The effect of fluoromethyl groups on the diastereoselectivity in the electrophilic alkylation

The effect of fluoromethyl groups on the diastereoselectivity in the electrophilic alkylation is described. In particular, the electrophilic alkylation of enolates with a trifluoromethyl group was proceeded with highly diastereofacial selectivity based on the steric and/or electrostatic effect of substituent with strong electron withdrawing.     

Asymmetric hydrogenation of trisubstituted olefins with iridium-phosphine thiazole complexes: a further investigation of the ligand structure

New chiral bidentate phoshine thiazoles have been prepared and successfully applied as ligands in the homogeneous iridium-catalyzed asymmetric hydrogenation of aryl alkenes and aryl alkene esters. The ligands are designed to be highly modular and have one common chiral intermediate, from which diversity can be introduced at a late stage in the synthetic pathway. It was found that a six-member-ring backbone of the rigid ligand structure was preferred over seven- or five-member rings. In this study it is shown that the substituent pattern of the ligands has a major influence on the stereochemical outcome of the products. By applying the selectivity model proposed in this study, it is possible to match different substrates against different catalysts. In this way, good to excellent enantioselectivity can be obtained for typically difficult substrates. Geometrically different derivatives of alpha- and beta-methyl cinnamic acid ethyl esters were hydrogenated, to demonstrate the validity of the selectivity model and to verify the importance of steric and electronic matching of the catalyst and the substrate.     

Platinum Nanoparticles: The Crucial Role of Crystal Face and Colloid Stabilizer in the Diastereoselective Hydrogenation of Cinchonidine

The preparation of stable metal nanoparticles requires a strong interaction between the (organic) stabilizer and the metal surface that might alter the catalytic properties. This behavior has been described as “poisoning” since the stabilizer normally decreases the catalytic activity due to site blocking. Here we show a striking influence of the stabilizer on the selectivity in the hydrogenation of cinchonidine (CD) over poly(acrylic acid) (PAA)‐stabilized Pt nanoparticles with well‐defined shape distributions. In the hydrogenation of the heteroaromatic ring of cinchonidine in toluene, the diastereomeric excess of the (S)‐hexahydrocinchonidine increased upon increasing Pt{111}/Pt{100} ratio, but this distinct shape selectivity was observed only after the oxidative removal of PAA at 473 K. The use of the as‐prepared nanoparticles inverted the major diastereomer to R, and this isomer was formed also in acetic acid. This striking change in the diastereoselectivity indicates that poly(acrylic acid), which remains on the Pt surface after preparation, interacts with CD during hydrogenation almost as strongly as the solvent acetic acid. The PAA stabilizer plays a dual role: it allows one to control the size and shape of the nanoparticles during their synthesis, and it affects the rate and diastereoselectivity of the hydrogenation of CD probably through a “surface‐localized acidification”.     

Spectroscopic detection of the most stable carbonic acid, cis-cis H2CO3

Carbonic acid had not been detected by any spectroscopic means for a long period. Recently, we have reported the detection of its second most stable conformer, cis-trans H(2)CO(3), as the first spectroscopic detection of the isolated carbonic acid molecule. In the present work, the most stable conformer of carbonic acid, cis-cis H(2)CO(3), in the gas phase has been successfully produced in a supersonic jet using a pulsed discharge nozzle, and pure rotational transitions of this molecule have been observed by a Fourier-transform microwave spectrometer. In addition to cis-cis H(2)CO(3), its deuterated isotopologue, cis-cis D2CO3, has been observed, yielding the r(0) structure of the cis-cis conformer. Furthermore, hyperfine constants of the deuterated cis-trans conformers were also determined. The two structures for the stable isolated carbonic acid molecule, those of the cis-cis and cis-trans conformers, are considered to provide basic information for the understanding of chemical reactions involving carbonic acid The present result is accurate enough to be used in radio astronomical observations, where the ortho∕para ratio of cis-cis H(2)CO(3) may be used as an important probe of interstellar chemistry.     

Origin of 1,3-induction in the addition of alkyl lithium to imines bearing an N-stereogenic center

The origin of diastereoselectivity in the addition of alkyl lithium to chiral Schiff bases has been investigated experimentally and theoretically and the formation of the major diastereomer can be explained from the energy minimized structure of the Schiff base in which the phenyl group has been found to orient in such a manner that it posed lesser steric hindrance to the incoming nucleophile as compared to the alkyl group.     

Origins of stereoselectivity in the Diels-Alder addition of chiral hydroxyalkyl vinyl ketones to cyclopentadiene: a quantitative computational study

Modest basis set level MP2/6-31G(d,p) calculations on the Diels-Alder addition of S-1-alkyl-1-hydroxy-but-3-en-2-ones (1-hydroxy-1-alkyl methyl vinyl ketones) to cyclopentadiene correctly reproduce the trends in known experimental endo/exo and diastereoface selectivity. B3LYP theoretical results at the same or significantly higher basis set level, on the other hand, do not satisfactorily model observed endo/exo selectivities and are thus unsuitable for quantitative studies. The same is valid also with regard to subtle effects originating from, for example, conformational distributions of reactants. The latter shortcomings are not alleviated by the fact that observed diastereoface selectivities are well-reproduced by DFT calculations. Quantitative computational studies of large cycloaddition systems would require higher basis sets and better account for electron correlation than MP2, such as, for example, CCSD. Presently, however, with 30 or more non-hydrogen atoms, these computations are hardly feasible. We present quantitatively correct stereochemical predictions using a hybrid layered ONIOM computational approach, including the chiral carbon atom and the intramolecular hydrogen bond into a higher level, MP2/6-311G(d,p) or CCSD/6-311G(d,p), layer. Significant computational economy is achieved by taking account of surrounding bulky (alkyl) residues at 6-31G(d) in a low HF theoretical level layer. We conclude that theoretical calculations based on explicit correlated MO treatment of the reaction site are sufficiently reliable for the prediction of both endo/exo and diastereoface selectivity of Diels-Alder addition reactions. This is in line with the understanding of endo/exo selectivity originating from dynamic electron correlation effects of interacting pi fragments and diastereofacial selectivity originating from steric interactions of fragments outside of the Diels-Alder reaction site.     

Asymmetric Induction in [3 + 2] Dipolar Cycloaddition Reactions of Nitrile Oxides with Chiral (α-Oxyallyl)silanes

The dipolar cycloaddition reactions of(α-oxyallyl)silanes 12a-g with 2,2-dimethylpropanenitrile oxide and benzonitrile oxide have been studied. Mixtures of anti (14a-g and 16a-g) and syn (15a-g and 17a-g) Δ²-isoxazolines are formed. The direction and magnitude of asymmetric induction depends on the allylie oxygen substituent: a free hydroxy provides a modest excess of the syn diastereomer, a silyl ether shows good selectivity for the anti diastereomer, and various acyl derivatives show low diastereoselectivity. The significance of these results is discussed in terms of two current models for asymmetric induction.     

Exploring the coordination chemistry of isomerizable terpyridine derivatives for successful analyses of cis and trans isomers by travelling wave ion mobility mass spectrometry

The photochemical cis-trans isomerization of the 4-{4-[2-(pyridin-4-yl)ethenyl]phenyl}-2,2':6',2'-terpyridine ligand (vpytpy) was investigated by UV-vis, NMR and TWIM-MS. Ion mobility mass spectrometry was performed pursuing the quantification of the isomeric composition during photolysis, however an in-source trans-to-cis isomerization process was observed. In order to overcome this inherent phenomenon, the isomerization of the vpytpy species was suppressed by complexation, reacting with iron(ii) ions, and forming the [Fe(vpytpy)(2)](2+) complex. The strategy of "freezing" the cis-trans isomerizable ligand at a given geometric conformation was effective, preventing further isomerization, thus allowing the distinction of each one of the isomers in the photolysed mixture. In addition, the experimental drift times were related to the calculated surface areas of the three possible cis-cis, cis-trans and trans-trans iron(ii) complex isomers. The stabilization of the ligand in a given conformation also allows us to obtain the cis-cis and cis-trans complexes exhibiting the ligand in the metastable cis-conformation, as well as in the thermodynamically stable trans-conformation.     

Nucleophilic epoxidation of gamma-hydroxyvinyl sulfoxide derivatives

The nucleophilic epoxidation of simple (gamma-silyloxy)vinyl sulfoxides takes place with complete stereocontrol and high yields. For substrates bearing an additional substituent at the gamma position, a reinforcing/nonreinforcing scenario is operative. While E and Z silylated substrates undergo a primarily sulfur directed epoxidation with good to excellent diastereocontrol, the related (E)-(2-methoxyethoxy)methyl ethers display diminished selectivity for the diastereomer derived from the nonreinforcing scenario.     

Dynamic Kinetic Stereoselective Glycosylation via RhII and Chiral Phosphoric Acid-Cocatalyzed Carbenoid Insertion to the Anomeric OH Bond for the Synthesis of Glycoconjugates

Chemical synthesis of glycoconjugates is essential for studying the biological functions of carbohydrates. We herein report an efficient approach for the stereoselective synthesis of challenging α-linked glycoconjugates via a Rh^II/chiral phosphoric acid (CPA)-cocatalyzed dynamic kinetic anomeric O-alkylation of sugar-derived lactols via carbenoid insertion to the anomeric OH bond. Notably, we observed excellent anomeric selectivity, excellent diastereoselectivity, broad substrate scope, and high efficiency for this glycosylation reaction by exploring various parameters of the cocatalytic system. DFT calculations suggested that the anomeric selectivity was mainly determined by steric interactions between the C2-carbon of the carbohydrate and the phenyl group of the metal carbenoid, while π/π interactions with the C2−OBn substituent on the carbohydrate substrate play a significant role for diastereoselectivity at the newly generated stereogenic center.     

Diastereoselectivity in the Epoxidation of Substituted Cyclohexenes by Dimethyldioxirane(1)(,)(2)

Three series of compounds based on the cyclohexene framework have been epoxidized by dimethyldioxirane. A pronounced dependence of epoxide diastereoselectivity on substituent has been observed. In addition there is a solvent influence on this stereoselectivity. The results have been explained by invoking steric, H-bonding, and dipole-dipole influences on the epoxide stereochemistry.     

Stereoselective hydrogenation of methylcyclohex-2-ene-1,4-diols used in the synthesis of ampelomins and deoxy-carbasugars

Stereoselective hydrogenation of methylcyclohex-2-ene-1,4-diols used as important intermediates for the preparation of ampelomins and deoxy-carbasugars was studied. These olefins were obtained in few steps from a chiral cis-diol resulting from microbial oxidation of toluene. Although the stereoselective hydrogenation of this type of substrates is difficult, high yields were obtained for heterogeneous hydrogenation using Adam’s catalyst, where steric hindrance controlled the stereochemical outcome of the process. On the other hand, for homogeneous hydrogenation of similar olefins using Crabtree’s catalyst, coordination with the allylic alcohols allowed for a controlled hydrogen addition from the more hindered face. In this manner two protocols for the hydrogenation of these types of substrates resulting in complementary stereoselectivities are described.     

Investigation into the enantioselection mechanism of ruthenium-arene-diamine transfer hydrogenation catalysts using fluorinated substrates

The effects of both steric and electronic properties of ketones on the selectivity in asymmetric transfer hydrogenation have been studied with aryl alkyl/fluoroalkyl ketones using four ruthenium based catalysts and two different media. The 1-arylethanones, 1-aryl-2-fluoroethanones and 2,2-difluoroacetophenones could be reduced with medium to high ee (86-99%), while the 1-aryl-2,2,2-trifluoroethanones were reduced with low selectivity in most systems. The change in enantioselectivity upon structural variation has been rationalised aided by regression analysis with substituent constants and the partial charge of the carbonyl carbon as predictors. The steric bulk of the alkyl/fluoroalkyl chain was found to be the major factor in determining selectivity in formic acid/triethylamine, while for reduction of a series of substituted 1-arylethanones and 1-aryl-2-fluoroethanones, the selectivity was found to depend on the electronic properties of the aromatic ring, supporting previous evidence that π-π interaction between the substrate and catalyst is important in determining the selectivity. For reductions in water using sodium formate as the hydrogen donor, altered and more complex selectivity mechanisms were observed. Experiments and regression focused on the variation of the alkyl/fluoroalkyl group of phenyl and 1-naphthyl ketones, showed that the selectivity correlated with the size of the substituent, but also the partial charge of the carbonyl carbon.     

Effect of the substituent position on the enantioselective hydrogenation of methoxy-substituted 2,3-diphenylpropenoic acids over palladium catalyst

The enantioselective hydrogenation of mono and dimethoxy-substituted 2,3-diphenylpropenoic acids has been studied over cinchonidine modified supported Pd catalyst. The hydrogenation of the six monosubstituted methoxy derivatives of (E)-2,3-diphenylpropenoic acid showed that the position of the substituent has a decisive influence on the initial reaction rate and the enantioselectivity. High enantioselectivities, 86–90%, were obtained in the hydrogenation of mono-substituted derivatives with a favourable substituent position. The results were rationalized in terms of either the electronic or the steric effects of the methoxy substituent determined by its position. These suggestions were also applicable in interpreting the results obtained in the hydrogenation of substituted (Z)-2,3-diphenylpropenoic acids and selected dimethoxy (E)-2,3-diphenylpropenoic acids. The combined steric and electronic effects of the substituents on the α- and β-phenyl rings ensured the highest enantioselectivities, up to 92% ee, in the hydrogenation of (E)-2-(2-methoxyphenyl)-3-(4-methoxyphenyl)propenoic acid.     

Asymmetric synthesis of 2-methyl cyclohexane carboxylic acids by heterogeneous catalysis: mechanistic aspects

The catalytic hydrogenation of (S)-alkyl-N-(2-methylbenzoyl)pyroglutamates was studied over supported rhodium and ruthenium catalysts at room temperature and a pressure of 5 MPa. The reaction was diastereoselective with the predominant formation of (1S,2R)-2-methylcyclohexane carboxylic acid with a diastereomeric excess (de) of up to 96%. The most stable conformation was determined by means of a combination of modelling calculations, NMR spectroscopy and X-ray structural determination. In this conformation, the carbonyl group of the pyroglutamate auxiliary shields one face of the aromatic ring. The observed selectivity may thus be explained by a preferential adsorption at the unshielded face which avoids steric repulsion by the C=O group to result in a cis hydrogenation. The addition of an amine, the nature of the support (alumina or active carbon) or of the metal (Rh or Ru) were shown to give additional stabilisation of the adsorption at the unshielded face to increase the diastereoisomeric excess.     

Diastereotopos-Differentiation in the Rh-Catalyzed Amination of Benzylic Methylene Groups in the α-Position to a Stereogenic Center

The diastereoselectivity of the Rh-catalyzed C-H amination was examined with 18 chiral open-chain substrates, which bear a benzylic methylene group in the α-position to a stereogenic center (-CHMeX), and with four chiral cyclic tetralins, in which the stereogenic center was positioned at carbon atom C2. The C-H amination was performed using trichloroethoxysulfonyl-substituted amine (H(2)NTces) as the nitrogen source, a diacyloxyiodobenzene as the oxidant, and bis[rhodium(α,α,α',α'-tetramethyl-1,3-benzenedipropionate)] [Rh(2)(esp)(2)] as the catalyst. For acyclic substrates a high syn diastereoselectivity (dr > 95/5) was found if the substituent X was Br, PO(OEt)(2), SO(2)Ph, or OOCCF(3) (eight examples). Moderate to good syn selectivities (dr = 80/20 to 91/9) were found for X = NO(2), OAc, COOMe, and CN (eight examples). Only two substrates gave a low diastereoselectivity. Kinetic isotope effect (KIE) experiments revealed that there is no secondary KIE when replacing -CHMeCOOMe by -CDMeCOOMe, but there is a significant primary KIE at the benzylic methylene position (4.8 ± 0.7). Deuteration experiments provided evidence that the reaction proceeds stereospecifically with retention of configuration. A preferred conformation is proposed, which explains the outcome of the reaction. In this conformation the X substituent is antiperiplanar to the C-H bond, which is diastereoselectively attacked, and steric strain between the remaining substituents at the stereogenic and the prostereogenic center is minimized. DFT calculations support this model. They suggest, however, that the reaction is not concerted but occurs via hydrogen atom abstraction and subsequent radical rebound. Further support for an antiperiplanar attack relative to a given substituent X = Br, COOMe, or CN was obtained with the respective 2-substituted tetralins. Attack at C1 provides almost exclusively the trans-amination product. If the size of the X substituent increases [Br < CN < COOMe < PO(OEt)(2)], attack at the carbon atom C4 prevails, delivering the respective trans-amination products at this position.     

Enecarbamates as selective substrates in oxidations: chiral-auxiliary-controlled mode selectivity and diastereoselectivity in the [2+2] cycloaddition and ene reaction of singlet oxygen and in the epoxidation by DMD and mCPBA

The stereochemical course of the oxidation of chiral oxazolidinone-substituted enecarbamates has been studied for singlet oxygen ((1)O(2)), dimethyldioxirane (DMD), and m-chloroperbenzoic acid (mCPBA) by examining of the special structural and stereoelectronic features of the enecarbamates. Valuable mechanistic insight into these selective oxidations is gained. Whereas the R(1) substituent on the chiral auxiliary is responsible for the steric shielding of the double bond and determines the sense of the pi-facial diastereoselectivity, structural characteristic such as the Z/E configuration and the nature of the R(2) group on the double bond are responsible for the extent of the diastereoselectivity. Stereoelectronic steering by the vinylic nitrogen functionality controls the mode selectivity (ene reaction vs [2+2] cycloaddition) in the case of (1)O(2).     

Additions to Fe(CO)3-dienal complexes: dependence of diastereoselectivity on Lewis acid

Lewis acid mediated additions to Fe(CO)3-2,4-dienal complexes are explored. Silyl enol ether and allylstannane nucleophiles both undergo aldehyde addition with good diastereoselectivity. However, with TiCl4 as the catalyst, the psi-exo diastereomer is the major product while with BF3.Et2O the psi-endo diastereomer is favored. Lewis acid/substrate interactions are studied by VT-NMR, and a hypothesis that accounts for the observed diastereoselectivity is presented.     

Stereoselective Synthesis of α-Methylene-β-Hydroxy-γ-Alkoxy Esters and Ketones

The amine catalysed aldol-type addition of vinylcarbonyl units to α-alkoxy aldehydes proceeds with reasonable diastereoface selectivity to afford the title compounds in good yield.     

Populations of carbonic acid isomers at 210 K from a fast two-electron reduced-density matrix theory

Parametrization of the 2-electron reduced density matrix (2-RDM) rather than the many-electron wave function yields a new family of electronic-structure methods that are faster and more accurate than traditional coupled electron-pair methods including coupled cluster with single and double excitations. Deriving the parametrization from N-representability conditions generates a 2-RDM that captures significant correlation from triple and higher-order excitations at the cost of double excitations. We apply the parametric 2-RDM method to confirm recent experiments determining the relative thermodynamic populations of the cis-cis and cis-trans isomers of carbonic acid. In 2010 Bernard et al. showed by infrared spectroscopy that the populations of cis-cis and cis-trans isomers have a 10:1 ratio at 210 K. By use of the parametric 2-RDM method, we predict a 8:1 ratio at 210 K. Comparable ab initio methods overestimate the stability of the cis-cis isomer with 24:1 and 21:1 ratios. These 2-RDM-based methods promise to have significant applications throughout chemistry.