition state (TS3C−SiRe) are also shown.

Figure 8. MEP for the stereoselective cyclopropanation of experimental system C (L = (R)-DTBM-SEGPHOS). Except for the energy reference, the styrene structure was included in all calculations but not represented for clarity. Free energy values (in kcal/mol) refer to the sum of reacting species (Alkyne bound to the gold complex on one hand and styrene on the other) computed separately in the presence of solvent at the ωB97XD/ 6-31G*_SDD//ωB97XD/6-311+G*_SDD (SMD, solvent = nitromethane) level of theory.

reacting complex 1C is, in this case, 16.4 kcal/mol more stable than the noninteracting reactants, and thus the energy profile substantially differs from that of system A. The activation barriers for the 1,2-migration step, namely, TS1C and TS2C, are very low (2.0 and 1.9 kcal/mol, respectively). Taking as reference the reacting complex, the migration step on system C is kinetically disfavored relative to system A (18.4 and 18.3 kcal/mol, respectively, for C and 7.0 and 11.2 kcal/mol, respectively, for A). In addition, in contrast to system A, barriers for both migrations are virtually the same (only 0.1 kcal/mol difference). As discussed above for system A, the carbene species 3C is also the highest-energy reaction

not allow such a compact overlap being established between the reaction centers in the ReRe and SiSi relative to those of the alternative ReSi and SiRe facial approaches, as shown by the corresponding carbene−olefin bond angles (Figure 7). Figure 8 depicts the MEP computed for the enantioselective cis-cyclopropanation reaction of styrene using the catalytic conditions of model system C. The relative energies of the computed species differ substantially from those of model system A at the same level of theory, which should primarily be due to the greater relevance of steric interactions in these bulkier complexes. The main overall structures and geometric parameters do not significantly vary within the series. The 7670



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intermediate, but its relative energy is now 1.4 kcal/mol. The energy barrier for the cyclopropanation step is 4.3 kcal/mol and therefore 20.7 kcal/mol relative to 1C. In contrast to system A, the rearrangement to the Au(I)−alkylidene dioxolane complex 3C is not the rate-limiting step because it shows lower energy values than the cyclopropanation step via TS3. Therefore, the (R)-DTBM-SEGPHOS ligand not only plays the role of a chiral envelope for the stereoselective cyclopropanation step but also determines this to be the ratelimiting step of the catalytic cycle. Our structural and energetic analysis indicates that the main structural factors playing a key role in the enantioselectivity of the reaction appear to be the bulkiness of the propargylic ester reactant and the substituent pattern on the aryl groups of the Au(I)-enantiopure bis-phosphine ligand, in accordance with the experimental results.21 Using alternative chiral phosphine ligands such as BINAP or xylyl-BINAP of the same absolute configuration, the enantioselectivity was found to be lower than in the case of (R)-DTBM-SEGPHOS. Moreover, the experimental enantiomeric ratio was found to increase with the substitution pattern of the aryl phosphine substituents (22% ee for BINAP and 44% ee for o-xylyl-BINAP). On the other hand, when less bulky propargylic esters were used as reactants, a lower experimental enantioselectivity was observed (60% ee for acetate and 68% ee for benzoate). Furthermore, the substitution on the styrene appears to play a minor role in the enantioselectivity of the cyclopropanation, which is consistent with the outward location of the styrene aryl group in order to minimize destabilization by steric interactions. Lastly, it could be hypothesized that the use of bulkier propargylic esters and Au(I)/phosphine ligands with alternative substitution patterns on the aryl group (such as 4tert-butyl-3,5-dimethylbenzene) could improve the enantioselectivity of the intermolecular cyclopropanation reaction.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.9b00250.

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Computational methods, comparison of systems A and B, comparison with the results reported by Soriano and Marco-Contelles, solvent effects in optimization, alternative ester migrations, stepwise cyclopropanation, and XYZ coordinates and thermodynamic parameters (PDF)

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected] (A.B.G.-P.). *E-mail: [email protected]. Fax: +34 986 811940. Phone: +34 986 812316 (A.R.d.L.). ORCID

Pedro Villar: 0000-0002-5729-1182 Angel R. de Lera: 0000-0001-6896-9078 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank the Spanish MINECO (SAF2016-77620-RFEDER), Xunta de Galicia (Consolidación GRC ED431C 2017/61 from DXPCTSUG; ED-431G/02-FEDER “Unha maneira de facer Europa” to CINBIO, a Galician research center 2016−2019). The authors thank CESGA for generous allocation of computational resources.

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DEDICATION To Dr. Elena Soriano, In Memoriam.

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CONCLUSIONS Our density functional theory calculations have confirmed the reported mechanistic features of the Au(I)-catalyzed cycloaddition of propargylic esters and styrene to afford stereoselectively the cis-cyclopropane products and in addition provided a rationale for the enantioselective reaction using the (R)-di-chloro,di-gold-SEGPHOS complex. For the catalytic diastereoselective version of the process using PPh3 as the Au(I) ligand, a sequence of steps involving the coordination of the propargylic ester π-system to the gold complex, followed by the rate-limiting 1,2-rearrangement and the alkenyl−Au(I) carbene intermediate-promoted cyclopropanation to afford the cis-cyclopropane derivative with high cis/trans diastereomeric ratio, was computed. When the (R)-di-chloro,di-gold-DTBMSEGPHOS complex is used as the catalyst, facial discrimination was found to result from a combination of steric and electronic factors on the rate-determining cyclopropanation transition state. The relative orientations of both reactants and the structural arrangements converge in a more favorable direction to lower the transition-state energy for the formation of the 1R,2S cyclopropane diastereomer, thus justifying the major enantiomer experimentally obtained in the cyclopropanation reaction. Our computational insights into the structural features of the rate-determining diastereo- and enantioselective version of the reaction allowed us to suggest possible modifications on the Au(I)−enantiopure ligand aimed to improve the formation of cis-cyclopropane products with higher enantioselectivity in this reaction.

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