Bi-functional Organic Small Molecule Catalytic Asymmetric Synthesis Reactions Theoretical Research

As a catalytic method with the same status of enzyme catalysis and metalcatalysis, organocatalysis has been an important tool for building the molecularscaffold owing to the high efficiency and selectivity. At present, the focus of organicsynthetic chemistry is asymmetric synthesis which is mainly used in the fields ofpharmacy, materials, biology and so on. Recently, new asymmetric catalytic reactionshave been discovered continuously. The organocatalysts have been developed withhigh efficiency, high selectivity and high universality. Thereby the asymmetricorganocatalysis is in the golden period of vigorous development. The investigation onthe mechanism of various asymmetric reactions and the activation of differentorganocatalysts could facilitate understanding of catalytic reaction process, explainingthe experimental results, revealing the catalyst structure-activity relationship and thenproviding theoretical guidance for the development of new high-efficiency catalysts.In this dissertation, five series of typical organocatalysts were selected for study. Theyare dual chiral, bisphosphine, thiourea, secondary amine and chiral guanidinederivated bifunctional catalysts. Eight catalytic asymmetric reactions wereinvestigated and discussed in detail by using theoretical calculation methods. In theprocess of exploring the reactive mechanism of different units in catalysts, weproposed many innovative ideas.The specific research and conclusions are as following:The mechanism of enantioselectivie control of organocatalyst with central andaxial chiral elements in Michael addition of 2,4-pentandione to nitroalkene isinvestigated using density functional theory (DFT) calculation. Two enantioselectivechannels are characterized in detail. Enantioselectivity is determined in the C-C bondformation and the proton transfer is identified as the energetic bottleneck. Generally,the level of enantioselectivity of catalysts depends on geometrical match or mismatchof two asymmetric elements. The"closed"geometry of catalyst makes thecooperation of two chiralities possible, so that the central and axial chirality work together to enhance the enantioselective control. The"open"structure of catalystmakes the cooperation of two asymmetric elements impossible, so that itsenantioselectivity dominated only by one type of chirality is decreased.Thiourea-tertiary amine-catalyzed enantioselective aza-Morita Baylis Hillmanreaction of nitroalkene and N-tosylimine has been investigated using DFT method.Enantioselectivity is dominated by the cooperative effect of non-covalent and weakcovalent interactions imposed by different units of catalyst. As Lewis base, the tertiaryamine unit activates nitroalkene via weak covalent bond. The weak covalentinteraction orients the reaction in a major path with smaller variations of this bond.The aromatic ring unit activates N-tosylimine viaÏ€-Ï€stacking. The non-covalentinteraction selects the major path with smaller changes of the efficient packing areas.Thiourea unit donates more compact H-bonded network in species of the major path.Our conclusion is supported by ee value in solution phase of xylene (97.6%) muchhigher than DMF (27.2%).The H-bond activation mechanism and enantioselectivity of hydroxyl-thioureacatalyst in conjugate amine addition of O-benzyl hydroxylamine to pyrazole crotonate,is investigated using density functional theory (DFT) calculations. Two competingactivation models are explored in detail. C-N bond formation is stepwise in both ofthe two models. The enantioselective (S)-channel is more favorable than (R)-channelvia the calculated barriers. The enantioselectivity originated from si face preferablethan re face can be attributed to the H-bonded network provided by thiourea andhydroxyl groups in rate-determining step. The enantiomeric excess (ee) valuespredicted through ONIOM calculations are in line with the experiment.TangPhos-catalyzed asymmetricγaddition of thiols to allenoates has beeninvestigated according to density functional theory. The uncatalyzed addition occursatβ-carbon via a process which involves C-S bond formation and proton transfer fromS toγ-carbon. Theβ-thioester is generated. In TangPhos-catalyzed case, thenucleophilic thiol attacksγ-carbon after the addition of TangPhos toβ-carbon. Theproton transfers firstly from P of TangPhos to carbonyl O and then toβ-carbon. Theγ-thioester is obtained. Step1 is rate-limiting. As nucleophilic catalyst, P2 forms strong covalent bond withβ-carbon which shifts the positive charge of C2, leaving C3as the electrophilic center forγaddition. The regioselectivity is consequently altered.As Lewis base, P1 deprotonates thiol enhancing the nucleophility of S and facilitatesthe proton transfer toβ-carbon as a medium. Among four competitive pathways, ERpath is the most favorable one with smallest rotation of the single bond linking twochiral rings in TangPhos. The primary domination on enantioselectivity of chiral ringsis assisted by t-butyl group, which also prefers ER path with the least steric hindrance.Our conclusion is supported by NBO analysis and the predicted ee values according tothe experiment.In next work, we investigated important intermediates and key transition states ofthe organocatalyzed cascade double Michael addition using DFT method. Thecalculated results suggest that the reaction contains intermolecular nucleophilicaddition and intramolecular cyclization, both involving the formation of twostereocenters. The iminium–enamine catalysis of secondary amine unit enables thecascade addition to proceed consecutively. As an electron transport, the iminiumattracts the electron stream to promote the nucleophilic addition. Then enamineimpulses the electron stream to catalyze the cyclization. As H bond donor, the catalystforms three types of C–H···O H bond with substrates. The enantioselectivity anddiastereoselectivity are dominated by the catalyst backbone. Two group links ofpyrrole–phenyl and pyrrole–silyl ether orient the reaction in paths with smallerrotations of the linked single bonds. Our conclusion is supported by NBO analysis andthe predicted ee, dr values according to the experiment.Enantioselective Biginelli reaction of aldehyde,β-ketoester, and urea catalyzedby natural (2R, 3R)-tartaric acid has been investigated using density functional theory(DFT) calculations. The results indicate that the most favorable pathway involves aprotonated imine from aldehyde and urea in the first step. Tartaric acid forms H bondsnetwork with substrates enhancing the electrophilicity of protonated imine and thenucleophilicity ofβ-ketoester. (R)-3, 4-dihydropyrimidin-2-(1H)-ones (DHPMs) ispreferable in the reaction. The solvent effect is discussed in the prediction ofenantiomeric excess (ee) values in ethanol and in water. Density functional theory calculations are used to study the reaction mechanismand origins of high stereoselectivity in chiral guanidine-catalyzed asymmetric1,4-addition of 5H-oxazol-4-ones. The reaction involves proton abstraction of5H-oxazol-4-one, C-C bond formation and proton transfer. N1 atom of chiralguanidine exchanges its character as base and acid to activate 5H-oxazol-4-one and tofacilitate the product formation. The role of N2 H2 is not only H bond donor for5H-oxazol-4-one but also electron accepter for N1. The enantioselectivity related withrate-limiting step1 and Z/E selectivity determined in step2 are primarily influenced byfive–six-membered ring link in the backbone of chiral guanidine. The reactionproceeds along the favorable path with smaller rotations of the linked bonds. Theenantioselectivity is improved with guanidine involving electron-deficient and bulkysubstituent. With methyl ether-protected hydroxy in structure, the catalytic ability andenantioselective control of guanidine are extraordinarily low affording oppositeenantiomer as major product. Z-isomers are preferred all the while.Chiral cinchona alkaloid salts-catalyzed asymmetric epoxidation of2-cyclohexen-1-one with hydrogen peroxide (H₂O₂) has been investigated usingdensity functional theory (DFT). The ring-closure step is rate-limiting in the catalyticreaction. The enantioselectivity-determining step is initial nucleophilic additioninvolving two orientations of axial and equatorial. In (S)-catalyst j-mediated processaxial pathway is favored over equatorial leading to the major epoxide [2S,3S]-3. Anopposite enantiomer [2R,3R]-3 is primarily generated in (R)-catalyst k-assisted casepreferring equatorial pathway. The results indicate that the enantioselectivity ofepoxidation is dominated by central chirality of the bifunctional catalysts in theactivation of enone by primary amine salt via iminium formation and of H₂O₂bytertiary amine reacting as a general base. The substituent effect is also discussed toclarify a tendency existing in experiment.