Asymmetric Trifunctional Organocatalysts As Small Enzyme Mimics for Cooperative Enhancement of Both Rate and Enantioselectivity with Regulation

CHIRALITY (2013)

Review Article The Upside of Downsizing: Asymmetric Trifunctional Organocatalysts as Small Enzyme Mimics for Cooperative Enhancement of Both Rate and Enantioselectivity With Regulation

FEI LIU* Department of Chemistry and Biomolecular Sciences, Macquarie University, Sydney, Australia

ABSTRACT Small molecule organic catalysts (organocatalysts) are widely used in asymmetric catalysis and synthesis. Compared to their enzymatic and transition-metal counterparts, organocatalysts have advantages in catalytic scope and efficiency but are more limited in proficiency. Chiral trifunctional organocatalysts, in which multiple catalytic motifs act cooperatively on a chiral scaffold, are an emerging class of organocatalysts with improved proficiency. Cooperativity design that enables both enantioselectivity and rate enhancement is essential to developing future generations of organocatalysts in biomimetic asymmetric catalysis. Chirality 00:000–000, 2013. © 2013 Wiley Periodicals, Inc.

KEY WORDS: multifunctional organocatalysts; catalytic proﬁciency; REAP factor; enantioselective activation; proton transfer; organocatalysis regulation; catalytic assembly

INTRODUCTION Enzymes, transition-metals, and small organic molecules are the three main classes of molecular catalysts for asymmetric reactions. What defines an “ideal” catalysis? High enantioselectivity and yields; fast rates; low loading; ambient and “green” reaction conditions, preferably in water or recyclable solvents; and facile In 1900, the formal term coining of an organic catalyst appeared in catalyst recovery. These are essential criteria on which most an article by Wilhelm Ostwald,3 who discussed some of the catalytic can agree. It is also possible that catalyst renewability may nature of enzymes (“die Fermente”), along two other types of cata- become a requirement in the near future. Furthermore, good lysts, organic catalysts (“organische Katalysatoren”) and inorganic reaction scope with rapid and cost-effective customization is catalysts (“anorganische Katalysatoren”). The conception of catal- paramount to the applicability of any catalyst at the preparative ysis by small organic molecules, inorganic molecules, or enzymes scale. alike was already evident. The field of “organocatalysis” continued on, without much Enzymes generally meet most, if not all, of the above 4 criteria, and have served as inspirations for designed systems, fanfare. In 1913, Bredig and Fiske's hydrocyanation reaction particularly in terms of catalytic proficiency. Designed, catalyzed by quinine or quinidine exhibited slight asymmetric smaller organic molecules, or organocatalysts, with catalytic induction (eq. 3). proficiency, may offer advantages over enzymes or transition metals. By tracing the developmental steps of asymmetric organocatalysis, and examining some of its current challenges, the questions on cooperativity design for enzyme-mimicking proficiency are discussed here.

ASYMMETRIC ORGANOCATALYSIS: FROM CONCEPT TO PRACTICE Langenbeck, after Dakin's report of amino acids as catalysts,5 further The earliest demonstration of a small organic catalyst possibly “ ” th 1 popularized the term organische Katalysatoren in aminocatalysis came in the mid 19 century when Justus von Liebig used with bifunctional catalysts such as N-methylglycine.6,7 In 1960 aqueous acetaldehyde to facilitate formation of oxamide from Pracejus8 reported the ﬁrst signiﬁcantly enantioselective conversion dicyan (eq. 1). of methyl phenyl ketene to its propionate ester catalyzed by benzoylquinine with 76% ee (eq. 4).

*Correspondence to: Fei Liu, Department of Chemistry and Biomolecular Emil Knoevenagel later in 18962 referred to the amines in his Sciences, Macquarie University, Sydney, Australia. E-mail: [email protected] β Received for publication 29 April 2013; Accepted 05 June 2013 aldol condensation of -ketoesters or malonates with aldehydes DOI: 10.1002/chir.22214 or ketones as “Kontaktsubstanz,” a species actively involved in Published online in Wiley Online Library the reaction but not consumed (eq. 2). (wileyonlinelibrary.com).

The asymmetric induction capacity of organic catalysts, however, was not deﬁnitively recognized until 1970, when the Hajos-Parrish- Eder-Sauer-Wiechert reaction used (S)-proline to catalyze an intramolecular aldol reaction with 92% ee (eq. 5).9–12

The Lipton, Jacobsen, and Corey groups reported hydrocyanation In 1975, shortly after Långström's repot,13 Wynberg and Helder14 of imines catalyzed by a cyclic dipeptide, a thiourea, and a guani- revealed a signiﬁcantly enantioselective Michael addition with dine, respectively (eqs. 10, 11, and 12) 76% ee catalyzed by a cinchona alkaloid via H-bonding catalysis (eq. 6),

and started his group's asymmetric organocatalysis work with rigorous mechanistic characterization.15,16 Yet in those years asymmetric organocatalysis did not experience rapid growth, possibly due to its somewhat inconsistent proﬁciency in asymmetric induction. In the 80s and 90s, asymmetric organic catalysts with high ee's continued to appear. Dolling et al.’s17 cinconinium bro- mide as a phase-transfer catalyst furnished alkylated indanones with up to 95% yield, 92% ee, at 10 mol% loading (eq. 7). with enantioselectivity up to 99% at 2–10 mol% loading.21–23 Con- currently, the Miller group reported an N-alkylimidazole tripeptide for catalyzing kinetic resolution of alcohols at 84% ee (eq. 13).24

The Yang and Shi groups used chiral ketones in epoxidation with up to 95% ee (eqs. 8, 9), which scope-wise improved from Juliá's poly-alanine catalyst (“synthetic enzymes”).18–20 However, the 300–1000 mol% loading levels may contest their role as catalysts but rather auxiliaries in trans.

Scheme 1. A plausible proline catalysis mechanism. Chirality DOI 10.1002/chir THE UPSIDE OF DOWNSIZING: ASYMMETRIC TRIFUNCTIONAL ORGANOCATALYSTS AS SMALL ENZYME MIMICS

Hatakeyama in 1999 catalyzed a Baylis–Hillman reaction with a activation mechanism as a “microaldolase” for direct chiral quinidine at 99% ee and 10 mol% loading (eq. 14).25 intermolecular aldol reactions with up to 96% ee (eq. 15).

fi – While the banner of “asymmetric organocatalysis” was absent, Concurrently, the rst imidazolidinone catalyzed Diels these examples demonstrated clearly the validity of this catalytic Alder reaction between enals and dienes via a proposed iminium approach. intermediate was reported by the McMillan group with up to 96% ee (eq. 16).30 Meanwhile in the parallel world of biocatalysis, investigations of enzyme catalytic theories and mechanisms,26 coupled with technical development for rapid and diversified protein synthesis and manipulation, gave birth to catalytic antibodies in the 80s.27 In particular, a catalytic antibody catalyzed an intermolecular aldol reaction between a ketone and aldehyde 28 via an enamine intermediate. Five years later, in 2000, Crystal clear, finally, was the idea that asymmetric organocatalysis (S)-proline was used by List et al.29 to mimic this enamine could be a general approach beyond just “sporadic” examples. In a

Scheme 2. An example of cooperative catalysis. a) Povarov reactions between N-aryl imines and electron rich oleﬁns. b) A Povarov reaction catalyzed by HOTf and 1. c) An energy diagram of the cooperative catalysis by HOTf and 1.

Chirality DOI 10.1002/chir LIU

– little over a decade, this field is in full swing,31 35with extensive and structural investigations have collectively explained proline 36,37 applications in complex synthesis. A century and a half after catalysis in terms of the geometry of the enamine intermediate Liebig's observation, organocatalysts are now accepted alterna- (Scheme 1),45–47 and other modes of organoactivation have tives to enzyme and transition-metal catalysts in addressing 48 fi demanding synthetic needs. been elucidated. High ef ciency has been demonstrated by a solid-phase bound chiral thiourea that maintained 98% yield, 93% ee after 10 recycles in gram-scale hydrocyanation of THE REAP FACTOR: REQUIREMENTS FOR REAPING imines.49,50 Multifunctional peptide catalysts, synthesized THE BENEFIT modularly, can be adapted for a wide range of reactions by an In hindsight, one might attempt to identify the ingredients iterative process of screening and selection.51,52 On catalytic necessary for maturation of a catalytic approach. Four charac- proficiency (high rate, high enantioselectivity, and low teristics are proposed here to be important in catalysis: loading), asymmetric organocatalysis perhaps is still in its rationale, efficiency, adaptability, and proficiency (the REAP infancy, with limited examples. Rawal and co-workers53 used factor). The catalytic rationale relies on mechanistic investiga- TADDOL to catalyze a day-long hetero-Diels–Alder reaction tion and underpins the ability to discover new catalysis. with only one enantiomeric product detected (eq. 17), Catalytic efficiency refers to the overall cost–benefit ratio of the process in practical terms. Catalytic adaptability requires the catalyst design to be modular such that customization can proceed expediently. Catalyst proficiency, defined by the intrinsic potency of a catalyst, refers to the level of rate enhancement and asymmetric induction. Organic catalysts, while in use the earliest, did not begin to establish their role under these criteria until much later. Enzyme catalysis meets albeit at 20 mol% loading. Wang et al.54 reported, for a Michael– the criteria of rationale, efficiency, and proficiency,38 but its Michael cascade process, a thiourea catalyst at 2 mol% loading adaptability can be limited, although directed evolution may with 97% ee and 86% yield in 15 hours at room temperature offer viable alternatives.39–41 Transition-metal catalysts are (eq. 18). often highly proficient, with low catalyst loading, easily adapt- able by sampling metal centers and ligands, and mechanisti- cally articulated to guide the catalyst design.42,43 However, the use of precious or toxic metal centers with potentially prohibitive cost from purification may reduce the catalytic efficiency.44 For asymmetric organocatalysis, the issues of rationale, Most recently, Maruoka's group55 reported asymmetric conjugate adaptability, and efficiency have been extensively addressed. additions catalyzed by chiral phosphonium salts with up to 91% For example, computational, kinetic,spectroscopic,spectrometric, ee at 0.1 mol% loading (eq. 19).

Scheme 3. Multivalent catalysts and multicatalysis. a) An example of bifunctional catalysis with multivalent H-bonding sites. b) An example of multicatalysis acting in different stages of a cascade hydride transfer–αC ﬂuorination reaction. Chirality DOI 10.1002/chir THE UPSIDE OF DOWNSIZING: ASYMMETRIC TRIFUNCTIONAL ORGANOCATALYSTS AS SMALL ENZYME MIMICS

Scheme 4. A trifunctional organocatalyst for an enantioselective 1,3-dipolar cycloaddition. a) A trifunctional organocatalyst for asymmetric 1,3-dipolar cycloaddition. b) Enantioselective organocatalysis of 1,3-dipolar cycloaddition between enones and azomethine imines.

enantiomeric outcomes are often differentiated by steric factors. Lowering reaction temperatures may maximize the steric bias but this also reduces reaction rates. The catalyst loading can be high unless the rate-limiting step is also effectively catalyzed. To improve on proficiency, one approach is to combine multiple activation motifs cooperatively. An example of acid activated organocatalysis in the Povarov Nonetheless, mild, fast, and highly enantioselective reactions at reaction demonstrates a general strategy for cooperative low catalyst loading are rare in organocatalysis. Addressing this 62 N fi fi catalysis. The Povarov reaction refers to the cycloaddition of - pro ciency issue will not only rmly secure asymmetric fi organocatalysis as the third pillar of modern catalysis but also aryl imines and electron-rich ole ns to form tetrahydroquinolines, answer some fundamental questions in catalytic hypotheses. which can be catalyzed by HOTf via imine protonation (Scheme 2a). Chiral additives, containing multidentate H-bond CATALYTIC PROFICIENCY AND COOPERATIVITY: TWO donors (urea, thiourea, and sulfinamide) and steric-directing SIDES OF THE SAME COIN? groups, can bind to both the conjugate base of HOTf and the Catalytic proficiency for enzymes is defined by the intrinsic protonated imine in a particular orientation, thus enabling catalytic rate, often for only one enantiomeric product, and enantiofacial selectivity (up to 99% ee). the binding affinity of the substrate.56–60 For example, However, such cooperativity in enantioselectivity is not al- triosephosphate isomerase catalyzes the transfer of a proton ways mirrored in rate enhancement. The organocatalysis of in D-glyceraldehyde-3-phosphate to form dihydroxyacetone this Povarov reaction by the strong Brønsted acid HOTf phosphate from the si face with 1010-fold rate acceleration alone, which is not enantioselective, is faster without the (eq. 20).56 weaker, chiral Brønsted acid additive such as 1 (Scheme 2b). The addition of 1 presents the reaction with two concurrent catalytic directions, A (racemic catalysis without 1)andB (enantioselective catalysis with 1) (Scheme 2c). The rate-limiting step in A is about 5-fold faster than that of B (ΔEaA < ΔEaB). The dece- Within the transition state binding theory, the rate enhancement leration of pathway B is due to nearly 99% of the protonated and enantioselectivity in enzyme catalysis is inherently coupled imine binding to 1 (ÀΔGB > ÀΔGA)withclearenantiopreference as its active site has evolved to activate only the cognate reaction ÀΔG > ÀΔG ’ fi ( B B ). The binding of 1 increases the steric demand pathway. Enormous catalytic pro ciency is harnessed by coopera- ΔE < ΔE ’ tively organizing mild acids or bases in the active site, as best of the transition structure for enantiofacial bias ( aB aB )at exemplified by orotidylate decarboxylase with 1017-fold rate theexpenseoftherate.Also,thereactiontemperatureislowered enhancement.61 substantially to À50°C with prolonged reaction time. As shown In enantioselective organocatalysis, rate-coupled asymmetric by this example, enantioselectivity may be associated with ki- induction remains a challenge, when the pathways to different netic deceleration, in the absence of cooperative kinetic

Scheme 5. A trifunctional organocatalyst for a transesteriﬁcation reaction. a) A trifunctional mimic of the catalytic triad of esterases. b) An organocatalytic transesteriﬁcation reaction with large rate enhancement. Chirality DOI 10.1002/chir LIU

Scheme 6. A trifunctional organocatalytic system for enantioselective aza-MBH reactions. a) A general MBH reaction mechanism. b) Trifunctional organocatalysts for asymmetric aza-MBH reactions. c) Enantioselective organocatalysis of aza-MBH reactions.

activation. The joint rise of enantioselectivity and rate in asym- in rate in the lower-order catalysis and result in low metric organocatalysis remains a challenge in its cooperativity enantioselectivity, low rate, or both. design. Such design difficulty is, however, offset by the new opportunities in trifunctional organocatalysis whereby mild motifs with cooperativity may be effectively assembled TRIFUNCTIONAL ORGANOCATALYSIS: TOWARD without the need of strong modes of activation. In general, COOPERATIVITY IN ASYMMETRIC INDUCTION AND such asymmetric cooperative catalysis with mild motifs aims RATE ENHANCEMENT to selectively accelerate one enantiomeric pathway over the Trifunctional organocatalysis is conferred by synergistic background or noncooperative pathways, as typically seen action of three different catalytic motifs. The definition of a in enzyme active sites. More proficient catalysis may be catalytic motif follows the List formalism, in which acid or possible with enantioselective activation compared to the base activation can be enabled by Lewis acids, Lewis bases, approach of rate deceleration for enantio-bias, in which case Brønsted acids, and Brønsted bases.63 Trifunctional the rate is reduced for all pathways and the least suppressed organocatalysis is differentiated here from “multifunctional pathway delivers the observed enantioselectivity. organocatalysis,” a term used loosely without clear distinction Thus far, three trifunctional organocatalytic systems, with between catalytic motifs and catalytic valencies. For example, distinct functional assignment of each catalytic motif and an organocatalyst, with one Brønsted base, such as a tertiary demonstration of trifunctional cooperativity, are known and amine, and several weak Brønsted acids as H-bond donors, discussed in chronological order. The first trifunctional will be considered here as a bifunctional catalyst, while it catalyst, reported in 2007 by Chen et al.,67 is a cinchona may be considered a “multifunctional” organocatalyst by alkaloid derivative, 2, with a primary amine, a tertiary amine, others simply due to the multivalency of the interaction and a phenol (Scheme 4a). An achiral acid is added as a between the H-bond donors and acceptors (Scheme 3a).64 cofactor. This catalytic system promotes an enantioselective Trifunctional organocatalysis is also differentiated from 1,3-diploar cycloaddition reaction between cyclic enones and “multistage” or “multicatalyst” organocatalysis where two or azomethine imines in excellent yields (67–99%) and more catalytic platforms operate at different bond forming enantioselectivity (86–95% ee) (Scheme 4b). The primary sites in one-pot.65 For example, MacMillan and co-workers amine acts as a Lewis base and forms an imine with the enone showed that enamine and iminium activation modes could be substrate, which is further protonated by the acid additive to combined to sequentially functionalize an enal by hydride addi- form a ketoiminium ion pair as the activated dipolarophile. tion and αC fluorination with the use of two different The phenol acts as a Brønsted acid and binds to the imidazolidinone catalysts at two different loading levels azomethine carbonyl for activation and orientating the dipole. (Scheme 3b).66 The tertiary amine acts as a Brønsted base to form an ion pair Unlike its predecessors, such as monofunctional or bifunc- with the acid additive for instigating the enantiofacial bias. As tional organocatalysts, trifunctional organocatalysts operate in a bifunctional control, catalyst 2a without the phenol group a more complex catalytic landscape where it is in competition was tested and found to be inferior in both rate and with the monofunctional or bifunctional background pathways. enantioselectivity. While the mechanistic details of this system If the synergy, or positive cooperativity, of its three catalytic are not fully disclosed, the positive cooperativity of the Lewis motifs is low, then trifunctional catalysis may not outcompete base, Brønsted acid, and Brønsted base is likely the basis for Chirality DOI 10.1002/chir THE UPSIDE OF DOWNSIZING: ASYMMETRIC TRIFUNCTIONAL ORGANOCATALYSTS AS SMALL ENZYME MIMICS the observed joint rise in enantioselectivity and rate under near- conditions, both electron-rich and electron-poor N-tosyl imines ambient reaction conditions. The enantioselectivity of the reac- reacted with MVK in good rates (3–24 h for 86–94% isolated tion is also preserved at 2 mol% catalyst loading. yields) and enantioselectivity (up to 92% ee), catalyzed by 4 The second case is the Sakai-Ema catalyst 3, reported in containing the Lewis base–Brønsted acid–Brønsted base triad 2008 for a transesterification reaction between vinyl acetates in the presence of benzoic acid. A second-generation catalyst, and alcohols (Scheme 5).68 This trifunctional organocatalyst 5, in some cases produced near quantitative conversion at contains a general base (pyridine), a nucleophile (alcohol), 10 mol% loading in 15 min at ambient temperature with good and a Brønsted acid (thiourea). The three catalytic motifs enantioselectivity.70 are mimics of the catalytic triad in the active site of serine An intriguing feature is highlighted by the regulatory hydrolase. In the enzymatic site, a general base (histidine) function of the external acid additive (Scheme 6c, arrow to activates the hydroxy nucleophile from a serine residue for the left). In the absence of the external benzoic acid additive, attacking the acyl carbonyl of the substrate. The oxyanion the catalysis by the chiral catalyst 4 is not only slow but also intermediate from this nucleophilic acyl addition is then non-enantioselective. However, in the presence of benzoic stabilized by an “oxyanion hole”—a network of H-bond acid, enantioselective catalysis is enabled with a joint rise of donors formed by peptide backbone amide hydrogens. Such rate and enantioselectivity (up to 94% ee), which suggests that a Brønsted base–Lewis base–Brønsted acid catalytic triad is the cooperativity between 4 and benzoic acid is essential to recapitulated in the Sakai-Ema catalyst to achieve astonishing this enantioselective activation. Further structure-based rate enhancement of 105-fold compared to the uncatalyzed mechanistic analysis is ongoing in order to unravel the molecular rate. More important, the bifunctional controls of the basis to this regulated catalytic assembly. trifunctional catalyst, 3a–3c, whereby only two of the three Two of the aforementioned enantioselective trifunctional catalytic motifs are present, show only background reaction organocatalytic systems, 2 and 4, do not have enzymatic rates and demonstrate convincingly that the positive counterparts in nature, although the engineered candidates cooperativity requires all three motifs for rate enhancement. are emerging.81 The 1,3-dipolar reactions and aza-MBH While it is a racemic catalyst and still far from reaching the reactions they catalyze represent some of the most facile and proficiency of its natural counterparts, the Sakai-Ema catalyst enantioselective versions for these reactions by organocatalysts. 3 represents a seminal case toward mechanism-based, posi- All three trifunctional systems are most active at ambient or tive cooperativity design with rigorous controls for biomi- near-ambient temperatures, which is advantageous over metic organocatalysis of impressive rates. approaches that require lower temperatures for improving The third case is the Liu–Garnier trifunctional catalytic enantioselectivity. For our catalyst 4, lowering temperature in system, represented by 4, that we reported in 2009 for an fact only impedes the rate, with little improvement in enantioselective aza-Morita–Baylis–Hillman (MBH) reaction enantioselectivity. At this stage, none of these systems has been (Scheme 6).69–71 The MBH or aza-MBH reaction is a three-step adapted for catalysis at the preparative scale under greener reaction sequence with complex mechanisms (Scheme 6a).72–80 conditions. Nevertheless, these systems stand to encourage The reaction is initiated by a Lewis base, usually an amine or further development in higher-order organocatalysis toward phosphine, that undergoes a Michael addition to form a enzyme-like proficiencies under more environmentally zwitterionic phoshonium enolate from the starting enone. benign conditions to promote preparative applications, parti- The electrophile, either an aldehyde or imine, then undergoes cularly for reactions that do not have enzymatic versions. an aldol-like reaction with the enolate, where a carbon–carbon bond is formed. Both of these two steps are reversible, and the reaction is not productive until the third, proton transfer– FUTURE DIRECTIONS: BIOMIMETIC ASYMMETRIC elimination (PTE) step releases the catalyst and forms the ORGANOCATALYSIS WITH REGULATION final MBH product. Because the final product contains a protic Enzymes remain the most proficient class of catalysts, from source, the MBH reaction is rate-limited by the PTE step only which a few lessons on catalyst design can be learned. during early conversion but later switches to the aldol step As discussed above, the activation modes and motifs in with the MBH product itself catalyzing the PTE step. enzymatic active sites are a rich source of inspiration to This complexity and autocatalysis inherent in the MBH designed systems, and much has been developed in mechanism, where the stereogenecity is controlled by both organocatalysis to achieve high rate and enantioselectivity thermodynamic and kinetic factors in all three steps, has under mild reaction conditions.82,83 made its catalysis difficult, with often low rate, capricious Enzymatic catalysis, however, exhibits many more marvel- substrate scope, and inconsistent enantioselectivities. We ous characteristics in terms of regulation and cooperativity. focused our attention on activating selectively only one PTE Enzyme catalysis can be turned on and off by cofactors, pathway in a model aza-MBH reaction between methyl vinyl allosteres, or post-translational modifications.84,85 One en- ketones (MVK) and N-tosyl imines by cooperative trifunctional zyme can adopt multiple forms with varying substrate speci- organocatalysis. The prototype system 4 contains a phosphine, ficity or catalytic rate. In biosynthetic pathways, multiple an exo-amino group, and a phenol (Scheme 6b). An external, enzymatic active sites are clustered to form mega-enzymes achiral carboxylic acid is also required as a catalytic cofactor. that assemble several building blocks into structurally Three bifunctional controls, 4a–4c,weretestedtoelucidate complex natural products.86 Such supramolecular struc- the role of each catalytic motif and demonstrated that all three tures act cooperatively and perform regulated cascade are required for the observed positive cooperativity. The catalysis in a sequence-defined manner; that is, the enzy- phosphine acts as the Lewis base to initiate the Michael step. matic assembly line not only sequesters reactivity but also The exo-amino group is required for enabling the activation of orders it. Such exquisite catalytic control, with regulation, diver- the external acid, and the phenol is essential for enhancing sification, and timing, is currently unknown to designed the rate and enantioselectivity. Under ambient reaction systems. Chirality DOI 10.1002/chir LIU

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Chirality DOI 10.1002/chir