Self-Assembled Tetrahedral Hosts as Supramolecular Catalysts

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Article Cite This: Acc. Chem. Res. 2018, 51, 2447−2455

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Self-Assembled Tetrahedral Hosts as Supramolecular Catalysts Published as part of the Accounts of Chemical Research special issue “Supramolecular Chemistry in Confined Space and Organized Assemblies”. Cynthia M. Hong, Robert G. Bergman,* Kenneth N. Raymond,* and F. Dean Toste*

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Chemical Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, United States Department of Chemistry, University of California, Berkeley, California 94720, United States CONSPECTUS: The field of supramolecular chemistry has its foundation in molecular recognition and selective binding of guest molecules, often with remarkably strong binding affinities. The field evolved to leverage these favorable interactions between the host and its guest to catalyze simple, often biomimetic transformations. Drawing inspiration from these early studies, self-assembled supramolecular hosts continue to capture a significant amount of interest toward their development as catalysts for increasingly complex transformations. Nature often relies on microenvironments, derived from complex tertiary structures and a well-defined active site, to promote reactions with remarkable rate acceleration, substrate specificity, and product selectivity. Similarly, supramolecular chemists have become increasingly intrigued by the prospect that self-assembly of molecular components might generate defined and spatially segregated microenvironments that can catalyze complex transformations. Among the growing palette of supramolecular catalysts, an anionic, water-soluble, tetrahedral metal−ligand coordination host has found a range of applications in catalysis and beyond. Early work focused on characterizing and understanding this host and its various host−guest phenomena, which paved the path for exploiting these features to selectively promote desirable chemistries, including cyclizations, rearrangements, and bimolecular reactions. Although this early work matured into achievements of catalysis with dramatic rate accelerations as well as enantioenrichment, the afforded products were typically identical to those produced by background reactions that occurred outside of the host microenvironment. This Account describes our recent developments in the application of these anionic tetrahedral hosts as catalysts for organic and organometallic transformation. Inspiration from natural systems and unmet synthetic challenges led to supramolecular catalysis displaying unique divergences in reactivity to give products that are inaccessible from bulk solution. Additionally, these tetrahedral assemblies have been shown to catalyze a diverse range of transformations with notable rate acceleration over the uncatalyzed background reaction. The pursuit of complexity beyond supramolecular catalysis has since led to the integration of these tetrahedral catalysts in tandem with natural enzymes, as well as their application to dual catalysis to realize challenging synthetic reactions. Variation in the structure, including size and charge, of these tetrahedral catalysts has enabled recent studies that provide insights into connections between specific structural features of these hosts and their reactivities. These mechanistic studies reveal that the solvent exclusion properties, hydrophobic effects, confinement effects and electrostatic effects play important roles in the observed catalysis. Moreover, these features may be leveraged for the design of supramolecular catalysis beyond those described in this Account. Finally, the supramolecular chemistry detailed in this Account has presented the opportunity to emulate some of the mechanisms nature engages to achieve catalysis; however, this relationship need not be entirely unidirectional, as the examples describe herein can stand as simplified model systems for unravelling more complex biological processes.

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INTRODUCTION The canonical reaction within a flask limits synthetic chemists’ control over reactivity to macroscopic parameters: temperature, solvent, reagent concentrations, and the exclusion of circumstantially deleterious components (e.g., water, oxygen, and light). This necessitates that all individual mechanistic steps and reaction intermediates must be amendable to the chosen © 2018 American Chemical Society

parameters and yield the intended outcome, which constrains the scope of transformations performed in synthetic chemistry. Supramolecular assemblies with well-defined cavities present a rare opportunity for synthetic chemists to surpass these Received: July 3, 2018 Published: October 1, 2018 2447

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Accounts of Chemical Research limitations by generating internal microenvironments that are distinct from bulk solution. Upon encapsulation, guests are influenced by the host at the molecular level via these microenvironments, not parameters defined at the macroscopic level. Common manifestations of this control include (i) segregation of guests from solvent and nonencapsulated constituents, (ii) conformational control over the guest, (iii) shifts in equilibria to generate reactive species, and (iv) dramatic increases in effective concentrations upon binding multiple guests. These phenomena, among others, control the relative energetics of the ground and transition states of substrates and ultimately grant new opportunities to achieve a wealth of homogeneous applications including catalysis,1 reactive intermediate stabilization,2 chemical sensing,3 and the mimicry of biological processes such as signal transduction,4 multicatalytic cascades,5 configurationally adaptive binding,6 and information transfer.7 Supramolecular chemists draw inspiration from nature’s precise chemistry.8 In biological systems, complex reactions featuring high uncatalyzed energetic barriers proceed efficiently with excellent selectivities, despite limited temperature control and an abundance of reactive species. Enzymes’ exquisite command over substrates is achieved by the isolation of substrates into customized active sites. The parallels between enzymatic active sites and the microenvironments of supramolecular hosts are self-evident, as both rely on molecular recognition, substrate isolation, and conformational control. Thus, the development of supramolecular chemistry necessitates the interpretation and application of insights gleaned from enzymatic catalysis. The broad range of supramolecular architectures applied to catalysis spans from early covalent structures to self-assembled systems constructed via a number of assembly motifs.8−11 In this Account, we survey recent advancements within a fruitful collaboration between the Toste, Raymond, and Bergman groups studying self-assembled metal−ligand tetrahedra with well-defined, isolated cavities. In contrast to previous topical reviews, we focus on the divergent reactivities achieved, as well as the development of complex multicatalytic systems and mechanistic probes. To demonstrate the strategies employed in our pursuit of catalysis, we begin with a discussion of the structural characteristics of the tetrahedron and revisit select host−guest studies to give context to crucial insights regarding the effects of encapsulation. We then connect lessons learned from those works to recent developments in utilizing the host itself as a catalyst to access new products via divergent reactivities. Generally, our approaches aim to exploit intrinsic host properties established from earlier work, such as electrostatic effects, confinement effects, and solvent exclusion. Finally, more complex examples that involve multicatalytic reaction cascades with biological and synthetic systems, as well as examples where broader mechanistic insights can be obtained from studying reactions with diversified catalysts, are discussed.

Figure 1. (a) Crystal structure of tetrahedral host 2. (b) Schematic representation of host 2 [K12(Ga416)].

substitution pattern in 1 (Figure 1b).13 While several III and IV oxidation state metal hosts have been prepared, Ga(III) is most commonly used to generate 2 [K12(Ga416)]. Because each Ga(III)−triscatecholate has a formal trianionic charge, 2 is overall dodecaanionic. By virtue of this high charge, the host is soluble in water and polar organic solvents. In terms of size, the host falls just within the nanoscale regime, measuring about 13 Å from vertex to vertex. For catalysis, the most pertinent feature of the host is the microenvironment within. Like many enzymatic active sites, this microenvironment excludes the bulk solution by virtue of the tightly geared hydrocarbon walls. The 1,5-substitution pattern of the naphthalene in 1 sets the metal-binding catecholamide (CAM) moieties apart, enabling the arene walls of 2 to “breathe” via amide bond rotation about the C−N bond to accommodate guests of variable sizes and shapes, including spherical, prolate, and cylindrical, as evidenced by NMR spectroscopy, high resolution mass spectrometry, UV−vis spectroscopy, and singlecrystal X-ray diffractometry.12 Below the size exclusion limit, cationic guests are often strongly bound (log Ka up to 4.61) due to electrostatic enthalpic and solvation-related entropic driving forces, while neutral guests are bound by the hydrophobic effect.14,15 The exceptional flexibility of 2 bears consequences for the kinetics and mechanism of host−guest association. Guest encapsulation and self-exchange are known to proceed through an aperture dilation mechanism, rather than host rupture by partial ligand dissociation.16 This mechanism constitutes an additional parallel with biological systems, wherein enzymes accommodate their substrates by architectural deformation and configurationally adaptive binding. A useful metric for studying enzyme structures is the rates of amide hydrogen−deuterium exchange. These exchange kinetics measurements provide a quantitative characterization of the stereoelectronic factors that influence dynamic protein−water interactions, as well as hydrophobic, noncovalent interactions within the active site. Although 2 is water-soluble, the microenvironment of this host is highly hydrophobic due to the naphthalene walls. To compare with proteins, we studied amide hydrogen−deuterium exchange kinetics of 2 at various pD values and with different guests (Figure 2).17 These experiments confirmed that the hydrophobic character of the interior mimics those of well-isolated active sites and revealed that the internalized amide protons of 2 react with encapsulated water through acid-, base-, and water-mediated mechanisms. The acid-mediated pathway is significantly favored compared to natural systems due to the high anionic charge of the host. In many biological systems, rates of proton transfer define enzymatic activities and correlate with the degree of solvent exclusion. This study not only divulged proton transfer reactions within 2 that mimic enzymes, but also revealed that this technique is useful for studying synthetic catalysts.

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PROPERTIES OF THE HOST The featured supramolecular host is self-assembled from six bisbidentate ligands 1 and four metal ions to form a cage with metal−triscatecholate vertices. The tetrahedron has ligands spanning the six edges, as evidenced by crystallographically obtained geometric parameters and its T symmetry (Figure 1a).12 This architecture was predesigned by fixation of the C2axis of symmetry of ligand 1 about the C3-axis of the metal− triscatecholates, as well as the geometry of the 1,5-naphthalene 2448

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Figure 2. Internal amide hydrogen bonds monitored for H−D exchange.

Figure 4. (a) Acceleration of aryl amide bond rotations. (b) Hindered C−C bond rotations in benzyl phosphoniums.

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REACTIVITY INSIDE THE HOST An understanding of the host structure and the driving forces for guest encapsulation provided a framework for the pursuit of reaction promotion within the host. Specifically, the hydrogen− deuterium exchange studies revealed the potential to promote reactions of guests by acid−base chemistry, while the high affinity for monocationic guests suggested that such intermediates may be stabilized. Indeed, effective pKa shifts of up to 4.5 units were observed in encapsulated amine and phosphine Brønsted bases via significant degrees of protonation despite the basic exterior bulk solution (Figure 3a).18 The indication that 2

We next demonstrated that 2 could promote electrocyclizations and sigmatropic rearrangements via molecular confinement and constriction. These transition states are generally less polar than their precursors, and encapsulation confines the substrate in a conformation resembling the transition state relative to the linear conformation in bulk solution, destabilizing the ground state. We observed that cationic allyl-enammonium substrates such as 3 are readily encapsulated and can undergo aza-Cope rearrangements with rate accelerations of up to 850-fold.23 Furthermore, rapid hydrolysis of products such as 4 to corresponding aldehyde 5 enabled turnover of 2, which was further developed into an early example of true catalysis within the host (Figure 5).

Figure 5. Constrictive binding effects within 2 promote the aza-Cope rearrangement of allyl enammonium ions. Figure 3. (a) Effective pKa shifts of Brønsted bases. (b) Formation of unfavored iminium ions. (c) Formation of unfavored phosphonium− ketone adducts.

Beyond rate accelerations, nature is extremely proficient at asymmetric transformations. While proteins owe their inherent chirality to the biased availability of L-amino acids, 2 is composed of achiral components. However, metal−triscatecholates occupy Δ or Λ configurations, and excellent mechanical coupling among all vertices leads to the formation of 2 as racemic mixtures of ΔΔΔΔ and ΛΛΛΛ hosts.13 In early studies, we had observed that 2 is capable of enantiodiscrimination, as each enantiomer of the host generates diastereomerically distinct host−guest pairs with either R or S guest (Figure 6). To exploit this discrimination for asymmetric transformations, a protocol was developed for the optical resolution of 2.24 AzaCope rearrangements such as those discussed above could be performed by ΔΔΔΔ-2 with enantiomeric excesses as high as 78%, demonstrating enantioinduction despite the lack of specific substrate−catalyst interactions.25 A final example of stoichiometric reactivity in 2 highlights an unprecedented photochemical reaction that is inaccessible in bulk solution. Upon encapsulation, cinnamylammonium substrates such as 6 rearrange from the lower energy linear isomer to the higher energy branched isomer 7 upon photoexcitation of 2 (Figure 7a).26 This unexpected reactivity arises from the cooperation of solvent exclusion and constrictive binding effects that facilitate and stabilize radical intermediates that form upon

drives the formation of monocationic species coupled with its solvent exclusion led us to attempt shifts in other intrinsic equilibria by encapsulation. This outcome was achieved when amines and aldehydes, which do not generate observable quantities of condensed iminium ions in aqueous conditions, were found to form quantitatively within 2 (Figure 3b).19 Similarly, phosphines were observed to react with ketones to generate β-hydroxyphosphonium ions, which are undetected in bulk solution (Figure 3c).20 Next, the utilization of confinement effects within 2 were probed. The observation that guests bearing amide bonds have their barrier of C−N bond rotation lowered by up to 3.6 kcal/ mol upon encapsulation in 2 was ascribed to stabilization of the dipole-minimized transition state by the hydrophobic interior of host 2 (Figure 4a).21 In contrast, C−C bond rotations in benzylphosphines were found to have their barriers raised by 3− 6 kcal/mol upon encapsulation within 2 (Figure 4b).22 This difference in barrier correlated with guest size and shape and was attributed to conformational “locking” effect on the guest upon encapsulation. 2449

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some evidence that this amine can reversibly encapsulate, fast decay of the radical ion pair by electron donation back to the host generates carbenium ion 9, which is rapidly sequestered by the amine to give product 7 (Figure 7b). Though this reaction is currently the only example of photosensitization via 2, it represents a new direction of research for our collaboration and joins a growing field of synergy between photochemical and supramolecular chemistry.27

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DIVERGENT CATALYSIS WITHIN THE HOST The insights revealed by these early reactivity studies provided the context and incentive for further advancement of 2 as a catalyst. As a result of continued work, 2 currently boasts a prolific portfolio as a catalyst in which reactions are promoted with significant rate accelerations and excellent catalytic turnovers.1 Of these, perhaps the most intriguing cases are those that feature divergent reactivities. Here, we discuss three such recent examples where new modes of reactivity are enabled within the host that yield products that do not form in detectable amounts from analogous transformations in bulk solution. Though some advancements are owed to serendipity, we describe the rational approaches that led to explorations of these reactivities. The factors that promote these divergent products are generally biomimetic, drawing from solvent exclusion, confinement effects, and chiral discrimination properties revealed by the early work discussed above. The first example is the 2-catalyzed Prins cyclization of citronellal and its derivatives.28 Initial inspiration for this work was the broad class of terpene synthases, which convert terpene substrates into numerous natural products ranging from simple molecules to complex polycyclic structures. Terpene synthases are distinguished by 1,5-diene cyclizations performed via cationic carbenium intermediates and remarkable degrees of product selectivity achieved by substrate preorganization. Furthermore, these enzymes rely on a controlled termination of such carbocation cascades via deprotonation or nucleophilic capture by water, which is in turn governed by a controlled degree of solvent exclusion. Given that substrate preorganization could facilitate the azaCope rearrangement, we turned our attention to cyclization reactions similar to those performed by terpene synthases. The demonstrated driving force for the generation of monocationic charge within 2 was hypothesized to favor the formation of carbenium ions upon a nucleophilic olefin attack, which might be driven by amplified protonation of a heteroatom substrate. By analogy to dramatic pKa shifts in amines and phosphines, we predicted that oxygen bases may undergo such shifts in pKa. To

Figure 6. Enantiodiscrimination of chiral guests by each enantiomer of 2 leads to diastereomeric host−guest pairs.

Figure 7. Proposed mechanism for PET-induced rearrangements of cinnamylammonium substrates within 2.

photoinduced electron transfer (PET) from host 2 to the substrate. The proposed mechanism, derived from spectroscopic experiments (UV−vis absorption, fluorescence, and transient absorption) and cyclic voltammetry, stipulates that host 2 is initially excited by incoming light to generate the excited charge transfer state 6⊂2*, which acts as the PET agent for the 1,3-rearrangement. Donation of an electron from excited 2* to acceptor 6 induces heterolytic C−N bond cleavage, generating free amine and radical ion pair 8. Although there is

Figure 8. Catalysis of the Prins cyclization by 2 forms alkene products, in contrast to bulk solution acid catalysis. 2450

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Figure 9. (a) The aza-Prins cyclization of amine-tethered olefins generates unprecedented piperidine products. (b) The proposed mechanism of the 2catalyzed aza-Prins cyclizations features rate-limiting encapsulation.

explore this possibility, terpene-based citronellal 10 was heated with catalytic amounts of 2 under basic conditions, and indeed, cyclized products were observed. Specifically, unsaturated cyclization product 11 was catalytically formed via deprotonation as the carbenium ion terminating step. This generates a new alkene by means similar to terpene synthases, which reinforces the notion of excellent water exclusion within 2. Uncatalyzed cyclization was very minimal in the absence of 2 (kcat/kuncat of up to 1.9 × 105) without acidification of the bulk solution to pH < 4.29 However, the uncatalyzed reactivation under acidic conditions favored capture of the carbenium ion by water to generate the hydrated product 12 rather than 11 (Figure 8). Thus, 2 was shown to effectively divert the acid catalysis of a Prins reaction to give unsaturated products from basic solution despite the abundance of bulk water. Inspired by the success of the 2-catalyzed Prins cyclization, we sought to expand this reaction manifold and discovered a surprising divergence in product selectivities. We hypothesized that akin to the pKa shifts of aldehydes in the Prins cyclization, the stabilization of transient iminium ions could be exploited to affect a similar olefin capture event, followed by proton elimination. To explore this possibility, amine-tethered olefin substrates such as 12 were subjected to catalytic amounts of 2 and excess formaldehyde.30 As expected, cyclized products were generated via nucleophilic olefin capture; however, the products were unanticipated dealkylated piperidines such as 13 (Figure 9a)! Further experiments supported a mechanistic rationale where iminium adduct 14 is captured by 2, followed by rapid nucleophilic alkene attack. The resulting carbenium ion 15, rather than being quenched by water or deprotonation, undergoes an unprecedented transannular 1,5-hydride shift due to confinement effects to generate iminium products, which hydrolyze upon egress to furnish piperidine 13 (Figure 9b). Kinetic analysis of the reaction revealed that encapsulation was the rate-limiting step of the reaction, rather than the Michelis− Menten profile that most supramolecular catalysts take. This study provided the first observation of rate-limiting encapsula-

tion, which is attributed to the fast reactivity of the constrained iminium adduct. Similar to the 2-catalyzed Prins cyclization, the driving force for monocationic charge, confinement effects, and excellent solvent exclusion properties led to divergent catalysis within 2. However, the strong steric influence on internalized configurations of 14 resulted in the serendipitous discovery of this unusual transannular 1,5-hydride shift, which has otherwise never been observed in simple substrates. The final example highlights an unusual divergence in stereochemical, rather than regiochemical outcomes. As one of the fundamental transformations in organic chemistry, nucleophilic substitution at carbon sp3 centers is described in the context of two classic mechanisms, SN1 and SN2. For either mechanism, there is an associated stereochemical outcome, with SN2 being stereospecific for inversion and SN1 mechanisms resulting in stereochemical erosion due to the intermediacy of an achiral carbenium ion. Initially, we were interested in utilizing the stabilization of carbocations and the chirality of these hosts to explore asymmetric substitution reactions. In the course of these efforts, we discovered that our tetrahedral hosts catalyzed solvolysis of trichloroacetimidates with retention of stereochemistry, a complete reversal from the inversion of solvolysis in bulk solution!31 While enzymes that excel at stereochemical control are commonplace, enzymes that can reverse the intrinsic stereochemical course of a reaction are less common, and this is apparently unprecedented in supramolecular catalysis. This work featured the modified tetrahedral host 16, which substitutes CAM binding moieties for terephthalamides (TAM) functionalized with chiral directing groups (Figure 10). The chirality of these distal amides directs the Δ or Λ gearing of the metal−triscatecholates such that enantiopure hosts can be directly prepared.32 Upon the discovery that solvolysis was proceeding with stereochemical retention, we sought to understand the origin of this stereochemical reversal. Remarkably, it was observed that either enantiomer of substrate 17 leads to substantial retention of stereochemistry in both the ether and alcohol products, 18 and 19, and that absolute catalyst chirality 2451

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Figure 10. (a) Modified tetrahedral host 16, which features chiral terephthalmides that form enantiopure hosts. (b) The proposed reaction intermediate, which features a cation−π interaction between a naphthalene wall and the transient carbocation. Adapted with permission from ref 31. Copyright 2014 American Chemical Society.

Figure 12. (a) Me3PAu+⊂2 is an improved catalyst for hydroalkoxylation of alcohol-tethered allenes. (b) Kinetic resolution and cyclization of ester-tethered allenes via an integrated enzyme− supramolecular catalyst approach.

has no impact on the product stereochemistry (Figure 11a). This outcome contrasts with solvolysis catalyzed by an achiral

20, which are otherwise unreactive to Me3PAu+⊂2. The resolved alcohol products such as 21 would then undergo Me3PAu+⊂2-catalyzed hydroalkoxylation to give enantioenriched cyclized products 22 (Figure 12b). Indeed, we found that a range of natural enzymes can achieve this sequence with Me3PAu+⊂2 where both catalysts are necessary for product formation.5 Enzyme and Me3PAu+ in the absence of 2 led to catalyst deactivation, indicating that the supramolecular sequestration of Me3PAu+⊂2 inhibits adverse interactions between free Me3PAu+ and the enzyme. The successful integration of biological and synthetic microenvironment catalysts under aqueous conditions encouraged us to seek further tandem reactivity with transition metals in 2. We were able to demonstrate such a union following the initial discovery that 2 catalyzes reductive eliminations from high-valent transition metal complexes. A common challenge in cross-coupling chemistry is the judicious selection of a ligand set that promotes all steps of the catalytic cycle. However, because conditions promoting one elementary step often perform at the detriment of other steps, selective catalysis of one elementary step is highly desirable. Transition metal complexes are encapsulated by 2 with concomitant dissociation of an X-type ligand.35 Relatedly, it is known that kinetically unfavorable reductive eliminations can be accelerated by halide abstraction. The recognition of cationic intermediates within 2 manifests in the strong encapsulation of appropriately sized transition metal complexes with concomitant halide dissociation within 2. We discovered that complexes such as Pt(IV) 23 and Au(III) 24 generate the cationic encapsulated complexes, leading to dramatic accelerations of alkyl−alkyl reductive eliminations of up to 1.9 × 107-fold via a Michaelis−Menten-type mechanism (Figure 13a)!36 Notably, these accelerations may also be partially due to constrictive binding effects, bringing the elimination partners closer together. This example (at the time of this writing) is the largest supramolecular rate acceleration to date, resulting from the unusual application of a biomimetic strategy to accelerate an entirely synthetic reaction. With a strategy in hand for enabling prohibitive reductive eliminations, we sought to complete a challenging crosscoupling reaction with tandem dual catalysis.37 The catalytic system featuring Pt(IV) complex 23, which is prohibitively slow at reductive elimination of ethane, was successfully activated by supramolecular tandem catalysis by 16 (Figure 13b). This

Figure 11. Solvolysis is catalyzed by either enantiomer of host 16, leading to retention of product stereochemistry rather than inversion.

phosphoric acid, suggesting that the stereointegrity of the substrate is well-preserved throughout the course of the substitution reaction. We propose that there is a strong stabilizing effect at the backside of the developing carbocation by the electron rich naphthalene walls (Figure 11b). This stabilization leads to overall stereochemical retention caused by an effective double inversion: the first inversion by the host’s naphthalene wall, followed by a second inversion by the incoming solvent nucleophile. Cation−π interactions are often implicated in many enzymes and supramolecular systems, but this example constitutes one of the more unusual applications of this interaction.

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THE HOST BEYOND SINGLE-SITE CATALYSIS Looking beyond a single catalytic process, supramolecular chemists seek the development of complex, multicomponent systems as well as deeper insights into the driving forces and mechanisms of microenvironment reactivity.33 Multicomponent systems offer the prospect of performing traditionally incompatible synthetic steps in one pot, similar to biological systems. Here, we present two examples of tandem catalysis where either biological or synthetic catalyst partners are integrated. Our initial foray into tandem catalysis aimed to unify our supramolecular approach with the reactivity of natural enzymes. We had previously shown that 2 can encapsulate, stabilize, and enhance the reactivity of Me3PAu+ in the hydroalkoxylation of alcohol-tethered allenes via encapsulation of the monocationic Au(I) species with solvent exclusion (Figure 12a).34 In this case, 2 does not act as the catalyst but instead enhances reactivity and longevity of Au(I) as the active catalyst complex Me3PAu+⊂2. We envisioned that esterases and lipases could kinetically resolve and cleave amide- and ester-tethered allene substrates such as 2452

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Figure 13. (a) Challenging reductive eliminations are catalyzed from high-valent transition metal complexes. (b) A dual catalytic cross-coupling reaction enabled by a supramolecular approach to catalyzed reductive elimination.

unique approach to dual catalysis is distinct from enzymatic examples, where two independent catalysts cooperate to transform one starting material. Instead, an arrested transition metal catalyst can be consumed as a substrate in a supramolecular approach to catalysis of an elementary step, which restores overall catalytic activity in the transition metal catalyst.

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THE HOST STRUCTURE AS A PROBE A commonality between enzymes and supramolecular catalysts is the specificity of structure to reactivity. Thus, structure− activity relationship (SAR) studies of supramolecular catalysts offer the opportunity to gain insights into the factors that influence microenvironment catalysis and draw connections between specific structural features and reactivities. However, structural variation of self-assembled systems is significantly challenging and there is a subsequent dearth of supramolecular SAR studies. We discuss here two examples that demonstrate how diversified tetrahedral hosts enable mechanistic studies to provide fundamental insights into supramolecular reactivity. Studies such as these are rare opportunities to isolate and deconvolute specific governing features of supramolecular reactivity, such as electrostatic effects, confinement effects, and host substitution effects. Toward structural diversification of these hosts, we have introduced a variation in chelators (CAM-2 to TAM-16) as well as a variation in spacer size (naphthalene-2 to pyrene-24, and TAM-16 to TAM-pyrene-25) (Figure 14).29 In conjunction with structurally diversified substrates, this set of hosts was used to study the terpene synthase-like Prins cyclization in further depth. Although the chelator was not found to impact catalysis rate significantly, increases in spacer size led to improved catalytic efficiencies and selectivities for certain stereoisomers of product. The trends that could be extracted by variation of catalysts as well as substrates enabled a better understanding of supramolecular microenvironment catalysis of the Prins cyclization in terms of chemo-, diastereo-, and enantioselectivities. While studies regarding the effect of size, constrictive binding, and binding moieties are important for understanding steric parameters of microenvironment catalysis, another unmet challenge lies in characterizing the effect of electric fields and

Figure 14. Diversification of host 2 by modification of chelators and spacers.

Coulombic forces. The stabilization of monocationic charge has been a staple in driving reactivity in 2, and this stabilization is ascribed to the electrostatic effect resulting from its dodecaanionic charge. Although electrostatic charge is implicated in a wide range of enzymatic and supramolecular catalyst systems, the complete isolation and study of this effect is rare.38 To experimentally probe electrostatic charge and its implication in our catalysis, an isostructural octaanionic Si(IV)-based analog 26 was developed and shown to be identical to 2 in the solid state as well as the solution phase (Figure 15a).39 The similarity in structure between 26 and 2 was further supported by the identical rate accelerations measured in both 2- and 26-catalyzed aza-Cope rearrangements, which are net neutral and driven by constrictive binding. In contrast, a Nazarov cyclization, which 2453

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Accounts of Chemical Research *E-mail: [email protected]. *E-mail: [email protected]. ORCID

Cynthia M. Hong: 0000-0002-2563-219X F. Dean Toste: 0000-0001-8018-2198 Notes

The authors declare no competing financial interest. Biographies Cynthia M. Hong, Texan, earned her B.A./M.S. in chemistry from Northwestern University in 2013 before moving west to the University of California, Berkeley. There, she joined the collaborative supramolecular project to obtain her Ph.D. in 2018 under the supervision of Prof. Kenneth N. Raymond and Prof. F. Dean Toste. She now continues her career in chemistry at Merck & Co. in Rahway, NJ. Robert G. Bergman received his B.A. at Carleton College and his Ph.D. with Jerome A. Berson at the University of Wisconsin. After a postdoctoral study with Ronald Breslow at Columbia, he began his academic career at the California Institute of Technology in 1967. He moved his research group to Berkeley in 1978, where he has held joint appointments at the University of California, Berkeley, and the Lawrence Berkeley National Laboratory. His research interests lie at the interface between organic and inorganic chemistry, with a primary focus on catalysis, supramolecular chemistry, and the study of reaction mechanisms.

Figure 15. (a) Octaanionic Si(IV) catalyst 26 is an isostructural analog to dodecaanionic catalyst 2. (b) Differences in catalytic activities give insights on the role of anionic charge in catalysis.

Kenneth N. Raymond obtained a B.A. in chemistry at Reed College in 1964 and Ph.D. from Northwestern University in 1968 and began his faculty appointment at the University of California at Berkeley in 1967. He served as Vice Chair of the Berkeley Chemistry Department (1982− 1984 and 1999−2000) and Chair (1993−1996). He has received many awards and honors, including election to the National Academy of Sciences and the American Academy of Arts and Sciences. He is a cofounder (2001) of Lumiphore Inc. He is the author of 24 US Patents, 11 International Patents, and 572 research publications.

features protonation of substrate 27 and the generation of a carbocation, showed a 680-fold difference in rates of catalysis, standing as the first experimental probe for the dramatic effect of anionic host charge in cation-mediated catalysis (Figure 15b). Moreover, the parallels between enzymatic actives sites and supramolecular microenvironments generated an opportunity for these studies to inform on the governing principles of enzymatic catalysis by investigation of supramolecular catalysts.

F. Dean Toste received his B.Sc. and M.Sc. from the University of Toronto and completed his Ph.D. studies at Stanford University under the guidance Professor Barry Trost. After a postdoctoral appointment with Professor Robert Grubbs at the California Institute of Technology, he took an Assistant Professorship at the University of California, Berkeley, in 2002. In 2006, he was promoted to Associate Professor and is currently Gerald E. K. Branch Distinguished Professor of Chemistry.

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CONCLUDING REMARKS The recognition of how supramolecular microenvironments can isolate and influence molecular guests has been the key to the development of a wide range of synthetic catalysis, as well as more complex systems such as tandem reaction cascades, integration with biological systems, and the development of mechanistic tools to understand supramolecular reactivity. In particular, a thorough understanding of what drives molecular recognition enabled us to leverage those stabilizing forces to promote and catalyze many reactions by ground state destabilization effects, as well as transition state stabilization. These manifest as the recognition and electrostatic stabilization of monocationic charge, excellent solvent exclusion, constrictive binding effects, and compatibility with basic aqueous media. We have been fortunate to study a host that is amenable to these applications and features unique properties to dissect and exploit. As available supramolecular hosts grow in number, we anticipate that the field will progress with great strides with applications surpassing those reported thus far.

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REFERENCES

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*E-mail: [email protected]. 2454

DOI: 10.1021/acs.accounts.8b00328 Acc. Chem. Res. 2018, 51, 2447−2455

Article

Accounts of Chemical Research (7) Stross, A. E.; Iadevaia, G.; Núñez-Villanueva, D.; Hunter, C. A. Sequence-Selective Formation of Synthetic H-Bonded Duplexes. J. Am. Chem. Soc. 2017, 139, 12655−12663. (8) Raynal, M.; Ballester, P.; Vidal-Ferran, A.; van Leeuwen, P. W. N. M. Supramolecular Catalysis. Part 2: Artificial Enzyme Mimics. Chem. Soc. Rev. 2014, 43, 1734−1787. (9) Raynal, M.; Ballester, P.; Vidal-Ferran, A.; van Leeuwen, P. W. N. M. Supramolecular Catalysis. Part 1: Non-Covalent Interactions as a Tool for Building and Modifying Homogeneous Catalysts. Chem. Soc. Rev. 2014, 43, 1660−1733. (10) Kang, J.; Rebek, J. Acceleration of a Diels−Alder Reaction by a Self-Assembled Molecular Capsule. Nature 1997, 385, 50−52. (11) Kaanumalle, L. S.; Gibb, C. L. D.; Gibb, B. C.; Ramamurthy, V. Controlling Photochemistry with Distinct Hydrophobic Nanoenvironments. J. Am. Chem. Soc. 2004, 126, 14366−14367. (12) Pluth, M. D.; Johnson, D. W.; Szigethy, G.; Davis, A. V.; Teat, S. J.; Oliver, A. G.; Bergman, R. G.; Raymond, K. N. Structural Consequences of Anionic Host−Cationic Guest Interactions in a Supramolecular Assembly. Inorg. Chem. 2009, 48, 111−120. (13) Caulder, D. L.; Powers, R. E.; Parac, T. N.; Raymond, K. N. The Self-Assembly of a Predesigned Tetrahedral M4L6 Supramolecular Cluster. Angew. Chem., Int. Ed. 1998, 37, 1840−1843. (14) Sgarlata, C.; Mugridge, J. S.; Pluth, M. D.; Zito, V.; Arena, G.; Raymond, K. N. Different and Often Opposing Forces Drive the Encapsulation and Multiple Exterior Binding of Charged Guests to a M4L6 Supramolecular Vessel in Water. Chem. - Eur. J. 2017, 23, 16813−16818. (15) Biros, S. M.; Bergman, R. G.; Raymond, K. N. The Hydrophobic Effect Drives the Recognition of Hydrocarbons by an Anionic Metal− Ligand Cluster. J. Am. Chem. Soc. 2007, 129, 12094−12095. (16) Davis, A. V.; Raymond, K. N. The Big Squeeze: Guest Exchange in an M4L6 Supramolecular Host. J. Am. Chem. Soc. 2005, 127, 7912− 7919. (17) Hart-Cooper, W. M.; Sgarlata, C.; Perrin, C. L.; Toste, F. D.; Bergman, R. G.; Raymond, K. N. Protein-like Proton Exchange in a Synthetic Host Cavity. Proc. Natl. Acad. Sci. U. S. A. 2015, 112, 15303− 15307. (18) Pluth, M. D.; Bergman, R. G.; Raymond, K. N. Making Amines Strong Bases: Thermodynamic Stabilization of Protonated Guests in a Highly-Charged Supramolecular Host. J. Am. Chem. Soc. 2007, 129, 11459−11467. (19) Dong, V. M.; Fiedler, D.; Carl, B.; Bergman, R. G.; Raymond, K. N. Molecular Recognition and Stabilization of Iminium Ions in Water. J. Am. Chem. Soc. 2006, 128, 14464−14465. (20) Brumaghim, J. L.; Michels, M.; Raymond, K. N. Hydrophobic Chemistry in Aqueous Solution: Stabilization and Stereoselective Encapsulation of Phosphonium Guests in a Supramolecular Host. Eur. J. Org. Chem. 2004, 2004, 4552−4559. (21) Pluth, M. D.; Bergman, R. G.; Raymond, K. N. Acceleration of Amide Bond Rotation by Encapsulation in the Hydrophobic Interior of a Water-Soluble Supramolecular Assembly. J. Org. Chem. 2008, 73, 7132−7136. (22) Mugridge, J. S.; Szigethy, G.; Bergman, R. G.; Raymond, K. N. Encapsulated Guest−Host Dynamics: Guest Rotational Barriers and Tumbling as a Probe of Host Interior Cavity Space. J. Am. Chem. Soc. 2010, 132, 16256−16264. (23) Fiedler, D.; Bergman, R. G.; Raymond, K. N. Supramolecular Catalysis of a Unimolecular Transformation: Aza-Cope Rearrangement within a Self-Assembled Host. Angew. Chem. 2004, 116, 6916−6919. (24) Davis, A. V.; Fiedler, D.; Ziegler, M.; Terpin, A.; Raymond, K. N. Resolution of Chiral, Tetrahedral M4L6 Metal−Ligand Hosts. J. Am. Chem. Soc. 2007, 129, 15354−15363. (25) Brown, C. J.; Bergman, R. G.; Raymond, K. N. Enantioselective Catalysis of the Aza-Cope Rearrangement by a Chiral Supramolecular Assembly. J. Am. Chem. Soc. 2009, 131, 17530−17531. (26) Dalton, D. M.; Ellis, S. R.; Nichols, E. M.; Mathies, R. A.; Toste, F. D.; Bergman, R. G.; Raymond, K. N. Supramolecular Ga4L612− Cage Photosensitizes 1,3-Rearrangement of Encapsulated Guest via

Photoinduced Electron Transfer. J. Am. Chem. Soc. 2015, 137, 10128− 10131. (27) Ward, M. D. Photo-Induced Electron and Energy Transfer in Non-Covalently Bonded Supramolecular Assemblies. Chem. Soc. Rev. 1997, 26, 365−375. (28) Hart-Cooper, W. M.; Clary, K. N.; Toste, F. D.; Bergman, R. G.; Raymond, K. N. Selective Monoterpene-like Cyclization Reactions Achieved by Water Exclusion from Reactive Intermediates in a Supramolecular Catalyst. J. Am. Chem. Soc. 2012, 134, 17873−17876. (29) Hart-Cooper, W. M.; Zhao, C.; Triano, R. M.; Yaghoubi, P.; Ozores, H. L.; Burford, K. N.; Toste, F. D.; Bergman, R. G.; Raymond, K. N. The Effect of Host Structure on the Selectivity and Mechanism of Supramolecular Catalysis of Prins Cyclizations. Chem. Sci. 2015, 6 (2), 1383−1393. (30) Kaphan, D. M.; Toste, F. D.; Bergman, R. G.; Raymond, K. N. Enabling New Modes of Reactivity via Constrictive Binding in a Supramolecular-Assembly-Catalyzed Aza-Prins Cyclization. J. Am. Chem. Soc. 2015, 137, 9202−9205. (31) Zhao, C.; Toste, F. D.; Raymond, K. N.; Bergman, R. G. Nucleophilic Substitution Catalyzed by a Supramolecular Cavity Proceeds with Retention of Absolute Stereochemistry. J. Am. Chem. Soc. 2014, 136, 14409−14412. (32) Zhao, C.; Sun, Q.-F.; Hart-Cooper, W. M.; DiPasquale, A. G.; Toste, F. D.; Bergman, R. G.; Raymond, K. N. Chiral Amide Directed Assembly of a Diastereo- and Enantiopure Supramolecular Host and Its Application to Enantioselective Catalysis of Neutral Substrates. J. Am. Chem. Soc. 2013, 135, 18802−18805. (33) Ueda, Y.; Ito, H.; Fujita, D.; Fujita, M. Permeable Self-Assembled Molecular Containers for Catalysts Isolation Enabling Two-Step Cascade Reactions. J. Am. Chem. Soc. 2017, 139, 6090−6093. (34) Wang, Z. J.; Brown, C. J.; Bergman, R. G.; Raymond, K. N.; Toste, F. D. Hydroalkoxylation Catalyzed by a Gold(I) Complex Encapsulated in a Supramolecular Host. J. Am. Chem. Soc. 2011, 133, 7358−7360. (35) Fiedler, D.; Leung, D. H.; Bergman, R. G.; Raymond, K. N. Enantioselective Guest Binding and Dynamic Resolution of Cationic Ruthenium Complexes by a Chiral Metal−Ligand Assembly. J. Am. Chem. Soc. 2004, 126, 3674−3675. (36) Levin, M. D.; Kaphan, D. M.; Hong, C. M.; Bergman, R. G.; Raymond, K. N.; Toste, F. D. Scope and Mechanism of Cooperativity at the Intersection of Organometallic and Supramolecular Catalysis. J. Am. Chem. Soc. 2016, 138, 9682−9693. (37) Kaphan, D. M.; Levin, M. D.; Bergman, R. G.; Raymond, K. N.; Toste, F. D. A Supramolecular Microenvironment Strategy for Transition Metal Catalysis. Science 2015, 350, 1235−1238. (38) Burschowsky, D.; van Eerde, A.; Ö kvist, M.; Kienhöfer, A.; Kast, P.; Hilvert, D.; Krengel, U. Electrostatic Transition State Stabilization Rather than Reactant Destabilization Provides the Chemical Basis for Efficient Chorismate Mutase Catalysis. Proc. Natl. Acad. Sci. U. S. A. 2014, 111, 17516−17521. (39) Hong, C. M.; Morimoto, M.; Kapustin, E. A.; Alzakhem, N.; Bergman, R. G.; Raymond, K. N.; Toste, F. D. Deconvoluting the Role of Charge in a Supramolecular Catalyst. J. Am. Chem. Soc. 2018, 140, 6591−6595.

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DOI: 10.1021/acs.accounts.8b00328 Acc. Chem. Res. 2018, 51, 2447−2455