CHIRALITY 25:675–683 (2013)

Review Article

The Upside of Downsizing: Asymmetric Trifunctional Organocatalystsas Small Enzyme Mimics for Cooperative Enhancement of Both Rate

and Enantioselectivity With RegulationFEI LIU*

Department of Chemistry and Biomolecular Sciences, Macquarie University, Sydney, Australia

© 2013 Wiley Perio

ABSTRACT Small molecule organic catalysts (organocatalysts) are widely used in asymmetriccatalysis and synthesis. Compared to their enzymatic and transition-metal counterparts, organocatalystshave advantages in catalytic scope and efficiency but aremore limited in proficiency. Chiral trifunctionalorganocatalysts, in whichmultiple catalyticmotifs act cooperatively on a chiral scaffold, are an emergingclass of organocatalysts with improved proficiency. Cooperativity design that enables bothenantioselectivity and rate enhancement is essential to developing future generations of organocatalystsin biomimetic asymmetric catalysis. Chirality 25:675–683, 2013. © 2013 Wiley Periodicals, Inc.

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

*Correspondence to: Fei Liu, Department of Chemistry and BiomolecularSciences, Macquarie University, Sydney, Australia. E-mail: fei.liu@mq.edu.auReceived for publication 29 April 2013; Accepted 05 June 2013DOI: 10.1002/chir.22214Published online 22 August 2013 in Wiley Online Library(wileyonlinelibrary.com).

INTRODUCTIONEnzymes, transition-metals, and small organic molecules are

the three main classes of molecular catalysts for asymmetricreactions.What defines an “ideal” catalysis?High enantioselectivityand yields; fast rates; low loading; ambient and “green” reactionconditions, preferably in water or recyclable solvents; and facilecatalyst recovery. These are essential criteria on which mostcan agree. It is also possible that catalyst renewability maybecome a requirement in the near future. Furthermore, goodreaction scope with rapid and cost-effective customization isparamount to the applicability of any catalyst at the preparativescale.Enzymes generally meet most, if not all, of the above

criteria, and have served as inspirations for designed systems,particularly in terms of catalytic proficiency. Designed,smaller organic molecules, or organocatalysts, with catalyticproficiency, may offer advantages over enzymes or transitionmetals. By tracing the developmental steps of asymmetricorganocatalysis, and examining some of its current challenges,the questions on cooperativity design for enzyme-mimickingproficiency are discussed here.

ASYMMETRIC ORGANOCATALYSIS: FROM CONCEPTTO PRACTICE

The earliest demonstration of a small organic catalyst possiblycame in the mid 19th century when Justus von Liebig1 usedaqueous acetaldehyde to facilitate formation of oxamide fromdicyan (eq. 1).

Emil Knoevenagel later in 18962 referred to the amines in hisaldol condensation of β-ketoesters or malonates with aldehydesor ketones as “Kontaktsubstanz,” a species actively involved inthe reaction but not consumed (eq. 2).

dicals, Inc.

In 1900, the formal term coining of an organic catalyst appeared inan article by Wilhelm Ostwald,3 who discussed some of the catalyticnature of enzymes (“die Fermente”), along two other types of cata-lysts, organic catalysts (“organische Katalysatoren”) and inorganiccatalysts (“anorganische Katalysatoren”). The conception of catal-ysis by small organic molecules, inorganic molecules, or enzymesalike was already evident.The field of “organocatalysis” continued on, without much

fanfare. In 1913, Bredig and Fiske's4 hydrocyanation reactioncatalyzed by quinine or quinidine exhibited slight asymmetricinduction (eq. 3).

Langenbeck, after Dakin's report of amino acids as catalysts,5 furtherpopularized the term “organische Katalysatoren” in aminocatalysiswith bifunctional catalysts such as N-methylglycine.6,7 In 1960Pracejus8 reported the first significantly enantioselective conversionof methyl phenyl ketene to its propionate ester catalyzed bybenzoylquinine with 76% ee (eq. 4).

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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 anintramolecular aldol reaction with 92% ee (eq. 5).9–12

In 1975, shortly after Långström's repot,13 Wynberg and Helder14

revealed a significantly enantioselective Michael addition with76% ee catalyzed by a cinchona alkaloid via H-bonding catalysis(eq. 6),

and started his group's asymmetric organocatalysis work with rig-orous mechanistic characterization.15,16

Yet in those years asymmetric organocatalysis did notexperience rapid growth, possibly due to its somewhatinconsistent proficiency in asymmetric induction. In the80s and 90s, asymmetric organic catalysts with high ee'scontinued to appear. Dolling et al.’s17 cinconinium bro-mide as a phase-transfer catalyst furnished alkylatedindanones with up to 95% yield, 92% ee, at 10 mol% loading(eq. 7).

The Yang and Shi groups used chiral ketones in epoxidationwith up to 95% ee (eqs. 8, 9), which scope-wise improvedfrom Juliá's poly-alanine catalyst (“synthetic enzymes”).18–20

However, the 300–1000 mol% loading levels may contest theirrole as catalysts but rather auxiliaries in trans.

Scheme 1. A plausible prolin

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The Lipton, Jacobsen, and Corey groups reported hydrocyanationof imines catalyzed by a cyclic dipeptide, a thiourea, and a guani-dine, respectively (eqs. 10, 11, and 12)

with enantioselectivity up to 99% at 2–10 mol% loading.21–23 Con-currently, the Miller group reported an N-alkylimidazole tripeptidefor catalyzing kinetic resolution of alcohols at 84% ee (eq. 13).24

e catalysis mechanism.

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Hatakeyama in 1999 catalyzed a Baylis–Hillman reaction with achiral quinidine at 99% ee and 10 mol% loading (eq. 14).25

While the banner of “asymmetric organocatalysis” was absent,these examples demonstrated clearly the validity of this catalyticapproach.Meanwhile in the parallel world of biocatalysis, investiga-

tions of enzyme catalytic theories and mechanisms,26 coupledwith technical development for rapid and diversified proteinsynthesis and manipulation, gave birth to catalytic antibodiesin the 80s.27 In particular, a catalytic antibody catalyzed anintermolecular aldol reaction between a ketone and aldehydevia an enamine intermediate.28 Five years later, in 2000,(S)-proline was used by List et al.29 to mimic this enamine

Scheme 2. An example of cooperative catalysis. a) Povarov reactions between N-and 1. c) An energy diagram of the cooperative catalysis by HOTf and 1.

activation mechanism as a “microaldolase” for directintermolecular aldol reactions with up to 96% ee (eq. 15).

Concurrently, the first imidazolidinone catalyzed Diels–Alder reaction between enals and dienes via a proposed iminiumintermediate was reported by the McMillan group with up to96% ee (eq. 16).30

Crystal clear, finally, was the idea that asymmetric organocatalysiscould be a general approach beyond just “sporadic” examples. In a

aryl imines and electron rich olefins. b) A Povarov reaction catalyzed by HOTf

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little over a decade, this field is in full swing,31–35with extensiveapplications in complex synthesis.36,37 A century and a half afterLiebig's observation, organocatalysts are now accepted alterna-tives to enzyme and transition-metal catalysts in addressingdemanding synthetic needs.

THE REAP FACTOR: REQUIREMENTS FOR REAPINGTHE BENEFIT

In hindsight, one might attempt to identify the ingredientsnecessary for maturation of a catalytic approach. Four charac-teristics are proposed here to be important in catalysis:rationale, efficiency, adaptability, and proficiency (the REAPfactor). The catalytic rationale relies on mechanistic investiga-tion and underpins the ability to discover new catalysis.Catalytic efficiency refers to the overall cost–benefit ratio ofthe process in practical terms. Catalytic adaptability requiresthe catalyst design to be modular such that customizationcan proceed expediently. Catalyst proficiency, defined bythe intrinsic potency of a catalyst, refers to the level of rateenhancement and asymmetric induction. Organic catalysts,while in use the earliest, did not begin to establish their roleunder these criteria until much later. Enzyme catalysis meetsthe criteria of rationale, efficiency, and proficiency,38 but itsadaptability can be limited, although directed evolution mayoffer viable alternatives.39–41 Transition-metal catalysts areoften 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 potentiallyprohibitive cost from purification may reduce the catalyticefficiency.44

For asymmetric organocatalysis, the issues of rationale,adaptability, and efficiency have been extensively addressed.For example, computational, kinetic, spectroscopic, spectrometric,

Scheme 3. Multivalent catalysts and multicatalysis. a) An example of bifunctionacting in different stages of a cascade hydride transfer–αC fluorination reaction.

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and structural investigations have collectively explained prolinecatalysis in terms of the geometry of the enamine intermediate(Scheme 1),45–47 and other modes of organoactivation havebeen elucidated.48 High efficiency has been demonstrated bya solid-phase bound chiral thiourea that maintained 98% yield,93% ee after 10 recycles in gram-scale hydrocyanation ofimines.49,50 Multifunctional peptide catalysts, synthesizedmodularly, can be adapted for a wide range of reactions by aniterative process of screening and selection.51,52 On catalyticproficiency (high rate, high enantioselectivity, and lowloading), asymmetric organocatalysis perhaps is still in itsinfancy, with limited examples. Rawal and co-workers53 usedTADDOL to catalyze a day-long hetero-Diels–Alder reactionwith only one enantiomeric product detected (eq. 17),

albeit at 20 mol% loading. Wang et al.54 reported, for a Michael–Michael cascade process, a thiourea catalyst at 2 mol% loadingwith 97% ee and 86% yield in 15 hours at room temperature(eq. 18).

Most recently, Maruoka's group55 reported asymmetric conjugateadditions catalyzed by chiral phosphonium salts with up to 91%ee at 0.1 mol% loading (eq. 19).

al catalysis with multivalent H-bonding sites. b) An example of multicatalysis

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.

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Nonetheless, mild, fast, and highly enantioselective reactions atlow catalyst loading are rare in organocatalysis. Addressing thisproficiency issue will not only firmly secure asymmetricorganocatalysis as the third pillar of modern catalysis but alsoanswer some fundamental questions in catalytic hypotheses.

CATALYTIC PROFICIENCY AND COOPERATIVITY: TWOSIDES OF THE SAME COIN?

Catalytic proficiency for enzymes is defined by the intrinsiccatalytic rate, often for only one enantiomeric product, andthe binding affinity of the substrate.56–60 For example,triosephosphate isomerase catalyzes the transfer of a protonin D-glyceraldehyde-3-phosphate to form dihydroxyacetonephosphate from the si face with 1010-fold rate acceleration(eq. 20).56

Within the transition state binding theory, the rate enhancementand enantioselectivity in enzyme catalysis is inherently coupledas its active site has evolved to activate only the cognate reactionpathway. Enormous catalytic proficiency is harnessed by coopera-tively organizing mild acids or bases in the active site, as bestexemplified by orotidylate decarboxylase with 1017-fold rateenhancement.61

In enantioselective organocatalysis, rate-coupled asymmetricinduction remains a challenge, when the pathways to different

Scheme 5. A trifunctional organocatalyst for a transesterification reaction. a) Atransesterification reaction with large rate enhancement.

enantiomeric outcomes are often differentiated by stericfactors. Lowering reaction temperatures may maximize thesteric bias but this also reduces reaction rates. The catalystloading can be high unless the rate-limiting step is alsoeffectively catalyzed. To improve on proficiency, one approachis to combine multiple activation motifs cooperatively. Anexample of acid activated organocatalysis in the Povarovreaction demonstrates a general strategy for cooperativecatalysis.62 The Povarov reaction refers to the cycloaddition of N-aryl imines and electron-rich olefins to form tetrahydroquinolines,which can be catalyzed by HOTf via imine protonation(Scheme 2a). Chiral additives, containing multidentate H-bonddonors (urea, thiourea, and sulfinamide) and steric-directinggroups, can bind to both the conjugate base of HOTf and theprotonated imine in a particular orientation, thus enablingenantiofacial selectivity (up to 99% ee).However, such cooperativity in enantioselectivity is not al-

ways mirrored in rate enhancement. The organocatalysis ofthis Povarov reaction by the strong Brønsted acid HOTfalone, which is not enantioselective, is faster without theweaker, chiral Brønsted acid additive such as 1 (Scheme 2b).The additionof1presents the reactionwith twoconcurrent catalyticdirections, A (racemic catalysis without 1) and B (enantioselectivecatalysis with 1) (Scheme 2c). The rate-limiting step in A isabout 5-fold faster than that of B (ΔEaA<ΔEaB). The dece-leration of pathway B is due to nearly 99% of the protonatedimine binding to1 (�ΔGB>�ΔGA)with clear enantiopreference(�ΔGB>�ΔGB’). The binding of 1 increases the steric demandof the transition structure for enantiofacial bias (ΔEaB<ΔEaB’) atthe expense of the rate. Also, the reaction temperature is loweredsubstantially to �50°C with prolonged reaction time. As shownby this example, enantioselectivity may be associated with ki-netic deceleration, in the absence of cooperative kinetic

trifunctional mimic of the catalytic triad of esterases. b) An organocatalytic

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

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activation. The joint rise of enantioselectivity and rate in asym-metric organocatalysis remains a challenge in its cooperativitydesign.

TRIFUNCTIONAL ORGANOCATALYSIS: TOWARDCOOPERATIVITY IN ASYMMETRIC INDUCTION AND

RATE ENHANCEMENTTrifunctional organocatalysis is conferred by synergistic

action of three different catalytic motifs. The definition of acatalytic motif follows the List formalism, in which acid orbase activation can be enabled by Lewis acids, Lewis bases,Brønsted acids, and Brønsted bases.63 Trifunctionalorganocatalysis is differentiated here from “multifunctionalorganocatalysis,” a term used loosely without clear distinctionbetween catalytic motifs and catalytic valencies. For example,an organocatalyst, with one Brønsted base, such as a tertiaryamine, and several weak Brønsted acids as H-bond donors,will be considered here as a bifunctional catalyst, while itmay be considered a “multifunctional” organocatalyst byothers simply due to the multivalency of the interactionbetween the H-bond donors and acceptors (Scheme 3a).64

Trifunctional organocatalysis is also differentiated from“multistage” or “multicatalyst” organocatalysis where two ormore catalytic platforms operate at different bond formingsites in one-pot.65 For example, MacMillan and co-workersshowed that enamine and iminium activation modes could becombined to sequentially functionalize an enal by hydride addi-tion and αC fluorination with the use of two differentimidazolidinone catalysts at two different loading levels(Scheme 3b).66

Unlike its predecessors, such as monofunctional or bifunc-tional organocatalysts, trifunctional organocatalysts operate ina more complex catalytic landscape where it is in competitionwith the monofunctional or bifunctional background pathways.If the synergy, or positive cooperativity, of its three catalyticmotifs is low, then trifunctional catalysis may not outcompete

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in rate in the lower-order catalysis and result in lowenantioselectivity, low rate, or both.Such design difficulty is, however, offset by the new

opportunities in trifunctional organocatalysis whereby mildmotifs with cooperativity may be effectively assembledwithout the need of strong modes of activation. In general,such asymmetric cooperative catalysis with mild motifs aimsto selectively accelerate one enantiomeric pathway over thebackground or noncooperative pathways, as typically seenin enzyme active sites. More proficient catalysis may bepossible with enantioselective activation compared to theapproach of rate deceleration for enantio-bias, in which casethe rate is reduced for all pathways and the least suppressedpathway delivers the observed enantioselectivity.Thus far, three trifunctional organocatalytic systems, with

distinct functional assignment of each catalytic motif anddemonstration of trifunctional cooperativity, are known anddiscussed in chronological order. The first trifunctionalcatalyst, reported in 2007 by Chen et al.,67 is a cinchonaalkaloid derivative, 2, with a primary amine, a tertiary amine,and a phenol (Scheme 4a). An achiral acid is added as acofactor. This catalytic system promotes an enantioselective1,3-diploar cycloaddition reaction between cyclic enones andazomethine imines in excellent yields (67–99%) andenantioselectivity (86–95% ee) (Scheme 4b). The primaryamine acts as a Lewis base and forms an imine with the enonesubstrate, which is further protonated by the acid additive toform a ketoiminium ion pair as the activated dipolarophile.The phenol acts as a Brønsted acid and binds to theazomethine carbonyl for activation and orientating the dipole.The tertiary amine acts as a Brønsted base to form an ion pairwith the acid additive for instigating the enantiofacial bias. Asa bifunctional control, catalyst 2a without the phenol groupwas tested and found to be inferior in both rate andenantioselectivity. While the mechanistic details of this systemare not fully disclosed, the positive cooperativity of the Lewisbase, Brønsted acid, and Brønsted base is likely the basis for

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the observed joint rise in enantioselectivity and rate under near-ambient reaction conditions. The enantioselectivity of the reac-tion is also preserved at 2 mol% catalyst loading.The second case is the Sakai-Ema catalyst 3, reported in

2008 for a transesterification reaction between vinyl acetatesand alcohols (Scheme 5).68 This trifunctional organocatalystcontains a general base (pyridine), a nucleophile (alcohol),and a Brønsted acid (thiourea). The three catalytic motifsare mimics of the catalytic triad in the active site of serinehydrolase. In the enzymatic site, a general base (histidine)activates the hydroxy nucleophile from a serine residue forattacking the acyl carbonyl of the substrate. The oxyanionintermediate from this nucleophilic acyl addition is thenstabilized by an “oxyanion hole”—a network of H-bonddonors formed by peptide backbone amide hydrogens. Sucha Brønsted base–Lewis base–Brønsted acid catalytic triad isrecapitulated in the Sakai-Ema catalyst to achieve astonishingrate enhancement of 105-fold compared to the uncatalyzedrate. More important, the bifunctional controls of thetrifunctional catalyst, 3a–3c, whereby only two of the threecatalytic motifs are present, show only background reactionrates and demonstrate convincingly that the positivecooperativity requires all three motifs for rate enhancement.While it is a racemic catalyst and still far from reaching theproficiency of its natural counterparts, the Sakai-Ema catalyst3 represents a seminal case toward mechanism-based, posi-tive cooperativity design with rigorous controls for biomi-metic organocatalysis of impressive rates.The third case is the Liu–Garnier trifunctional catalytic

system, represented by 4, that we reported in 2009 for anenantioselective aza-Morita–Baylis–Hillman (MBH) reaction(Scheme 6).69–71 TheMBH or aza-MBH reaction is a three-stepreaction sequence with complex mechanisms (Scheme 6a).72–80

The reaction is initiated by a Lewis base, usually an amine orphosphine, that undergoes a Michael addition to form azwitterionic phoshonium enolate from the starting enone.The electrophile, either an aldehyde or imine, then undergoesan aldol-like reaction with the enolate, where a carbon–carbonbond is formed. Both of these two steps are reversible, and thereaction is not productive until the third, proton transfer–elimination (PTE) step releases the catalyst and forms thefinalMBH product. Because the final product contains a proticsource, the MBH reaction is rate-limited by the PTE step onlyduring early conversion but later switches to the aldol stepwith the MBH product itself catalyzing the PTE step.This complexity and autocatalysis inherent in the MBH

mechanism, where the stereogenecity is controlled by boththermodynamic and kinetic factors in all three steps, hasmade its catalysis difficult, with often low rate, capricioussubstrate scope, and inconsistent enantioselectivities. Wefocused our attention on activating selectively only one PTEpathway in a model aza-MBH reaction between methyl vinylketones (MVK) and N-tosyl imines by cooperative trifunctionalorganocatalysis. The prototype system 4 contains a phosphine,an exo-amino group, and a phenol (Scheme 6b). An external,achiral carboxylic acid is also required as a catalytic cofactor.Three bifunctional controls, 4a–4c, were tested to elucidatethe role of each catalytic motif and demonstrated that all threeare required for the observed positive cooperativity. Thephosphine acts as the Lewis base to initiate the Michael step.The exo-amino group is required for enabling the activation ofthe external acid, and the phenol is essential for enhancingthe rate and enantioselectivity. Under ambient reaction

conditions, both electron-rich and electron-poor N-tosyl iminesreacted with MVK in good rates (3–24 h for 86–94% isolatedyields) and enantioselectivity (up to 92% ee), catalyzed by 4containing the Lewis base–Brønsted acid–Brønsted base triadin the presence of benzoic acid. A second-generation catalyst,5, in some cases produced near quantitative conversion at10 mol% loading in 15 min at ambient temperature with goodenantioselectivity.70

An intriguing feature is highlighted by the regulatoryfunction of the external acid additive (Scheme 6c, arrow tothe left). In the absence of the external benzoic acid additive,the catalysis by the chiral catalyst 4 is not only slow but alsonon-enantioselective. However, in the presence of benzoicacid, enantioselective catalysis is enabled with a joint rise ofrate and enantioselectivity (up to 94% ee), which suggests thatthe cooperativity between 4 and benzoic acid is essential tothis enantioselective activation. Further structure-basedmechanistic analysis is ongoing in order to unravel themolecularbasis to this regulated catalytic assembly.Two of the aforementioned enantioselective trifunctional

organocatalytic systems, 2 and 4, do not have enzymaticcounterparts in nature, although the engineered candidatesare emerging.81 The 1,3-dipolar reactions and aza-MBHreactions they catalyze represent some of the most facile andenantioselective versions for these reactions by organocatalysts.All three trifunctional systems are most active at ambient ornear-ambient temperatures, which is advantageous overapproaches that require lower temperatures for improvingenantioselectivity. For our catalyst 4, lowering temperature infact only impedes the rate, with little improvement inenantioselectivity. At this stage, none of these systems has beenadapted for catalysis at the preparative scale under greenerconditions. Nevertheless, these systems stand to encouragefurther development in higher-order organocatalysis towardenzyme-like proficiencies under more environmentallybenign conditions to promote preparative applications, parti-cularly for reactions that do not have enzymatic versions.

FUTURE DIRECTIONS: BIOMIMETIC ASYMMETRICORGANOCATALYSIS WITH REGULATION

Enzymes remain the most proficient class of catalysts, fromwhich a few lessons on catalyst design can be learned.As discussed above, the activation modes and motifs inenzymatic active sites are a rich source of inspiration todesigned systems, and much has been developed inorganocatalysis to achieve high rate and enantioselectivityunder mild reaction conditions.82,83

Enzymatic catalysis, however, exhibits many more marvel-ous characteristics in terms of regulation and cooperativity.Enzyme catalysis can be turned on and off by cofactors,allosteres, or post-translational modifications.84,85 One en-zyme can adopt multiple forms with varying substrate speci-ficity or catalytic rate. In biosynthetic pathways, multipleenzymatic active sites are clustered to form mega-enzymesthat assemble several building blocks into structurallycomplex natural products.86 Such supramolecular struc-tures act cooperatively and perform regulated cascadecatalysis in a sequence-defined manner; that is, the enzy-matic assembly line not only sequesters reactivity but alsoorders it. Such exquisite catalytic control, with regulation, diver-sification, and timing, is currently unknown to designedsystems.

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Onemay argue that the conceptual foundation of asymmetricorganocatalysis has always been intimately connected to thatof enzymatic catalysis, starting from Ostwald's conclusion in1900.87 Following the initial examples of enamine/iminiumcatalysis, a few enzymatic activation modes have now beenincorporated into asymmetric organocatalysts with very highenantioselectivity.88–91 The use of multiple organocatalyticpathways in one pot to convert simple building blocks into highlyelaborate structures is an exciting frontier of cooperativemultidentate organocatalysis that potentially may grow intomimics of biosynthetic enzyme assembly lines.92,93

The complexity embedded in enzyme catalysis will continueto challenge the design of next-generation organocatalysts. Asmore and more organocatalytic systems appear, however, thequestions of proficiency and cooperativity will intensify asemerging limits of this field.Much of this development will relyon rigorous characterization of organocatalytic mechanismssuch that cooperativity can be approached rationally. Newmimics of enzyme catalytic mechanisms should also unlocknew catalytic activation modes and motifs needed to samplenew catalytic space. To achieve ultimate catalytic proficiencyand efficiency, regulation design is likely to be essential fordeveloping assembled organocatalysis with complexcooperativity in the near future.

ACKNOWLEDGMENTS

This review is based in part on the Athel Beckwith Lecture-ship to FL from the Organic Chemistry Division of the RoyalAustralian Chemical Institute.

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Chirality DOI 10.1002/chir

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Title Chirality: the pharmacological, biological, and chemicalconsequences of molecular asymmetry

ISSN 0899-0042

Publisher John Wiley & Sons, Inc.

Country United States

Status Active

Start Year 1989

Frequency 10 times a year

Language of Text Text in: English

Refereed Yes

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Website http://www3.interscience.wiley.com/journal/37532/home

Description Brings out scientific work on the role of molecular asymmetry in bothbiologically active and non-biologically active molecules in respect to theirpharmacological, biological, and chemical properties.

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