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Attractive Noncovalent Interactions in Asymmetric Catalysis: Links Between Enzymes and Small Molecule Catalysts

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Attractive Noncovalent Interactions in Asymmetric Catalysis: Links Between Enzymes and Small Molecule Catalysts Attractive noncovalent interactions in asymmetric catalysis: Links between enzymes and small molecule catalysts Robert R. Knowles and Eric N. Jacobsen1 Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138 Edited by David W. C. MacMillan, Princeton University, Princeton, NJ, and accepted by the Editorial Board September 5, 2010 (received for review May 8, 2010) Catalysis by neutral, organic, small molecules capable of binding and activating substrates solely via noncovalent interactions—particularly H-bonding—has emerged as an important approach in organocatalysis. The mechanisms by which such small molecule catalysts induce high enantioselectivity may be quite different from those used by catalysts that rely on covalent interactions with substrates. Attractive noncovalent interactions are weaker, less distance dependent, less directional, and more affected by entropy than covalent interactions. However, the conformational constraint required for high stereoinduction may be achieved, in principle, if multiple noncovalent attractive interactions are operating in concert. This perspective will outline some recent efforts to elucidate the cooperative mechanisms respon- sible for stereoinduction in highly enantioselective reactions promoted by noncovalent catalysts. enantioselectivity | H bonding | organocatalysis | transition state stabilization ttractive noncovalent interactions state assemblies leading to the undesired ous challenge to achieving high enantio- play a central role in pharma- configuration of the product are destabi- selectivity. This may be overcome, in Aceutical design, supramolecular lized by repulsive steric interactions with principle, through implementation of chemistry, molecular biology, substituents on the catalyst. Consequently, multiple noncovalent attractive inter- sensing applications, materials, crystal en- only the transition states that avoid these actions operating in concert, because this gineering, and a host of other fields in steric interactions are kinetically viable. can afford the conformational constraint the chemical sciences (1–8). As a result of The question of whether selectivity is required for high stereoinduction (22, 23). this broad importance, intensive research achieved primarily through stabilizing or This cooperative model of binding is efforts have been directed toward eluci- destabilizing interactions represents a fun- adefining feature of both biological and dating and quantifying these interactions, damental difference in the way macromo- synthetic receptors, and also underlies which include hydrogen bonding, elec- lecular and small molecule catalysts are enzymatic catalysis. π–π –π trostatic effects, , cation , hydropho- thought to operate. Several well-known asymmetric catalytic – — bic, and Van der Waals forces (9 14). Steric interactions as modeled by the processes involving Lewis acids and tran- — These studies have focused primarily on Lennard-Jones potential are strongly sition metals have invoked attractive non- molecular recognition phenomena, shed- distance dependent, such that the desta- covalent interactions as elements of ding light on the thermodynamic stabili- bilizing effect can be alleviated by a very stereocontrol, including the Sharpless zation of bound complexes. Attractive small reorganization (Table 1) (see ref. 10, dihydroxylation, the Noyori transfer hy- noncovalent interactions also play a key pp 109–121). As such, steric destabiliza- drogenation, and Corey’s oxazaborolidine- role in catalysis by lowering the kinetic tion is most effective as a defining element catalyzed cycloadditions (24–26). How- barriers to reactions through transition of stereocontrol in strongly bound and state stabilization (15, 16). In fact, these conformationally restricted complexes, ever, over the past decade, remarkably simple organocatalytic systems have been forces are responsible for many of the re- where any structural reordering away from fi markable rate accelerations and stereo- equilibrium incurs a substantial energetic identi ed that operate exclusively through selectivities characteristic of enzymatic penalty. This is generally the case in re- noncovalent interactions and yet induce catalysis, wherein cooperative noncovalent actions mediated by organometallic com- high levels of enantioselectivity in syn- interactions with specific active site resi- plexes, Lewis acids, secondary amines, and thetically important transformations. Elu- dues can stabilize the electrostatic char- other important classes of small molecule cidation of the attractive forces acting in acter of a bound transition structure catalysts, in which transition structures concert in such systems presents a signifi- complex (Fig. 1) (17). are associated to the catalyst through well- cant challenge to modern mechanistic Although enzymes are understood to defined covalent interactions (Fig. 2). chemistry but one that seems well justified achieve selectivity through transition state By contrast, noncovalent interactions given the design principles and general stabilization, with the rate of the dominant are not only generally weaker but also less insights into noncovalent interactions that pathway preferentially accelerated relative directional and less distance dependent could emerge. Here we discuss four chiral to competing reactions, small molecule than covalent and dative bonds (Table 1) hydrogen-bond donor catalyst systems de- chiral catalysts are generally proposed to (10, p 28). As such, in a complex where veloped in our laboratories that have be- follow a fundamentally different principle a catalyst interacts with its substrate gun to provide a wealth of information in for achieving enantioselectivity. The vast through a single noncovalent interaction, that regard. majority of stereochemical models for many geometrical orientations of the sub- small molecule catalysts invoke steric strate relative to the catalyst may be very Author contributions: R.R.K and E.N.J. wrote the paper. fi interactions as a rationalization for ener- similar in energy. Thus, signi cant struc- The authors declare no conflict of interest. getic differentiation of the pathways lead- tural reorganizations can occur without This article is a PNAS Direct Submission. D.W.C.M. is a guest ing to enantiomeric products (e.g., Fig. 2) energetically destabilizing the binding in- editor invited by the Editorial Board. – (18 21). In this conceptual framework, it teraction to any large extent. Such a lack 1To whom correspondence should be addressed. E-mail: is generally understood that transition of conformational order presents an obvi- [email protected]. 20678–20685 | PNAS | November 30, 2010 | vol. 107 | no. 48 www.pnas.org/cgi/doi/10.1073/pnas.1006402107 Downloaded by guest on September 30, 2021 SPECIAL FEATURE: PERSPECTIVE Table 1. Distance dependencies of noncovalent interactions Noncovalent interaction Energy dependence on distance Charge–charge 1/r Charge–dipole 1/r2 Dipole–dipole 1/r3 Charge-induced dipole 1/r4 Dipole-induced dipole 1/r5 Dispersion 1/r6 Fig. 1. Noncovalent interactions between a tran- sition state analog and active site residues of H-bond Complicated ∼1/r2 chorismate mutase. These attractive interactions stabilize the electrostatic character of the pericy- clic transition state converting chorismate to pre- 12 phenate, resulting in rate accelerations of up to 106. Steric repulsion 1/r Discussion Dependencies for entries 2–5 are only valid at values of r several times greater than the lengths of the Claisen Rearrangement. Rate enhancement interacting dipoles. At or near the Van der Waals distances operating in the catalytic reactions discussed of the Claisen rearrangement by hydrogen- in the text, these interactions become largely electrostatic, displaying a ∼1/r dependence. bond donors is known to occur in enzy- matic systems (Fig. 1) and has also been demonstrated with protic solvents and With this precedent in mind, we sought selective Claisen rearrangements of ester- electron-deficient diaryl ureas (Fig. 3) (27– to develop a chiral H-bond donor catalyst substituted allyl vinyl ethers (Fig. 4) (33). 29). The observed accelerations are most system for enantioselective Claisen rear- Structural and computational investi- pronounced with allyl vinyl ethers bearing rangements (33). Substoichiometric gation into the origins of enantioselec- electron-withdrawing and/or electron- quantities of diols, phosphoric acids, or tivity indicates that several attractive donating substituents, an effect attribut- thioureas were not found to induce mea- noncovalent interactions may be acting able to the notion that such substrates surable rate accelerations, but cationic in concert to serve as the basis for ster- undergo rearrangement through polar diphenyl guanidinium ion displayed sig- eoinduction in these transformations. In transition states with substantial “eno- nificant catalytic activity in rearrange- the lowest-energy conformation of the late”/“allyl cation” character. Electrostatic ments of a diverse range of electronically catalyst, both pyrrole rings of 3 are en- stabilization of the transition state can be activated allyl vinyl ethers. Extensive de- gaged in cation–π interactions with the imparted through H-bond interactions, velopment and optimization studies led to cationic NH2 of the guanidinium ion, which disperse the augmented anionic the identification of chiral C2-symmetric splaying the pendant phenyl substituents character of the partially broken C–O guanidinium
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