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. Author manuscript; available in PMC: 2022 Jun 30.
Published in final edited form as: J Am Chem Soc. 2021 Jun 21;143(25):9585–9594. doi: 10.1021/jacs.1c03992

A Case Study in Catalyst Generality: Simultaneous, Highly-Enanti-oselective Brønsted- and Lewis-Acid Mechanisms in Hydrogen-Bond-Donor Catalyzed Oxetane Openings

Daniel A Strassfeld 1, Russell F Algera 1, Zachary K Wickens 1, Eric N Jacobsen 1
PMCID: PMC8564877  NIHMSID: NIHMS1747425  PMID: 34152759

Abstract

Generality in asymmetric catalysis can be manifested in dramatic and valuable ways, such as high enantioselectivity across a wide assortment of substrates in a given reaction (broad substrate scope), or as applicability of a given chiral framework across a variety of mechanistically distinct reactions (privileged catalysts). Reactions and catalysts that display such generality hold special utility, because they can be applied broadly and sometimes even predictably in new applications. Despite the great value of such systems, the factors that underlie generality are not well understood. Here we report a detailed investigation of an asymmetric hydrogen-bond-donor catalyzed oxetane opening with TMSBr that is shown to possess unexpected mechanistic generality. Careful analysis of the role of adventitious protic impurities revealed the participation of competing pathways involving addition of either TMSBr or HBr in the enantiodetermining, ring-opening event. The optimal catalyst induces high enantioselectivity in both pathways, thereby achieving precise stereocontrol in fundamentally different mechanisms under the same conditions and with the same chiral framework. The basis for that generality is analyzed using a combination of experimental and computational methods, which indicate that proximally localized catalyst components cooperatively stabilize and precisely orient dipolar enantiodetermining transition states in both pathways. Generality across different mechanisms is rarely considered in catalyst discovery efforts, but we suggest that it may play a role in the identification of so-called privileged catalysts.

Graphical Abstract

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INTRODUCTION

The birth of the field of modern asymmetric catalysis can be tied to the discovery made over a half century ago that chiral small molecules can promote reactions of interest with very high, “enzyme-like” levels of enantioselectivity.1 The practical and fundamental implications of such transformations became well-appreciated, fueling intensive research in the ensuing years that has produced a continuously expanding list of enantioselective catalytic organic reactions. A small subset of those reactions has proven to be remarkably accommodating of changes in substrate structure, enabling their broad application (e.g., Figure 1A).2 The development of such reactions remains a challenging and rarely met objective, but from a conceptual standpoint their generality can be rationalized fairly simply: in such processes, the chiral catalyst exerts precise geometric control on the prochiral reaction site, but selectivity does not rely on interactions with the variable substituents on the substrate.3 Another, quite different type of generality emerged unexpectedly throughout the development of the field of asymmetric catalysis, wherein certain chiral scaffolds have proven to be effective at inducing high levels of enantioselectivity across a wide range of mechanistically unrelated reactions (e.g., Figure 1B).4 These so-called privileged chiral catalysts or frameworks have proven enormously enabling for the discovery of new enantioselective, catalytic processes. Indeed, there are examples of extraordinarily useful new transformations5 and new modes of catalysis6 or new classes of reactions7 that were developed relying on chiral frameworks that were identified previously for different purposes. Analysis of privileged chiral scaffolds identified to date has provided some insight into their common features, most notably structural rigidity achieved through chelation of a ligand to a reactive metal center and C2 symmetry to create stereochemically equivalent reactive sites.4a,8 However, these characteristics are also common to many chiral frameworks that are not broadly applicable in asymmetric catalysis, and are absent from several of the privileged frameworks that have been identified. Unfortunately, fuller elucidation of the structural features that underlie the privileged nature of such catalysts is confounded by the dificulty of studying systems that differ not only in mechanism, but also in nearly every other key reaction parameter (e.g. identity of substrates, additives and other reagents, solvents, temperature, etc.)

Figure 1.

Figure 1.

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A) The Sharpless epoxidation represents a prototypical example of substrate generality in an asymmetric catalytic reaction. Even though the reaction scope is limited to allylic alcohols, it tolerates extensive variation in the alkenyl substituents, thereby enabling its broad application in synthesis. B) The cinchona alkaloids are prototypical privileged chiral frameworks for asymmetric catalysis. Such systems are capable of inducing high enantioselectivity across a range of mechanistically unrelated reactions (refs. 4a, 10). C) The addition of TMSBr to oxetanes catalyzed by chiral squaramide 1a can proceed simultaneously by fundamentally different, yet highly enantioselective Lewis- and Brønsted-acid mechanisms.

Over the past decade, thioureas, ureas, and squaramides with the general structure 1 (Figure 1C) have emerged as a privileged class of organocatalysts capable of inducing high levels of enantioselectivity in transformations proceeding through a variety of mechanisms, including ion-pairing catalysis involving nucleophilic addition to sp2 and sp3-hybridized cationic electrophiles, concerted nucleophilic substitution reactions, enantioseletive proton transfers, and direct activation of electrophiles via LUMO lowering.9 As part of this body of work, we recently reported that squaramide 1a catalyzes the highly enantioselective opening of a structurally diverse set of 3-substituted oxetanes with TMSBr (Figure 2A).9l Here we report a detailed mechanistic investigation revealing that the reaction proceeds through competing Brønsted-acid and Lewis-acid mechanisms (Figure 1D), both of which contribute significantly to product formation under typical reaction conditions. The participation of multiple, highly enantioselective reaction channels leading to the same enantiomer of product in a single transformation provided an opportunity to study the catalyst features that underlie mechanistic generality without the confounding variables that typically hinder such comparisons. Analysis of the mechanism of stereoinduction in the competing pathways revealed the engagement of co-localized, reinforcing secondary interactions that cooperatively stabilize the transition state leading to the major enantiomer of product in both mechanisms. We advance that the presence of such reinforcing sites may be a common feature in privileged catalysts that operate via attractive non-covalent interactions.

Figure 2.

Figure 2.

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A) Chiral squaramide-catalyzed addition of TMSBr to oxetanes (ref 9l). B) Original mechanistic hypothesis for the oxetane ring-opening reaction. C) Catalyst 1a reproducibly affords highly enantioenriched products, but reactions catalyzed by other, structurally-similar H-bond donors fail to provide reproducible levels of enantioselectivity.

RESULTS AND DISCUSSION

Earlier studies from our lab established that chiral squaramide derivatives capable of dual H-bond-donor interactions promote heterolysis of silyl triflates via anion abstraction and activate the resulting electrophile-triflate ion-pairs through anion-binding catalysis.9e,9h,11 We initially reasoned that a similar Lewis-acid-activation mechanism could be operative in the oxetane-opening with TMSBr (Figure 2B).9l However, observations made during the development of that reaction provided compelling evidence that this proposal was at best incomplete. In particular, the rate of the reaction was found to decrease quite dramatically with increasing scale (Figure S4), an effect that could not be ascribed simply to changes in mass transport given the homogeneous nature of the reaction mixtures. Additionally, an important difference was observed between the behavior of optimal catalyst 1a and other chiral squaramide dertivatives in the same family: the reaction catalyzed by 1a afforded product 3 with reproducibly high levels of enantioselectivity (e.e.), whereas suboptimal catalysts such as 1b-1d afforded product with highly variable e.e.’s (Figure 2C).

The hydrolysis of Lewis acids or metal salts to yield Brønsted acids as potentially active reagents is well documented in racemic chemistry,12,13 and has also been considered in the context of asymmetric catalysis.14-18 One example directly relevant to the system analyzed here can be found in the asymmetric chiral phosphoric acid-catalyzed oxetane opening developed by Sun and co-workers, which relies on the controlled hydrolysis of a silyl chloride to generate HCl.19 We considered whether HBr generated by the hydrolysis of TMSBr could account for the observed variability in reaction performance. Using the enantioselective conversion of 3-phenyloxetane (2) to trimethylsilyl-protected bromohydrin 3 as a model reaction, we tested this hypothesis by controlled generation of HBr through the addition of i-PrOH as a proton source. High levels of enantioselectivity were maintained upon introduction of catalytic loadings of HBr low concentrations of i-PrOH (up to 20 mol% with 2 mol% catalyst 1a),20 but reaction rates were increased by over an order of magnitude compared to the reaction carried out with the rigorous exclusion of HBr (Figure 3A/Table S1).21,22

Figure 3.

Figure 3.

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A) Effect of HBr (generated by the photochemical reaction of Br2 in toluene) on reaction rate (black dots) and enantioselectivity (red dots) ([1a] = 0.002 M, [2]0 = 0.1 M, [TMSBr]0 = 0.2 M). The reaction with [HBr]=0 was conducted in the presence of TMSCHN2 as a base (see text). Reaction rates were determined via in situ FTIR monitoring using a ReactIR (see General Procedure for ReactIR experiments in the Supporting Information). B) Enantioselective addition of HBr to 2 promoted by 1a.

The positive rate dependence on added proton source suggested that HBr—rather than TMSBr—could be the active reagent in the oxetane-opening reaction. Consistent with that hypothesis, stoichiometric quantities of squaramide 1a were shown to mediate the reaction of oxetane 2 with HBr23 to afford bromohydrin 4 in 98% e.e. (Figure 3B). In addition, 1a proved effective as a catalyst (2 mol% loading) for the opening of 2 with HCl, affording the chlorohydrin analogue of 4 in 92% e.e. at 4 °C (Figure S42).24 Taken together, these results implicate a mechanism involving co-catalysis by 1a and HBr wherein enantioselective oxetane ring opening by HBr is followed by silylation of bromohydrin 4 by TMSBr to afford 3 and regenerate HBr.

The identification of the HBr co-catalyed mechanism accounts for the variation of rate with reaction scale given that adventious water is expected to be present in greater ratios in small-scale reactions. However, it does not provide a satisfactory explanation for the irreproducible enantioselectivies observed with sub-optimal catalysts (Figure 2C). Provided temperature is well controlled, variability in enantioselectivity is indicative of competing reaction mechanisms. The obvious candidate for such a competing pathway would be the racemic, uncatalyzed ring-opening addition of HBr to the oxetane. However, under the relevant, low [HBr] reaction conditions the uncatalyzed reaction is very slow and cannot account for the observed variability in e.e. (Figure S48). Thus, the data are most consistent with competing catalytic mechanisms being involved, and we hypothesized that the originally proposed silyl-Lewis-acid mechanism might also be operative. To test this possiblity, we sought to identify a base that could completely suppress the HBr pathway without interfering with the activity of the HBD catalyst. The additive had to be selected carefully, because salts introduced either as anionic bases or as the conjugate acids of neutral bases are generally strong inhibitors of anion-binding pathways due to competitive association to the hydrogen-bond-donor active site.25 Gratifyingly, trimethylsilyldiazomethane, which has previously been demonstrated to function as a non-interfering base in hydrogen-bond-donor catalyzed cation-olefin cyclizations,9p was found to neutralize HBr rapidly and quantiatively without any deleterious effect on the squaramide catalyst under the standard reaction conditions (Figure 4A). In the presence of TMSCHN2 the reaction of oxetane 2 with TMSBr was observed to proceed at appreciable rates but more slowly and with similar levels of enantioselectivity relative to the HBr-co-catalyzed reaction (Figure 4B). A distinct TMSBr-mediated reaction must therefore be operative alongside the HBr co-catalyzed pathway, with both pathways contributing to the formation of product 3 with high levels of enantioenrichment in the presence of catalyst 1a. Moreover, this phenomenon is not limited to model oxetane 2. A survey of the 1a-catalyzed opening of 2 and 6 additional oxetanes selected to represent the diversity of the originally-reported reaction scope (3-aryl, 3-alkyl, 3-heteratomic, and 3,3-disubstituted oxetanes) revealed an average difference of <5% e.e. between the two mechanisms.26

Figure 4.

Figure 4.

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A) Reaction time-course measured using in situ FTIR monitoring. Upon the addition of TMSCHN2 (green - 4000 s) the rate of consumption of 2 (black) decreases but continues at a lowered rate. Upon the addition of HCl (8000 s), the TMSCHN2 is rapidly consumed. Following complete consumption of TMSCHN2 the rate of oxetane consumption increases. B) The reaction run in the presence of TMSCHN2 proceeds with high enantioselectivity, and at a rate that is slower but still competitive with the HBr co-catalyzed pathway.

The observations outlined above and extensive ground state and kinetic analyses conducted in the presence (Figures S9, S12-S24) and absence (Figures S36-S41) of added TMSCHN2 are consistent with a scenario in which the two catalytic mechanisms outlined in Figure 6A are operating simultaneously in the 1a-catalyzed ring-opening addition of TMSBr to oxetanes. In the Lewis-acid pathway, which is the only pathway operative in the presence of TMSCHN2, kinetic analysis revealed a 1st-order dependence on the concentrations of squaramide 1a, oxetane 2, and TMSBr, which is consistent with rate-determining oxetane ring-opening via bromide addition.27 In the absence of TMSCHN2, both the Lewis-acid and Brønsted-acid pathways are operative. Under these conditions and at steady-state,28 a 1st-order dependence on TMSBr, a 1st-order dependence on [1a], and a positive order in [2] with a non-zero y-intercept are observed. The positive order in [2] can be ascribed to contribution of the Lewis-acid pathway, while the non-zero intercept reflects a 0th-order dependence on [2] for the Brønsted-acid pathway. Based on the combination of this 0th-order dependence and positive orders for TMSBr, 1a, and HBr concentrations (Figure 3B), the alcohol silylation step that affords 3 with regeneration of the squaramide-HBr complex29 is proposed to be rate-determining in the Brønsted acid pathway. A primary kinetic isotope effect was observed in a one-pot competition experiment between unlabeled and 2,4-13C2-2 in the presence of TMSCHN2 (see Supporting Information for details). Taken together with the previously-reported9l primary KIE observed in an analogous experiment in the absence of TMSCHN2, we conclude that bromide delivery is enantiodetermining for both mechanisms.

Figure 6.

Figure 6.

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A) Proposed reaction mechanisms consisting of competing Brønsted and Lewis acid pathways. B) Computed lowest energy major (R) and minor (S) transition states for the Brønsted acid pathway (ΔΔE‡ = 2.6 kcal/mol). C) Computed lowest energy major (R) and minor (S) transition states for the Lewis acid pathway (ΔΔE‡ = 2.5 kcal/mol). Transition states were optimized at SMD (Et2O) – B97D/def2-SVP. The electronic energies were corrected by single-point refinement at SMD (Et2O) – B97D3/def2-TZVP

The recognition that two distinct catalytic pathways are operative in the enantioselective oxetane-opening reaction catalyzed by 1a enabled the successful development of a scalable protocol. In the case of substrate 2, the challenge of reproducibily achieving optimal rates without compromising enantioselectivity can be met by maximizing the HBr-co-catalyzed pathway without participation of the racemic uncatalyzed reaction that intervenes at high [HBr] (Figure 3A).30 The conversion of 1 g of 2 to 3 was thus achieved in 89% yield and 97% e.e. using 1 mol% of 1a and 6.5 mol% added H2O (Figure 5). Catalyst 1a was re-isolated from the reaction in 90% yield and displayed undiminished activity and enantioselectivity in a subsequent reaction (Figure S6).

Figure 5.

Figure 5.

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The addition of trace water allows for high reactivity and enantioselectivity with reduced loadings of squaramide 1a in a gram-scale reaction of oxetane 2 with TMSBr.

The enantiodetermining ring-opening transition states for the Brønsted and Lewis acid pathways were modeled computationally in order to assess the catalyst features responsible for high stereocontrol in both pathways (complete computational details and computational references are provided in the SI). In the Brønsted acid co-catalyzed pathway, TSprotic-R and TSprotic-S were identified as the lowest energy transition states leading to the major and minor product enantiomers (Figure 6B). TSsilyl-R and TSsilyl-S were the lowest energy enantiomeric transition states located for the Lewis acid pathway (Figure 6C). The computational model was validated by comparison of predicted and measured enantioselectivity for a series of chiral catalysts with varied aryl pyrrolidine fragments (Figure 7). Although the computational models overestimate the magnitude of the enantioselectivities, the model reproduces the trends in the data (R2 = 0.92) including the inversion in the sense of enantioinduction for the Lewis acid pathway with catalyst 1g.31

Figure 7.

Figure 7.

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Predicted ΔΔE‡ vs experimental ΔΔG‡ for the Lewis acid pathways for catalysts 1a-1g and the Brønsted acid pathway for catalyst 1a. See Figure 8 for catalyst structures, Table S11 for tabulated data, and Figures S7 and S34 for experimental details.

Qualitative analysis of TSsilyl-R and TSsilyl-S reveals significant similarity between the two transition structures: in both, the forming C-Br and breaking C-O bonds are positioned almost identically relative to the catalyst, and the two transition structures can be overlaid to a significant degree (Figure S64). However, the developing α-silyloxy methylene group, which is predicted to bear much of the positive electrostatic potential (Figure S63), is positioned differently in the two structures. In TSsilyl-R this methylene group points toward the amide and the 9-phenanthryl substituent of the catalyst, in an ideal orientation for stabilizing cation-π and cation-dipole interactions.32 In contrast, the methylene is oriented away from the arene and amide in TSsilyl-S, resulting in attenuated stabilizing interactions relative to those in the major pathway. In the Brønsted acid pathway, additional conformational constraint is provided by a hydrogen-bonding interaction between the protonated oxetane and the amide. This interaction can be readily accommodated in the transition state leading to the major enantiomer, such that the position and conformation of the oxetane as it undergoes ring opening in the catalyst active site is similar in TSsilyl-R and TSprotic-R, allowing the cation-π interaction to be maintained. However, in TSprotic-S maintaining the anchoring H-bond requires disrupting the rest of the network of interactions between the catalyst and substrate, including the proposed cation-π interaction.

The computationally-derived hypothesis that cation-π interactions play a critical role in enantioinduction was tested experimentally by evaluating the extended series of aryl-pyrrolidinosquaramides 1a–1g in the reactions of 2 with TMSBr and HBr (Figure 8A). Consistent with the models, selectivity for the R-enantiomer in both pathways was observed to correlate with the ability of the aryl substituent to engage in a cation-π interaction, with electron-deficient or less polarizable arenes affording decreased selectivity for the R-enantiomer.32,33 Furthermore, all catalysts induced higher selectivity for the R-product in the HBr co-catalyzed reactions of 2 relative to the Lewis acid pathway, consistent with the proposed reinforcing hydrogen-bonding interaction in the Brønsted acid mechanism. The results in Figure 8A and 8B also provide a clear explanation for why enantioselectivities under the original screening conditions were more consistent with catalyst 1a than with less selective catalysts (Figure 2C): squaramide 1a is the only catalyst tested that is highly enantioselective for both the Brønsted acid and the Lewis acid pathways, with every other catalyst showing large differences in e.e. or even favoring alternate enantiomers of product for the two pathways. Under the original reaction conditions employed for the catalyst optimization studies—in which the concentration of HBr was not controlled carefully—both pathways are kinetically competent and therefore contribute significantly to product formation. As the optimization experiments were designed, only a catalyst that is highly enantioselective for both mechanisms can generate product in consistently high e.e.’s.

Figure 8.

Figure 8.

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A) Enantioselectivity for the reaction of 2 catalyzed by 1a-1g determined both for the HBr-promoted reaction and with TMSBr in the presence of TMSCHN2 (average of two runs, see Figures S7 and S33 for details). B) Graphical representation of relative enantioselectivities of the Brønsted and Lewis acid mechanisms for reactions of 2 catalyzed by 1a-1g.

The fact that catalyst 1a induces high enantioselectivity across different mechanisms in the oxetane ring-opening is intriguing and touches on the broader phenomenon of privileged chiral catalysts.4a The electrostatic potential map of 1a (Figure 9A) reveals an electron-rich pocket (in red) defined by the amide and 9-phenanthryl substituent positioned adjacent to the H-bond donor motif (in blue). While the protonated and silylated transition states in the oxetane opening present dramatically different steric features, they possess dipoles that display charge similarly within the catalyst active site (Figures 9B and 9C). The precise nature (i.e. cation-π, charge-dipole, H-bonding) and relative strengths of the stabilizing interactions differ between the two pathways (see Figures S68 and S69 for a detailed analysis), but through cooperation between the arene and the amide the catalyst can stabilize positive charge in the major transition states to a significant degree from both the protonated and the silylated oxetane. The presence of multiple, reinforcing sites for secondary interactions may be a general feature of privileged scaffolds that facilitates their selective stabilization or destabilization of a diverse range of transition states.

Figure 9.

Figure 9.

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A) Electrostatic potential map of catalyst 1a using the geometry from TSsilyl-R (scale from −0.03 to +0.03). B) Electrostatic potential map of the Lewis acid transition state using the geometry from TSsilyl-R (scale from −0.06 to +0.06). C) Electrostatic potential map of the Brønsted acid transition state using the geometry from TSprotic-R (scale from −0.06 to +0.08). All ESPs were computed at SMD (Et2O) – B97-D3/Def2-TZVP and plotted with a density isovalue of 0.0004.

CONCLUSION

Given the intrinsic challenges associated with attaining stereocontrol with small-molecule catalysts, observation of high enantioselectivity might in principle be taken as evidence of a “well behaved” transformation that proceeds through a single mechanistic pathway (or an ensemble of closely related transition states), rather than through distinct, completing mechanisms.34 The unexpected discovery detailed here that the squaramide-catalyzed ring opening of oxetanes with TMSBr proceeds through competing Lewis- and Brønsted-acid reaction pathways adds to a growing body of evidence35 that high enantioselectivity can be manifested despite the availability of distinct mechanistic pathways to the same product. It is noteworthy that the participation of competing mechanisms remained unrecognized throughout the course of our reaction development and scope studies, only becoming apparent upon scale-up efforts and subsequent careful mechanistic analysis. Thus, in optimizing enantioselectivity in the oxetane opening, we unwittingly optimized a catalyst for generality across two different mechanisms. Caution should of course be exercised before attempting to draw general conclusions from a specific case study such as this one, but given that detailed mechanistic investigations of new asymmetric reactions rarely if ever precede catalyst optimization efforts, such scenarios could be more common than is generally appreciated. Given the truism that “you get what you screen for,”36 this study raises the intriguing question of whether the discovery of remarkably general chiral catalysts over the past several decades might be tied in part to the optimization of reactions that are not always “well behaved.”

Supplementary Material

Supporting Information

ACKNOWLEDGMENT

Financial support for this work was provided by the NIH through GM043214 and a postdoctoral fellowship to Z.K.W.

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  • (23).Generated as an anhydrous solution in toluene through the photochemical reaction of Br2 and toluene, see General Procedure C in the Supporting Information for additional information.
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  • (27).Alternatively, rate-determining TMSBr heterolysis with nucleophilic assistance by the oxetane cannot be ruled out on the basis of the kinetic data. However, this proposal would require that silyl transfer between 2-Me3Si+ and 2 is rapid relative to reversion to the starting materials (i.e. TMSBr heterolysis is irreverisble) and that the former process is rapid relative to bromide delivery to 2-Me3Si+ to account for the 13C KIE observed for the silyl pathway in one-pot competition experiments.
  • (28).At the start of the reaction the resting state is the squaramide-HBr complex. In the first turnover, the HBr is consumed and the steady-state regime depicted in Figure 6A is established. As consumption of 2 approaches completion, the concentration of 2 will be much lower than that of TMSBr, because TMSBr is used in excess. Consequently, the resting state can shift back to the catalyst-HBr complex at high conversion. For a detailed discussion see Figure S10.
  • (29).Studies of catalyst 1a, the 1a-HBr complex, the corresponding urea and thiourea, and their HBr complexes using in-situ infrared spectroscopy support the depicted structure wherein the the t-leucine amide is protonated by HBr. This is also supported by computational modelling and comparisons between predicted and measured IR spectra, which indicate a bridging interaction between the protonated amide and the squaramide-bound bromide. See Figures S15-S17 for a detailed discussion.
  • (30).With substrates for which the Lewis-acid pathway affords higher levels of enantioselectivity than the Brønsted-acid pathway (see Note. 26 and Figures S8 and S35), reactions run on larger scale are expected to provide product in higher levels of e.e. than reactions run on screening scale and the addition of a proton source is anticipated to be detrimental to enantioselectivity. The slow rate of the uncatalyzed reaction at low [HBr] (Figure S48) allows an alternate tactic for accelerating large-scale reactions of substrates where the Lewis-acid pathway is more enantioselective: rather than adding a proton source, the concentration of the reaction can be increased. This approach was successfully implemented for the gram-scale synthesis of pretomanid detailed in ref. 9l. Prior to scaling up reactions of interest, the relative enantioselectivities of the two pathways for any substrate of interest should first be determined by comparing the results obtained on screening scale using General Procedure C and General Procedure D (detailed in the Supporting Information).
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Supporting Information
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