Organocatalysis

Eric N. Jacobsena,1 and David W. C. MacMillanb,1 aDepartment of Chemistry & Chemical Biology, Harvard University, Cambridge, MA 02138; and bMerck Center for Catalysis at Princeton University, Princeton, NJ 08544-1009

The use of small-molecule organic catalysts in organic synthesis has flourished over the past decade. Examples of defining concepts and cutting-edge results are provided in the papers in this Special Feature.

catalysis | stereochemistry | organic synthesis | enzymes

he field of asymmetric catalysis is nonamine-centered Lewis bases (7–10). Al- onto and activates an α,β-unsaturated car- dedicated to the development of though there are fewer established modes bonyl by lowering the energy of the low- Tefficient catalytic methods for the of generic activation that fall into this cate- est unoccupied molecular orbital (LUMO), construction of chiral molecules gory, the potential for reaction discovery in Jiang et al. (3) developed a simple, one-pot and has been dominated by the use of this arena is evident from the highlighted protocol for the synthesis of chiral allylic organometallics and enzymes for most examples, which represent quite disparate alcohols and amines. After an enantiose- of its history. However, in the past de- modes of activation arising from phospho- lective epoxidation or aziridination of cade, the concept of organocatalysis has rus, chalcogen, and N-heterocyclic carbene enones, they showed that a subsequent emerged as a discrete strategy for ad- catalysts. Finally, several papers highlight Wharton transposition of the α,β-cyclized dressing modern day challenges in chem- the development of transformations through carbonyl enables an approach to a family of istry. It has become widely appreciated the combined action of multiple activation chiral products that had either previously that small molecule organic catalysts can modes. This is illustrated in the final group- been accessible mainly through organo- hold a wide range of practical advantages ing of articles on noncovalent interactions metallic means or in the case of the qua- relative to macromolecular or precious (11, 12). Either through combination with ternary variants, previously been less easily metal catalysts, including air and water established covalent-based modes of activa- accessed. Next, in an effort to build a firmer stability, low cost, availability from re- tion or in concert with other noncovalent mechanistic understanding of the related newable resources, and relative non- approaches, these manuscripts make it evi- activation mode of enamine catalysis, in toxicity. With the dramatic recent dent that anion-binding and hydrogen- which tautomerization of an iminium in- expansion of research efforts in organo- bonding catalysis represent rich areas for the termediate leads to carbonyl activation catalysis throughout the world, syntheti- development of reactivity concepts. by the raising of the highest occupied mo- cally useful transformations based on new lecular orbital (HOMO), Bock et al. (4) reactivity concepts have been identified, Desymmetrizations isolated and characterized a family of al- often with no counterpart in the more es- Inspired by design elements found in nature’s dehyde- and ketone-derived proline en- tablished catalysis regimens. principal catalysts (macromolecular peptidic aminones. Analysis of the crystal structures To that end, this PNAS Special Feature enzymes), Jordan et al. (1) have developed of these intermediates provides insight into on organocatalysis offers a sampling of the a pentapeptide catalyst incorporating a tet- the geometric configurations involved in current state of the field and how some razole-functionalized amino acid within a β- enamine catalysis. Melchiorre et al. (5) of the most significant challenges are being turn structural framework. The tetrazole have, in turn, provided a useful extension of addressed by its leading researchers. To residueservedasaLewisbasecatalystfor the enamine concept by achieving enan- make the different catalysis concepts readily catalytic phosphite transfer to myo-inositol. tioselective carbon–carbon bond forma- apparent, the papers in this issue are or- Enantioselective induction from the peptide tion at the γ-position of a carbonyl. Using ganized based on modes of catalytic re- backbone enabled the selective desymmetri- cinchona-based amine catalysts and β- activity. In many cases, these generic modes zation of this carbohydrate, and subsequent substituted cyclic enones, they were able to of reactivity are executed by very different kinetic resolution using the same catalyst develop a system that favors dienamine types of catalyst scaffolds. For example, enabled a concise, enantioselective synthesis formation, which selectively promotes vi- fi the rst pair of manuscripts highlights of D-myo-inositol-6-phosphate. An alternate nylogous Michael additions that yield desymmetrization reactions catalyzed by desymmetrization, based on the alcoholysis γ- rather than α-alkylation (5). Finally, Lewis base organocatalysts with either of meso cyclic anhydrides, was examined by Mastracchio et al. (6) make use of an a tetrazole-bearing peptide or primary Deng et al. (2) through their use of a cin- Umpolung strategy, whereby an in situ one- amine scaffold (1, 2). The next subset of chona alkaloid-derived primary amine cata- electron oxidation of an intermediate en- manuscripts represents the alternative case, lyst. By synthesizing conformationally rigid amine provides a polarity-reversed radical in which relatively similar types of amino- cinchona alkaloid derivatives, they were able cation whose SOMO is prone to addition catalysts provide paths to a diverse array of to elucidate a stereochemical model for the by π-nucleophilic alkylating reagents. By α β γ catalytic platforms for the -, -, and - desymmetrization, which enabled their de- introducing a family of chiral imidazolidi- functionalization of carbonyl compounds velopment of an improved cinchona-based none catalysts that are designed with dis- – (3 6). This section highlights examples from catalyst that is accessible through a shortened crete enantio-discriminating elements for fi the elds of iminium, enamine, dienamine, two-step synthesis from menthol. ketone substrate recognition and reactivity, and singly occupied molecular orbital (SOMO) catalysis, in which mechanistic in- Amine-Catalyzed α-, β-, and γ-Func- tionalization of Carbonyls Through sight, reaction partner scope, or product Author contributions: E.N.J. and D.W.C.M. wrote the accessibility has been expanded in significant Iminium, Enamine, Dienamine, and paper. ways. The next classification of articles is SOMO Catalysis The authors declare no conflict of interest. somewhat broader and includes those In a creative application of iminium catal- 1To whom correspondence may be addressed. E-mail: modes of activation that are catalyzed by ysis, whereby a Lewis basic amine condenses [email protected] or [email protected].

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they achieved a set of enantioselective tioselective hetero-Diels-Alder reaction destabilizing interactions that disfavor for- α-alkylations of cyclic ketones through over homoenolate-mediated cyclopentene mation of minor stereoisomers, their ap- direct functionalization of the carbonyl formation (9). Alternatively, Filloux et al. proach mimics that of enzymes in favoring starting material. (10) used an achiral N-heterocyclic car- a particular stereoisomer through selective bene catalyst in combination with a chiral stabilization of its transition state. Although Non-Amino Lewis Base Catalysis: prolinol derivative to affect an asymmetric these noncovalent interactions are weaker, Phosphine, Calcogen, and N-Heterocyclic cascade involving a Michael addition less directional, and less distance-dependant Carbenes and subsequent Stetter reaction sequence, than their covalent counterparts, they have Using a chiral, naphthyl-based phosphine promoted by their respective catalysts. been shown to operate in concert, providing catalyst, Sinisi et al. (7) also showed Through this protocol, they showed that high levels of enantioselectivity through a pioneering example of carbon–carbon a family of asymmetric benzofuranones a cooperative effect. The conclusions drawn bond formation at the γ-position of a car- could be accessed by combining salicy- in this final perspective offer an approach bonyl. In their system, stereoablative laldehydes with alkynes or allenes. for designing chiral small molecule cat- addition of a phosphine catalyst to racemic alysts and draw attention to the many po- allenoates and allenamides enables enan- Catalysis Through Noncovalent tential directions remaining in the field of tioselective γ-addition of malonates and Interactions organocatalysis. 1,3-dicarbonyl nucleophiles. Alternatively, In an alternative multicatalytic approach, Of course, with the vast expansion of Denmark and Burke (8) investigated the Uehara et al. (11) combined a bifunctional research in the areas of organocatalysis in viability of Lewis base catalysis in halo- thiourea/amine-catalyzed Michael addi- recent years, it is impossible to compile lactonization and -etherification reactions. tion with a base-catalyzed Henry reaction a comprehensive survey of the many on- Through a series of mechanistic studies, in a cascade sequence, which provides going incarnations of this discipline, and they observed the relationship between asymmetric access to talo- and manno- inevitably, some important areas of re- privileged chalcogen catalysts and their configured carbohydrates. Subjecting iso- search have been left out (for instance, respective reaction rates and selectivity, lated intermediates to each of the developed phase transfer and Lewis acid-catalyzed which they suggest offers a path to an Henry reaction conditions provides a mech- processes, although not part of this issue, enantioselective variant for the trans- anistic rationale for the role of the base in will likely be among the important future formation using this approach. Kaeo- enabling epimerization and providing the advances in the field). Ultimately, as the bamrung et al. (9) developed conditions by respective pyranose configurations. Finally, field continues to develop and offer sol- which they are able to access chiral ester Knowles and Jacobsen (12) addressed hy- utions to the challenges faced by the enolate intermediates, in preference to drogen-bonding catalysis in the context of chemical community, new goals will con- homoenolates, through the condensation reviewing four illustrative examples from tinually need to be defined, and we antic- of chiral N-heterocyclic carbene catalysts their laboratories of highly enantioselective ipate PNAS will continue to showcase the onto α,β-unsaturated aldehydes. This se- catalytic systems based solely on non- development and broad impact of orga- lectivity, governed by the identity of the covalent interactions. In contrast to typical nocatalysis on the materials and bio- catalytic base used, promotes highly enan- models of stereoinduction, which rely on logical sciences.

1. Jordan PA, Kayser-Bricker KJ, Miller SJ (2010) 5. Bencivenni G, Galzerano P,MazzantiA,BartoliG,Mel- enolate equivalents from α,β-unsaturated aldehydes Asymmetric phosphorylation through catalytic P(III) chiorre P (2010) Direct asymmetric vinylogous Michael for enantioselective Diels–Alder reactions. Proc Natl phosphoramidite transfer: Enantioselective synthesis addition of cyclic enones to nitroalkenes via dienamine Acad Sci USA 107:20661–20665. of D-myo-inositol-6-phosphate. Proc Natl Acad Sci USA catalysis. Proc Natl Acad Sci USA 107:20642–20647. 10. Filloux CM, Lathrop SP, Rovis T (2010) Multicatalytic, 107:20620–20624. 6. Mastracchio A, Warkentin AA, Walji AM, MacMillan DWC asymmetric Michael/Stetter reaction of salicylaldehydes 2. Li H, Liu X, Wu F, Tang L, Deng L (2010) Elucidation (2010) Direct and enantioselective α-allylation of ketones and activated alkynes. Proc Natl Acad Sci USA 107: of the active conformation of cinchona alkaloid via singly occupied molecular orbital (SOMO) catalysis. Proc 20666–20671. catalyst and chemical mechanism of alcoholysis of Natl Acad Sci USA 107:20648–20651. 11. Uehara H, Imashiro R, Hernandez-Torres G, Barbas CF meso anhydrides. Proc Natl Acad Sci USA 107:20625– 7. Sinisi R, Sun J, Fu GC (2010) Phosphine-catalyzed (2010) Organocatalytic asymmetric assembly reactions 20629. asymmetric additions of malonate esters to γ-substi- for the syntheses of carbohydrate derivatives by inter- 3. Jiang H, Holub N, Jorgensen KA (2010) Simple strategy tuted allenoates and allenamides. Proc Natl Acad Sci molecular Michael-Henry reactions. Proc Natl Acad Sci for synthesis of optically active allylic alcohols and USA 107:20652–20654. USA 107:20672–20677. amines by using enantioselective organocatalysis. Proc 8. Denmark SE, Burk MT (2010) Lewis base catalysis 12. Knowles RR, Jacobsen EN (2010) Attractive non- Natl Acad Sci USA 107:20630–20635. of bromo- and iodolactonization, and cycloetherifi- covalent interactions in asymmetric catalysis: Links 4. Bock DA, Lehmann CW, List B (2010) Crystal structures cation. Proc Natl Acad Sci USA 107:20655–20660. between enzymes and small molecule catalysts. Proc of proline-derived enamines. Proc Natl Acad Sci USA 9. Kaeobamrung J, Kozlowski MC, Bode JW (2010) Chiral Natl Acad Sci USA 107:20678–20685. 107:20636–20641. N-heterocyclic carbene-catalyzed generation of ester

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