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Published in final edited form as: J Am Chem Soc. 2021 Mar 22;143(12):4801–4808. doi: 10.1021/jacs.1c01303

Ligand Conformational Flexibility Enables Enantioselective Tertiary C–B Bond Formation in the Phosphonate-Directed Catalytic Asymmetric Alkene Hydroboration

Huiling Shao †,‡, Suman Chakrabarty §,^, Xiaotian Qi †, James M Takacs §,||,*, Peng Liu †,∇,*
PMCID: PMC8324071  NIHMSID: NIHMS1724964  PMID: 33750118

Abstract

Conformationally flexible ancillary ligands have been widely used in transition metal catalysis. However, the benefits of using flexible ligands are often not well understood. We performed DFT and experimental studies to elucidate the mechanisms and the roles of conformationally flexible TADDOL-derived ligands on the reactivity and selectivity in the Rh-catalyzed asymmetric hydroboration (CAHB) of alkenes. DFT calculations and deuterium labeling studies both indicated that the most favorable reaction pathway involves an unusual tertiary C–B bond reductive elimination to give high levels of region- and enantioselectivities. Here, the asymmetric construction of the fully substituted carbon center is promoted by the flexibility of the TADDOL backbone, which leads to two ligand conformations with distinct steric environments in different steps of the catalytic cycle. A pseudo-chair ligand conformation is preferred in the rate-limiting tertiary benzylic C–B reductive elimination. The less hindered steric environment with this conformation allows the benzylic group to bind to the Rh center in an η3 fashion, which stabilizes the C–B reductive elimination transition state. On the other hand, a pseudo-boat ligand conformation is involved in the selectivity-determining alkene migratory insertion step, where the more anisotropic steric environment leads to greater ligand-substrate steric interactions to control the π-facial selectivity. Thus, using a conformationally flexible ligand is beneficial for enhancing both reactivity and enantioselectivity by controlling ligand-substrate interactions in two different elementary steps.

Graphical Abstract

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Introduction

Ligand design is of pivotal importance in developing effective transition metal catalysts for regio- and stereoselective functionalization of alkenes.1 Altering the steric and electronic properties of the ligand and ligand-substrate noncovalent interactions have led to improved reactivity and selectivity in many catalytic processes.2 However, when the rate and selectivity are determined in different elementary steps, rational ligand design becomes more challenging because different steric or electronic properties of the ancillary ligand may be desirable in separate transition states. We surmise that conformationally flexible ligands are privileged in catalytic reactions where reactivity and selectivity are controlled in distinct mechanistic steps (Figure 1a). The different steric and electronic properties of the ligand upon conformational change may allow the catalyst to function effectively in two separate elementary steps in a catalytic cycle.

Figure 1.

Figure 1.

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Conformationally flexible TADDOL-derived phosphonate ligands and their potential roles in promoting the regio- and enantioselective Rh-catalyzed CAHB of aryl alkenes.

The Takacs group has reported a series of catalytic asymmetric hydroboration (CAHB) reactions employing cationic rhodium catalysts derived from the conformationally flexible TADDOL-derived phosphite ligands (e.g., T1).3 Among the diverse alkene substrates used in these studies, the regio- and enantioselective hydroboration of allylic 1,1-disubstituted aryl alkenes with a phosphonate-directing group is arguably the most mechanistically intriguing.4 These reactions feature high levels of branched regioselectivity to construct the sterically congested tertiary C–B bonds (Figure 1b), forming tertiary boronic esters, which bear high significance in asymmetric synthesis.5 Several mechanistic questions remain to be addressed: Are the reactivity, regio-, and enantioselectivity determined in the same step or in different steps? What are the roles of the ancillary ligand? How does the ligand affect the reactivity and selectivity in a synergetic fashion? Understanding the flexibility of the TADDOL-derived phosphite ligands holds the key to these questions. TADDOL ligands possess a flexible seven-membered cyclic backbone, adopting two different conformations (Figure 1c).6 The chair conformer (T1_chair) is more stable as a free ligand, which creates a relatively isotropic steric environment after binding to a metal center.7 On the other hand, in the more distorted boat conformation (T1_boat), one of the Ar groups attached to the backbone (Ar4) points toward the metal center and forms an η2 π-benzene complex. This ligand conformation creates an anisotropic steric environment that blocks one of the quadrants (IV) much more significantly than others. The boat conformer is more commonly observed in X-ray crystal structures of transition metal complexes supported by TADDOL-derivatives.8

Considering the conformational flexibility of TADDOL-derived ligands, a critical question that remains to be addressed is whether the two different conformations can be involved in the same catalytic cycle. If so, this type of ligand scaffold would be especially promising in catalytic reactions where two distinct sets of ligand properties are required to promote more than one elementary step. For example, in one of the possible CAHB reaction pathways leading to the tertiary boronic ester product (Figure 2a), the chiral ligand would need to provide an asymmetric steric environment to control π-facial selectivity in the migratory insertion (TSb) and, in a different step, to enhance the reactivity of the tertiary C–B bond reductive elimination (TSc). The distinct steric environments of the two conformers of T1 can potentially provide the desired ligand-substrate interactions in both steps (Figure 2b). We surmised that the anisotropic steric environment of the T1_boat conformation is beneficial for the π-facial selective migratory insertion that determines the product stereoselectivity. On the other hand, the less sterically hindered T1_chair conformation may allow the tertiary C–B reductive elimination (TSc) to proceed with an η3benzylic complexation,9 which can stabilize the transition state of this sterically encumbered bond formation event.

Figure 2.

Figure 2.

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a) A possible reaction pathway of the CAHB reaction to form branched product. b) Different ligand conformations in the enantioselectivity- and rate-determining steps.

In this work, we carried out density functional theory (DFT) calculations and experimental mechanistic studies to elucidate the most favored reaction mechanism to form tertiary boronic esters in the Rh-catalyzed directed CAHB reaction. We performed a detailed investigation on the effects of the conformationally flexible T1 ligand on the π-facial selectivity in migratory insertion and on reactivity in tertiary C–B bond reductive elimination.

Computational Methods

All geometry optimizations were performed in the gas phase using the dispersion-corrected B3LYP-D310,11 functional with a mixed basis set of SDD12 for Rh and 6–31G(d) for other atoms. Because geometry optimizations of TS12 and TS18 were not successful after multiple attempts, the geometries of these transition states were optimized using B3LYP-D3 with the LANL2DZ13 basis set for Rh and the same 6–31G(d) basis set for other atoms. Single point energies were calculated with the M0614-D3 functional and the def2-TZVP15 basis set. We have also studied the most favorable pathway (Path A) at other levels of theory to compare results from different density functionals (see SI for details). All DFT methods produced consistent predictions. Solvation effects were considered by performing single point energy calculations with the SMD16 model in THF (ε = 7.4).17 All calculations were performed with Gaussian 1618 on Pitt CRC and XSEDE19 supercomputers. Vibrational frequencies were computed to confirm whether the optimized structures are intermediates (no imaginary frequency) or transition states (only one imaginary frequency). The reported Gibbs free energies and enthalpies include zero-point vibrational energies and thermal corrections at 298 K. Because the harmonic-oscillator approximation may lead to spurious results for the computed entropies in molecules with low-frequency vibrational modes, the quasiharmonic approximation from Grimme was applied to compute the thermal corrections with a cut-off frequency of 50 cm−1.20 The quasiharmonic approximations were calculated using GoodVibes.21

Results and discussion

Computational and Experimental Mechanistic Studies

The four possible pathways of the Rh-catalyzed alkene hydroboration to form the two regioisomeric products are summarized in Figure 3.22 All four pathways initiate via the bidentate coordination of the alkene and the phosphonate directing group (DG) to the Rh(I) center, followed by a B–H oxidative addition of HBpin to form a five-coordinated Rh(III) intermediate 7. Subsequent migratory insertion of the alkene may occur via insertion into either the Rh–H (i.e., hydride migration, Paths A and C) or the Rh–B bond (i.e., boryl migration, Paths B and D) of 7 with two different regioisomeric approaches. The branched product is formed via either a 2,1-hydride migration (Path A) or a 1,2-boryl migration (Path B). The resulting 5- and 6-membered rhodacycles (8 and 9) undergo tertiary C–B and primary C–H reductive elimination, respectively, to release the branched CAHB product. On the other hand, the linear CAHB product may be formed via either the 1,2-hydride migration followed by primary C–B reductive elimination (Path C) or the 2,1-boryl migration followed by tertiary C–H reductive elimination (Path D).

Figure 3.

Figure 3.

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Proposed reaction pathways of directed CAHB (DG = directing group, L = (R,R)-T1).

We calculated the reaction energy profile of all four competing pathways of the CAHB with the simplified alkene 1b.23 We have carefully considered the possible geometric isomers and conformers of all intermediates and transition states in these competing pathways (see SI for the higher energy isomers and conformers). For the sake of clarity, only pathways to form the (R)-products, the major enantiomeric products observed in experiment, are presented in Figure 4 (see later sections for discussions on the origins of enantioselectivity). The computed Gibbs free energies and enthalpies are with respect to [LRh(III)(H)(Bpin)]+ (12), a common intermediate in the competing pathways, which is formed via a facile B–H oxidative addition of HBpin (see SI for details).

Figure 4.

Figure 4.

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Reaction energy profile of the Rh-catalyzed hydroboration of alkene 1b. All energies are with respect to the Rh(III) complex 12.26

Among the four possible pathways, Path A is the most kinetically favored route with relatively low barriers in both hydride migration (TS10) and C–B reductive elimination (TS14) steps. The two linear-selective pathways (Paths C and D) both require about 3 kcal/mol higher barriers. This is consistent with the high branched selectivity observed in experiment (Figure 1b). The low kinetic barrier in the 2,1-hydride migration (TS10) is due to two factors. First, this step forms a benzylic C–Rh bond that stabilizes the partial negative charge building up at the benzylic carbon.24 Second, hydride migration is kinetically more favorable than boryl migration, which is consistent with previous computational studies of Rh-catalyzed alkene hydroboration reactions.25 Although the stability of TS10 is well expected, the low barrier to the subsequent C–B bond reductive elimination (TS14) is quite surprising because of the steric encumbrance of the forming tertiary C–B bond. Therefore, we performed deuterium labeling experiments to validate this computationally predicted pathway.

Deuterium labeling experiments were performed on substrate 1a using deuterated pinacolborane (DBpin) under standard CAHB conditions. When the CAHB of 1a using DBpin is quenched before the complete consumption of the starting material, recovery of the “unreacted substrate” reveals partial deuterium incorporation into 1a, yielding a mixture of monodeuterated (E)- and (Z)-3-d-1a (Figure 5a). Deuterium incorporation in the recovered substrate indicates that the initial H/D–B oxidative addition and 2,1-deuteride (or hydride) migration must be reversible; initial deuteration followed by C–C bond rotation and β-hydride elimination would lead to (E)- and (Z)- 3-d-1 (see the SI for details). Complete CAHB of 1a using DBpin affords, after oxidation, three isotopomers of chiral tertiary alcohol (S)-18 (Figure 5b). These include the non-deuterated product (S)-18 (18%), the predominant monodeuterated product 3-d1-(S)-18 (74%), and the dideuterated product 3,3-d2-(S)-18 (8%). Direct CAHB of DBpin to proteo substrate 1, followed by oxidation, accounts for the predominant monodeuterated product 3-d1-(S)-18. However, H/D exchange, coupled with the exchange of bound deuterated substrate for non-deuterated one, explains the formation of non-deuterated product (S)-18, in the CAHB of 1a using DBpin. Similarly, the addition of DBpin to (E)- and (Z)- 3-d-1a leads to the formation of dideuterated product 3,3-d2-(S)-18, after oxidation. These deuterium labeling experiments support Path A (Figure 3), which involves reversible hydride migration prior to C–B bond formation. In contrast, the formation of the C–B bond before C–H bond formation (Path B, Figure 3) would not account for competitive H/D exchange in the substrate or the formation of dideuterated product using DBpin.

Figure 5.

Figure 5.

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Deuterium labeling experiments performed on substrate 1a using DBpin.

Effects of Ligand Conformation on Reactivity and Selectivity

To investigate the role of ligand T1 in promoting the unusual tertiary C–B bond formation, we performed a careful conformational search of the T1 ligand in both hydride migration and C–B reductive elimination steps (Figure 6). The boat conformation of T1, commonly observed in X-ray crystal structures of T1-supported transition metal complexes, is more favorable in the Rh (III) complex 12, the hydride migration transition state TS10, and rhodacycle intermediate 13. On the other hand, the chair conformation is more favorable by 7.4 kcal/mol in the C–B reductive elimination transition state (TS14). These results indicated that the flexible T1 ligand adopts two different conformations in these two key elementary steps. As such, we next investigated why the different conformations are favored and, more importantly, how the ligand conformers affect the enantioselectivity and reactivity in migratory insertion (TS10) and reductive elimination (TS14), respectively.

Figure 6.

Figure 6.

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Preferred conformers of the T1 ligand in the migratory insertion and C–B reductive elimination steps of CAHB of 1b.

The migratory insertion transition states leading to the R- and S-enantiomers of the CAHB product are shown in Figure 7. Transition states with the boat ligand conformation (TS10 and TS10_S) are more stable than those with the chair conformer of the ligand (TS10_R_chair and TS10_S_chair). TS10, which eventually leads to the experimentally observed R enantiomer of the CAHB product, is 4.4 kcal/mol more stable than TS10_S, leading to the S-enantiomer. This activation energy difference is consistent with the high levels of enantioselectivity observed in the experiment.4 On the other hand, when the ligand adopts the chair conformation in migratory insertion, not only are the transition states both less stable, but also closer in energy to each other, leading to diminished π-facial selectivity (Figure 7b, ΔΔG‡ = −0.8 kcal/mol).

Figure 7.

Figure 7.

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π-Facial selectivity in the migratory insertion with boat and chair ligand conformers.29

The impact of ligand conformations on the stabilities of the transition states and the π-facial selectivity can be rationalized by the ligand-substrate interactions as shown in the transition state quadrant diagrams (Figure 7). When the ligand adopts the less distorted, more symmetrical chair conformation, no obvious steric repulsions were observed in either R- or S-selective migratory insertion transition states, because all four quadrants are relatively evenly occupied. The absence of ligand-substrate steric interactions in this conformer leads to an insufficient level of π-facial selectivity. Transition states with boat ligand conformers are stabilized by stronger ligand binding energies (ERh-ligand interaction = −70.9 kcal/mol in TS10) than those with the chair ligand conformer (ERh-ligand interaction = −65.0 kcal/mol in TS10_R_chair). The enhanced interaction energies are mainly due to the noncovalent London dispersion interactions with Ar4 group, which is placed closer to the substrate.11,27,28 The through-space ligand-substrate dispersion in TS10 (Esubstrate-ligand dispersion = −43.1 kcal/mol) is considerably stronger than that in TS10_R_chair (Esubstrate-ligand dispersion = −33.7 kcal/mol). The stabilizing dispersion interactions compensate for the distortion required to achieve the boat conformation of T1, and more importantly, create an anisotropic steric environment for π-facial selectivity control. Both TS10 and TS10_S have square-based pyramidal geometry with the inserting hydride at the apical position, and the Bpin ligand and the phosphonate directing group are trans to each other. The sterically most demanding Bpin ligand is always located in the least occupied quadrant I and the phosphonate directing group is therefore placed in quadrant III. In the R-selective TS10, the small methylidene group is in quadrant IV, where no steric repulsion was observed with the Ar4 group occupying this quadrant. On the other hand, in the S-selective TS10_S, the methylidene group is now located in quadrant II and the Ph substituent on the alkene and the phosphonate directing group are both placed closer to the occupied quadrant IV, causing greater ligand-substrate steric repulsions. This steric effect distorts the Ph substituent on the alkene and leads to repulsions of the Ph substituent with the directing group (2.04 Å) and the methylidene group (2.06 Å).

Next, we investigated the ligand effects in promoting the reactivity of the sterically demanding tertiary C–B bond reductive elimination (TS14, Figure 8). This step takes place from a Rh(III) intermediate (13), which is stabilized by the π-coordination of one of the aryl substituents (Ar4) of the boat conformer of the ligand to the electron-deficient cationic Rh(III) center. The subsequent C–B reductive elimination with this ligand conformation (TS14_boat) requires relatively high activation energy of 22.7 kcal/mol with respect to 13. This transition state is destabilized by repulsions about the forming C–B bond and ligand-substrate steric repulsions with the Bpin and the tertiary benzylic carbon, which are both cis to the ligand T1. On the other hand, when the ligand adopts the less hindered chair conformation, dissociation of the chelating Ar4 group creates an empty coordination site to allow the benzylic group to bind to the Rh in an η3 fashion (13_chair). Although the η3-benzylic Rh complex 13_chair is 7.7 kcal/mol less stable than 13, the subsequent C–B reductive elimination from this isomer is much more favorable (TS14, ΔG‡ = 15.3 kcal/mol with respect to 13). The η3-benzylic coordination weakens Rh–C(benzylic) bond in 13_chair, which is evidenced by the elongated of Rh–C(benzylic) bond (2.21 Å) as compared to that in 13 (2.10 Å). In addition to the pre-activation effect, the η3-benzylic C–B reductive elimination is promoted by the less sterically encumbered five-membered cyclic transition state, as compared to the three-membered cyclic transition state from the η1-benzylic complex 13. Because this η3-benzylic coordination is only possible with the T1_chair conformation, the flexibility of the TADDOL backbone is a crucial factor in promoting the tertiary C–B reductive elimination.

Figure 8.

Figure 8.

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Tertiary C–B reductive elimination pathways with the chair (TS14) and boat (TS14_boat) conformers of the T1 ligand.

Conclusion

The computational and experimental mechanistic investigation on the Rh-catalyzed, phosphonate-directed CAHB reaction of 1,1-disubstituted aryl alkenes indicated that the most favorable reaction mechanism involves 2,1-hydride migration followed by rate-determining tertiary C–B reductive elimination.

The conformational flexibility of the TADDOL-derived ligand is critical to achieve the high reactivity, regio- and enantioselectivity of this transformation. In the enantioselectivity-determining hydride migration step, the ligand adopts a more distorted boat conformation. This is achieved by attractive London dispersion interactions that compensate the energy required to distort the ligand. In the boat ligand conformer, one of the Ar groups on the ligand is placed in close proximity to the metal center to enhance the π-facial selectivity in the hydride migration. The TADDOL-derived ligand also plays a unique role in promoting the reactivity of the tertiary C–B bond reductive elimination. A lower kinetic barrier in this sterically demanding bond formation step is desirable to out-compete pathways leading to the linear regioisomer. In the C–B bond reductive elimination transition state, the ligand adopts the less hindered chair conformation and facilitates the formation of an η3 benzylic complex. The η3 benzylic coordination weakens the benzylic Rh–C bond and promotes the tertiary C–B bond reductive elimination by alleviating the steric repulsions via a less crowded five-membered cyclic transition state. The mechanistic understanding revealed in this work demonstrated the importance of conformational flexibility and non-covalent interactions with TADDOL-derived phosphite-based ligands in designing asymmetric catalytic processes.

Supplementary Material

Supporting Information
Cartesian Coordinates

ACKNOWLEDGMENT

We acknowledge financial support from the NIH (R35GM128779, R01GM100101). DFT calculations were performed using supercomputer resources at the Center for Research Computing at the University of Pittsburgh, the Extreme Science and Engineering Discovery Environment (XSEDE), the Texas Advanced Computing Center (TACC), and the Minnesota Supercomputing Institute (MSI). We sincerely thank Dr. Martha D. Morton (UNL Chemistry instrumentation director) for assistance with multinuclear NMR experiments, and Nebraska Center for Mass Spectrometry (NCMS) for isotope analysis via High-Resolution Mass Spectrometry (HRMS).

Footnotes

The Supporting Information is available free of charge at http://pubs.acs.org.

Additional discussions of computational results, Cartesian coordinates, and energies of all computed structures (PDF)

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Associated Data

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Supplementary Materials

Supporting Information
NIHMS1724964-supplement-Supporting_Information.pdf (4.8MB, pdf)
Cartesian Coordinates
NIHMS1724964-supplement-Cartesian_Coordinates.pdf (1.1MB, pdf)

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