Enantioselective Organocatalyzed Transformations ... - ACS Publications

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Enantioselective Organocatalyzed Transformations of β‑Ketoesters Thavendran Govender,† Per I. Arvidsson,†,‡ Glenn E. M. Maguire,† Hendrik G. Kruger,† and Tricia Naicker*,† †

Catalysis and Peptide Research Unit, University of KwaZulu Natal, Durban, 4001, South Africa P. I. Arvidsson, Science for Life Laboratory, Drug Discovery and Development Platform and Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet SE-171 77 Stockholm, Sweden

‡

ABSTRACT: The β-ketoester structural motif continues to intrigue chemists with its electrophilic and nucleophilic sites. Proven to be a valuable tool within organic synthesis, natural product, and medicinal chemistry, reports on chiral β-ketoester molecular skeletons display a steady increase. With the reignition of organocatalysis in the past decade, asymmetric methods available for the synthesis of this structural unit has significantly expanded, making it one of the most exploited substrates for organocatalytic transformations. This review provides comprehensive information on the plethora of organocatalysts used in stereoselective organocatalyzed construction of β-ketoestercontaining compounds.

CONTENTS 1. Introduction 1.1. Organocatalysis 1.2. β-Ketoesters 2. Noncovalent Catalysis 2.1. Hydrogen-Bonding Organocatalysts 2.1.1. Reactions of β-Ketoesters and Nitroolefins 2.1.2. Reactions of β-Ketoesters with Unsaturated Aldehydes or Ketones 2.1.3. Reactions of β-Ketoesters with Imines 2.1.4. Reactions of β-Ketoesters with Maleimides 2.1.5. Reactions of Alkylidene-Type β-Ketoesters 2.1.6. Reactions of β-Ketoesters with Heteroatoms 2.1.7. Reactions of β-Ketoesters with Miscellaneous Substrates 2.1.8. Brønsted Acid Organocatalysts 2.1.9. Phase Transfer Organocatalysts 3. Covalent Catalysis 3.1. Aminocatalysts 3.1.1. Reactions via Direct β-Ketoester Activation 3.1.2. Reactions of β-Ketoesters via an Enamine Intermediate 3.1.3. Reactions of β-Ketoesters via an Iminium Intermediate 4. Opportunities for Industrial Applications 5. Conclusions and Outlook Author Information Corresponding Author Notes Biographies © 2016 American Chemical Society

Acknowledgments Dedication References

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1. INTRODUCTION 1.1. Organocatalysis

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Organocatalysis is a powerful methodology originating from a humble beginning (the Hajos Parrish Eder Wiechert Sauer reaction)1,2 that has led to successful breakthroughs in the world of chemical syntheses.3−5 The use of small chiral organic molecules as enantioselective catalysts, capable of either activating substrates or transforming them into more reactive forms, has rapidly attracted immense scientific growth.4,6−29 Considering that β-ketoesters are among the most widely exploited substrates for stereoselective construction of chiral molecules within the field of organocatalyzed reactions, we believe a comprehensive review in this area was well overdue.

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1.2. β-Ketoesters

β-Ketoesters and related diketo derivatives are of fundamental importance. Preparative organic chemists have relied on the unique properties of β-ketoesters30 for the synthesis of organic molecules of increasing complexity and sophistication since the discovery of the Claisen condensation reaction more than a century ago.31 The β-ketoester scaffold has proven to be a versatile synthetic substrate in the construction of new carbon− carbon and carbon−heteroatom bonds to yield products that can be further converted into a variety of valuable products. It has been used as a basic synthon for the synthesis of important natural products,32 such as, mokupalide33,34 (a hexaprenoid from a marine sponge), nonactin35 (an antibiotic), sitophilure36

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Received: February 29, 2016 Published: July 27, 2016 9375

DOI: 10.1021/acs.chemrev.6b00156 Chem. Rev. 2016, 116, 9375−9437

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Scheme 1. β-Keto Thioester Acetoacetyl Coenzyme A (AcCoA) is a Key Intermediate in the Biosynthesis of a Variety of Natural Products Such As Fatty Acids, Polyketides, Terpenes, And Alkaloids

(insect pheromone), and kermesic acid37 (food colorant additive), Figure 1.

Scheme 2. Comparison of pKa Values (H2O and DMSO) of Ethyl Acetate and Ethyl Acetoacetate (Left) and Keto-Enol Tautomerism of Ethyl Acetoacetate (Right).50

Figure 1. Molecular structure of some natural products that have been synthesized from a β-ketoester synthon.

This backbone also lends itself as a simple facile building block for the synthesis of several pharmaceutically active derivatives37,38 such as the barbiturates, pyrazolones, and benzimidazole/benzoxazoles families that are known for soporific,39 anthelmintic, analgesic,40 antipyretic,41 antiarthritic, uricosuric, anti-inflammatory42 as well as antimicrobial and antitumor properties.35 Selected examples of biologically active compounds that have been prepared starting from a β-ketoester skeleton include the commercial drugs Arone (edaravone) a neuro protective agent,43,44 Imitrex/Imigran (Sumatriptan) for the treatment of migrane headaches,45 and most recently a G protein-coupled receptor (GPR119) agonist as well as a peroxisome proliferator-activated receptor (PPARγ) modulator for the potential treatment of type 2 diabetes,46,47 Figure 2.

Enols are nucleophiles with reactivity in between that of alkenes and enolates, thus making them ideally suited for carbon−carbon bond formation under mild conditions. Although the keto−enol interconversion is normally represented as simple tautomerism (as in Scheme 2), it is important to recognize that this process may be catalyzed through both acids and bases (i.e., conditions readily attainable in aqueous- or other mild environments both with or without enzyme catalysis), Scheme 3. Scheme 3. Acid (Top) and Base (Bottom) Catalyzed KetoEnol Tautomerism of β-Ketoesters

Figure 2. Molecular structure of some medicinally important compounds synthesized from a β-ketoester synthon.

In view of the common use of β-ketoesters in the pharmaceutical, agrochemical, chemical, and polymer industries, considerable interest into the preparation of building blocks that contain this functionality are being explored, with asymmetric organocatalysis as a popular option. However, long before the term organocatalysis was coined, Mother Nature utilized β-keto thioesters in the form of acetyl coenzyme A for catalytic carbon−carbon bond formation during the biosynthesis of natural products such as fatty acids, polyketides, terpenes, and alkaloids, Scheme 1.48 β-Ketoesters represent a unique molecular skeleton with both electrophilic and nucleophilic functional groups. The electronwithdrawing character of the β-keto functionality increases the acidity of the α-protons of ester derivatives by approximately 10 pKa units.49 This decreased pKa in turn promotes a shift of the keto−enol tautomerism toward the enol form that is further stabilized by intramolecular hydrogen bonding and conjugation of the carbon−carbon double bond with the carbonyl group, Scheme 2.

As will be outlined in the remainder of this text, formation of asymmetric complexes between β-ketoesters and chiral acid and base catalysts is a keystone principle for organocatalytic transformations of β-ketoester substrates under noncovalent catalytic conditions. For example, a basic group in the organocatalyst may be used to increase nucleophilicity of the acarbon in the β-ketoester by promoting enol formation or stabilize an enolate intermediate as depicted in Scheme 3, while a hydrogen bonding group (e.g., a thiourea) in the catalyst may activate the electrophile toward nucleophilic attack by the enol or other nucleophiles, as outlined in Figure 3 and in section 2.1. Phase-transfer catalysis (PTC) represents a special case of Brønsted base catalytic activation of the β-ketoester. Typically, the catalyst is an organic molecule incorporating a quarternary nitrogen center with an ability to dissolve in both aqueous and 9376


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Scheme 5. Reaction of β-Ketoesters with Amines Leads to Enamines, Which Are Even More Nucleophilic than Enols Due to the Stronger Electron-Donating Power of Nitrogen

Figure 3. General activation for classic cinchona alkaloid or urea/ thiourea bifunctional hydrogen-bonding organocatalysts with a typical β-ketoester system in a Michael reaction.26

the past decade. This review has aimed to provide a comprehensive survey of the enantioselective organocatalysts that have been applied on substrates incorporating the widespread β-ketoester framework. The generic modes of organocatalytic activation of the β-ketoester group can be generally classified according to the noncovalent or covalent chemical nature of the substrate-organocatalyst interaction. The text herein is organized by mode of action as to how the organocatalyst is proposed to interact with the substrate, thereby inducing chirality into these reactions [i.e., we have thus divided the review into noncovalent (hydrogen bonding, Brønsted acid, and phase transfer) and covalent (aminocatalysts, e.g., enamine or iminium-ion intermediates) catalysis]. Within each mode of activation, we report in chronological order carbon−carbon bond formation reactions followed by carbon−heteroatom bond formation in which we attempted to group similar substrate classes. Applications of these asymmetric transformations in total synthesis of natural products and biologically active molecules, as well in larger-scale (above gram quantities) processes, are also highlighted.

organic solvents. The catalyst thereby carries an inorganic base (e.g., OH−) into the organic phase where it deprotonates the βketoester, and the chiral catalyst forms an ion-pair between the positive quarternary amine and the enolate anion, which attacks the electrophile, Scheme 4.51 When a chiral phase-transfer catalyst is used to enforce asymmetric induction, a tight ion-pair and/or a directing group is required to direct the attack to the electrophile. Scheme 4. General Principle for Phase Transfer Catalysis (PTC)

2. NONCOVALENT CATALYSIS 2.1. Hydrogen-Bonding Organocatalysts

The employment of chiral hydrogen bond donors is a major activation strategy within asymmetric organocatalysis. There are several valuable reviews7,26,53−75 that highlight this subject. The most widely employed hydrogen-bonding organocatalysts include chiral-(thio)ureas, diols, phosphoric acids, and various cinchona alkaloid derivatives. The dual initiation of the hydrogen bond donor/s and Brønsted/Lewis base functional groups within a chiral framework have led to the discovery of several successful bifunctional organocatalysts applied on β-ketoester substrates. Typically the hydrogen bond donor site activates the electrophile, and the Brønsted/Lewis basic site within the chiral scaffold76 activates the β-ketoester nucleophile (by exploiting the keto−enol tautomerism), Figure 3. The protonated Brønsted base finally facilitates a second proton transfer that releases the reaction product and regenerates the organocatalyst.76 The preorganization of both reaction components within the transition state by these catalysts allows for a high degree of stereochemical control in these chiral transformations. As discussed in section 1.2 above, enol formation of βketoesters may be catalyzed by both acid and base. Thus, certain bifunctional hydrogen bond catalysts may operate by an orthogonal activation of the reactants under slightly different reaction conditions (i.e., rather than the activation outlined in Figure 3 above). A corresponding acid of the protonated base may activate the electrophile, and the hydrogen bond motif may activate the β-ketoester by partial protonation as depicted in

β-Ketoesters may also be activated through a covalent bond with the catalyst. The keto−enol equilibrium of β-ketoesters may be forced toward the nucleophilic enol form by formation of enamines through reaction of the keto-derivative with primary or secondary amines, Scheme 5. As will be presented in section 3.1, the use of a temporary covalent interaction between a chiral amine and the β-ketoester represent a major catalytic principle for functionalization of βketoesters through organocatalysis.52 Given the propensity of β-ketoesters for keto−enol tautomerization under mild conditions, it is not surprising that βketoesters have been widely applied as substrates for organocatalyzed transformations. The reactivity patterns displayed by the β-ketoester structural motifs when used in conjunction with organocatalysis facilitates unique reactivities for either nucleophilic or electrophilic activations thereby paving the way for their vast use as a prochiral substrates in asymmetric synthesis during 9377


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enantioselectivities (85−92% ee). First they tested the domino reaction in toluene in the presence of 10 mol % of the catalyst but this failed, yielding only the acyclic intermediates. Upon treatment of the acyclic adducts with 0.1 equiv of 1,1,3,3tetramethylguanidine (TMG) at various temperatures (0 °C reported as the best), they were able to furnish the desired cyclic adducts with respectable ee’s (85−92%) (Scheme 7).85

Figure 4. Both these transition states have been supported by experimental and theoretical results.77

Scheme 7. Takemoto’s Thiourea and TMG-Catalyzed Domino Michael Addition Figure 4. Alternative activation model bifunctional hydrogen-bonding organocatalysts.

Bifunctional hydrogen bond catalysts may operate under orthogonal modes of activating the substrates depending on the nature of the catalyst and/or the exact reaction conditions. Opposite to the activation depicted in Figure 3, the conjugate acid of the base may activate the electrophile and the hydrogen bond donor may activate the β-ketoester through hydrogen bond donation (general acid catalysis). These possibilities of bifunctional catalysis is supported by additional theoretical and experimental results (Figure 3 and 4).78−82 Similarly under the second possibility, there has been evidence in which one of the acidic NH’s on the thiourea activates and orientates the electrophile and the deprotonated nucleophile is hydrogenbonded to both the protonated amine and the remaining thiourea hydrogen bond donor.83 As outlined below, noncovalent bifunctional hydrogenbonding organocatalysts have been widely explored to active βketoesters in Michael addition reactions. 2.1.1. Reactions of β-Ketoesters and Nitroolefins. The first bifunctional organocatalysts was described in 2003 by Takemoto and co-workers84 for the Michael addition reaction of malonates to nitroolefins. They discussed the use of an additional basic, nucleophile-activating group present in the thiourea catalyst 184 (Scheme 6). This allowed for the simultaneous

Unfortunately the authors did not reveal the time required for the reaction at lower temperatures. They have utilized this approach to synthesize the biologically active natural product, (−)-epibatidine. In 2005, Takemoto and his group continued their efforts with the bifunctional urea catalyst by reacting other 1,3-dicarbonyl compounds with nitroolefins. Employing the same catalyst as earlier (catalyst 1), this system provided excellent yields with variable diastereoselectivities and good enantioselectivities (Scheme 8).86 The reaction times for α-unsubstituted βScheme 8. Takemoto’s Thiourea-Catalyzed Michael Addition of Cyclic and Acyclic β-Ketoesters to Nitroolefins86

Scheme 6. Takemoto’s Thiourea-Catalyzed Michael Addition of Malonates to Nitroolefins

ketoesters were faster than for α-substituted analogues; however, such substrates resulted in quaternary stereocenters and were the first report of their kind. This approach tolerated acyclic and cyclic ketoesters with the latter requiring lower reaction temperatures (down to −60°C) for better selectivities. In this reaction, the pronucleophile and nitroolefin were proposed to be activated by the amino group and NH of the thiourea moiety of the catalyst, respectively. In the same study,86 the authors gathered valuable information about the mechanism of the catalytic system. NMR experiments confirmed that protic solvents such as methanol lowered the yield of the reaction due to solvation of the nitro group. The reaction is first order for 1,3-dicarbonyl substrates, and the active catalytic species is monomeric. On the basis of the configuration of the final product, the following intermediate/complex leading

activation of the nucleophile and the nitroolefin through hydrogen bonding. Initially they attempted the reaction with a range of cyclohexyl amine thioureas at room temperature to form the Michael adduct. The best results came from catalyst 1, bearing a thiourea group and tertiary amine that was applied to aliphatic and aromatic nitroolefins with toluene as the solvent (74−95% yield and 81−93% ee). It thus appeared that thioureas as a basis for bifunctional organocatalysis showed great promise. A year later, the same group reported 85 the first enantioselective double Michael addition of γ,δ-unsaturated βketoesters to nitrostyrene with catalyst 1 and 1,1,3,3tetramethylguanidine (TMG), which provided 4-nitrocyclohexanone derivatives with three continuous stereogenic centers in good yields (65−87%), excellent dr’s (63:37−99:1), and 9378


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to the correct stereochemistry of the product was proposed (Figure 5).

Scheme 10. Cinchona Derivative Catalyzed Michael Addition of Cyclic and Acyclic β-Ketoesters to Nitroolefins

Figure 5. Proposed hydrogen-bonded complex between nitrostyrene, βketoester, and thiourea catalyst 1.86

Selectivity was also dependent on the reaction temperature as improved results were obtained at lower temperatures. In this study, the authors also proposed a stereochemical model for this type of transformation94 (Figure 6).

This transition state allows for the catalyst to favorably orientate the enolate and nitroolefin via a hydrogen-bonded complex as depicted in Figure 5. Natural cinchona alkaloids as asymmetric catalysts was established 41 years ago by the seminal studies carried out by Wynberg and co-workers.87 Their extensive work on the use of cinchona alkaloids as chiral Lewis base/nucleophilic catalysts showed that these compounds were potential catalysts for a broad spectrum of enantioselective transformations.88 With regards to the β-keto scaffold, from 2004 onward, Deng’s group expanded on the hydrogen-bonding premise by Takemoto’s group by employing a different structural moiety to achieve a bifunctional catalytic system.89,90 They examined the potential of cinchona alkaloid91,92 catalysts for the addition of β-keto nucleophiles to trans-nitrostyrene.90 Their optimized conditions were achieved with catalyst 2 (cupreine)90,93 and gave 93% yield and 91% ee for ethyl acetoacetate as a substrate (Scheme 9). A

Figure 6. Stereochemical model for Michael additions catalyzed by cinchona catalyst 3.

Catalyst 3 exists as a gauche-open conformer to simultaneously activate and position the Michael donor and the acceptor by means of hydrogen -bonding interactions invoking a bifunctional mode of catalysis. The substituents of the two bond-forming carbons are in a staggered rather than eclipsed arrangement. The application of this model was confirmed by the stereochemical outcome of the reaction products confirmed by X-ray structure analysis. This particular Michael reaction (i.e., 2-oxocyclopentanecarboxylate and nitrostyrenes) became a popular benchmark reaction for the evaluation of organocatalysts. In 2008, Wang and co-workers95 reported a novel trifunctional amine thiourea catalyst, 4,95,96 with multiple hydrogen-bonding donors, which was used for efficient additions of various symmetric and asymmetric 1,3-diketones to nitro-olefins (Scheme 11). A variety of aryl nitro-olefins reacted smoothly with β-ketoesters to provide the corresponding products in high yields, excellent diastereoselectivities (up to 98:2 dr), and enantioselectivities (90−99% ee). The substitution on the aromatic ring of the nitroolefin had a negligible effect on reactivities and selectivities. The catalyst was also applied to other cyclic and acyclic trisubstituted β-ketoesters with nitro-styrene providing high diastereoselectivities (up to 99:1) and enantioselectivities (up to 98% ee). Also in 2008, the Ma group reported a chiral bifunctional saccharide based tertiary amine-thiourea organocatalyst 5 for the addition of malonates to nitrostyrene, they extended the application of this catalyst to only one βketoester with excellent yield (99%) with good diastereo- and enantioselectivity (90:10 dr and 89% ee).97 Abundant natural and unnatural α-amino acids were employed as a chiral source for the development of several excellent bifunctional guanidine catalysts by Feng and co-workers.98 These are known to possess high pKa values and dual hydrogenbonding modes for the molecular recognition of β-ketoester anions.99 The organocatalysts were designed to promote the asymmetric Michael addition of β-ketoesters to nitroolefins with

Scheme 9. Cupreine-Catalyzed Michael Addition of Ethyl 3Oxobutanoate to Nitrostyrene

quinidine alkaloid derivative bearing a 6-hydroxyquinoline ring afforded significantly higher enantioselectivities and faster reaction rates than those bearing a 6′-methoxyquinoline ring. Further investigation by this group, introduced catalyst 3,90 obtained from readily accessible alkaloids, for conjugate additions of a wide range of trisubstituted carbon nucleophiles to various nitroalkenes (bearing aryl, heteroaryl, and alkyl groups with varying electronic and steric properties).94 The cinchona catalyst 3 offered both high enantioselectivities and diastereoselectivities for cyclic and acyclic β-keto nucleophilic substrates (Scheme 10). The reaction proceeded at significantly higher stereoselectivities in aprotic (THF, ether, and toluene) rather than protic solvents (MeOH, EtOH), which could compete for hydrogen bonding to the catalyst or substrate. 9379


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Scheme 11. Organocatalyzed Michael Addition of βKetoesters to Nitroolefins

catalysts that can be prepared by a simple and practical microwave approach.106 These organocatalysts were the first of their kind based on a TIQ framework incorporating a guanidine moiety. The reaction of 2-oxocyclopentanecarboxylate and nitrostyrene using the TIQ-based organocatalyst 8106 (Scheme 11) resulted in the formation of the chiral Michael products in quantitative chemical efficiencies (up to 99% yields) and moderate ee’s (up to 82%). In 2008, Rawal’s group reported the first application of the bifunctional squaramide type scaffold in organocatalysis for the Michael addition of several 1,3-dicarbonyl compounds to nitroolefins (Scheme 12).107 With an impressive 0.5 mol % of Scheme 12. Organocatalyzed Michael Addition of Cyclic and Acyclic β-Ketoesters to Nitroolefins

dual activation (Scheme 11). The newly developed catalyst 6100 demonstrated high stereoselectivities (up to >99:1 dr and 97% ee) and yields (up to 99%) for a wide range of substrates. It was also revealed that both the guanidine group and the NH proton of the amide are important for the dual-activation mode by comparative experiments and X-ray diffraction analysis of the catalyst. The reactions were easily scaled up (up to 7.0 mmol) to facilitate the concise synthesis of ramipril analogues. In 2010, Pedrosa and co-workers101 reported the asymmetric conjugate addition of β-ketoesters to nitroolefins, catalyzed by a chiral thiourea, 7,102,103 which was easily prepared from L-valine. They found that only 2 mol % of catalyst 7 provided the products with two contiguous tertiary and quaternary stereocenters in high yields and excellent diastereoselectivies (up to >98:2 dr) and enantioselectivies (90−98% ee) (Scheme 11).101 Application of this method enabled them to synthesize GW3600 (closely related to rolipram), which is a potent inhibitor of PDE4. Molecules possessing the tetrahydroisoquinoline (TIQ) scaffold have been extensively evaluated due to their biological and pharmaceutical properties; however, they have been sparsely used as a source of chirality during the synthesis of ligands for asymmetric catalysis.104,105 In 2012, our group reported the Michael addition reaction of malonates and β-ketoesters with nitroolefins, employing a TIQ-based chiral guanidine organo-

cinchonine derived catalyst 9108 in DCM at room temperature, the β-ketoester substrates displayed high yields (up to 90%) and ee’s (up to 97%) with moderate diastereoselectivity (50:50−98:2 dr). The cyclic pronucleophiles displayed better dr’s when compared to the acyclic substrates; albeit, offering lowered yields and enantioselectivities. Following the interest in the use of greener solvents in organic chemistry, Song and co-workers reported the hydrogen-bonding mediated organocatalyzed enantioselective Michael addition reaction of 1,3-dicarbonyl compounds, including some cyclic β9380


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ketoesters, to nitrostyrene with brine as the solvent.109 With the employment of the bifunctional quinine derived squaramide organocatalyst 10,110 the Michael addition was dramatically accelerated with a higher level of enantioselection and reaction rates compared to that in organic solvents due to the hydrophobic hydration effect (Scheme 12). The optically active products were obtained in excellent yields (up to >99%) and enantioselectivities (up to >99% ee) with low catalyst loadings of 0.5 mol % in less than 20 min. A series of novel bifunctional squaramide multiple hydrogen bond donor organocatalysts were synthesized by the incorporation of well-known chiral scaffolds such as indanol and cinchona alkaloids by Dong’s group.108 These catalysts were evaluated on the Michael addition of various 1,3-dicarbonyl compounds and nitroolefins (Scheme 12). In the presence of just 1 mol % of catalyst 11,111 both acyclic and cylic β-ketoester containing product adducts were obtained in high yields (84− 90%) and with good to high selectivities (89−96% ee). The mechanism of the chiral bifunctional squaramide organocatalyst was also proposed by the transition state depicted in Figure 7, in

yield of the reaction decreased with an increase in size of the ester group on the acyclic ketoesters. Soos and Papai’s team used a joint experimental−theoretical study to compare the reactivity models of bifunctional squaramide-amine-catalyzed Michael reactions (ethyl 2-oxocyclopentane carboxylate and nitrostyrene using a simplified chiral bifunctional squaramide-amine catalyst) with bifunctional thiourea catalysis.77 Some important points of their study included: (1) the mechanism of the squaramide-catalyzed reaction is similar to that reported for thiourea catalysis with regard to the basic elementary reaction steps, (2) the observed stereoselectivity can be attributed to the protonated amine unit of the catalyst activating the electrophile, (3) in a squaramidecatalyzed reaction, other reaction pathways may become accessible (i.e., electrophile being activated by hydrogen bond donor unit of the catalyst), implying that a single pathway may not be sufficient to explain the stereoselectivity outcome, (4) the extended distance between the N−H bonds of the squaramide can offer alternative binding modes for the acceptor sites, and (5) the protonated catalyst forms a geometrically invariant chiral oxyanion hole that determines which transition pathway is followed and which enantiomer will be provided. Lu and co-workers113 used an extension of the Tan’s catalyst114 design by derivatizing the primary amine of their cinchona alkaloid core. Reaction studies of indanone βketoesters to nitroolefins in the presence of these urea and tosylated secondary amine of quinidine catalysts were undertaken (Scheme 13). Catalyst 14 yielded highly functionalized allScheme 13. Organocatalyzed Michael Addition of Cyclic βKetoesters to Nitroolefins

Figure 7. Proposed transition state of catalyst 11 for the Michael addition.

which the squaramide N−Hs and the indanol O−H activate the nitroolefin, while the cinchona alkaloid tertiary amine activates the 1,3-dicarbonyl compound. Therefore, the authors rationalized the nucleophilic attack to occur from the Si-face, leading to (S)-configuration in the product (which was assigned by comparison of the retention times with the reported literature). The additional hydrogen bond in this squaramide system plays a crucial role in enhancing the stereoselection, which was supported by methylation of the indanol OH group in catalyst 11 (Figure 7) that only gave 24% ee. Pursuing their work in the field of new chiral squaramide organocatalysts, Dong and co-workers introduced a BINOL based organocatalyst 12 (Scheme 12).112 This organocatalyst was evaluated on the Michael addition of various 1,3-dicarbonyl compounds to nitroalkenes. With the optimized conditions, the reaction proceeded well for a variety of aromatic nitroalkenes on 5- and 6-membered cyclic β-ketoesters (up to 99% ee and 99:1 dr) in good yields. The use of acyclic β-ketoesters resulted in a sharp decrease in diastereoselectivity (83:17 dr); however, excellent ee’s were maintained (up to 97% ee). In 2012, Pericàs and co-workers reported the immobilization of a chiral squaramide organocatalyst onto a polystyrene resin.111 Organocatalyst 13111 proved to be a remarkably active (at 2 mol %), easily recoverable, and highly reusable (up to 10x) organocatalyst for the asymmetric Michael addition of a variety of 1,3-dicarbonyl compounds to β-nitrostyrenes (Scheme 12). The β-ketoester containing products were obtained with good yields (60−98%) and excellent ee’s (89−96%). For acyclic substrates, the diastereoselectivities were negligible, while the cyclic pronucleophiles displayed better results. In addition, the 9381


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carbon quaternary Michael adducts with excellent enantioselectivities (90−96% ee) with no impact from substitution on the aromatic rings of the pronucleophile or the electrophile. On the basis of the observed experimental results, they proposed that the reaction proceeded via a dual activation model, in which the ketoesters and nitroolefins are simultaneously activated through their unique hydrogen-bonding interactions with the quinidine-derived sulfonamides, as demonstrated in Figure 8.

Figure 9. Possible activation models of the imidazoline catalyst 16, βketoester and nitrostyrene.

and stereoselectivities were as a result of changing from an ethylto a benzyl ester on the β-ketoesters. The authors proposed bifunctional organocatalysis was taking place in which the tertiary amine stabilized the ketoester enol intermediate and the 6hydroxy activated the nitroolefin, thereby creating a favorable hydrogen-bonding network in order for the reaction to proceed. Cascade reactions are useful in creating highly functionalized building blocks for the preparation of biologically active compounds. The use of asymmetric organocatalysis in this type of transformations has become a powerful tool for the synthesis of complex molecules with multiple stereogenic centers. Zhong and his team demonstrated the organocatalytic asymmetric domino Michael-Henry reaction (Scheme 14)

Figure 8. Proposed activation of catalyst 14 in Michael addition.

In 2010, Lai and Xu’s team reported the efficient organocatalyzed Michael addition of 1,3-dicarbonyl indane (β-ketoester derivative) compounds to nitrostyrenes.115 They tested a number of different diamine organocatalysts of which TsDPEN 15116 showed good yields (72−93%) and enantioselectivities (up to 84%) for a variety of substituted indanone pronucleophilic derivatives and nitrostyrenes (Scheme 13). Oxazolines are one of the most utilized structures for asymmetric synthesis, and imidazolines have been developed as their analogs.117 Since there are various substituents that can be introduced on the nitrogen atom of imidazolines for tuning the steric environment and electron density, their use as chiral ligands has grown rapidly.118 In 2010, Fujioka and co-workers119 designed and synthesized C3-symmetric molecules with three C2-symmetric components as Brønsted base catalysts for the enantioselective conjugate addition of α-substituted β-ketoesters to nitroolefins. This was the first report of a highly enantioselective reaction mediated by imidazoline derivatives as organocatalysts. The C3-symmetric chiral trisimidazoline 16119 catalyzed the reaction of β-ketoesters and nitroolefins, to afford the corresponding adducts with quaternary and tertiary stereocenters in one step (Scheme 13). Good to excellent yields (up to 99%) with high diastereo- and enantioselectivities (up to 96% ee) were attained using several nitroolefins and β-ketoesters. On the basis of the results that the catalyst required two imidazolines for the successful enantioselective addition to proceed, and that it acts as a Brønsted base in order to activate the β-ketoester, the authors postulated two activation models as depicted in Figure 9. The first model (A) involved the β-ketoester enolate could be hydrogen bonded to both imidazolines in order to discriminate the enantiotopic sides of the ester substrate. The second model (B) depicted that each imidazoline could hydrogen bond to the β-ketoester enolate and the nitroolefin, respectively. In both cases, the imidazoline moiety acted as a Brønsted base and proton donor. In 2014, Liu and co-workers reported the first Michael addition of β-fluoroalkyl-α-nitroalkenes to both cyclic and acyclic β-ketoesters.120 Upon evaluation of several cinchona alkaloid catalysts, the hydroxy derivative 17121 proved to be optimal in providing constantly high dr’s (up to 95:5) and excellent ee’s (up to 99%) under mild conditions (Scheme 13). The higher yields

Scheme 14. Cinchona-Derived Primary Amine Catalyzed Domino Michael-Henry Addition

catalyzed by 9-amino-9-deoxyepiquinine (18122).123 The thiourea derivative of 18 was initially investigated but the yields and selectivities could not be improved beyond 85% and 80%, respectively. The nucleophile was varied at the ester position without any change to yields or ee’s but led to a reduction in dr in the case of the methyl ester. The reaction scope was investigated to include various substituted nitrostyrenes and one example of a nitrodiene. The reaction was efficiently catalyzed by the plain primary amine catalyst 18, to provide cyclohexanes, with four stereogenic carbons, including two quaternary stereocenters in excellent selectivities (up to 99% ee and up to >99% dr). This was the first highly enantioselective Henry reaction of α-substituted β-ketoesters to nitroolefins catalyzed by an amino cinchona catalyst. The mechanism proposed by this group123 is presented in Figure 10. Both reagents form hydrogen bonds with the catalyst. 9382


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Figure 11. Proposed mechanism for domino Michael-Henry reaction with catalyst 19.

Figure 10. Proposed mechanism for domino Michael-Henry reaction with catalyst 18.

activates the 1,3-dicarbonyl species while the tertiary amine simultaneously activates the nitro group, thereby allowing the domino reaction with excellent stereoselectivity. Another example of a Michael/Henry domino reaction was reported by Enders and co-workers in 2014. They presented an asymmetric synthesis of highly functionalized indanols bearing four contiguous stereogenic centers, including a quaternary center through the use of very low loadings of a squaramide catalyst 10 with a quinine backbone (Scheme 16).124

The “Michael reagent” is proposed to interact with aliphatic tertiary amine, while the “Henry reagent” forms a hydrogen bond complex with the NH2 group. This preorganizes the reagents for subsequent asymmetric ring formation. In the same year, this group improved the scope of the amino quinine organocatalyst 18 for the facile enantioselective domino Michael-Henry synthesis (Scheme 14) of highly functionalized chiral cyclopentanes with four stereogenic centers (two quaternary and two tertiary stereocenters) with generally excellent yields (90−95%), enantioselectivities (88−96% ee), and complete diastereoselectivities.114 It was intriguing to note that a change of solvent to toluene and a lower temperature, as compared to their first report (diethyl ether and room temperature), resulted in improved enantioselectivity for the cyclopentane derivatives. Zhong and co-workers explored the feasibility of employing the quinine thiourea 19127 to catalyze the domino MichaelHenry reaction between trisubstituted carbon nucleophiles (β− ketoester derivatives) and nitroolefins (Scheme 15).80

Scheme 16. Quinine-Derived Squaramide Catalyzed Domino Michael/Henry Reaction

Scheme 15. Cinchona-Derived Primary Amine Catalyzed Domino Michael-Henry Addition This reaction allows easy access to polyfunctionalized indanes within 15−25 min at an impressive 0.5 mol % catalyst loading. The reaction was proposed to be triggered by the nucleophilic attack of cyclic 1,3-dicarbonyl derivatives such as β-ketoesters and 1,3-diketones. Catalyst 10 demonstrated high stereoselectivities (up to >99:1 dr. and 99% ee) and yields (better for nonfused cyclic β-ketoesters) for a wide range of substrates, thus facilitating a concise synthesis of polyfunctionalized indanes. In the same report, they also achieved a direct one-pot synthesis of the thermodynamic diastereomers of the cascade product via a facile dual-catalytic sequential protocol. Moreover, the catalyst loadings could be further reduced to 0.1 mol % in a gram-scale reaction without any detrimental effect on the diastereo- and enantio-selectivities of the product. In 2012, this group reported on the one-pot asymmetric organocatalytic synthesis of polyfunctionalized cyclohexanes via Michael/Michael/Aldol addition sequence, using the bifunctional norephedrine-based thiourea catalyst 20. They found that after stirring the β-ketoesters, nitroalkenes, and α,β-unsaturated aldehydes with catalyst 20, the corresponding products were formed with six contiguous stereocenters, including one quaternary center. The reactions proceeded with poor to good yields (22−70%) but generally with excellent diastereoselectiv-

The reaction proceeded smoothly to form the highly functionalized bicyclo[3.2.1]octanes with four stereogenic centers including two quaternary carbons with excellent yields (up to 93%) and enantioselectivities (92−96% ee) with complete diastereomic control. The substrate scope of the nitrolefin was successfully extended to a range of acceptors that contained neutral, electron-donating, electron-withdrawing groups, and heteroatoms on the phenyl ring. In order to gain theoretical insight on selectivity of this reaction, the authors performed conformational analysis of the possible transition states using DFT calculations. This confirmed a new the dual activation model (Figure 11) in which the thiourea group and an acidic proton present in the phenyl ring 9383


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Michael addition was followed by an in situ aza-cyclization/ dehydration reaction to give 1,4-dihydroquinolines (Scheme 20).129 The use of Taekemoto’s bifunctional thiourea catalyst 1 gave only the Michael adduct, and a Lewis acid was required to facilitate the second step. The Lewis acid was useful in activating the ketone and also catalyzing the dehydration. The authors evaluated catalyst 1 and cinchona-derived thiourea catalysts such as 19 that afforded poor to moderate yields. The most promising results for the benchmark reaction was obtained with the squaramide catalyst 10 in good yield (78% yield) and selectivity (90% ee). Varying the substituents on the aromatic ring of the nitro styrene did not significantly affect the yields or ee’s except when the group was NO2. The Michael donors were well tolerated, except with a lower yield when the ester was bulkiest (R = t-Bu). Also in 2012, Lu and his group modified the Feist− Benary130,131 reaction and synthesized L-threonine-derived tertiary amine/thiourea bifunctional catalysts that were used for the enantioselective domino Michael synthesis of highly functionalized 2,3-dihydrofurans in good yields and with excellent enantioselectivities. They evaluated several catalysts and observed that L-threonine-derived tertiary amine thiourea 21132 was most effective in yielding diastereomerically pure products with high enantioselectivities. The ester moiety had little influence on the reaction, but excess β-ketoester under dilute reaction conditions and lower reaction temperatures resulted in improved yields and selectivities. They also reported for the first time that the reaction proceeded well with a bromonitroolefin and an alkyl group, which is considered to be a challenging substrate (Scheme 21).133 Michael reactions of α-fluorinated pronucleophilic ketoesters with nitroolefins in the presence of cinchona alkaloids were reported by Lu and co-workers and was facilitated by catalyst quinidine thiourea 19,127,134,135 (Scheme 22).136 The results demonstrated that the substituent group at the α-position could improve the selectivities of the Michael adducts. The choice of the ketone moieties as the nucleophiles was also important for efficient stereochemical control. The combination of phenyl ketone and α-fluorinated groups on the ketoester yielded the desired products with moderate diastereoselectivities (60:20− 95:5 dr) but excellent enantioselectivities (96−99% ee). The products were subsequently converted to pyrrolidine and lactam derivatives. Also in 2009, Gong’s group reported the same reaction between nitrostyrene with α-fluorinated β-ketoesters

ities (up to >95:5 dr) and enantioselectivities (up to 99% ee) (Scheme 17).125 Scheme 17. Norephedrine-Derived Thiourea-Catalyzed Michael/Michael/Aldol Addition

This work was followed up by a report in 2015 whereby the α,β-unsaturated aldehyde was replaced with 2-arylidene indandiones to form spirocyclohexane indan-1,3-diones bearing five adjacent stereogenic centers (Scheme 18) utilizing catalyst 9.126 The initial Michael reaction between the nitro alkene and βketoester gave an adduct of which the authors were unable to determine its stereoselectivity. They continued to the final product with the addition of α,β-unsaturated indandi-one and a base. Seven cinchona-derived squaramide catalysts and one thiourea bifunctional catalyst was evaluated with very close results with respect to yields and selectivities. Aliphatic nitroolefins did not result in product formation, while all forms of the aromatic versions did with acceptable yields (47−68%) and stereoselectivies (1:1−20:1 dr and 28−92% ee). Substitutions on R2 of the 2-arylideneindanone gave results that were scattered. In 2012, the Enders group introduced a one-pot thioureacatalyzed synthesis of polyfunctionalized chroman derivatives via domino Michael−hemiacetalization and domino Michael− lactonization reactions. Quinine thiourea catalyst 19 gave good yields (up to 86%) for cyclopentanone pronucleophile with significantly lower rates and yields for the cyclohexane analogue. The ee’s (83−99%) were also more favorable for the smaller ring size β-ketoester, and excellent dr’s were obtained in all cases. Subsequently, the intermediate chromanols were transformed to acetals, lactones, and hexahydrocyclopenta chromenes containing up to three contiguous stereocenters (Scheme 19).128 Another example of a cascade reaction by an asymmetric Michael addition of β-ketoesters with β-nitrostyrenes via organocatalysis was reported by the group of Kim in 2015. The

Scheme 18. Cinchona-Derived Squaramide-Catalyzed Michael/Michael/Aldol Addition

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Scheme 19. Cinchona-Derived Thiourea-Catalyzed Domino Michael−Hemiacetalization or Lactonization and Dehydration Reaction

Scheme 20. Cascade Michael Addition and Followed by an in Situ Aza-Cyclization and Dehydration Reactions

affect the stereochemical outcome of the reaction, and the absolute stereochemistry of the products was confirmed by single X-ray crystal analysis. The corresponding product was converted to synthetically useful chiral pyrrolidines by RANEY-Nimediated hydrogenation.137 2.1.2. Reactions of β-Ketoesters with Unsaturated Aldehydes or Ketones. As an extension to the enantioselective Michael addition reactions,138 Szöllösi and Bartok139 exploited the addition of cyclic β-ketoesters to methyl vinyl ketone derivatives catalyzed by cinchona alkaloids. They employed basic derivatives of cinchonine and quinine with various substitutions at position C6′ and a hydroxyl group on C9. The results revealed that the induced enantioselectivities were significantly influenced by both the structure of the catalyst and the substrate. The presence of a methoxy group at C6′ decreased the reaction rate but enhanced the enantioselectivity as can be observed with quinidine (22)140,141 as the catalyst. The effect of the structure of the alkaloid on the enantioselectivity of this reaction revealed interesting differences in the case of the three β-ketoesters that were studied (Scheme 23). The results for ethyl 2-oxocyclo-

Scheme 21. L-Threonine-Derived Thiourea-Catalyzed Domino Michael Alkylation between Ethyl 3-Oxobutanoate and Bromonitrostyrenes

using another cinchona derived catalyst (i.e., 3 with similar results) (Scheme 22).137 Upon screening of the reaction conditions, 10 mol % of the amino quinine catalyst 3 in DCE at room temperature was found to be optimum; the reaction proceeded smoothly for both aromatic and aliphatic nitroolefins. The electronic nature of substituents on the aromatic rings of the nitroolefins did not 9385


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these reactions, while lower reaction temperatures did not improve the optical purity. The polymer-supported cinchona alkaloid for the conjugate addition of β-ketoester and methyl vinyl ketone was introduced by d’Angelo and Cavé with catalyst 24 (Scheme 24).144 They reported that the 7 atom-length spacer between the support and quinine was optimum for chiral induction.

Scheme 22. Cinchona Derivative Catalyzed Michael Addition of Fluorinated β-Ketoesters to Nitroolefins

Scheme 24. Cinchona-Derived Catalyzed Michael Addition of Indanone-Derived β-Ketoester to Methyl Vinyl Ketone

Scheme 23. Organocatalyzed Michael Additions of Cyclic βKetoesters to Methyl Vinyl Ketone or Acrolein In 2006, Hodge and his team described the first organocatalyzed Michael reaction on a continuous benchtop flow system.145 This presented an interesting application of the Michael addition of β-ketoester to acrolein using polymersupported cinchonidine 25145 as the organocatalyst that provided the product in 97% yield and 51% ee (Scheme 24). Comparable results were obtained for both regular cinchonidine (91%, 58% ee) and the polymer-supported cinchonidine (98%, 47% ee) under batch conditions (at 5 mol %). The procedure appeared to have operational simplicity, where the reagents in toluene are pumped through a tube filled with catalyst and the product is collected at the top. To maintain the desired reaction temperature, the tube was placed in a water bath. In 2006, Wang’s group reported the conjugate addition reaction of various nucleophilic enol intermediates and α,βunsaturated systems. They employed a bifunctional cinchona alkaloid thiourea catalytic system with 26146 that displayed acid− base interactions. The β-ketoester product was obtained in 93% yield and 90% ee but with poor diastereoselectivity (Scheme 25).147 Deng and co-workers reported the conjugate addition of αsubstituted β-ketoesters to methyl vinyl ketones, employing a pentanecarboxylate were reasonable (90% yield with 83% ee). However, the same reaction conditions with ethyl 2oxocyclohexanecarboxylate or 2-acetylbutyrolactone gave poor yields and stereocontrol. To improve selectivities, a new class of catalysts was designed by Jørgensen and co-workers.142 Amination of the C5 position on the hydrocupreidine derivative of 2 resulted in cinchona alkaloids with nonbiaryl atropisomeric functionalization. It was observed that hindered rotation around the N-CAryl bond rendered the compounds chiral atropisomers. The effectiveness of aminated quinine catalyst 23142,143 and its diasteromers or chiral atropisomers for the Michael addition of β-ketoesters to acrolein and methyl vinyl ketone was demonstrated with up to 99% yields and 93% ee’s, respectively (Scheme 23). Solvent screening revealed that iodobenzene was the most effective for

Scheme 25. Cinchona-Derived Thiourea-Catalyzed Michael Addition of Ethyl 2-Oxocyclopentanecarboxylate to Chalcone

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derivative of their earlier developed catalyst 2.90 The quinoline OH was protected with more sterically demanding ether groups on the secondary alcohol.148 The quinine catalyst, 3, provided the optimal results (Scheme 26). Substrates with adjacent

Scheme 28. Cinchona Derivative Catalyzed Michael Addition of Indanone β-Ketoesters to Acrylic Esters

Scheme 26. Cinchona Derivative Catalyzed Michael Addition of Cyclic and Acyclic β-Ketoesters to Vinyl Ketones

Michael acceptors with aromatic R1-groups, such as benzylideneacetone and chalcones, gave poor or no yields. The products were easily transformed to the synthetically useful hexahydrophenanthrene structures via the Robinson annulation under mild conditions and in good yields. 2.1.3. Reactions of β-Ketoesters with Imines. The asymmetric Mannich reaction is another powerful carbon− carbon bond forming tool, and it allows for the preparation of optically enriched β-amino carbonyl compounds.153,154 Traditionally, asymmetric Mannich reactions were catalyzed by chiral transition−metal complexes.155−157 The first organocatalytic Mannich reaction was described in 2000 by List utilizing Lproline as a catalyst.158 Since then, many asymmetric Mannich reactions involving organocatalysis have been developed.159−161 The Jørgensen group presented the first account of highly enantioselective and diastereoselective two component Mannich reactions between β-ketoesters and α-imino esters in which they extended the use of α-aryl cyanoacetates to β-ketoesters with αimino esters (Scheme 30).162 In the presence of a commercially available cinchona derivative (DHQD)2PYR (28)163,164 as the chiral organocatalyst, this reaction yielded the product with 96% ee and 98:2 dr. In 2005, Schaus and colleagues165 reported a two component Mannich reaction in which acyl imines were reacted with βketoesters (Scheme 31) using the commercially available cinchonine as the catalyst 29.166 The mixtures of diastereomeric products were subjected to decarboxylation facilitated by Pd(II) or formation of the Z enamine with benzylamine and Yb(OTf)3. These Mannich products were obtained with excellent yields and 81−96% ee and 50:50−99:1 dr. The products were further utilized for the synthesis of enantio-enriched dihydropyrimidones and β-amino alcohols. Schaus’s team also developed organocatalytic methods to synthesize the pharmaceutically relevant SNAP-7941, a potent melanin-concentrating hormone receptor antagonist.167 The first method utilized a cinchonine alkaloid-catalyzed Mannich reaction of β-ketoesters to acylimines, while the second was the chiral phosphoric acid-catalyzed three-component Biginelli reaction (vide infra). These methods gave rise to the enantioenriched dihydropyrimidone core that was subjected to selective urea formation at the N3 position with 3-(4-phenylpiperidin-1yl)propylamine as the side chain fragment to furnish SNAP7941. The results showed that both procedures were equally effective. For the two-component Mannich reaction of βketoesters and acylimines, cinchonine (29) proved to be the optimal organocatalyst, providing high yields and selectivities of the desired intermediate heterocycles (Scheme 32). In 2009, the group of Kim168 reported the two component Mannich reaction of β-ketoesters with N-Boc-aldimines in the

quaternary−tertiary stereocenters were reported to undergo enantioselective and diastereoselective conjugate additions of cyclic/acyclic pronucleophiles to β-substituted α,β-unsaturated ketones with up to 99% yield and 99% ee.148 Deng’s group149 demonstrated that α,β-unsaturated aldehydes could also be used as efficient electrophiles to generally give excellent yields and ee’s (Scheme 27). Catalyst 3 was effective for a broad range of conjugate additions of various α,β-unsaturated aldehydes to α-substituted β-ketoesters. Scheme 27. Cinchona Derivative Catalyzed Michael Addition of Cyclic and Linear β-Ketoesters to α,β-Unsaturated Aldehydes

In 2008, the Dixon group further extended the scope of the Michael addition reaction to indanone-derived β-ketoesters with acrylic esters, thioesters, and N-acryloyl pyrrole, employing a range of catalysts. The best result obtained was with Deng’s bifunctional alkaloid-derived90,94,148 organocatalyst 3, in which the methoxy group was removed from the quinolone moiety and the secondary alcohol converted into an ether with the application of either a benzyl or phenanthrene (PHN) group. The adducts were obtained with yields up to 96% and excellent enantioselectivities (67−98% ee) (Scheme 28).150 It was demonstrated that superior results are obtained with hexafluoroisopropyl esters on the pronucleophile. Acyclic β-ketoesters were found to react slower and with reduced enantioselectivies. In 2010, Ye’s group151 reported an efficient approach for the enantioselective Michael addition reaction between tetralone type β-ketoesters to α,β-unsaturated ketones. They employed a novel multifunctional quinine thiourea organocatalyst 27152 in these reactions (Scheme 29). The resulting Michael products were obtained in good to excellent yields (75−98%), diastereoselectivities (up to >99:1), and enantioselectivities (up to 97% ee) for a variety of alkyl vinyl ketones. However, 9387


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Scheme 29. Cinchona-Derived Thiourea-Primary Amine Catalyzed Michael Addition of Cyclic β-Ketoesters to α,β-Unsaturated Ketones

O-ethyl tetronic acid derivatives in a one-pot intramolecular cyclization reaction in the presence of triethylamine; products were formed in moderate to good enantioselectivities (60−91% ee). The para-substituent at the phenyl ring on the imine seemed to have a significant effect on the ee’s (i.e., lower enantioselectivities), irrespective of whether electron-withdrawing or electron-donating groups were introduced, whereas orthoand meta-substituents improved results. Cyclohexyl on the NBoc-imine provided a lower yield and enantioselectivity when compared with the phenyl N-Boc-imine substrate. Furthermore, the authors modified the products so they could be readily converted into heteroatomic mimics of prostaglandins, known for antiaggregatory effects (Scheme 34).174 In 2015, Jacobsen and Roche’s team reported Takemoto’s thiourea catalyst 1 induced chloride abstraction of αchloroglycine ethyl ester to generate an electrophilic acyliminium ion that was available for nucleophilic addition with various βketoesters (Scheme 35).175 The corresponding Mannich products were obtained with moderate-to-high enantioselectivity and tolerated electron-neutral or -deficient aryl ketone groups, the electron-deficient substituents afforded the highest enantioselectivities, whereas sterically large benzhydryl esters significantly increased the enantioselectivity of the reaction. Although the specific mechanism of this type of hydrogen-bonding catalysis was not yet confirmed, based on experimental observations, the authors concluded that interactions involving aromatic substituents on the substrates played a vital role

Scheme 30. Dihydroquinidine-Catalyzed Mannich Reaction of a Benzyl 1-Oxo-2,3-dihydro-1H-indene-2-carboxylate and α-Imino Esters

presence of binaphthyl-based bifunctional organocatalysts, 30.169 This catalyst was developed by Schaus and co-workers165,167,170,171 and applied to the enantioselective Michael addition of 2,4-pentandione to nitroalkenes. It was then adopted by Kim and co-workers in two alternative organocatalytic reactions.169,172 For the Mannich reactions, the catalyst gave overall excellent diastereoselectivities (up to 99:1 dr) and enantioselectivities (up to 99% ee) of the adducts (Scheme 33). In 2011, Yan and co-workers173 reported the organocatalytic asymmetric Mannich reaction of ethyl 4-chloro-3-oxobutanoate with N-Boc-imines facilitated by the pyrrolidine-based thioureatertiary amine catalyst 31.84 The catalysts were based on those of Takemoto84 but with increased steric hindrance. They prepared

Scheme 31. Cinchonine-Catalyzed Mannich Reaction of Linear β-Ketoesters with Acylimines

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Scheme 32. Cinchonine-Catalyzed Mannich Reaction as Part of the Synthesis for SNAP-7941

compared to the aliphatic analogues. The resulting products were converted to β-amino acids and β-lactams with good efficiencies (Scheme 36). In 2011, Kim and co-workers177 improved on this conversion by employing their previously most successful organocatalyst 30. This resulted in obtaining the β-aminated α-fluoro-β-ketoesters with good yields and excellent enantioselectivities (81−98%) (Scheme 36). 2.1.4. Reactions of β-Ketoesters with Maleimides. The group of Bartoli and Melchiorre introduced the first asymmetric conjugate addition of β-ketoesters to maleimides promoted by commercially available quinine 33270 and quinidine 22 as the organocatalysts (Scheme 37).178 The optimized reaction tolerated a range of cyclic and acyclic β-ketoesters with N-benzyl maleimide (up to 99% yield, 99% ee, and 92:8 dr). A decreased reactivity was observed for the acyclic β-ketoesters, and in these cases the larger ester group resulted in significantly higher stereoselectivity. For the same reaction, the Cui group showed that a polymersupported quinine organocatalysts could be successfully applied.179 Catalyst 34 was evaluated on cyclic and acyclic βketoesters with up to 90% yield and moderate selectivity of up to 86% ee (Scheme 37). The reaction at lower temperature marginally improved the enantioselectivity (88% ee). The catalyst proved to be recycled 6 times with only a slight decrease (86 to 79% ee) in selectivity while the reaction proved to be scaled up 100 times without any loss of the catalyst efficiency. In 2014, Cui followed up this work by introducing the silica supported quinine organocatalyst 35.180 It improved the enantioselectivity and diastereoselectivity to 91% ee and 96:4 dr, respectively, at 0 °C. In 2009, Tan and co-workers reported a highly enantioselective and diastereoselective reaction using α-fluorinated βketoester as the nucleophile similar to the work of Lu and colleagues136 at the time.181 In the presence of 5.0 mol % of bifunctional guanidine-based organocatalyst 36,182 2-substituted benzoylacetates such as substituted aryl α-fluoro-β-ketoesters and various N-alkyl maleimides underwent conjugate additions to afford Michael adducts (Scheme 38) with excellent yields (80−99%). The reaction product adducts, having a chiral fluorine atom and contiguous chiral centers, were obtained in excellent enantioselectivities (83−99% ee) and diastereoselectivities (up

Scheme 33. Binaphthyl-Derived Thiourea-Catalyzed Mannich Reaction of Methyl 2-Oxocyclopentanecarboxylate with N-Boc-Aldimines

Scheme 34. Pyrrolidine-Derived Thiourea-Catalyzed Mannich Reaction of Ethyl 4-Chloro-3-oxobutanoate and NBoc-imines and the Cyclisation to O-Ethyl Tetronic Acid Derivatives

controlling both reactivity and enantioselectivity on this Mannich reaction. In 2009, Lu’s group176 synthesized tryptophan-based bifunctional thiourea derivatives from natural amino acids which were utilized for the asymmetric Mannich reaction between α-fluoroβ-ketoesters and N-Boc-imines. These catalysts proved to be superior to urea-quinidine analogues. Here the designed catalyst 32176 provided the required products with fluorinated quaternary and tertiary stereocenters in a range of dr’s (50:50−99:1) and respectable ee’s (81−99%). Generally, good selectivities were observed with aromatic α-fluorinated β-ketoesters when 9389


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Scheme 35. Takemoto’s Thiourea-Catalyzed Mannich Reaction of β-Ketoesters with Acyliminium Ions

Scheme 36. Organocatalyzed Mannich Reaction of Fluorinated β-Ketoesters and N-Boc-imines

Scheme 37. Cinchona-Derived Catalyzed Michael Additions of β-Ketoesters to Various N-Benzyl Maleimide

to >99:1 dr). The origin of the remarkable stereoselectivities and the mechanism of the catalytic reactions were investigated by DFT methods. The authors proposed that the reaction was initiated by a proton transfer (i.e., fluoro-β-ketoester) to the bifunctional catalyst; this in turn created a hydrogen-bonded network between the guanidinium cation and the ketoester anion. The most energetically favored transition state was that which led to the (S,R)-stereoisomer product (Figure 12), in agreement with the observed experimental results. Remarkably, a hydrogen bond with guanidinium NH proton was formed with only one of the two carbonyl oxygens from the β-ketoester in all cases. A halogenated cinchona catalyst 37183 was later evaluated for this reaction by Zhang and colleagues (Scheme 38).184 Although the results did not improve on the earlier report, it demonstrated that the catalyst attached with a perfluoroalkyl tag could be efficiently recovered by fluorous solid-phase extraction (F-SPE). Also in 2013, Zhang’s group demonstrated that N-alkylated maleimides were efficient electrophiles with fluorinated βketoesters to obtain the corresponding products in excellent yields (90−98%) with good to excellent ee (77−94%) and dr (99:1).185 This was achieved with recyclable fluorous bifunctional organocatalyst 38 (Scheme 38). 2.1.5. Reactions of Alkylidene-Type β-Ketoesters. Alkylidene or unsaturated β-ketoesters have recently become popular substrates in the field of asymmetric catalysis;186 however, reports within the circle of enantioselective organocatalysis remain few. Interestingly, the role of the β-ketoester changes to become the electrophile in these cases, as compared

to being the nucleophilic reaction partner in the examples above. Scheidt and co-workers communicated the first example of an asymmetric intramolecular oxo-conjugate addition of unsaturated β-ketoesters with quinine thiourea type organocatalyst 39187 (Scheme 39).187 The intramolecular ring closure furnished flavanone and chromanone derivatives in high enantioselectivities upon subsequent acid-catalyzed decarboxylation (Scheme 39). The reactions did not proceed in the absence of the ester moieties on the pronucleophiles, and the authors concluded that a second basic site was necessary for additional interaction with the hydrogen-bonding catalyst to favor cyclization and increase reactivity. The saturated analogue of the starting β-ketoester material (Scheme 39) was also reacted with hydrocinnamaldehyde in a tandem Knoevenagel-conjugate addition reaction to provide the natural product flindersiachromanone in a 77% overall yield and with 80% ee after decarboxylation. In 2011, Zhao’s group reported that this intramolecular cyclization could be efficiently catalyzed by quinidine catalyst 40166 (Scheme 39).188 The authors also extended the study to use other 9390


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Scheme 38. Organocatalyzed Michael Additions of Fluorinated β-Ketoesters to Various N-Alkyl Maleimides

addition. All examples led to the desired flavanone derivatives in high yields (82−97%) and (72−90% ee) under mild reaction conditions. In 2012, Ghosh and co-workers showed application to Schiedt’s method in the total synthesis of (−)-lithospermic acid, a potent anti-HIV agent in which this oxa-Michael reaction formed one of the many synthetic steps (Scheme 39).189 It was achieved with the respective β-ketoester and catalyzed by chiral quinidine-derivative catalyst 17. The resulting product was treated with acid to provide the desired chromanone intermediate in 97% yield and 99% ee after recrystallization. The first example of an enantioselective intramolecular azaMichael addition using unsaturated β-ketoesters was reported by

Figure 12. Transition state between the maleimide and guanidinium/ ketoester ion-pair leading to the product, as calculated with DFT.

electrophiles (methyl vinyl ketone, N-bromosuccinimide, and Nchlorosuccinimide) instead of acid treatment to promote an electrophilic cascade reaction after the intramolecular Michael

Scheme 39. Cinchona-Derived Thiourea-Catalyzed Intramolecular Ring Closing Oxo-Conjugate Addition of Unsaturated βKetoesters

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You’s group catalyzed by the binaphthyl derived N-triflyl phosphoramide 41 (Scheme 40).190

reaction provided the Michael adducts with high selectivities of up to 98% ee, 99:1 dr, and yields up to 96%. The saturated βketoester moieties in combination with nitro-alkanes were also utilized as nucleophiles in another Michael addition with methyl vinyl ketone (MVK) in a tandem reaction with excellent enantioselectivities but moderate yields. In 2011, Lu and his group reported another application of their tryptophan-derived tertiary amine-thiourea catalyst 32 with application in the oxa-Michael−Michael cascade reaction between alkylidene β-ketoesters and nitroolefins. Organocatalyst 32,176 which they had previously used for asymmetric Mannich reactions of α-fluorinated β-ketoesters, afforded the 3,3disubstituted 4-chromanones cascade products as a single diastereoisomer and high enantioselectivities (Scheme 42).193 Markedly, the reaction was applicable to nitroalkenes containing either hetereocyclic rings or alkyl functional groups. Electronrich aryl substituted alkylidene β-ketoesters promoted the reaction more efficiently, while the electronically neutral phenol-substituted analogues afforded the products with excellent ee’s, although in moderate yields. The products were easily converted to biologically applicable fused and spiro tricyclic chromans. In 2013, continued efforts by Bella reported the addition of imides to alkylidene type/unsaturated β-ketoesters (Scheme 43).194 An integrated approach was developed by screening various organocatalysts with Lewis acid additives, as well as the exploration of a computer-aided setup of the experiments incorporating a variety of parameters. Cinchonidine-derived thiourea organocatalyst 43194 emerged to be optimal with the addition of camphor sulfonic acid (CSA), which was applied to a variety of imides providing moderate reaction yields and high selectivities up to 91% ee and 95:5 dr (Scheme 43). Generally, the phthalimide substrates resulted in much lower diastereoselectivities. Furthermore, the amide and ester functionalities of products were cleaved to afford biologically interesting cyclic hydroxy amino acid analogues. Bella’s team also pioneered the use of unsaturated β-ketoesters with prolinol-derived aminocatalysts, extending their methodology to aldehydes (vide infra). In 2009, Zhao reported another tandem intramolecular oxaMichael addition/electrophilic fluorination reaction to access chiral fluorinated flavanones (Scheme 44).195 The alkylidene substrate first underwent an intramolecular oxa-Michael addition in the presence of a quinidine-derived catalyst 44 followed by electrophilic fluorination with N-fluorobenzenesulfonimide. The monofluorinated flavanones were obtained in high enantioselectivities (up to 96% ee), and excellent yields (up to >99%) were obtained for most of the substrates under mild conditions forming only one diastereomer in all cases. Although the reaction proceeded well for aromatic substituents on the alkane, aliphatic groups resulted in lowered enantioselectivity. In order to obtain the R-configured product, the oxygen nucleophile had to attack the Re face of the double bond on the electrophilic unsaturated β-ketoester. The authors then proposed the hydrogen-bonding interactions with the bifunctional catalyst as the transition state model for the enantiodiscriminating oxaMichael addition step (Figure 14). The Liu and Feng group performed an enantioselective azaMichael addition reaction/electrophilic bromomination with Nbromosuccinimide (NBS) leading to chiral dihydroquinones.196 Bisguanidium organocatalyst 45 promoted the reaction of a variety of unsaturated β-ketoesters (Scheme 44). In contrast, the intramolecular cyclization reaction prior to bromination also

Scheme 40. Organocatalyzed Intramolecular Ring Closing Aza-Conjugate Addition of Unsaturated β-Ketoesters

Similar to Scheidt’s results, the tert-butyl ester was necessary to activate the double bond for any reactivity. Following the acidcatalyzed decarboxylation step, the enantioenriched 2-aryl-2,3dihydroquinolin-4-(1H)-one products was obtained in excellent yields (77−98%) with up to 82% ee. In the same year, Lu and coworkers reported a similar transformation using a tosyl-protected nitrogen on the alkylidene ketoester rather than an acetyl group that was used by You (Scheme 40) with catalyst 41.191 In comparison, Lu’s reaction proceeded with slightly lower yields (70−91%) but higher selectivity (78−98% ee) for the aromatic substrates using the bifunctional thiourea catalyst 42. The authors proposed that the thiourea moiety on the catalyst binds to the substrate via hydrogen-bonding interactions (Figure 13).

Figure 13. Proposed model of the reaction transition state.

This allows removal of the acidic sulfonamide proton by the tertiary amine group on the catalyst, in order to facilitate the conjugate addition from its Si face in order to furnish the observed major stereoisomer. In 2010, Bella and team made use of α,β-unsaturated βketoesters as an electrophile in the Michael-type addition reaction with nitro-alkanes, which were activated as nucleophiles with quinidine as the organocatalyst 22 (Scheme 41).192 The 9392


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Scheme 41. Quinidine-Catalyzed Michael-Type Additions on Unsaturated β-Ketoesters

Scheme 42. Tryptophan-Derived Thiourea oxa-Michael−Michael Cascade Reaction with Unsaturated β-Ketoesters and Nitroolefins

Scheme 43. Cinchona-Derived Thiourea-Catalyzed Addition of Unsaturated β-Ketoesters with Imides

Scheme 44. Organocatalyzed Intramolecular Ring Closing Aza or Oxo-Conjugate Addition Unsaturated β-Ketoesters

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ketoesters with dibenzyl azodicarboxylate.201 The acyclic pronucleophiles (i.e., the ketoesters) displayed much slower reaction rates and moderate selectivities. However, the cyclic βketoesters readily underwent the reaction in poor to good ee’s (77−90%) and yields (51−99%). Very good reactivities and ee’s ranging from 42−64% were also obtained with cyclic β-keto lactones. As expected, cinchonidine (47)202 and cinchonine (29) gave opposite enantiomers as the major product. Generally, marginally better enantioselectivities were achieved with cinchonine compared to cinchonidine. Quinine and quinidine yielded significantly poorer results, which the authors attributed to the small difference in basicity of the methoxyquinoline functionality or to conformational differences of these cinchona alkaloids (Scheme 45). In 2006, Takemoto and co-workers203 investigated the organocatalytic α-hydrazination of β-ketoesters with azodicarboxylates as electrophiles facilitated by their previously reported urea catalyst, 48204,205 (that was also independently reported by Berkessel’s group in the same year).204,206 Efficient results were obtained for mono and bicyclic 1,3-dicarbonyl compounds; however, the catalyst was intolerable to acyclic β-ketoesters. Furthermore, the authors transformed the obtained products into optically active amino acid derivatives, which are valuable chiral building blocks containing a nitrogen-substituted quaternary stereocenter (Scheme 45). Terada and co-workers207 developed a new class of binaphthyl-derived guanidine bases as highly active and enantioselective catalysts for a 1,4-addition reaction of nitroalkenes with 1,3-dicarbonyl compounds. They improved the design of their initial catalyst through a new type of axially chiral guanidine catalyst within a seven-membered-ring structure. Upon protonation of the catalyst 49,207,208 the guanidinium ion allowed for potential formation of multihydrogen bonds through the N−H protons and renders the catalyst C2 symmetric. These catalysts were explored for the electrophilic amination of unsymmetrically substituted 1,3-dicarbonyl compounds. Following the optimization of the reaction conditions, they investigated the scope of the catalytic enantioselective amination of βketoesters. Utilizing the organocatalyst 49 (Scheme 45), the corresponding products were obtained in good yields with high ee’s (up to 98%) even when the catalyst loading was decreased from 2 to 0.05 mol %. The dramatic change that was observed in the stereochemical outcome between the cyclic and acyclic pronucleophiles could be ascribed to the differences in the preferred mode of binding. In their proposed mechanism (Figure 15), multihydrogen bonding interactions between oxygen atoms and the N−H protons generates two binding modes of the ion pairs from 49

Figure 14. Proposed model of the reaction transition-state with organocatalyst 44.

performed well with the same catalyst for a range of substrates with excellent yields and dr (up to 99%). 2.1.6. Reactions of β-Ketoesters with Heteroatoms. Brønsted base catalysis has also been employed for reactions of βketoesters with heteroatom-containing substrates. In an effort to expand the substrate generality of the first organocatalytic, highly enantioselective, amination of substituted α-cyanoacetates, Jørgensen and co-workers197 developed the α-amination of various β-ketoesters with di-tert-butyl azodicarboxylate. The quinidine-derived alkaloid β-isocupreidine (ICD) 46198,199 (or Hatakeyama’s catalyst200) as was the organocatalyst of choice; the reaction proceeded smoothly for both acyclic and cyclic βketoesters that yielded the desired aminated products with excellent yields (86−99%) and ee’s (83−90%) (Scheme 45). In 2004, Pihko and Pohjakallio reported the use of simple cinchona alkaloids (i.e., cinchonidine, cinchonine, quinine, and quinidine) as organocatalysts for the α-amination reactions of βScheme 45. Organocatalyzed α-Amination of Cyclic and Acyclic β-Ketoesters with Azodicarboxylates

Figure 15. Binding mode of the ion pair derived from catalyst 49 with enolate β-ketoester. 9394


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Scheme 46. Organocatalyzed α-Amination of Cyclic and Acyclic β-Ketoesters with Azodicarboxylates

could possibly activate the quinoline ring in 50 toward the FridelCrafts amination that led to its decomposition. While the equilibrium between acyclic β-ketoester and its corresponding enol exists, the equilibrium with the cyclic analogue was more favourable towards the enol, which promotes the formation of the catalyst-substrate complexes hence disfavoring the formation of the dimer or oligomer. This results in suppression of the decomposition of the catalyst while enhancing the enantioselective amination of the cyclic β-ketoesters. This methodology was also utilized for the synthesis of α-methylserine, an intermediate used in the total synthesis of conagenin, a small molecule immunomodulator. In 2010, Rawal and his group211 developed a new family of squaramide hydrogen-bonding catalysts for this transformation. Squaramide 51 211 turned out to be superior in the enantioselective α-hydrazination of cyclic β-ketoesters with azodicarboxylates. High yields (90−99%) and high enantioselectivities (88−98% ee) were achieved with low catalyst loading (0.1−2.0 mol %) under relatively mild conditions. It demonstrated application to a wide scope of cyclic β-ketoesters and was not significantly affected by the electronic and steric variations of the substrate’s ester group (Scheme 46). Interestingly, the pronucleophiles, bearing six- and sevenmembered rings, were also well tolerated, yielding high yields and selectivities in fairly short reaction times. In 2011, Wang and team reported the efficient asymmetric amination of cyclic β-ketoesters with dialkyl azodicarboxylates using bifunctional amine-thiourea organocatalyst 5296,212 bearing multiple hydrogen bond donors213 (Scheme 46) that plays a significant role in enhancing the reactivity and enantioselectivity. Upon catalyst screening, the presence of the CF3 groups on the aromatic ring of sulfonamide was necessary for efficiency. The amount of catalyst was crucial for this reaction as the enantioselectivity decreased from 81% to 54% when the catalyst loading was reduced from 10 to 5 mol %. Protic solvents gave racemic products (due to a background reaction or reaction between the catalyst and the azodicarboxylate), and solvents such as DCM, PhMe, and DMSO gave poor selectivities, while the ethereal solvents provided best results. With the utilization of 10

along with an enolate form of the substrate. During catalyst screening, 49 was clearly superior to reported organocatalysts for the enantioselective amination with respect to the catalyst loading, catalytic activity, and asymmetric induction.207 Simón and Goodman used computational techniques to determine the mechanism of the chiral amination of β-ketoesters by azadicarboxylates, catalyzed by Terada’s axial 3,3′-substituted BINOL guanidine organocatalyst.209 They used Onion calculations with DFT for the substrate and the atoms of the catalyst involved in hydrogen bonding with the substrate. The transition states for both acyclic and cyclic β-keto esters was calculated and enantioselectivity predicted correctly. The results show that the catalyst acts simultaneously as a Brønsted base and an acid catalyst, the mechanism is similar to that proposed by Terada. They also concluded the configuration of the cyclic (Z configuration) and acyclic enolates (E configuration) in the transitions state led to the reversal of the stereochemistry in the respective products. Although this was observed experimentally in many publications, this was the first theoretical study to justify this reversal in optical configuration. In 2009, Deng and his group reported the highly enantioselective amination of α-alkyl β-ketothioesters, trifluoroethyl α-methyl α-cyanoacetate, and β-ketoesters employing a bifunctional cinchona alkaloid catalyst 5090 (Scheme 46).210 This study was initiated by the amination of cyclic β-ketoesters, which proceeded well to the corresponding products in excellent yield and enantioselectivity with just 1 mol % or less catalyst loading. The amination of the acyclic versions of the pronucleophiles proceeded in less than 20% conversion and afforded the products in very poor ee’s even when 10 mol % of 50 was employed. Upon analysis of the reaction mixture, a Friedel−Crafts amination of the catalyst with di-tert-butyl diazocarboxylate had occurred resulting in decomposition of the catalyst. The authors were then able to rationalize the cause of the dramatic difference between the 50-catalyzed amination of cyclic-α-substituted βketoesters and that of acyclic β-ketoesters210 due to dimerization or oligoromization of the catalyst by which the hydrogen bond interactions between the 6′-OH and the quinuclidine nitrogen 9395


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mol % of catalyst 52, the α,α-disubstituted amino acid products were achieved with 86−98% yields and 69−97% ee’s. Steric bulk of the ester substituent of the azodicarboxylate had no influence on the selectivity, which was the opposite trend as compared to Takemoto’s thiourea catalyst203 for the same transformation. In 2015, Dong and co-workers extended the application of their BINOL-quinine-squaramide organocatalyst 12112 to the enantioselective α-amination of β-ketoesters as well as αsubstituted α-cyanoacetates with azodicarboxylates (Scheme 46).214 It afforded chiral α-amino acid precursors in high yields and excellent enantioselectivities (up to 99% ee). Varying both the ester on the oxocyclopentane backbone and various protecting groups on the azodicarboxylates afforded the corresponding products in excellent ee and yield (up to 99%). The results for this transformation appear to be the best achieved so far. The squaramide organocatalyst also proved to be recovered and reused for five catalytic cycles without loss of activity and enantioselectivity. The authors postulated a transition state model to explain the excellent results in which the organocatalyst was assumed to form multiple hydrogen bonds with both substrates as depicted in Figure 16.

Scheme 47. Organocatalyzed α-Amination of Cyclic and Acyclic Fluorinated β-Ketoesters with Azodicarboxylates

generally poor enantioselectivities were obtained with the catalyst 5479 under optimized conditions. The authors proposed that the benzimidazole first acts as a base, allowing the βketoester to form the enolate, followed by dual activation of the enolate and azodicarboxylate via hydrogen bonding that facilitates the reaction (Figure 17). In 2004, Jørgensen and his group reported the α-hydroxylation reaction of β-ketoesters (Scheme 49).219 Screening of this reaction was performed with 5-chloro-1-oxoindan-2-carboxylic acid methyl ester and various cinchona-alkaloid derivatives with organic peroxides. The reactions proceeded with high yields (up to 98%) and provided optically active products (66−80% ee) using dihydroquinine catalyst 55220,221 and cumyl hydroperoxide (CHP) as the optimal oxidation reagent. The yields and enantioselectivities proved relatively independent of the ester substituent on the pronucleophiles. The preparation of optically active unique anti-diols from the reaction products was also presented when the initial products were subjected to a series of reducing agents. In 2012, Meng and co-workers 222 presented the αhydroxylation of β-ketoesters catalyzed by chiral (S)-timolol derivatives. After screening various aryloxy aminopropanol organocatalysts derived from the β-blocker inhibitor (S)-timolol, aminopropanol 56222,223 turned out to be the optimal catalyst. Using tert-butyl hydroperoxide as the oxidant and 56 as an organocatalyst in hexane, the α-hydroxylation reaction of βketoesters afforded the corresponding products (Scheme 49) in excellent yields but poor to good enantioselectivities. In 2013, Nagasawa’s group 224 developed a catalytic enantioselective α-hydroxylation reaction of 1-tetralone-derived β-ketoesters. They employed a guanidine-urea bifunctional organocatalyst 57 with CHP. This reaction provided the corresponding α-hydroxy-β-ketoesters in 60−99% yield with high enantioselectivities (78−95% ee). The scope of the substrate for this reaction revealed that the substituents on the aromatic ring of β-ketoester did not affect the yields or selectivities. Changing the methyl ester group of the substrates to bulkier isopropyl or tert-butyl groups improved the selectivities. They successfully applied this methodology to synthesize a key intermediate of the anticancer agent daunorubicin. In 2014, the same group modified catalyst 57 by adding chiral centers located outside the urea groups and tested it

Figure 16. Proposed transition state with catalyst 12 for amination.

Furthermore, they proposed that the quinine nitrogen acted as a base to depronate the α-carbon of the ketoester, thereby forming the enolate to attack the electrophilic azodicarboxylate. In 2008, Kim and Mang215 studied the enantioselective αamination of α-fluoro-β-ketoesters with azodicarboxylates as the electrophilic nitrogen source. They employed the binaphthyl derived urea catalyst 30.269 This catalyst was also reported by Kim’s group in two other papers169,172 as well as Shao and Peng216 in the same year. The desired α-aminated products were obtained in excellent yields (up to 95%) and good enantioselectivities (70−95% ee) (Scheme 47). Later, Lu and co-workers217 reported the stereoselective aminations of fluorinated ketoesters by using novel guanidine cinchona alkaloid-derived catalyst 53.217 The fluorine quaternary stereogenic centered products were obtained in excellent yields (78−96%) and with moderate to high enantioselectivities (47− 92% ee) (Scheme 47) for aryl ketoesters. Aliphatic ketoester substrates proceeded with lower reactivities and moderate enantioselectivities. tert-Butyl ketoester derivatives gave better selectivities, but the reactivities were signifcantly lower. This suggested that both the steric and electronic effects on the pronucleophiles play a role in this reaction. Most recently, Baeza and co-workers reported on the use of a cyclohexanediamine benzimidazole hydrogen-bonding catalysts for the electrophilic amination of various cyclic β-ketoesters with azodicarboxylates (Scheme 48).218 The best results were obtained in a range of nonpolar solvents, but diethyl ether was chosen since it gave comparable values at ambient temperature. Excellent yields (with the exception of 6membered β-ketoester substrates that displayed 50:1 and an enantiomeric excess of up to 87%. This was attributed to the presence of the oxygen atom on the benzoyl group, which resulted in stronger ion pairing between the quaternary ammonium salt of 83 and the 9408


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nucleophile. The generality of the catalytic enantioselective SNAr reaction was demonstrated for various aromatic substrates by reacting with 2-carboethoxy-cyclopentanone and pyrrolidines. The product was readily converted to oxoindoles bearing a chiral quaternary carbon center. The authors showed how a one-pot (4step) synthesis leads to spiro[pyrrolidone- 3,3′-oxoindoles] in 70% yield and showed further that the optically active reaction products could be mildly reduced to its β-hydroxyester and an unexpected ring opening when treated with various nucleophiles. Jørgensen and co-workers345 in 2006 reported the first catalytic enantioselective vinylic substitution reaction that proceeded with virtually complete retention of the doublebond configuration (Scheme 74). This was the first report for

Scheme 75. Cinchona-Derived Phase Transfer Catalyzed Mannich Reaction of Cyclic β-Ketoesters and α-Amido Sulfones

Scheme 74. Cinchona-Derived Phase Transfer Catalyzed Vinylic Substitution of Cyclic β-Ketoesters and Halopropenones

aromatic and aliphatic groups. It also tolerated a range of fused and nonfused cyclic β-ketoesters. The cyclohexanone- and cycloheptanone-derived β-ketoesters required the use of stronger base (K3PO4) in order to obtain the products. The presence of water in the reaction was found to be vital for high enantioselectivities, the authors postulated this was a result of the contribution of hydrogen bonding to conformational rigidity of the catalyst. Previous reports on the construction of propargylic stereocenters relied on the catalytic formation of optically active metalacetylides, which added to various prochiral electrophiles. Jørgensen’s group envisioned an alternative approach, whereby the reactivity would be inverted by equipping triple bonds with leaving groups for a carbanion nucleophilic addition−elimination reaction (Scheme 76).348 This led to the first enantioselective

what became known as a privileged PTC catalyst for the electrophilic functionalization with a range of β-ketoesters in a generally highly stereoselective manner. The novel cinchoninederived catalyst with bulkiness of the 9-anthracenylmethyl group attached to the quinuclidine nitrogen atom and the 1-adamantoyl at the 9-O position 84346 exhibited optimal asymmetric induction. Substitution at the 9-OH of the catalyst gave better performance than the unsubstituted parent compound both in terms of conversions and enantioselectivities. In addition, cyclopentanone 2-carboxylates with bulkier ester groups, such as tert-butyl, had a positive effect on the selectivity confirming earlier trends. Various aromatic, heteroaromatic, and aliphatic βhalopropenones were reported to be suitable substrates for the catalytic reaction, offering good yields and enantioselectivities (over 90% ee’s), when reacted with a variety of cyclic βketoesters. The corresponding optically active products formed in generally high yields and a decrease in selectivities with increasing ring-sizes. However, poor results were obtained with acyclic β-ketoesters, thus revealing the limitation of this catalytic system (Scheme 74). The E-isomers of the products were accessible by either using the E-form of the electrophile or via a catalytic conversion of the Z-products with tri-n-butyl phosphine. The authors rationalized the retention of configuration through an AdN−E mechanism that is initiated by complexation of the chiral PTC to the β-keto enolate which facilates the enantioselective addition to the α,β-unsaturated carbonyl compound in an initial rate-determining step followed by elimination of the halide. The Bernardi and Ricci group studied the asymmetric Mannich reaction with imines that are generated in situ from the bench-stable α-amido sulfones. Catalyst 85 in the presence of 50% w/w K2CO3 promoted the reaction of a variety of both amidosulfones with cyclic β-ketoesters (Scheme 75).347 The reaction proceeded smoothly with a range of protecting groups on the sulfone, such as Boc and Cbz as well as other

Scheme 76. Cinchona-Derived Phase Transfer Catalyzed Acetylenic Substitution with Cyclic and Acyclic β-Ketoesters and β-Halo-alkynes

organocatalytic direct α-alkylation of β-ketoesters and 3-acyl oxindoles with α-halo-alkynes catalyzed by chiral phase-transfer compounds in high yields and excellent enantioselectivities (Scheme 76). They administrated various alkylating reagents with chlorides and bromides as the leaving groups and electronwithdrawing substituents such as allyl and alkyl esters, amides, ketones, and sulfones. These reactions proceeded with good to excellent yields and ee’s in the presence of adamantoyl dehydrocinchonine catalyst 84. Cyclic β-ketoesters with various ring-sizes and oxindoles were employed as nucleophiles with 5- and 6membered cycles exhibiting better tolerance. Furthermore, the authors proposed an addition−elimination mechanism for the alkynylation (Scheme 77). The aqueous base allows for deprotonation of the β-ketoester forming the alkalimetal enolate (A), which undergoes a cation exchange with the PTC leading to the ammonium enolate (B). The enantioselective addition of the enolate to the haloalkyne (C) then takes place, resulting in the ammonium allenolate (D) which 9409


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Scheme 77. Proposed Mechanism for the Acetylenic Substitution Reaction

Scheme 78. Binaphthylene-Derived Phase Transfer Catalyzed Alkynylation with Ethynylbenziodoxolone (EBX) Reagents

controlling the selectivity with organometallic reagents. The account of the first organocatalytic anti-Michael reaction was reported by Jørgensen’s group.352 They utilized sulfones for the regulation of the regioselectivity and to simultaneously serve as a leaving group under PTC conditions. With the special properties of sulfones, they were able to synthesize an α,α-branched terminal double bond side chain joined to a quaternary center (Scheme 79). The reaction conditions were optimized with indanone β-ketoester derivatives and (E)-3-(phenylsulfonyl)acrylonitrile and 84 as the catalyst. As expected from previously mentioned results,345 a tert-butyl ester is favorable for higher selectivities, but in this case, it was also found to be sluggish in providing the final product. Therefore, NaOH was necessary to

eliminates X resulting in release of the product (E). It should be noted the authors discussed the mechanism in much further detail within the paper.348 In a continued search for electrophilic acetylene synthons to αfunctionalized carbonyl compounds and to make this umpolung alkynylation more useful, Waser and co-workers developed an asymmetric alkynylation reaction with ethynylbenziodoxolone (EBX) reagents349 using commercially available binaphthyl ammonium salt also known as Maruoka’s catalyst 86350,351 on indanone β-ketoesters and amides (Scheme 78). After extensive optimization of the reaction conditions, the highest enantiometric excess obtained for the tert-butyl β-ketoester indanone was only 65%. Replacement of one methyl group on the tert-butyl ester on the substrate with a phenyl group increased the selectivity to 79% ee. Unfortunately, more bulky adamantyl or anthracenylmethylene esters lowered the selectivities. Interestingly, asymmetric induction in this transformation was only observed with benziodoxolone reagents as compared to the alkynyliodonium salts. This was attributed to the decoordination of the catalyst in the alkynyliodonium salt when attack of the enolate oxygen of the ketoester on the iodine atom of the hypervalent iodine reagent occurs; this has led to the absence of chirality on the carbon−carbon bond-forming step. However, in the case of benziodoxolone reagents, even after the attack on the hypervalent iodine reagent, the carboxylate portion of the reagent remained coordinated to the chiral catalyst, thus providing asymmetric induction for subsequent steps. Anti- or contra-Michael reactions are described as the addition at the α-position of Michael acceptors and are usually effected by

Scheme 79. Cinchona-Derived Phase Transfer Catalyzed antiMichael Addition of Cyclic and Acyclic β-Ketoesters with Phenylsulfonyl Acrylonitrile.

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facilitate elimination of the sulfone group after the reaction was complete but could not be used as the sole base due to a nonselective background reaction. The reaction of the indanone derivatives proceeded with good yields and up to 94% ee’s but was not efficient for 1-tetralone-, 1-benzosuberone-, and nonphenyl-fused β-ketoesters. Jørgensen and co-workers reported the first organocatalytic enantioselective 1,6-addition of stabilized enolates to electronpoor δ-unsubstituted dienes.353 The group’s dihydrocinchonine and dihydrocinchonidine-derived phase transfer catalysts bearing a 9-anthracenylmethyl substituent at the quinuclidine nitrogen atom and a 1-adamantoyl group at the oxygen atom (catalyst 84) were chosen for this transformation. The optimized conditions for the addition of 1-indanone-derived tert-butyl β-ketoester and the activated diene gave the product as a single E-isomer with 96% ee. Base strength and reaction temperatures were identified as crucial parameters in order to obtain significant conversions. They rationalized that the kinetic protonation of the extended enolate controls the site of the double bond attack in a nonconjugated position along with its E-stereochemistry. The scope of the dienes included activation through ketones, esters, and sulfones as substituents to give the corresponding optically active addition products in excellent yields and selectivities (Scheme 80) when 1-indanone-derived β-ketoester

Scheme 81. Cinchona-Derived Phase Transfer Catalyzed Conjugate Addition of Cyclic β-Ketoesters and Various Allenes

conditions needed to be fine-tuned with respect to the base and temperature for each of the cyclic pronucleophiles evaluated. In 2008, the Dixon group355 reported the first enantioselective catalytic alkylation reactions of methine pronucleophiles with Nsulfonyl aziridines under phase transfer conditions. The products contained the amino ethylene group attached to a stereogenic quaternary carbon in high enantiomeric excesses. Their initial attempts employed tert-butyl indanone carboxylate and Nmesitylene sulfonyl aziridine as representative substrates with bifunctional cinchona catalysts in dichloromethane as solvent, which produced the alkylation product in low yields and enantioselectivities. The indanone adduct was realized under phase transfer conditions, employing cinchonine catalyst 84 with a promising result of 91% ee, albeit a slow reaction (35% conversion in 48 h). By changing the solvent and nitrogen protecting group on the aziridine from mesitylene to o(trifluoromethane)benzenesulfonyl, they observed complete conversion after 48 h even at low temperatures (−20 °C) and obtained the product in 97% ee (Scheme 82). Aromatic-

Scheme 80. Cinchona-Derived Phase Transfer Catalyzed Reaction between Cyclic β-Ketoester and Various Dienes

Scheme 82. Cinchona-Derived Phase Transfer Catalyzed Alkylation Reaction between Cyclic β-Ketoester and Aziridine was used as the model substrate. The scope of the β-ketoesters included a comparison between acyclic and cyclic analogues for which only the latter showed selectivity. Indanone derivatives were more reactive and gave excellent ee’s while the tetralone and nonfused β-ketoester derivatives required stronger bases to provide satisfactory yields and selectivities. PTC 84 was also found to be efficient for the conjugate addition of cyclic β-ketoesters to electron-deficient allenes.354 Results showed that the corresponding chiral α,β-unsaturated carbonyl compounds were exclusively formed under phasetransfer conditions using the catalyst 84. The base of choice was K2CO3 in terms of conversion and enantioselectivity at −20 °C (Scheme 81). The use of strong basic conditions led to competing polymerization of the allene, leaving the β-ketoester nearly unreacted. The allenes were varied to include a ketone or ester motif as the electron-withdrawing group, as well as various substituents in the 4-position; all provided the products in high yields and excellent diastereo- and enantioselectivities. The opposite enantiomer of the products could be obtained by applying the diastereomer of catalyst 84 with nearly similar results. Using racemic allenes gave the corresponding products with a high preference for one diastereomer. The protocol for the asymmetric conjugate addition of 1-indanone-derived βketoester to activated allenes was not very general; reaction

substituted indanone pronucleophiles gave the products in 91− 97% ee, while the tert-butyl cyclopentanone carboxylate required a stronger base and gave the product in only 82% ee. The utility of the reaction was increased by employing enantiopure chiral aziridines to allow products with substitution patterns that are not normally accessible for β-substituted nitro-olefin Michael 9411


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Scheme 83. Cinchona-Derived Phase Transfer Catalyzed Reaction between Indanone Type β-Ketoester and Various Aziridine357

Scheme 84. Cinchona-Derived Phase Transfer Catalyzed Conjugate Addition of 2-Alkoxycarbonyl-1-Indanones to Electron Deficient Olefins

reactions. N-Trifluoromethanesulfonyl-protected aziridine was found to be reactive even with non indanone pronucleophiles such as cyclopentanones, tetralones, lactams, and succinimides to give the products in high yields and in moderate to high ee (Scheme 82). In the same year, the Jørgensen group356 presented their contribution to this reaction. They confirmed that the protecting group on the aziridine was essential for reactivity under these catalytic conditions. In their investigations with the same catalyst 84, only five-membered, cyclic β-ketoesters were able to provide the adduct in good to excellent yields and enantioselectivities (Scheme 82). The reactivities of the aziridine electrophiles were dependent on having an electron-withdrawing sulfonyl-protecting group on the nitrogen. Dixon and colleagues reported the first enantioselective catalytic opening of N-sulfonyl azirdines cyclic sulfamidates as electrophiles with carbon-centered nucleophiles (β-ketoester derivatives) to provide the ethylene-amino unit containing products357 facilitated by catalyst 87.358,359 A range of

pronucleophiles was successfully alkylated using the azirdines as electrophiles with high enantioselectivities and good yields (Scheme 83). The tert-butyl ester group was replaced with the sterically large adamantoly group that resulted in a slight decrease in enantioselectivity. The reaction was then extended to chiral azirdines and different protecting groups on the azirdine functionality, which was also well-tolerated for this transformation. In addition, the tert-butyl indanone carboxylate was treated with 5- and 6-membered cyclic sulfamidates bearing various nitrogen-protecting groups. In order to investigate the scope of the nucleophiles, the authors described two methods for the preparation of a range of cyclic pronucleophiles bearing a tertbutyl ester substituent that included indanone, succinimide, lactone, and glutarimide (Scheme 83) derivatives. Indanone, succinimide, and lactone tert-butyl esters provided the corresponding alkylation products in good to high enantioselectivities. The N-methyl glutarimide derived β-ketoesters was an effective substrate with regard to generating high levels of stereoinduction while its N-butyl analogue was not. This report 9412


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Scheme 85. Cinchona Squaramide-Derived Catalyzed Michael Addition of Linear β-Ketoesters to Nitrostyrene360

Scheme 86. Cinchona-Derived Phase Transfer Catalyzed α-Cyanation of β-Ketoesters with Hypervalent Iodine(III)

pronucleophile were well-tolerated within 20 min, indicating that the open microstructure of heterogeneous catalyst allowed for easy access of the substrates, resulting in very high catalytic efficiencies. As a bifunctional catalyst, it displayed excellent catalytic activities and enantioselectivities in asymmetric Michael addition using brine as the solvent. This study represents an attractive approach to immobilize various organocatalysts with enhanced asymmetric catalytic performance in an environmentally friendly approach. In 2015, Zheng’s team reported the use of a cinchona alkaloidbased chiral quaternary ammonium salt 89 as the phase transfer catalyst of choice for the cyanation of β-ketoesters using hypervalent iodine(III) as the electrophilic cyanating reagent.361 It must be noted that Waser and co-workers reported the same reaction in 2015; however, they made use of cinchonidine (as a free amine) as the organocatalyst (Scheme 86). Zheng and coworkers reported that the use of a stoichiometric amount of an organic base (DMAP) was crucial for increased reactivity and enantioselectivity than compared to an inorganic base that is typically used for PTC reactions. With the optimized conditions, the ester group was varied; in general, the more bulky groups did not increase the enantioselectivity (up to 77% yield and 87% ee). Electron-donating substituents on the indanone ring of the βketoesters had a more positive effect on the enantioselectivity than the electron-withdrawing groups (up to 99% yield and 93% ee). Additional indanone β-ketoesters with heterocycles, alkynes, and other functional groups also proceeded easily. Nonfused and acyclic β-ketoesters substrates gave poor to moderate yields as well as diminished selectivity. Although the precise mechanism remains unclear, the authors proposed that protection at the C9-hydroxy group on the organocatalyst was required to ensure high enantioselectivity, which could potentially prevent mismatched interactions

also described a number of examples of pronucleophiles bearing an additional chiral center, but the yields and ee’s were lower. The Chinchilla and Nájera team reported on the reaction of βunsubstituted Michael acceptors to β-ketoesters under PTC conditions with quinine organocatalyst 82 (Scheme 84).342 The corresponding adducts bearing new quaternary stereocenters were usually obtained in high yields and up to 94% ee when using ammonium salts derived from quinidine and its pseudoenantiomer as organocatalysts. Use of diisopropylethylamine as an added base was preferred in the application of these cinchona alkaloid catalysts as it offered >98% yield and >98% ee. The major advantage of this dimeric catalyst is that it can easily be recovered by precipitation in ether and reused on a large scale. It must be noted that this reaction did not strictly follow phase transfer conditions with regard to the solvent and base used; however, further insight into the reaction mechanism is yet to be reported. In 2014, Liu and co-workers synthesized novel cinchona squaramide-functionalized silica-based heterogeneous catalyst 88360 (Scheme 85).360 Structural characterizations and spectroscopic analyses demonstrated that a well-defined single-site chiral cinchona-based squaramide active center was incorporated onto the organic−inorganic hybrid silica. The organic−inorganic hybrid support incorporated an imidazolium functionality within this silicate network, which allowed for a synergistic effect of the phase-transfer system with the squaramide species to promote the catalytic performance. This heterogeneous catalyst 88 was conveniently recovered and reused at least eight times without loss of catalytic activity when evaluated on the asymmetric Michael addition of acyclic β-ketoesters to nitrostyrene to furnish the corresponding products with quantitative conversion and 97−99% ee’s. The results were comparable to those of its homogeneous counterpart.107,109,110 Bulkier ester groups on the 9413


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between the free hydroxyl and the carbonyl groups of the ketoester. Bulky ester-protecting groups, such as 1-adamantoyl, were not necessary, which was a different observation to that reported by Jørgensen.348 As depicted in Figure 24, the transition

Scheme 87. Organocatalyzed Phase-Transfer Fluorination of Cyclic β-Ketoesters with NFSI


state involved the enolate of the ketoester to be positioned between the quinoline and the 3,5-di(trifluoromethyl)benzene system which likely forms a stacked interaction with the phenyl group of indanone ketoester. This observation could explain that electron-donating groups at this position enhanced the enantioselectivity of the reaction. The next section covers PTC reactions of β-ketoesters with heteroatom-containing substrates. The first account of enantioselective fluorination of β-ketoesters by phase-transfer catalysis employed the chiral cinchonine-based quaternary ammonium salt 81338,339 and was presented by Kim and Park.362 The reaction of β-ketoesters with NFSI as the halogen source (Scheme 87) under mild reaction conditions afforded the corresponding α-fluoro-β-ketoesters in excellent yields but poor to average stereoselectivities (up to 69% ee). The scope of the pronucleophile included indanones, tetralones, and an example of an acyclic β-ketoester (40% ee). In 2010, Maruoka explored the use of bis(diarylhydroxymethyl) substituents at 3,3′-positions on the chiral binaphthyl core as a phase transfer catalyst 90 for the asymmetric fluorination of cyclic β-ketoesters (Scheme 87).363 With the utilization of NFSI as the fluorine source, both five- and sixmembered cyclic β-ketoesters exhibited high enantioselectivity (85−98% ee). The electronics on the fused ring were found not to influence the enantioselectivity of the fluorinated products. The acyclic β-ketoesters showed low enantioselectivity, which the authors concluded was due to the formation of an E-enolate with linear β-ketoesters that was not suitable for inducing additional ionic interactions between the ammonium cation and the ester carbonyl as compared to Z-enolates formed with cyclic β-ketoesters. Making use of the 1-adamantoyl derivative PTC 84 developed by Jørgensen, Lu and colleagues performed the asymmetric fluorination of bicyclic β-ketoesters using NFSI since Selectfluor as the fluorinating agent resulted in racemic products (Scheme 87).364 Upon variation of base and temperature, the reaction was optimized to furnish the quarternised products 93% yield and 94% ee. Similar to the results of Maruoka, the cyclopentanone ketoester gave low selectivity. The authors also reported a chlorination protocol for the same cyclic β-ketoesters (90% yield and 91% ee) under the same reaction conditions using catalyst 84 with NCS as the chlorine source. In 2014, Novacek and Waser reported the 1,2-cyclohexane diamine thiourea PTC 91 for the asymmetric α-fluorination of bicyclic β-ketoesters (Scheme 87).365 The reaction proceeded with high yields up to 96% but moderate enantioselectivity up to

86% ee, the larger ester groups slightly increased the enantioselectivity. Analogous to the other reports, the cyclopentanone ketoester performed with decreased selectivity. The authors proposed a bifunctional activation model in which the ammonium group activates the enolate of the ketoester, and the thiourea donor group orientates the NFSI, creating a highly ordered transition state (Figure 25).


Due to the reactions need for stoichiometric equivalents of base for high selectivities, it was concluded that formation of the enolate to form this ion pair in a chiral environment was a crucial step. In addition, the reaction was also performed with catalyst analogues that did not possess the H-bonding donor unit and a 9414


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including the tetralone substrate bearing a 1-adamantyl ester, which demanded stronger basic conditions. Toste and co-workers introduced the first catalytic, enantioselective α-amination using aryldiazonium cations. This worked in conjunction with the BINAM-derived chiral phosphoric acid catalyst 94 (Scheme 89).369 It is referred to under the section of PTC as the chiral phosphoric acid is responsible for anion transfer of the insoluble aryldiazonium cations to generate a soluble chiral diazonium ion pair susceptible nucleophilic attack (by the β-ketoester). This diazenation methodology proved to be amenable for a wide range of bicyclic β-ketoester-derived indanones and one benzosuberone. Indanones with electron-rich and -poor groups as well as substitution on various positions on the fused ring provided their corresponding diazenes in good yields and enantioselectivities (up to 98% yield and 93% ee). Furthermore, a variety of aryl groups on the diazonium also proceeded smoothly. Application of this protocol was extended to the synthesis of biologically important precursor of Hai (5-hydroxy2-aminoindan-2-carboxylic acid), a conformationally constrained tyrosine analogue.370 Lately, there has been much development around efficient methods to incorporate a SCF3 group into small molecules for the pharmaceutical and agrochemical industries.371,372 So far, there have only been two enantioselective organocatalytic examples for the direct trifluoromethylthiolation on β-ketoesters by Shen271 and Rueping.272 Shen’s group reported that a quinine-derived PTC 95373 was required for the tetralone- or benzosuberone-derived β-ketoesters with a trifluoromethylthiolated hypervalent iodine reagent (Scheme 90).271 The corresponding products were obtained in good to moderate yields and enantioselectivity (up to 93% yield and 77% ee). The 1-benzosuberone-derived adamantyl β-ketoester yielded the product with excellent enantioselectivity (88% yield and 96% ee), while the cyclohexanone adamantyl ester and indanone-derived β-ketoester resulted in diminished ee’s. It is interesting to note the indanone-derived β-ketoester displayed a much higher enantioselectivity when quinine 22 alone was used as the organocatalyst (Scheme 62).

catalyst that lacked an ammonium group, both resulted in rather low enantioselectivity. In 2015, Duan and Lin’s group developed the quinine-based squaramide PTC 92 that was applied on the asymmetric αfluorination of bicyclic β-ketoesters (Scheme 87).366 Even though the product adducts were met with high yields (91− 97%) with either electron-donating and electron-withdrawing substituents on the fused ring of the β-ketoesters, the enantioselectivity was good to moderate (64−76% ee). The cyclopentanone provided the product as a racemate, while the tetralone-derived and acyclic ketoesters resulted in trace amount of products. This group also confirmed that for the bifunctional catalysts, the squaramide group and quaternary ammonium center was important to attain any enantioselectivity. Notably, even though a variety of chiral scaffolds as PTC’s have been evaluated on the asymmetric fluorination with relatively low catalytic loading, the monocyclic and acyclic ketoester substrates are yet to be achieved with high reactivity and selectivity. Meng’s group reported the first enantioselective direct αhydroxylation of β-ketoesters via phase-transfer catalysis.367 The best results to construct the tetrasubstituted stereogenic center at the α-position of 1-indanone-1-adamantyl ester was facilitated by catalyst 93367 in the presence of cumyl hydroperoxide, offering up to 91% yield and 74% ee (Scheme 88). This same group Scheme 88. Organocatalyzed Phase-Transfer αHydroxylation of Cyclic β-Ketoesters with CHP

3. COVALENT CATALYSIS 3.1. Aminocatalysts

Since List, Lerner, and Barbas374 established the use of L-proline to promote the enantioselective direct Aldol reaction between unmodified ketones and aldehydes, chiral cyclic secondary amines have been widely used to catalyze the asymmetric functionalization of carbonyl compounds.20,24,25,374 Aminocatalysis via enamine and iminium ion intermediates has now

reported improved results in 2012 to obtain up to a 95% yield and 90% ee when the privileged cinchona-derived catalyst 82 was employed for this transformation.368 Various other esters proved to be less effective in obtaining better yields and selectivities,

Scheme 89. Binaphthyl-Derived Phosphoric Acid Catalyzed α-Amination of β-Ketoesters

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Scheme 90. Cinchona-Derived Phase Transfer Catalyzed Trifluoromethylthiolation on β-Ketoesters

reactions that proceed via direct β-ketoester activation, enamine, and iminium ion intermediates). 3.1.1. Reactions via Direct β-Ketoester Activation. Xu and Yang’s group reported the enantioselective organocatalytic fluorination, promoted by cinchona alkaloid-derived chiral primary amines in the presence of various cocatalysts (Scheme 92).304 Results revealed that combined metal salts and organocatalysts resulted in poor conversion and enantioselectivities, whereas a combination of L-leucine and 18 as the dual primary amine catalyst led to promising catalytic activities. Although N-fluorodibenzenesulfonimide (NFSI) proved to be the best fluorine donor in terms of yield (99%), it provided poor enantioselectivity (5% ee). Interestingly, 1.2 equiv of Selectfluor in toluene produced 90% of the product but with rather low enantioselectivity (13% ee); however, the presence of L-leucine as an additive improved the ee to 55%. Various ester moieties were also studied for the fluorination of β-ketoesters in the presence of both 18 and L-leucine, and the fluorinated products were obtained in moderate enantioselectivities (39−55%) and in good to excellent yields (70−93%).304 The authors propose that enamine activation (A) is operational for the mechanism of this transformation (Scheme 93). The chiral primary amine condenses with the β-ketoester to form the nucleophilic enamine species (A). The enamine then undergoes an electrophilic fluorination (B), which upon hydrolysis releases the catalyst and forms the product. Addition of transition metal salts to the primary amine catalyst led to poor conversions and stereoselectivities, which the authors proposed was due to inhibition to form the nucleophilic enamine intermediate with the β-ketoester. The addition of various Brønsted acids yielded low to moderate enantioselectivities, whereas the addition of 4-dimethylaminopryidine (DMAP) led to good yields but low enantioselectivities. It was suggested that these results supported an enamine-mediated asymmetric induction since ammonium salts (from the primary amine catalyst) of Brønsted acids would react too slow, while a stronger base would compete with the enol species through a baseactivated fluorination. The ratio of amino acid to catalyst was found to be optimal at 2:1, suggesting that the chiral diamine molecule 18 combined with two molecules of leucine. These results indicated that for good asymmetric induction, formation of an enamine intermediate rather than an enolate was essential. Luo and co-workers developed an organocatalytic method for the N-nitroso Aldol reaction of β-ketoesters with N-protected hydroxamic acids using easily handled CuCl2 as the oxidant and primary chiral amine 96381 (derived from tert-leucine) as the catalyst under aerobic conditions (Scheme 94).382,383 This facile and robust method provided access to β-amino alcohols in moderate to good yields (up to 99%) with excellent

emerged as a powerful strategy for the synthesis of a plethora of optically active organic compounds as new transformations are continuously being discovered, and new catalysts are being designed and applied in asymmetric synthesis.375−377 In particular, aminocatalysis through enamine activation of the highest occupied molecular orbital (HOMO) rising appeared as a major contributor in the area of organocatalysis and has been applied in several asymmetric transformations/cascade reactions.376,378 This mode of activation involves catalytically generated enamine intermediates that are formed via deprotonation of an iminium ion, which in turn reacts with various electrophiles.19,379 There are examples in which the secondary amine catalysts are proposed to directly activate the β-ketoester system and in this way facilitate reaction with an electrophile (Scheme 91A). In other cases, the β-ketoester can act as the Scheme 91. General Aminocatalyst Activation for Reactions Involving β-Ketoesters

electrophile, and the catalyst forms an enamine with the nucleophilic reaction partner (Scheme 91B). Conversely, the lowest unoccupied molecular orbital (LUMO)-lowering effect is the underlying activation principle of iminium ion catalysis.379,380 This mode of activation is based on the ability of a chiral amine to reversibly condense with α,β-unsaturated carbonyls to form iminium intermediates, rendering their βcarbon atoms susceptible to nucleophilic attack by lowering the LUMO (Scheme 91C). In the latter mechanistic routes, the βketoester-containing substrate solely acts as the nucleophile and, hence, is not directly involved with activation by the chiral organocatalyst. The following is divided into three sections (i.e., 9416


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Scheme 92. Cinchona-Derived Primary Amine Catalyzed α-Fluorination of Cyclic β-Ketoesters with Selectfluor

Scheme 93. Proposed Activation of the β-Ketoester in the Presence of Chiral Primary Amine Catalyst 18

adduct in 85% yield and 97% ee, with the same configuration obtained under catalytic conditions, hence unambiguously verifying the enamine catalytic nature of this reaction. On the basis of this evidence, the transition state in Figure 26 was

Figure 26. Proposed transition state of catalyst 96 with β-ketoesters with N-protected hydroxycarbamate.

proposed, in which the protonated tertiary amine and the NH group of the enamine form a hydrogen-bonded network to stabilize the conformation of the catalyst and the configuration of the enamine. The complex facilitates the Re-face attacks of the enamine to give the desired adduct which was compared with the absolute configuration of known amination product. In a parallel study, the authors investigated the αhydrazination of β-ketoesters with azodicarboxylates (Scheme 95).384

enantioselectivities (up to 99% ee) for both the cyclic and acyclic pronucleophiles, including those with α-alkyl, α-allyl, and propargyl substituents. Besides benzyl-N-hydroxycarbamate, tert-butyl-N-hydroxycarbamates were also effective as an electrophilic nitrogen source, thus providing an additional option for synthetic manipulation of products. In order to gain insight on the mechanism of the reaction, the authors studied the stoichiometric reaction of acetoacetate and organocatalyst 96 with the addition of a catalytic amount of m-nitrobenzoic acid. The enamine product was isolated and characterized by NMR and X-ray analysis, which indicated the 96 (Z)-enamine geometry of this intermediate, as well as the hydrogen bonding between the enamine NH and the ester moiety. With the addition of water and an acid additive, this intermediate quickly equilibrated to its parent ketoester, which supported the catalytic turnover with the enamine intermediate under the optimal reaction conditions. The N-hydroxycarbamate was then added to the stoichiometric enamine reaction that furnished the amination

Scheme 95. Primary Amine-Derived tert-Leucine-Catalyzed α-Hydrazination of α-Substituted β-Ketoesters

Scheme 94. Primary Amine Derived tert-Leucine Catalyzed α-Hydroxyamination of Cyclic and Acyclic β-Ketoesters with NProtected Hydroxamic Acids

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While this transformation is well-established with cyclic βketoesters, the acyclic analogues normally produce low enantioselectivities. Catalyst 96 was again found to be the optimal for the benchmark reaction between acetoacetate and dibenzyl azidocarboxylate. The reaction proceeded at room temperature and with high yields (70−91%) and selectivities (91−95% ee) when the ester was ethyl, methyl, or n-butyl. The tert-butyl, benzyl, and allyl analogues required higher temperatures (40 °C) and provided moderate yields (58−64%) and enantioselectivities (55−87% ee). In fact, α-allyl and propargyl substituents at the α position of the substrate also required heating to obtain moderate results. In the same paper, Luo and co-workers reported on the use of this catalyst for a Robinson Annulation between acetoacetate and methyl vinyl ketone (MVK) (Scheme 96).384

was essential to use NaHCO3 to trap the in situ liberated HBr. Other inorganic or organic bases either gave inferior results or completely hindered the reaction. The reaction tolerated substitutions at the α carbon and R positions of the ketoester very well under the optimized conditions with moderate to good yields (30−96%) and excellent ee’s (>94% in most cases). The scope of the screening included acyclic and cyclic ketoester radical acceptors. The scope of the α-bromocarbonyl alkylating agents included electron-deficient and electron-donating groups on the aryl group. Luo and co-workers reported the first asymmetric αbenzoyloxylation of α-branched ketones using their primary amine catalyst to afford the construction of acyclic quaternary carbons (Scheme 98).387 Scheme 98. Asymmetric α-Benzoyloxylation of α-Substituted β-Ketoesters

Scheme 96. Primary Amine-Derived tert-Leucine-Catalyzed Robinson Annulation of β-Ketoesters with MVK/Acrolein

Optimisation of the model reaction between acetoacetate and benzoyl peroxide gave the desired product in 83% yield and 96% ee. The ratio of the peroxide to the β-ketoester, use of butylated hydroxytoluene (BHT), a radical inhibitor, and anaerobic atmosphere were crucial for obtaining good yields. The reaction tolerated various ester substitutions with excellent yields (72− 90%) and enantioselectivities (96−97% ee). The authors report that α-unsubstituted acetoacetate gave the racemic product, suggesting that it escapes catalytic control. The α-substituted acyclic substrates resulted in products with moderate to good yields (40−90%) and excellent stereoselectivities (96−99% ee’s). The results were just as good with the cyclic β-ketoesters, including the relatively unstable α-acetylbutyrolactone. The absolute configuration was determined by comparison of the optical rotation of a product with the literature value. On the basis of this, the transition state is similar to that described in Figure 26. The one-pot Biginelli reaction [β-ketoesters, aldehydes, and (thio)ureas] is another transformation in which the organocatalyst can directly activate the β-ketoester substrate. As already explained under the Brønsted acid section, this reaction has been comprehensively reviewed (including the importance of the DHPM products).38,291,308,309 A vast number of amino-based organocatalysts claim the enamine mode of activation; however, a summary of only the enantioselective catalysts will be presented (Scheme 99) with general trends pertaining to the ketoester and the reaction mechanism. Aminocatalyst development for the Biginelli reaction has evolved since the first chiral secondary amine reports of 97 by Juaristi388 and 98389 by Feng, respectively. The organocatalyst backbone has been varied from commonly used alkaloid 18, proline (98, 99,390 100,391 and 102392) and hydrocarbon scaffolds (97 and 104) to include calix[4]arenes (103393), carbohydrates (101394,395), and a sulphonimide 105 (Scheme 99).388−390,392,396−401 Early attempts focused on the use of chiral secondary amine organocatalysts, while chiral primary amine derived catalysts were being developed. Comparison of the

The authors describe two competing reaction pathways in this reaction system and the addition of the weak acid, m-nitrobenzoic acid, was essential to obtain the desired product in high yields and ee’s. Having the β-ketoesters in excess was also crucial to obtaining the desired reaction pathway, and a syringe pump addition of the MVK was convenient. The reaction tolerated both MVK and acrolein as Michael acceptors, but bulky substituents on the acetoacetate gave poor yields and selectivities. The absolute configuration of the cyclized product was determined by the X-ray structure, and through this the authors propose a similar catalytic mode as described for the amination reaction in Scheme 95. They also employed DFT calculations to substantiate their conclusions with respect to the mechanism.385 This chiral primary amine catalyst (96) was further explored to promote the α-alkylation of α-substituted β-ketocarbonyls under photoredox conditions (Scheme 97).386 The model reaction was with acetoacetate and phenacyl bromide and was optimized to give the desired alkylation product with the combined catalysts (96 and Ru(bpy)3Cl2) in 88% yield and 97% ee. In the previous two reaction schemes, the addition of a weak acid benefited this catalytic system. For this reaction, it Scheme 97. Primary Amine-Derived tert-Leucine-Catalyzed α-Alkylation of Cyclic and Acyclic β-Ketoesters with αBromocarbonyls

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Scheme 99. Organocatalyzed Biginelli Reaction with Linear β-Ketoesters

enantioselectivity of the DHPM adducts when using secondary amine organocatalysts proved to be somewhat inferior compared with many of those obtained using primary aminocatalysts. While excellent levels of enantiocontrol and yields (up to 99%) have been reached, there is much room for improvement with regard to catalyst loading and reaction time. All aminocatalyzed Biginelli reactions require the addition of an acid. In general, the aldehyde component is the most commonly varied of the three substrates. Typically, alkyl acetoacetates is employed as β-ketoester with unsubstituted (thio)ureas. β-Keto-substituted acetoacetates and thioesters, as well as β-diketones have also been successfully employed. Furthermore, urea is more commonly employed under this mode of activation compared to thioureas, that is, the opposite trend to that reported for Brønsted acid organocatalyst activation that was mentioned earlier. With regard to mechanism,

a study of all the proposed reaction pathways for aminocatalysts involve a generic transition state of dual activation as depicted in Figure 27.

Figure 27. Typical transition state for Biginelli reactions involving amino-based organocatalysts and β-ketoesters. 9419


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philic site of the β-ketoester moiety (Scheme 101).407 The bicyclic Aldol products were obtained under Krapcho decarboxylation conditions in 34−86% yields and up to 94% ee. In 2013, Biju and co-workers408 reported the enantioselective synthesis of dihydropyran-ones from the reaction of 2bromoenals with 1,3-dicarbonyl compounds or enamines in the presence of the triazolium salt 108 as the organocatalyst (Scheme 102). The triazolium salt 108409−411 is a N-heterocyclic carbene (NHC) was originally developed by Bode and coworkers as an organocatalyst.412 The combination of two bases (DABCO and LiOAc) was essential for better reactivity and selectivity. Under the optimized conditions, 108 catalyzed the reaction of 2-bromoenals with β-ketoesters resulting in the formation of dihydropyranones in very good yields (80−92%) and with excellent enantioselectivities (91−95% ee). In addition to β-ketoesters substrates, this reaction was successfully applied to β-diketones and vinylogous amides. The authors proposed a reaction mechanism which is likely initiated by the 1,2-addition of the NHC generated from 108 to 2-bromoenal, followed by proton transfer to generate the nucleophilic Breslow intermediate (A) and the homoenolate equivalent (B) (Scheme 103). The key α,β-unsaturated acylazolium intermediate (C) is then generated by rapid debromination of (B). The enol intermediate (D) is then delivered via nucleophilic addition of the β-ketoester to the Michael acceptor (C), which then undergoes proton transfer and intramolecular acylation to afford the dihydropyranones. The authors also supported the proposed mechanism with a DFT study in which the energies of crucial intermediates were calculated and correlated to experimental data. In 2013, our research group413 developed mild routes to novel carbapenem β-ketoester derivatives through C−C bond-forming reactions using L-proline20,24 as an efficient organocatalyst. The carbapenem core is a class of β-lactam antibiotics that have been recognized as one of the most powerful and broad-spectrum antibiotics in clinical use.414 In this study, we presented the Aldol reaction using the carbapenem β-ketoester and formaldehyde as the electrophile in the presence of 106 (Scheme 104).413 All of the Aldol products were obtained in good yields (up to 70%) and excellent diastereoselectivity (up to >99:1). We also explored the organocatalyzed Michael reaction to carbapenem intermediates using nitrostyrene and enones (Scheme 104). Next, we expanded the scope of the organocatalyzed Michael reaction to a carbapenem intermediate by further examining electrondeficient olefins, α,β-unsaturated ketones, and β,γ-unsaturated α-ketoesters.415 Moderate to good yields (up to 67%) and some excellent diastereoselectivities (up to >99:1) were obtained with this simple organocatalyst. This organocatalytic method of substitution thus may offer a widely sought after, new synthetic route to novel and potentially medically useful β-lactam antibiotics. Moreover, we also showed that the Michael products could be transformed into monobactams (another important

Initially, the chiral amine catalyst activates the β-ketoester by forming an enamine intermediate; simultaneously, the same catalyst forms hydrogen bonding that stabilize the acyl group of the imine that is generated from the aldehyde and urea. This allows for nucleophilic attack of the enamine onto the imine within a controlled chiral environment. This transition state also provided an explanation for the need of the acid additive that was to promote the condensation of the chiral amine and ketoesters as well as the formation of urea-based imines. Although not an aminocatalyst, in 2012, Bolm and co-workers reported the first chiral sulfoximine-thiourea derivative 105401 as an organocatalyst for desymmetrization of a cyclic meso-anhydride and Biginelli reaction (Scheme 99).401 A 10-fold dilution of the substrate concentration resulted in an increased selectivity from 16% to 44% ee. Although low to moderate enantioselectivities was observed, this report highlighted that the stereocontrolling element in a catalyst need not be exclusive to an asymmetrically substituted carbon. 3.1.2. Reactions of β-Ketoesters via an Enamine Intermediate. In comparison to the intramolecular Aldol reactions which are less well developed, the intermolecular Aldol reaction between aldehydes and ketones is firmly established.402 The Aldolization also plays an important role in organocatalysis as it offers the possibility to create highly functionalized compounds through carbon−carbon bond formation with high stereoselectivities.8,403,404 In 2006, London and co-workers presented the results of α-substituted β-ketoesters catalyzed by L-proline (106)405 (Scheme 100) and other optically pure Scheme 100. Proline-Catalyzed Aldol Reaction between Fluorinated Linear β-Ketoesters and Acetone

pyrrolidine derivatives.406 They focused on the use of acetone and α-fluorinated β-ketoesters in the Aldol reaction, affording δketo-β-hydroxy-α-fluoro esters in high yields. Low diastereoselectivities and high ee values (up to 83%) were obtained in the reaction of ethyl 2-fluoroacetoacetate and acetone in the presence of L-proline catalyst. Replacement of Lproline with D-prolinol resulted in an inversion of enantioselection of the product. Bella and co-workers who pioneered the use of unsaturated βketoesters with hydrogen-bonding organocatalysts, extended their methodology to aldehydes using an aminocatalyst.192,194 The nucleophilic enamine derived from diphenyl prolinol organocatalyst 107256 and the aldehydes acted on the electro-

Scheme 101. TMS-Protected Diphenyl Prolinol-Catalyzed Reaction of Unsaturated β-Ketoesters with Aldehydes

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Scheme 102. Triazaolium Salt Catalyzed Annulation of Linear β-Ketoesters with 2-Bromoenals

In 2015, we demonstrated that (S)-diarylprolinol silyl ether 107 was able to catalyze α-amination, α-hydroxylation, αsulfenylation, and α-selenylation reactions of the carbapenem core under mild reaction conditions (Scheme 106).417 The enamine intermediates formed between the carbapenem core and diphenyl prolinol-derived organocatalyst served as nucleophiles to mediate α-heterofunctionalization reactions leading to the formation of diverse products. This method showed broad substrate generality and provided easy access to a wide range of chiral heterosubstituted β-lactam derivatives bearing multiple stereocenters in moderate to good yields. High diastereoselectivity was observed in all of the reactions, as would be expected considering the inherent chirality of the starting carbapenem. 3.1.3. Reactions of β-Ketoesters via an Iminium Intermediate. The direct organocatalytic domino and cycloaddition reactions with β-ketoesters are among the various reactions that generate multiple stereogenic centers in one transformation. The first organocatalytic asymmetric domino Michael−Aldol reaction of acyclic β-ketoesters and unsaturated ketones to afford optically active cyclohexanones was presented by Jørgensen and co-workers in 2004.418 In all cases, only one diastereoisomer of the optically active products were formed with up to four stereogenic centers. The phenylalanine-derived imidazolidine catalyst 109419 was used. The reaction proceeded through an initial Michael addition of unsaturated ketones and βketoesters through iminium-ion formation (of the unsaturated ketone) using the organocatalyst 109 to generate the Michael adducts consisting of two chiral centers (Scheme 107). The intramolecular Aldol addition then progressed in a highly diastereoselective fashion to form the six-membered ring such that all large substituents were at equatorial positions and thus were controlled by the stable chiral centers formed in the initial Michael step. The scope of the reaction was also investigated using various α,β-unsaturated ketones carrying aromatic and heteroaromatic βsubstituents (Ar1), affording the cyclohexanones in moderate to good yields (up to 85%) and with excellent enantioselectivities. Furthermore, several other aromatic β-ketoesters could be employed in the reaction and led to the formation of cyclohexanones with excellent enantioselectivities (up to 99%), although the yields were moderate. To demonstrate the synthetic scope of the reaction, various optically active building blocks were easily constructed. Chiral cyclohex-2-enones are known to be versatile building blocks for the synthesis of a large number of naturally occurring products, and they are normally prepared by multistep synthesis.420,421 In 2006, Jørgensen and co-workers422 reported the first one-pot (5 steps) organocatalytic asymmetric Michael addition of β-ketoesters to α,β-unsaturated aldehydes that

Scheme 103. Proposed Mechanism of the NHC-Catalyzed 108 Annulation of 2-Bromoenals

class of antibacterial agents) by ring opening of the fivemembered ketone ring through a retro-Dieckmann condensation. Subsequently, in 2014, we also reported416 the threecomponent Mannich reaction of aromatic amines and formaldehyde with the carbapenem intermediate, in the presence of catalyst 106374 through enamine catalysis, resulting in Mannich base products (Scheme 105). Interestingly, the two-component Mannich reaction of benzyl imines with carbapenem intermediate resulted in the formation of diazabicyclo[4.2.1]nonanes through in situ rearrangement of the Mannich products (Scheme 105). This rearrangement was attributed to a combination of the proximity of the new bond and the nucleophilicity of the amine. No rearranged products were observed for the aromatic amines tested, and we attribute this to the lower pKa of these groups. The reported organocatalytic functionalization of the carbapenem intermediate was found to be completely diastereoselective as the stereochemical outcome was dictated by the chiral starting material rather that the catalyst. 9421


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Scheme 104. Proline-Catalyzed C−C Bond Formation on a Carabapenum Core

Scheme 105. Proline-Catalyzed Mannich Reaction on a Carabapenum Core Leading to Rearranged Diazabicyclo[4.2.1]nonanes

Scheme 106. TMS-Protected Diphenyl Prolinol Catalyzed α-Heterofunctionalization on a Carbapenem Core

prolinol organocatalyst 110256 to afford chiral cyclohex-2-enones Michael products. The addition of p-TSA as a second organocatalyst was essential for catalyzing the hydrolysis of the tert-butyl ester and for decarboxylation of the newly formed βketoacid. This Brønsted acid was also able to catalyze the Aldol condensation and the elimination reaction of the cyclic

proceeded in aqueous solutions or under solvent-free conditions (Scheme 108). This iminium ion catalyzed Michael reaction provides an efficient, practical, and flexible method to access a broad range of optically active cyclohex-2-enone derivatives. The initial enantioselective Michael addition of the β-ketoester to α,βunsaturated aldehydes was catalyzed by the TMS-protected 9422


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Scheme 107. Phenylalanine-Derived Imidazolidine Catalyzed Domino Michael−Aldol Reaction of Linear β-Ketoesters with α,βUnsaturated Ketones

Scheme 108. TMS-Protected Diarylprolinol Catalyzed Michael Addition of Linear t-Butyl-3-Oxo-Butyric Esters with α,βUnsaturated Aldehydes

Scheme 109. TMS-Protected Diarylprolinol-Catalyzed Michael Addition of Linear tert-Butyl-3-oxo-butyric Esters with SiliconSubstituted α,β-Unsaturated Aldehydes and Further Transformations of the Reaction Product

and aromatic, as well as α,β-unsaturated aldehydes were also successfully employed.422 The reaction proved to be a “green” process as the major byproducts formed were H2O, CO2, and isobutene.

intermediate to yield the cyclohex-2-enone product. Exploring the substrate scope of this reaction, good yields (72−98%) were obtained with enantioselectivities of the products ranging from 84−94% ee. Different substituted β-ketoesters, aliphatic, allylic, 9423


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Scheme 110. TMS-Protected Diphenyl Catalyzed Michael/Morita−Baylis−Hillman Tandem Reaction of β-Ketoesters (Derived Nazarov Reagent to Form Cyclohexenones) with α,β-Unsaturated Aldehydes

Then in 2008, co-workers of the same group423 presented the first asymmetric synthesis of 5-(trialkylsilyl)cyclohex-2-enones in satisfactory yields (42−69%) with excellent enantioselectivities (up to 99%) using the same TMS-protected prolinol organocatalyst 110 and p-TSA (Scheme 109). In this reaction, siliconsubstituted α,β-unsaturated aldehydes were introduced for the first time in organocatalysis, which opened the door to further interesting transformations; this was also the first synthesis of chiral (trialkylsilyl)cyclohex-2-enones that did not rely on kinetic resolution. This one-pot reaction occurs in a specific sequence (Scheme 109) in which different β-ketoesters reacted under iminium ion catalytic conditions with dimethylphenylsilylsubstituted α,β-unsaturated aldehydes in a Michael addition to form the cyclic 5-(trialkylsilyl)cyclo-hex-2-enone products. Subsequent acid addition catalyzed the decarboxylation and Aldol condensation forming the desired products (Scheme 109). The 5-(trialkylsilyl)cyclohex-2-enone product proved to be a highly modular building block. It underwent a copper-catalyzed 1,4-addition of bis(pinacolato)-diboron to trifunctionalized cyclohexanones (A) in very good yields (86−92%) and diastereoselectivities (99:1). Then, the short synthesis of the A-ring precursor for 19-nor-1R,25-dihydroxyvitamin D3 was developed (B). Finally, the reaction product was transformed into the corresponding protected 5-hydroxycyclohex-2-enone (C) by a Tamao-Fleming oxidation followed by protection in a yield of 54% over three steps with complete stereochemical retention. In 2008, Jørgensen’s group424 first described the diastereo- and enantioselective Michael/Morita−Baylis−Hillman tandem reaction of α,β-unsaturated aldehydes with β-ketoesters derived Nazarov reagent to form cyclohexenones, with both steps being catalyzed by chiral secondary amines (Scheme 110). They

showed that the TMS-protected prolinol organocatalyst 107256 (10 mol %) was able to catalyze the Michael addition by reacting with the aldehyde to form the iminium intermediate, which in turn reacted with the Nazarov reagent (cycle I Scheme 110). Hydrolysis of the intermediate (A) resulted in the formation of intermediate (B) and recovery of the catalyst 107. They then suggested that the liberated prolinol acted as a nucleophilic catalyst for the activation of the double bond in the intramolecular Morita−Baylis−Hillman reaction of (B) (Cycle II Scheme 110), although the authors acknowledged that at the time, no reports of enantioselective Morita−Baylis−Hillman reactions catalyzed by a secondary amine were described. The reaction proceeded in high enantio- and diastereoselectivity for a wide range of α,β-unsaturated aldehydes and different β-ketoesters, and it was the first chiral secondary amine catalyst reported for this reaction. Such reactions are very important as they minimize the cost, waste, manual effort, and allow for the rapid construction of structurally complex molecules from simple starting materials in one-pot. The scope of the reaction was also explored using a broad range of groups at the β-position of the aldehyde such as aromatic, heteroaromatic, and aliphatic; all were well-tolerated and afforded the corresponding products in high enantioselectivities (86−98%) and good yields (45−68%).424 The opposite enantiomer of the product was also easily obtained by carrying out the reaction with the (R)-enantiomer of catalyst 107. Jørgensen and co-workers reported the diarylprolinol silyl ether 110 catalyzed domino Michael-Knoevenagel condensation reaction of α,β-unsaturated aldehydes and a phosphoryl-derived β-ketoester (Scheme 111).425 This protocol worked well on a wide range of α,β-unsaturated aldehydes with both aromatic and 9424


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aliphatic substituents; however, the β-ketoester component was not varied.

corresponding cyclopropanes in excellent yields and selectivities. When aliphatic aldehydes were used, the dr and ee decreased while the yield remained high. Change of the alkyl group on the ester had a negligible effect on the cyclopropane products. The absolute configuration of the products (cyclopropane) was deduced from 2D NMR and mechanistic studies. The Constantieux group demonstrated their interests in multicomponent reactions when they reported the iminium activated enantioselective three-component reaction between βketoesters, enals, and N-(2-aminoethyl)pyrroles.431 The biologically relevant pyrrolopiperazines products were obtained through a reaction sequence involving an enantioselective Michael addition followed by an iminium ion trapping via Pictet−Spengler cyclization (Scheme 113). Possibilities for

Scheme 111. TMS-Protected Diphenyl-Catalyzed DominoKnoevenagal-Michael Addition of Ethyl 4Diethoxyphosphoryl-3-oxobutanoate and α,β-Unsaturated Aldehydes

Scheme 113. TMS-Protected Diphenyl Prolinol Catalyzed Michael Addition/Pictet−Spengler (MAPS) Sequence

Interestingly, the addition of hydroquinine proved to be essential for the reaction to proceed with high ee’s and yields; however, it had no major influence of the stereochemical outcome of the reaction products, which indicated its role as a base in order to promote the enol formation on the ethyl 4diethoxyphosphoryl-3-oxobutanoate while the aldehyde was activated via iminium catalysis with catalyst 110. The 6substituted-3-diethoxyphosphoryl-2-oxocyclohex-3-enecarboxylates were further transformed into various optically enriched cyclohexene and cyclohexane derivatives. The cyclopropanation reaction is regarded as one of the most important reactions in organic synthesis because cyclopropanes can undergo ring-opening reactions to generate new molecular skeletons.426 Cyclopropane derivatives are also used as templates for the construction of conformationally restricted amino acids and peptides.427,428 Chiral cyclopropanes can be prepared with organocatalysis,429 and a convenient novel approach for the synthesis of highly functionalized cyclopropanes was reported by Rios and co-workers430 through an organocatalytic domino reaction (Scheme 112). The addition of 2-bromo-3-ketoesters to

variation on all three-reaction partners were investigated and provided excellent enantioselectivities (up to 99%) and good yields (up to 69%) using catalyst 107.

4. OPPORTUNITIES FOR INDUSTRIAL APPLICATIONS Researchers have lately started to appreciate that organocatalytic transformations are not only attractive from an academic setting but can also be quite valuable for industrial applications.432 In the industrial arena, the current drawbacks of organocatalysis includes433 the relatively high catalyst loading (10−20 mol %), the use of excess reagents, the necessity for product purification with chromatography, the need for improved catalyst turnover numbers, and the relatively low reaction temperatures (not suitable for large scale operation) that warrant the design for more sustainable approaches within this area. To date, there is no organocatalyzed industrial application making use of β-ketoester substrates. However, the ease of chemical transformation coupled with the broad utility of this building block in the pharmaceutical, agrochemical, and polymer sectors, including examples of the scale up reactions,124,231,434,435 recyclable catalysts,112,185,248,274,360,435 and the continuous flow,145 highlighted in this review could initiate the potential use of βketoester substrates in industry.

Scheme 112. TMS-Protected Diphenyl Catalyzed Cyclopropanation of Brominated β-Ketoesters to Various α,β-Unsaturated Aldehydes

a variety of α,β-unsaturated aldehydes catalyzed by chiral secondary amine 110 resulted in the formation of substituted cyclopropanes with three stereogenic carbon centers inclusive of one a quaternary stereocenter. The reaction was efficiently catalyzed by commercially available chiral diphenyl prolinol 110 and afforded the corresponding cyclopropanes in high yields and up to 96:4 diastereomeric ratio and 99% enantiomeric excess. The scope of the reaction was also studied using different α,β-unsaturated aldehydes, and high levels of diastereo- and enantioselectivities were achieved in all examples. The reaction worked well with aldehydes bearing electron-withdrawing groups such as nitro, nitrile, or halides on the aromatic ring, leading to the

5. CONCLUSIONS AND OUTLOOK The β-ketoester structural motif is a privileged starting material, and chiral β-ketoester derivatives continue to be building blocks of key importance in organic synthesis, natural product, and medicinal chemistry due to the chemist’s ever increasing imagination of new transformations of these products. Over the past decades, the reignition of organocatalysis has significantly expanded the methods available for asymmetric synthesis in which β-ketoesters form one of the most widely used substrates for organocatalytic transformations. This review has depicted that most modes of organocatalytic activation [i.e., noncovalent (hydrogen bonding, Brønsted acid, and phase 9425


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Biographies

transfer) and covalent (aminocatalysts, that is, enamine or iminium-ion intermediates) catalysis] have all been employed to activate β-ketoesters as both the nucleophilic or electrophilic reactants in asymmetric transformations; herein, 110 chiral organocatalysts were outlined. Bifunctional hydrogen bond donor catalysts have dominated the activation of β-ketoesters; generally, the chiral catalyst backbone/scaffold has relied heavily on alkaloids, binaphthyl, or pyrrolidine moieties (although there are several other unique/customized backbones that have been introduced), resulting in highly enantioselective reactions. Although the rational design of organocatalysts for these substrates has been largely met, there still seems to be much room for a deeper mechanistic clarity on many organocatalyzed reaction pathways involving β-ketoesters, in order to gain insight on the factors contributing to reactivity and selectivity. This investigation also showed that the longstanding issues of high catalyst loading for organocatalyzed transformations are increasingly being met, that is 0.1−5 mol % catalyst quantities was the range for the lowest loadings within all of the classes of organocatalysts mentioned. Although low catalyst loadings are generally required, the complexity and prize of some catalysts suggest room for improving catalyst recovery (e.g., by developing more supported catalysts). The 1,3-dicarbonyl scaffold appeared to be adaptable to all classic organocatalytic modes of activation; however, examples utilizing counterion catalysis, SOMO (singly occupied molecular orbital) or multicatalytic/synergistic strategies are scarce. We could not note a clear trend in reactivity difference between cyclic/bicylic and acyclic β-ketoesters, although many studies reported decreased efficiency for the latter. The acyclic βketoesters showed lower enantioselectivity which some authors concluded was due to the formation of an E-enolate that was not suitable for inducing additional ionic interactions (with the catalyst) as compared to Z-enolate which was formed with cyclic β-ketoesters. The role of the substituents at the ester moiety also varied but did not exclusively show a linear relationship between size and enantioselectivity or reactivity. The activation of β-ketoesters started with relatively simple model reactions that created one or two stereogenic centers but gradually evolved into one-pot multicomponent reactions where several stereogenic centers were formed. The other tendency is that more research groups demonstrate that the organocatalytic methods can be applied for the synthesis of precursors to bioactive compounds or used in the total synthesis of complex molecules. Both these aspects are expected to grow over the next five years. Undoubtedly, the field of organocatalysis has made great strides; however, a formidable challenge that remains is the use of organocatalysis in more industrial applications, especially large scale processes, nonetheless also, for example, synthesis of new libraries on drug scaffolds or mild and facile modifications of complex drugs from natural origins. This key application of organocatalysis is anticipated to be the focus of several academic entrepreneurs in the future!

Thavendran Govender graduated from the University of KwaZulu Natal, South Africa, in 2005 under the supervision of Hendrik G. Kruger and Glenn E. M. Maguire in the field of asymmetric catalysis and host− guest chemistry. He undertook postdoctoral studies at Uppsala Universitet, in Sweden, with Prof. Per I. Arvidsson, where he worked on development of asymmetric organocatalytic reactions and Nmethylated peptide chemistry. In 2007, he became a lecturer at the University of KwaZulu Natal. He is currently a research professor in the College of Health Science and is a principle investigator at the Catalysis and Peptide Research Unit. Per I. Arvidsson has been a fractional research professor at the College of Heath Science, University of KwaZulu Natal since 2013. He is also Director of the national Swedish Drug Discovery & Development Platform at Science for Life Laboratory (SciLifeLab). Before joining SciLifeLab & Karolinska Institutet in 2013, Prof. Arvidsson held various roles at the CNS & Pain iMED at AstraZeneca, Södertälje, the last being Director for late stage preclinical and clinical neuroscience drug discovery. His accolades include several professorship positions at Uppsala University in Sweden and postdoctoral studies with Prof. D. Seebach at ETH Zurich, Switzerland. Prof. Arvidsson is named inventor on some 15+ patent applications and is coauthor on some 100 peerreviewed publications, two of which have won “most cited papers” awards. Glenn E. M. Maguire, a native of Ireland, completed his Ph.D. in Physical Organic Chemistry at Queens University Belfast, Northern Ireland, under the supervision of A. P. de Silva in 1993. This was followed by postdoctoral studies at UCLA’s School of Chemistry and Biochemistry with Donald J. Cram (funded by SmithKline Beecham) and then at the School of Molecular Biology and Pharmacology, Washington University Medical School, St. Louis, MO, with George W. Gokel (funded by Monsanto). His research interests range from catalysis to medicinal chemistry. He took up his current academic post in inorganic chemistry at the School of Chemistry and Physics, University of KwaZulu Natal, in 1999. He is currently a principle investigator at the Catalysis and Peptide Research Unit. Gert (H. G.) Kruger graduated from Potchefstroom University, South Africa, in 1996 under the supervision of Frans (F. J. C.) Martins and Attie (A. M.) Viljoen. His Ph.D. lineage is traced back to Rudolf Criegee (Wutzburg) via Johan Dekker (Karlsruhe). The Dekkers introduced cage chemistry to South Africa, and Kruger actively pursues the synthesis, computational chemistry, and biological application of cage compounds at the Catalysis and Peptide Research Unit, University of KwaZulu Natal as a research professor. Tricia Naicker received her Ph.D. from University of KwaZulu Natal, South Africa in 2011 on the development of new chiral organocatalysts under the supervision of Profs T. Govender and P.I. Arvidsson. Afterward, she joined Prof. K. A. Jørgensen’s research group at the Centre for Catalysis at Aarhus University, Denmark, as a postdoctoral fellow working on new asymmetric organocatalyzed reactions. Since 2013, she started her academic career and independent research endeavors at the Catalysis and Peptide Research Unit based at University of KwaZulu Natal. Her research interests are focused toward new methodologies in asymmetric organocatalysis for its application in the synthesis of new drugs and enhancement of old drugs within the field of HIV, TB, and antibacterials.

AUTHOR INFORMATION Corresponding Author

ACKNOWLEDGMENTS The authors wish to thank Zamani E.D. Cele, Nilay Bhatt, and Sukant K. Das for their contribution to the initiation of the review. The South African National Research Foundation, Aspen

*E-mail: [email protected]. Notes

The authors declare no competing financial interest. 9426


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Pharmacare-SA, and UKZN-College of Health Sciences are thanked for funding.

DEDICATION Dedicated to Prof. M. W. Makgoba in appreciation of his contributions to research as the first Vice Chancellor of the University of KwaZulu Natal, the right person for a difficult job! REFERENCES (1) Eder, U.; Sauer, G.; Wiechert, R. New Type of Asymmetric Cyclization to Optically Active Steroid Cd Partial Structures. Angew. Chem., Int. Ed. Engl. 1971, 10, 496−497. (2) Hajos, Z. G.; Parrish, D. R. Synthesis and Conversion of 2-Methyl2-(3-Oxobutyl)-1,3-Cyclopentanedione to the Isomeric Racemic Ketols of the [3.2.1]Bicyclooctane and of the Perhydroindane Series. J. Org. Chem. 1974, 39, 1612−1615. (3) Aleman, J.; Cabrera, S. Applications of Asymmetric Organocatalysis in Medicinal Chemistry. Chem. Soc. Rev. 2013, 42, 774−793. (4) Grondal, C.; Jeanty, M.; Enders, D. Organocatalytic Cascade Reactions as a New Tool in Total Synthesis. Nat. Chem. 2010, 2, 167− 178. (5) de Figueiredo, R. M.; Christmann, M. Organocatalytic Synthesis of Drugs and Bioactive Natural Products. Eur. J. Org. Chem. 2007, 2007, 2575−2600. (6) Dalko, P. I.; Moisan, L. Enantioselective Organocatalysis. Angew. Chem., Int. Ed. 2001, 40, 3726−3748. (7) Schreiner, P. R. Metal-Free Organocatalysis through Explicit Hydrogen Bonding Interactions. Chem. Soc. Rev. 2003, 32, 289−296. (8) Dalko, P. I.; Moisan, L. In the Golden Age of Organocatalysis. Angew. Chem., Int. Ed. 2004, 43, 5138−5175. (9) List, B. Enamine Catalysis Is a Powerful Strategy for the Catalytic Generation and Use of Carbanion Equivalents. Acc. Chem. Res. 2004, 37, 548−557. (10) Notz, W.; Tanaka, F.; Barbas, C. F. Enamine-Based Organocatalysis with Proline and Diamines: The Development of Direct Catalytic Asymmetric Aldol, Mannich, Michael, and Diels-Alder Reactions. Acc. Chem. Res. 2004, 37, 580−591. (11) Hayashi, Y.; Gotoh, H.; Hayashi, T.; Shoji, M. Diphenylprolinol Silyl Ethers as Efficient Organocatalysts for the Asymmetric Michael Reaction of Aldehydes and Nitroalkenes. Angew. Chem., Int. Ed. 2005, 44, 4212−4215. (12) Seayad, J.; List, B. Asymmetric Organocatalysis. Org. Biomol. Chem. 2005, 3, 719−724. (13) List, B. The Ying and Yang of Asymmetric Aminocatalysis. Chem. Commun. 2006, 819−824. (14) Guillena, G.; Ramon, D. J. Enantioselective Alpha-Heterofunctionalisation of Carbonyl Compounds: Organocatalysis Is the Simplest Approach. Tetrahedron: Asymmetry 2006, 17, 1465−1492. (15) Dalko, P. I. Do We Need Asymmetric Organocatalysis? Chimia 2007, 61, 213−218. (16) Guillena, G.; Najera, C.; Ramon, D. J. Enantioselective Direct Aldol Reaction: The Blossoming of Modern Organocatalysis. Tetrahedron: Asymmetry 2007, 18, 2249−2293. (17) Walji, A. M.; MacMillan, D. W. C. Strategies to Bypass the Taxol Problem. Enantioselective Cascade Catalysis, a New Approach for the Efficient Construction of Molecular Complexity. Synlett 2007, 2007, 1477−1489. (18) Marion, N.; Diez-Gonzalez, S.; Nolan, S. P. N-Heterocyclic Carbenes as Organocatalysts. Angew. Chem., Int. Ed. 2007, 46, 2988− 3000. (19) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Asymmetric Enamine Catalysis. Chem. Rev. 2007, 107, 5471−5569. (20) Gaunt, M. J.; Johansson, C. C. C.; McNally, A.; Vo, N. T. Enantioselective Organocatalysis. Drug Discovery Today 2007, 12, 8−27. (21) Tsogoeva, S. B. Recent Advances in Asymmetric Organocatalytic 1,4-Conjugate Additions. Eur. J. Org. Chem. 2007, 2007, 1701−1716. 9427


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