A priori theoretical prediction of selectivity in asymmetric catalysis: design of chiral catalysts by using quantum molecular interaction fields.
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Catalysis↗
Biomedical subjects
Marisa C Kozlowski
Publications and source records attributed to Marisa C Kozlowski.
Investigation of a convergent route to purpuromycin: benzofuran formation vs spiroketalization.
[Structure: see text] A mild and efficient [3+2] nitrile oxide/olefin cycloaddition allows coupling of the highly functionalized naphthalene and isocoumarin hemispheres of purpuromycin. A rationale of the inability of advanced keto alcohols to spirocyclize is presented based upon a systematic examination of the electronic factors present in these systems and suggests that the biosynthesis of purpuromycin does not proceed through open-chain intermediates.
Benzofurans↗
Catalytic asymmetric addition of dialkylzinc reagents to alpha-aldiminoesters.
[reaction: see text] The first catalytic, enantioselective addition of organozinc reagents to alpha-aldiminoesters is described. The use of a Lewis acid/Lewis base containing bifunctional catalyst preorganizes both reactive substrates to promote enantioselective addition over the racemic background reaction and alternative addition modes. Alcohol additives were found to enhance the enantioselection. The addition product was also found to cyclize with remaining substrate to provide imidazolidines.
Catalysis↗
De novo chiral amino alcohols in catalyzing asymmetric additions to aryl aldehydes.
[reaction: see text] A de novo structural class of chiral amino alcohol catalysts has been identified through a synergistic effort combining novel architectures from [4 + 3] cycloadditions and quantum mechanical interaction field predictions that closely match subsequent experimental measurements.
Aldehydes↗
Is the A-ring of sparteine essential for high enantioselectivity in the asymmetric lithiation-substitution of N-Boc-pyrrolidine?
The simplest chiral portion of sparteine, N,N'-dimethyl-2-endo-methylbispidine, was prepared and evaluated in the asymmetric lithiation-substitution of N-Boc-pyrrolidine. The results indicate that the complete A-ring of sparteine is essential for high levels of asymmetric induction. DFT-QSSR analyses of the diamine/Li(+) complexes and DFT calculations of the pertinent i-PrLi/diamine/N-Boc-pyrrolidine complexes are predictive and provide complementary pictures of the stereochemical features critical to this transformation.
Diamines↗
Enantioselective oxidative biaryl coupling reactions catalyzed by 1,5-diazadecalin metal complexes: efficient formation of chiral functionalized BINOL derivatives.
Chiral 1,5-diaza-cis-decalins have been examined as ligands in the enantioselective oxidative biaryl coupling of substituted 2-naphthol derivatives. Under the optimal conditions employing 2.5-10 mol % of a 1,5-diaza-cis-decalin copper(II) catalyst with oxygen as the oxidant, enantioselective couplings (44-96% ee) could be achieved for a range of 3-substituted 2-naphthols including the ester, ketone, phosphonyl, and sulfonyl derivatives. The relationship between the substitution of the naphthalene starting materials and reactivity/selectivity is determined by several factors which act in concert: (1) the effect of substituents on the oxidation potential of the substrate, (2) the ability of the substrate to participate in a chelated copper complex which depends on (a) the inherent coordinating ability of the 3-substituent and (b) substituent steric interactions that affect chelation between the 2-hydroxyl and 3-substituent, (3) the effect of substituents on dissociation of the product from the copper catalyst.
Journal Article↗
General approach for the synthesis of chiral perylenequinones via catalytic enantioselective oxidative biaryl coupling.
By using oxygen as the terminal oxidant, copper complexes derived from chiral 1,5-diaza-cis-decalin catalyze the enantioselective oxidative biaryl coupling of highly functionalized naphthols to provide octa- and decasubstituted binaphthalenes with high selectivity (86-90% ee). Products containing very electron-rich naphthalenes were prone to epimerization under the reaction conditions. This epimerization could be suppressed by employing naphthol starting materials with phenol protecting groups that attenuated the electron-rich nature of the naphthalenes. Direct oxidation of the resultant chiral 1,1'-binaphthol framework completed the first asymmetric synthesis of a perylenequinone containing only an axial chirality element.
Catalysis↗
Quantum mechanical models correlating structure with selectivity: predicting the enantioselectivity of beta-amino alcohol catalysts in aldehyde alkylation.
Quantitative structure selectivity relationship (QSSR) models are described that provide consistently reliable predictions for the asymmetric addition of Et2Zn to PhCHO catalyzed by beta-amino alcohols. Statistically valid two-variable linear regression models that correlate the structures of the chiral catalysts with their enantioselectivities are obtained from three-dimensional physical property grids. The strength of the present method is that statistical models obtained from a small set of experimentally determined selectivities and relatively simple theoretical calculations yield selectivity predictions that are as accurate as those derived from higher-level calculations of transition-structure energies. Only minutes of computing time are required. Simple models are obtained which permit straightforward physical interpretation and generate realistic predictions.
Aldehydes↗
Novel pathways for the formation of chiral binaphthyl polymers: oxidative asymmetric phenolic coupling alone and in tandem with the Glaser-Hay coupling.
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Journal Article↗
Computer-aided design of chiral ligands. Part 2. Functionality mapping as a method to identify stereocontrol elements for asymmetric reactions.
A computational method to determine the energetically favorable positions of functional groups with respect to the transition states of stereoselective reactions based on force field energy minimization is presented. The parameters of this functionality mapping, the characteristics of the target transition states, and the features of the probe structures are outlined. Our method was found to reproduce the positions of the stereodiscriminating fragments for some known chiral ligands including the Masamune dimethylborolane, dimenthylborane, the Corey stien reagent, the Roush allylboronate tartrates, and the secondary amine Diels-Alder catalysts described by MacMillan. Functionality mapping can be used to better understand the specific interactions in the transition states leading to the products by providing a quantitative measure of the stabilization/destabilization afforded by the different ligand components via nonbonded interactions. The method can determine if a chiral ligand imparts the observed selectivity by stabilizing one reaction pathway, by destabilizing a reaction pathway, or by a combination of both. Orientational as well as positional information about potential functional groups is readily obtained. In addition to its utility as an analytical tool, functionality mapping can be used to explore starting points for the design of new chiral ligands.
Boranes↗
Catalysis of the Michael addition reaction by late transition metal complexes of BINOL-derived salens.
Salen metal complexes incorporating two chiral BINOL moieties have been synthesized and characterized by X-ray crystallography. The X-ray structures show that this new class of Ni-BINOL-salen catalysts contains an unoccupied apical site for potential coordination of an electrophile and naphthoxides that are independent from the Lewis acid center. These characteristics allow independent alteration of the Lewis acidic and Brønsted basic sites. These unique complexes have been shown to catalyze the Michael reaction of dibenzyl malonate and cyclohexenone with good selectivity (up to 90% ee) and moderate yield (up to 79% yield). These catalysts are also effective in the Michael reaction between other enones and malonates. Kinetic data show that the reaction is first order in the Ni*Cs-BINOL-salen catalyst. Further experiments probed the reactivity of the individual Lewis acid and Brønsted base components of the catalyst and established that both moieties are essential for asymmetric catalysis. All told, the data support a bifunctional activation pathway in which the apical Ni site of the Ni*Cs-BINOL-salen activates the enone and the naphthoxide base activates the malonate.
Catalysis↗
Theoretical and experimental studies of asymmetric organozinc additions to benzaldehyde catalyzed by flexible and constrained gamma-amino alcohols.
The cis-decalin based gamma-amino alcohols, 1-5, were synthesized, resolved, and employed as catalysts in the addition of organozincs to benzaldehyde. Despite large facial differentiation in the RZn adducts of the ligands, the enantioselectivities were found to be moderate. Transition structure calculations were done using several quantum chemical methods to examine the underlying causes of the selectivity for three gamma-amino alcohols, 1, 2, and 3. The tricyclic mu-oxo (6/4/4), rather than the bicyclic six-membered (6/6), transition structures were found to explain the observed enantioselectivity for 2 and 3. MP2 calculations gave the best correlation to the experimental results compared to B3LYP and HF calculations. The conformational flexibility of the chiral ligands was found to be an important factor in the selectivity.
Amino Alcohols↗
Computer-aided design of chiral ligands. Part III. A novel ligand for asymmetric allylation designed using computational techniques.
[reaction: see text] Computer-aided design protocols to identify new chiral ligands for reactions proceeding through well-defined transition states are outlined. Ligand families are discovered via computational screening of large structural databases such as the Cambridge Structural Database. Using this method, a novel cis-decalin ligand has been identified as a chiral auxiliary for the allylboration of aldehydes. Synthesis, resolution, and evaluation revealed that this new auxiliary provided the aldehyde facial approach upon which the design was predicated.
Computer-Aided Design↗
SmI(2)-promoted oxidation of aldehydes in the presence of electron-rich heteroatoms.
[reaction: see text] The Evans-Tishchenko reaction provides an efficient and practical solution for the oxidation of aldehydes possessing sensitive electron-rich heteroatoms to the corresponding esters. Careful selection of the sacrificial beta-hydroxy ketone provides considerable subsequent flexibility to access the desired carboxylic acid.
Aldehydes↗
The first catalytic asymmetric addition of dialkylzincs to alpha-ketoesters.
[formula: see text] The first catalytic, enantioselective addition of organoznic reagents to alpha-ketoesters is described. Modular bifunctional salen catalysts that contain Lewis acid and Lewis base activating groups accelerate the carbonyl addition to a much greater extent than the competing carbonyl reduction. alpha-Hydroxyesters containing new quaternary stereogenic centers are obtained in high yield and moderate enantiomeric excess. Enrichment to 98% ee can be effected by recrystallization of the corresponding alpha-hydroxy acid.
Catalysis↗
Development of bifunctional salen catalysts: rapid, chemoselective alkylations of alpha-ketoesters.
Lewis acid-Lewis base salen complexes have been identified as highly efficient catalysts for the addition of dialkylzincs to alpha-ketoesters. In contrast to aldehydes or ketones, the reaction between diethylzinc and alpha-ketoesters is significant in the absence of catalyst. In the presence of catalyst, the reaction rate is increased over 100-fold relative to the background. Furthermore, the reduction product, which is a major coproduct with other catalysts, is not observed with these bifunctional salens. As a result, high yields of the addition products can be obtained (57-99%). Both the Lewis acid and Lewis base portions of the catalyst are critical to the reactivity and selectivity. The two separate portions of the catalyst have been shown to function in a cooperative manner.
Aldehydes↗
Control of the conformational equilibria in aza-cis-decalins: structural modification, solvation, and metal chelation.
A series of amino alcohol- and diamino-cis-decalins were synthesized and their conformational properties investigated. The equilibrium distributions of the conformational isomers were measured via NMR spectroscopy. The equilibrium ratios depend on the position of the substituents on the decalin ring system and the solvent. The 7-substituted 1-aza-cis-decalins are more likely to adopt the N-in form than the 5-substituted analogues. The N-in form is generally favored in nonpolar solvents, while the N-out form is favored in polar solvents. Complexation with LiClO4 and Et2Zn alters the equilibrium to favor the N-in decalin conformer. Both conformers coordinate lithium ions such that "on/off" conformational switching is not observed for these decalins. Comparison of the results with complexation studies of (-)-sparteine allows the criteria for an ideal "on/off" conformational switch to be defined.
Alcohols↗
Utility of calculated 13C NMR chemical shifts in differentiating conformational isomers: a study of metal-complexed and uncomplexed bispidines.
Calculated 13C NMR chemical shifts were key to assigning the structures of the conformational forms of complexed and uncomplexed bispidine derivatives.
Bridged Bicyclo Compounds, Heterocyclic↗