Computational Studies on Cinchona Alkaloid-Catalyzed Asymmetric

Article pubs.acs.org/accounts

Computational Studies on Cinchona Alkaloid-Catalyzed Asymmetric Organic Reactions Published as part of the Accounts of Chemical Research special issue “Computational Catalysis for Organic Synthesis”. Gamze Tanriver,† Burcu Dedeoglu,‡ Saron Catak,*,† and Viktorya Aviyente*,† †

Department of Chemistry, Bogazici University, Bebek, Istanbul 34342, Turkey Foundations Development Directorate, Sabancı University, Tuzla-Orhanlı, Istanbul 34956, Turkey

‡

CONSPECTUS: Remarkable progress in the area of asymmetric organocatalysis has been achieved in the last decades. Cinchona alkaloids and their derivatives have emerged as powerful organocatalysts owing to their reactivities leading to high enantioselectivities. The widespread usage of cinchona alkaloids has been attributed to their nontoxicity, ease of use, stability, cost effectiveness, recyclability, and practical utilization in industry. The presence of tunable functional groups enables cinchona alkaloids to catalyze a broad range of reactions. Excellent experimental studies have extensively contributed to this field, and highly selective reactions were catalyzed by cinchona alkaloids and their derivatives. Computational modeling has helped elucidate the mechanistic aspects of cinchona alkaloid catalyzed reactions as well as the origins of the selectivity they induce. These studies have complemented experimental work for the design of more efficient catalysts. This Account presents recent computational studies on cinchona alkaloid catalyzed organic reactions and the theoretical rationalizations behind their effectiveness and ability to induce selectivity. Valuable efforts to investigate the mechanisms of reactions catalyzed by cinchona alkaloids and the key aspects of the catalytic activity of cinchona alkaloids in reactions ranging from pharmaceutical to industrial applications are summarized. Quantum mechanics, particularly density functional theory (DFT), and molecular mechanics, including ONIOM, were used to rationalize experimental findings by providing mechanistic insights into reaction mechanisms. B3LYP with modest basis sets has been used in most of the studies; nonetheless, the energetics have been corrected with higher basis sets as well as functionals parametrized to include dispersion M05-2X, M06-2X, and M06-L and functionals with dispersion corrections. Since cinchona alkaloids catalyze reactions by forming complexes with substrates via hydrogen bonds and long-range interactions, the use of split valence triple-ζ basis sets including diffuse and polarization functions on heavy atoms and polarization functions on hydrogens are recommended. Most of the studies have used the continuum-based models to mimic the condensed phase in which organocatalysts function; in some cases, explicit solvation was shown to yield better quantitative agreement with experimental findings. The conformational behavior of cinchona alkaloids is also highlighted as it is expected to shed light on the origin of selectivity and pave the way to a comprehensive understanding of the catalytic mechanism. The ultimate goal of this Account is to provide an up-to-date overlook on cinchona alkaloid catalyzed chemistry and provide insight for future studies in both experimental and theoretical fields.

1. INTRODUCTION The development of organocatalysis made a remarkable impact in organic synthesis, particularly for asymmetric catalysis.1−3 The term organocatalysis was coined by MacMillan et al. for the enantioselective organo-catalyzed Diels−Alder reaction in 2000.4 Organocatalysts demonstrated wide applicability due to their nontoxic nature, availability, stability and recyclability compared to conventional metal catalysts.5,6 Cinchona alkaloids (CA), natural compounds and wellknown members of the organocatalyst family, are extensively used for chiral molecular recognition and enantioselective catalysis (Scheme 1).7 CA and their derivatives are highly effective in catalytic asymmetric reactions due to their structural diversity and conformational flexibility.6,7 Design, application, and choice of CA play a prominent role in the catalysis of specific reactions, yielding excellent stereoselectivities with © XXXX American Chemical Society

enhanced catalytic efficiency. In 1912, Bredig and Fiske reported the first asymmetric reaction using cinchona alkaloids.8 Subsequently, Pracejus,9 Wynberg and Hiemstra,10 MacMillan et al.,4 and Sharpless et al.11 provided invaluable contributions to the field. In recent years, cinchona alkaloids found widespread use as organocatalysts in general base12 and phase-transfer catalysis.13 Their versatility is mainly attributed to the presence of several functionalities and their ability to act as multisite receptors. In this context, development of novel CA derivatives is of considerable interest in asymmetric catalysis. To date, numerous experimental studies on cinchona alkaloid catalyzed organic reactions were reported; however, due to their large size and conformational flexibility, only a limited Received: February 12, 2016

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DOI: 10.1021/acs.accounts.6b00078 Acc. Chem. Res. XXXX, XXX, XXX−XXX

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Accounts of Chemical Research

DFT analysis.22 Berg et al. reported dihydroquinidine (DHQD) in anti-open and syn-closed conformations in a combined experimental/theoretical study.16 Zaera and co-workers reported a mixed NMR and computational study (B3LYP/631G(d,p)) on the effect of protonation of cinchonidine.21 Recently, Dedeoglu et al. investigated the conformational space of QN and QD with M06-2X/6-31+G(d,p), known to account for dispersion, and found Open(3) to be the most stable conformer for both QN and QD.15 The prominent open conformer, Open(3) or anti-open, was suggested to be responsible for the observed enantiodifferentiation in apolar solvents.17

Scheme 1. Widely Used CA Derivatives15

3. COMPUTATIONAL STUDIES ON CINCHONA ALKALOID CATALYZED REACTIONS Cinchona alkaloids catalyze a broad range of organic reactions. This section provides recent theoretical studies on well-known organic reactions catalyzed by CA. 3.1. Asymmetric Desymmetrization Reactions

CA-derived catalysts are central to many catalytic asymmetric reactions today, one of which is the asymmetric desymmetrization (AD) of meso-cyclic anhydrides.12,24,25 Two possible mechanisms were proposed for the AD of cyclic anhydrides: nucleophilic26 and general base27 catalysis (Scheme 2). Aviyente and co-workers investigated the mechanism of AD of meso-cyclic anhydrides in the presence of β-amino alcohols that closely resemble CA in structure.28 The general base catalysis pathway was shown to be energetically highly favored over the nucleophilic catalysis pathway (B3LYP/6-31+G(d,p)). Deng and co-workers identified the active conformation of the modified cinchona alkaloid catalyst as the app-closed conformation in the enantioselective methanolysis of cylic anhydrides and proposed a model consistent with the observed asymmetric induction.29 Song and co-workers reported excellent enantioselectivities for the methanolytic desymmetrization of cyclic anhydrides catalyzed by cinchona-based sulfonamide catalysts, and computational results (B3LYP/631G(d)) provided insight into the observed enantioselectivity.30 In a combined experimental/theoretical study, an inversion of enantioselectivity dependent on catalyst loading was observed during the quinine-mediated desymmetrization of glutaric meso-anhydrides.31 In a more recent computational study, much effort was invested by Yang and Wong to shed light on the origin of stereoselectivity in asymmetric methanolysis of meso-cyclic anhydrides catalyzed by CA lacking the −OH functionality, namely DHQD derivatives.32 A transition state (TS) model, in which the developing oxyanion is stabilized via C−H···O hydrogen bonds, was proposed (Scheme 3). Predicted enantioselectivities (M06-2X/6-311+G(d,p)//M06-2X/631G(d)) were reported in conjunction with Deng’s experimental findings. More recently, Dedeoglu et al. have reported the AD of mesocyclic anhydrides catalyzed by quinine and quinidine (M06-2X/ 6-31+G(d,p)) to understand the origins of stereoselectivity.15 The catalyst, which acts like a molecular tweezer, was shown to stabilize the oxyanion through conventional and nonconventional H-bonding interactions affording lower free energy barriers. Moreover, explicit solvation was crucial in understanding the role of methanol as a reaction partner leading to higher enantioselectivities.

number of computational studies were published on the specific catalytic role they play in these reactions.14 This Account focuses on computational investigations of cinchona alkaloid catalyzed organic reactions and presents examples of theoretical investigations, with particular emphasis on their catalytic role.

2. CONFORMATIONAL SPACE OF CINCHONA ALKALOIDS Many experimental and computational studies focused on the conformational behavior of CA.14−23 The first conformational study by means of NMR and molecular mechanics calculations was reported by Dijkstra et al.20 Four low-energy conformers (Figure 1) were located, and the first known X-ray structure was reported.20 Bü rgi and Baiker investigated the solvent-dependent conformational behavior of cinchonidine (CD) using a combined NMR and ab initio reaction field approach and located several new stable conformations.17 They later found additional stable conformers of CD by a combined NOESY-

Figure 1. Four lowest-energy conformers of quinidine.20 B


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Accounts of Chemical Research Scheme 2. Nucleophilic and General Base Catalysis Pathways for AD of meso-Cyclic Anhydrides28

Scheme 3. CA-Catalyzed Asymmetric Methanolysis of mesoCyclic Anhydrides32

Scheme 4. [3,3]- and [1,3]-Sigmatropic Rearrangements of O-Allylic Trichloroacetimidates33

Reproduced from ref 32. Copyright 2013 American Chemical Society.

3.2. [1,3]-Sigmatropic Rearrangements

Houk and co-workers described the mechanism of thermal [1,3]- and [3,3]-rearrangements of O-allylic trichloroacetamidates (Scheme 4).33 The reaction was initially modeled with NMe3 as model catalyst then applied to the real system (QD and QN) at the B3LYP/6-31G(d) level. The cinchona catalyzed mechanism with syn addition of the nucleophile is energetically favored over [3,3]-rearrangement pathway and the reaction includes a two-step SN2′ addition. Additionally, Hbonding interactions are crucial to determine the fast-reacting enantiomer. 3.3. Conjugate Addition Reactions

carbonyl substrate and a subsequent proton transfer from tertiary amine of the catalyst to nitronate carbon. QDNCONHPh (electron-withdrawing moiety) displays the highest catalytic activity by increasing N−H acidity of the protonated amine. The reaction showed improved reactivity in toluene compared to THF. Wynberg and co-workers proposed the asymmetric addition of aromatic thiols to cyclohexanones in the presence of CA to proceed via the formation of a thiolate-alkylammonium tight

Jiang et al. reported the conjugate addition of propanedioates to nitropropenes catalyzed by CA-derivatives at the B3LYP/6311++G(2df,2p)//B3LYP/6-31G(d,p) level, including solvent effects with PCM (Scheme 5).34 New catalysts were designed to enhance catalytic activity and investigate the tertiary amine’s effect on reactivity. Calculated results depict a stepwise pathway involving C−C bond formation through a proton transfer from the catalyst to the C


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by replacing the catalyst’s phenolic proton with methyl. B97-D/ 6-311+G(d,p)//M06L/6-31G(d) calculations were carried out to rationalize the enantioselective inversion with methylated βICD. The enantioselective inversion was attributed to TS stabilization by β-ICD’s phenolic hydroxy group, which activates the carbonyl oxygen of allenoate through hydrogen bonding. Alcohol additives improved the stereocontrol of the reaction.

Scheme 5. Conjugate Addition Reaction of Dimethyl Propanedioate to 1-Nitroprop-1-ene34

3.5. Intramolecular Aldol Reactions

Lam and Houk elucidated the enantiocontrol in the intramolecular aldol condensations of 4-substituted heptane-2,6diones (1−3), reported by List and co-workers, using CA primary amine catalyst (Cat) (B3LYP/6-31G(d) IEF-PCM in toluene (Scheme 7).38

pair and activation of the enone electrophile.10,35 Grayson and Houk revealed (M06-2X/def2-TZVPP-IEFPCM(benzene)// M06-2X/6-31G(d)-IEFPCM(benzene)) that the alkyammonium ion activates the enone by Bronsted acid catalysis and the catalyst’s hydroxyl group orients the thiolate nucleophile (Figure 2).36

Scheme 7. Catalytic Cycle for Aldol Cyclizations Catalyzed by Cat38

Model reactant and catalysts were used to identify the lowest energy conformers of the enamine and the reactive conformations. Computational results reveal that stereocontrol depends on both the chair preference of the substrate-enamine intermediate and the conformational preference of hydrogen bonded aldol transition states. Aldol transition structures favor the boat-chair conformation (Scheme 8). Furthermore, inclusion of dispersion (B3LYP-D3(BJ)) was found to improve the prediction of stereoselectivity.

Figure 2. Wynberg and Grayson/Houk models. Reproduced from ref 36. Copyright 2016 American Chemical Society.

3.4. Cycloaddition Reactions

Wang et al. recently developed a highly enanti-oselective synthesis of dihydropyran-fused benzofurans through [4 + 2] cycloaddition of allenoates and benzofuranone alkenes catalyzed by β-isocupreidine (β-ICD), CA-type organocatalyst (Scheme 6).37 They achieved chiral inversion in cycloadducts

3.6. Henry Reactions

Himo and co-workers investigated the enantioselective cinchona thiourea-catalyzed Henry reaction of benzaldehyde with nitromethane (B3LYP/(6-3111+G(2d,2p)//B3LYP/631G(d,p) in gas and CPCM in THF).39 They proposed two possible pathways for the formation of the C−C bond with comparable reaction barriers. Pathway A is slightly favored over Pathway B (Scheme 9). In agreement with experiment, formation of S enantiomer is preferred in both pathways.

Scheme 6. Enantiodivergent [4 + 2] Cycloadditions of Benzo-Furanone Alkenes with Allenoates37

3.7. Asymmetric Michael Additions

According to the dual activation model proposed by Takemoto et al.,40 the mechanism for adduct formation in catalytic Michael addition involves electrophile activation through nitroolefin binding to thiourea, yielding a ternary complex and C−C bond formation between activated components (Scheme 10). Enolic forms of 1,3-dicarbonyls interact with the tertiary amine group and a subsequent deprotonation results in D


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Accounts of Chemical Research Scheme 8. Lowest-Energy Aldol TS38

Reproduced from ref 38. Copyright 2015 American Chemical Society.

Scheme 10. Dual-Activation Model40

Scheme 9. Proposed Mechanisms for Cinchona ThioureaCatalyzed Henry Reaction39

can also be activated by the protonated amine group rather than thiourea’s H-bond donors (Scheme 11).41 Further mechanistic studies may be necessary to assess the generality of the proposed mechanism. Scheme 11. Enantioselective Michael Addition Catalyzed by Bifunctional CA41

Su et al. studied the mechanism of Michael addition of malonitrile to chalcones catalyzed by cinchona alkaloid aluminum(III) complex (Scheme 12).42 The reaction proceeds through a dual activation mechanism in which Al(III) acts as a Lewis acid and activates the electrophilic α,β-unsaturated carbonyl. Furthermore, the tertiary amine in CA works as a Lewis base and deprotonates the malonitrile. The reaction follows a stepwise pathway involving C−C bond formation followed by proton transfer from the catalyst to the carbonyl substrate. In the absence of the Al(III)-complex the CA activates the carbonyl substrate through hydrogen bonding. The ONIOM method was used to simulate the reaction. Su et al. also modeled the asymmetric 1,4 Michael addition of malonitrile to unsaturated aryl ketones catalyzed by 9-epiamino-chincona alkaloids with B3LYP and MP2/6-31++G(d,p) in THF (PCM) (Scheme 13).43 Calculations depict three

a highly nucleophilic enolate. Enantioselectivity is dictated by the binding mode of nitroolefin to thiourea. Hamza et al.’s calculations (B3LYP/6-311++G(d,p)// B3LYP/6-31G(d) PCM in toluene) prove that the electrophile E


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intermediate to adopt a preferred conformation to yield the more accessible Re-face attack in agreement with experiment. Cucinotta et al. investigated the mechanism of the asymmetric Michael addition of ketoesters to phenyl-maleimide catalyzed by QD and QN both experimentally and theoretically.44 The catalyst behavior was analyzed by a variety of computational methods including molecular dynamics, QM/ MM and correlated ab initio (RIMP2/aug-cc-pVDZ) calculations. The results supported the bifunctional mode of catalysis stabilizing the rate-determining step TS via H-bonds and accounted for the observed stereochemical outcome. A series of cinchona-based organocatalyst candidates was investigated by Károlyi et al., where the bond-forming step for the enantioselective Michael addition of nitromethane to 1,3diphenylpropenone was modeled (M06-2X/6-311G(d)// B3LYP/6-31G(d)). Besides the interaction of the substrates with the urea and the quinuclidine moiety, the importance of πstacking and H-bonding interactions between the electrophilic component and the catalyst was also highlighted. Through πstacking, the replacement of the widely used trifluoromethyl groups by nitro groups allows the interacting rings to get closer lowering the activation barrier of the C−C bond formation step.45 Zhu et al. performed an experimental (NMR) and theoretical (B3LYP/6-311++G(d,p)//B3LYP6-31G(d) in chloroform (CPCM)) study and described a new dual activation pathway for the Michael reaction of α,β-unsaturated γ-butyrolactam (Nu) and chalcone (EI) catalyzed by bifunctional CA-thiourea organocatalyst (Cat).46 The key feature of the new dual activation mechanism is the simultaneous activation of the nucleophile (Nu) by the thiourea moiety and the protonated catalyst amine. Thiourea also activates the electrophile (EI) (Scheme 14). C−C bond formation is both the ratedetermining and the stereoselectivity-controlling step, in agreement with the experiment. Li et al.47 synthesized optically enriched spirocyclic benzofuran-2-ones by bifunctional thiourea-base catalyzed double-Michael addition of benzofuran-2-ones to dienones (B3LYP/6-31G(d)//B3LYP/3-21G) (Scheme 15). Jiang et al. studied (M06-2X/6-31+G(2df,2p)//B3LYP/631G(d,p)) the mechanism of asymmetric Michael addition of trans-1-nitro-2-phenylethylene to 2-methylpropionaldehyde catalyzed by CA-derived primary amine and benzoic acid (Scheme 16).48

Scheme 12. Michael Addition Reaction Catalyzed by Cinchona Alkaloid Al(III) Complex42

Scheme 13. 1,4-Michael Addition of Malononitrile to Unsaturated Aryl Ketones by Bifunctional CA43

continuous stages in the overall reaction, namely, formation of the iminium intermediate, addition reaction of iminium to malonitrile, hydrolysis and regeneration of the catalyst. The energy barrier for the formation of the C−N bond decreases significantly, as a protonated catalyst activates the carbonyl substrate through H-bonding. Steric interactions between the aromatic substituent, the quinoline ring, and the alkene moiety of the unsaturated ketone force the ketiminium ion

3.8. Asymmetric Mannich Reactions

Xie et al. examined the mechanism for the Mannich reaction of diethyl malonate and benzothiazol esters catalyzed by quinidine

Scheme 14. New Dual Activation Mechanism46

Reproduced from ref 46. Copyright 2012 American Chemical Society. F


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Accounts of Chemical Research Scheme 15. Proposed Reaction Mechanism for the Synthesis of Spirocyclic Benzofuran-2-ones47

Scheme 16. Michael Addition of trans-1-Nitro-2phenylethylene to 2-Methylpropionaldehyde48

3.9. Asymmetric Epoxidations and Hydroperoxidations

Lu et al. investigated the mechanism of asymmetric epoxidation of 2-cyclohexen-1-one catalyzed by CA salt (BHandHLYP/631G(d,p)), quantitatively predicting experimental er values (Scheme 18).50 List and co-workers investigated the role of the catalyst in the asymmetric epoxidation and hydroperoxidation of α,β-unsaturated carbonyl compounds with hydrogen peroxide by NMR Scheme 18. Theoretically Proposed Catalytic Cycle for the Asymmetric Epoxidation of Cyclic Enones50

with experimental and theoretical approaches (M06-2X/6311G(d,p) in gas phase and dichloromethane (CPCM)) (Scheme 17).49 In line with experimental results, the S enantiomer is obtained as major product in the range of 81% to 95% ee and lower reaction temperature improves stereoselectivity. Scheme 17. Mannich Reaction of Benzothiazol-β-amino Esters49

G


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Figure 3. Stereoselectivity mnemonic for epoxidation reactions of unsaturated carbonyl compounds catalyzed by Cat. Reproduced from ref 51. Copyright 2013 American Chemical Society.

Scheme 20. Asymmetric Hydrogenation of α-Activated Ketones on Chirally-Modified Pt-Catalysts55

and computational techniques (B3LYP/def2-TZVP//BP86/ SVP).51 The reactions were applicable to aliphatic acyclic α,βunsaturated ketones, small, medium and large ring-sized cyclic α,β-unsaturated ketones, and α-branched α,β-unsaturated aldehydes, giving rise to an enantiomeric excess of generally above 95:5 er. The authors emphasized the role of the counteranion provided by the Brønsted acid cocatalyst, which translates remote chirality of the ammonium cation to the reaction center and functions as a base to activate the nucleophile (Figure 3).

cinchonidine, whereas cinchonine favors S-pantolactone, in agreement with experimental observations. The crucial interaction was identified as the H-bonding between the modifier’s quinuclidine nitrogen and the reactant’s α-carbonyl oxygen.56 In the hydrogenation of ethyl pyruvate, calculations (B3LYP/6-31G(d,p)) explained enantioselection led by Oether groups.57

3.10. Strecker Reactions

Asymmetric Strecker reactions of aldimines and ketoimines are one of the most efficient methods for asymmetric synthesis of α-amino acids. Feng and co-workers experimentally reported a highly efficient catalytic asymmetric Strecker reaction of aldimines involving the asymmetric activation of 2,2′-biphenol derivative with a chiral activator cinchonine through coordinative interaction with TiIV.52,53 Recently, they investigated the mechanism and origin of selectivity of the asymmetric Strecker reaction catalyzed by cinchona alkaloid/ [Ti(OiPr)4]/achiral 3,3′-disubstituted 2,2′-biphenol by DFT and ONIOM methods (Scheme 19).54 ONIOM calculations were employed on the actual system (B3LYP/6-31G(d) high level and HF/STO-3G low level) to elucidate the stereoselectivity.

3.12. Asymmetric Allylic Alkenylations

Yang et al. reported highly enantio/diastereoselective synthesis of β-methyl-γ-monofluoromethyl-substituted alcohols based on the allylic alkylations between bis(phenylsulfonyl)methane/ fluorobis(phenylsulfonyl) methane with Morita−Baylis−Hillman (MBH) carbonates catalyzed by CA-derivative, (DHQD)2AQN (B3LYP/6-31G(d,p)) (Scheme 21).58 TS leading to the formation of the R product is favored due to the increased steric interaction in Re-face approach. Scheme 21. Highly Enantioselective Allylic Alkylation between BSM and MBH Carbonates58

Scheme 19. Strecker Reaction of N-Ts-protected Aldimines54

Yang et al. also reported the asymmetric allylic alkenylation of MBH carbonates with N-itaconimides as nucleophiles using CA-catalysts in moderate to excellent yields and good to excellent enantioselectivities.59 B3LYP/6-31G(d,p) calculations were employed to highlight the reaction mechanism of the allylic alkenylation of MBH carbonate with N-itaconimide (Scheme 22).

3.11. Hydrogenation Reactions

Baiker and co-workers invested many efforts into enantioselective hydrogenation of α-activated ketones on cinchonamodified metal surfaces, achieving high enantioselectivities (Scheme 20). They conducted several theoretical studies to investigate the origins of enantioselectivity and to design suitable catalysts.55 Baiker and co-workers calculated stabilities of the complex between ketone and cinchona-modified platinum in the hydrogenation of ketopantolactone. Calculations including MM (MM2 force field), semiempirical (AM1), and ab initio (SCF/3-21G) methods indicated that formation of the complex affording R-(−)-pantolactone is energetically favored with

3.13. Staudinger Reaction

Lectka and co-workers developed a CA-catalyzed asymmetric synthesis of β-lactams (Scheme 23). Conformations of baseketene adducts were successfully located with molecular mechanics, the relative energies of the diastereomers reflected the enantioselectivity observed experimentally.60,61 3.14. Decarboxylation Reaction

Brunner and Schmidt reported the cinchona-catalyzed synthesis of a nonsteroidal anti-inflammatory drug, naproxen (Scheme 24).62 The critical decarboxylation step in this synthesis was modeled (B3LYP/6-31G//AM1) by Strassner and co-workH


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Accounts of Chemical Research Scheme 22. Proposed Catalytic Cycle for the Asymmetric Allylic Alkenylation59

Scheme 23. Proposed Mechanism for the BQ Catalyzed βLactam Synthesis60

bonding arrangements were shown to favor the formation of the (S)-enantiomer. Sengupta and Sunoj investigated the mechanism and origin of enantioselectivity in the decarboxylative protonation of αamino malonate hemiester catalyzed by epicinchona−thiourea hybrid organocatalyst along with a detailed conformational analysis of the catalyst using the M06-2X/6-311+G(d,p)// ONIOM2 methodology in solution with the SMD method.64 The differential H-bonding between the chiral epicinchonathiourea moiety and the prochiral enolate in the diastereomeric TSs were shown to account for the high enantioselectivity.

Scheme 24. Enantioselective Decarboxylation Step in the Synthesis of Naproxen62

3.15. Sulfinylations

Chiral sulfonate esters were synthesized by Ellman et al. to use CA in the dynamic kinetic resolution of racemic sulfinyl chlorides.65 The reaction requires a fast racemization of sulfinyl chlorides as well as an acceleration of the sulfinylation step by a base (Scheme 25). Maseras and co-workers investigated the effect of base on the sulfinylation step (B3LYP/6-31G(d) and B3LYP/LANL2DZ(ECP) for S and Cl, CPCM in toluene (Scheme 26).66 Scheme 25. Cinchona-Catalyzed Dynamic Kinetic Resolution of Sulfinyl Chlorides65

ers,63 revealing that a concerted decarboxylation/protonation mechanism was more favorable than the stepwise pathway. HI


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catalyst (Scheme 28).69 The origin of stereroselectivity was examined by kinetics, NMR and DFT (M06-2X/6-311+G-

Scheme 26. Possible Pathways for Sulfinylation66

Scheme 28. Friedel−Crafts Reaction of 1-Naphthol with Ketimine Derivative of Benzylisatin69

Nucleophilic substitution of chloride by alkoxy in sulfinyl derivatives proceeds through a simultaneous bond formation and elongation step. In this key step, alcohol H is transferred to the S-oxo group. The barrier for this step is quite high, but is substantially lowered (∼10 kcal/mol) by a base, which stabilizes the proton being transferred. This study on a model system constitutes a promising first step toward the rationalization of the interesting effects of the base on enantioselectivity in the cinchona-assisted dynamic kinetic resolution.

(d,p)//B3LYP/6-31G(d)). Computed results revealed that the Re face attack is more stable than the corresponding Si face attack. 3.18. Conia-Ene Reactions

Cooperative catalysis, a combination of both organo and transition metal catalysis under one-pot reaction conditions is promising for asymmetric catalysis.70 Dixon et al. investigated the enantioselective Conia-Ene reaction catalyzed by cinchonaderived amino urea precatalysts and CuI.71 The amino urea precatalyst Cat ligates to the CuI and promotes enolization, subsequent formation of a reactive copper enolate undergoes syn-carbocupration (Scheme 29). Computed relative energetics (M06-2X/6-31G(d) and LANL2DZ for Cu) for the diasteromeric transition structures

3.16. Alpha-Brominations

Lectka and co-workers developed an asymmetric catalysis for the α-chlorination of acid halides using CA-catalysts.67 Extending their method to α-bromination, led to lower enantioselectivities (Scheme 27).68 Guided by modeling Scheme 27. Catalytic Asymmetric α-Bromination68

Scheme 29. Proposed Catalytic Cycle−Conia−Ene Reaction71

(IMOMO), benzoylquinine (BQ) was replaced with a proline-quinine conjugate (ProQ), and the brominating agent 1a was replaced with 1b. In 1a, the preference for the Si addition was attributed to the better stabilization of the enolate through a H-bond network with the quinuclidine ring. There is a destabilizing contact between ketene enolate phenyl and the quinoline methoxy in the unfavored Re addition. 3.17. aza Friedel−Crafts Reactions

Kumari et al. reported an enantioselective aza-Friedel−Crafts reaction with cinchona based bifunctional thiourea as organoJ



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are in good agreement with observed enantioselectivities. The urea group of the precatalyst plays a key role through Hbonding with oxygen.

REFERENCES

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4. CONCLUSIONS As the number of experimental studies utilizing the cinchona alkaloids as organocatalysts has increased in recent years, corresponding computational studies have increased as well. The latter mainly deal with the mechanistic studies of syntheses in the presence of CA, which play a crucial role in the acceleration of the reaction and the enantiodifferentiation of the products. B3LYP72,73 with modest basis sets has been used in most of the studies; nevertheless, the energetics have been corrected with higher basis sets and Truhlar’s M05-2X,74 M062X,75 and M06-L75 functionals, parametrized to include dispersion for organic reactions, as well as functionals with dispersion corrections.15,32,33,37,38,45,48,49,69,71 Since CAs tend to form complexes with substrates via H-bonds and long-range interactions, the usage of split valence triple-ζ basis set including diffuse and polarization functions on heavy atoms and polarization functions on hydrogens are recommended. Organocatalysts are used in condensed media; thus, most of the studies have used the continuum-based models; in some cases explicit solvation was shown to yield better quantitative agreement with experimental observations.15,33,34,38,39,42,46,49,69,71

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. Notes

The authors declare no competing financial interest. Biographies Gamze Tanriver is a Ph.D. candidate at Bogazici University under supervision of Assoc. Prof. Şaron Ç atak. She received her B.S. in Chemistry from Ondokuz Mayıs University in 2007 and her M.S. from Bogazici University in 2010. Burcu Dedeoglu is currently a Visiting Instructor at Sabancı University. She received her Ph.D. degree in Chemistry under the guidance of Prof. Viktorya Aviyente and Assoc. Prof. Alimet Sema Ö zen at Bogazici University in 2015. Her research includes the application of quantum mechanical tools in fields ranging from material science to biological systems. Saron Catak is an Associate Professor at Bogazici University. She obtained a joint Ph.D. in Computational Chemistry from University of Lorraine (Nancy, France) and Bogazici University (Istanbul, Turkey) in 2007. Her research mainly focuses on simulations of organic reactions in solution and biochemical reactions in biological systems. Viktorya Aviyente is a Professor of Chemistry and the chairperson of the Chemistry Department at Bogazici University since 2009. She received her Ph.D. in Physical Chemistry from Bogazici University in 1983. Her research group studies organic, organometallic, and biological reactions using the tools of computational chemistry. She is a Fellow of the Science Academy in Turkey.

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ACKNOWLEDGMENTS The authors thank all scientists stated in this account for valuable contributions to the field. K


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Computational Studies on Cinchona Alkaloid-Catalyzed Asymmetric

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