Diastereoselective sulfur ylide promoted aldol/epoxidation

A mixture of cyclohexanone or 4-methylcyclohexanone and an aromatic aldehyde is treated with dimethylsulfoxonium methylide to effect a tandem aldol/epoxidation reaction. The resulting product contains three or four new stereocenters but only one of the possible four or eight diastereomers is formed.     

Organocatalytic asymmetric epoxidation and tandem epoxidation/Passerini reaction under eco-friendly reaction conditions

An eco-friendly synthesis of highly functionalized epoxides and their incorporation into an organocatalytic multicomponent approach are reported. For this, a modified class of diarylprolinol silyl ethers was designed to enable high catalytic activity in an environmentally benign solvent system. The one-pot procedure showed great efficiency in promoting stereoselective multicomponent transformations in a tandem, 'green' fashion. Because of its non-residual, efficient and selective character, this synthetic design shows promise for large-scale applications in both diversity and target-oriented syntheses.     

Enantio- and diastereoselectivities in chiral sulfur ylide promoted asymmetric aziridination reactions

Density functional theory investigation on the factors controlling enantio- and diastereoselection in asymmetric aziridination reaction by the addition of chiral bicyclic sulfur ylides to substituted aldimines is presented. High levels of enantioselection are predicted toward the formation of (2S,3S)-cis and (2R,3S)-trans aziridines by the addition of stabilized ylide (R = COMe) respectively to SO2Me and CO2Me protected aldimines. Similarly, high %ee is predicted for the formation of (2S,3R)-cis aziridines from semistabilized (R = Ph) ylide. Moderate to high levels of diastereoselectivity is noticed as well. The present study highlights that a correct prediction on extent of enantioselection requires the knowledge of the activation barriers for elementary steps beyond the initial addition step. In the case of stabilized ylides the ring-closure (or elimination of sulfur compound) is found to be crucial in controlling enantio- and diastereoselection. A cumulative effect of electronic as well as other weak interactions is identified as factors contributing to the relative energies of transition states leading to enantio- and diastereomeric products for the stabilized ylide addition to aldimines. On the contrary, steric control appears quite dominant with semistabilized ylide addition. With the smallest substituent on ylide (R = Me), high enantioselectivity is predicted for the formation of (2R,3R)-trans aziridines although the %de in this case is found to be very low.     

Theoretical study of molecular interactions of sulfur ylide with HF, HCN, and HN3

The molecular interactions between sulfur ylide (SY) and HX molecules (X = F, CN, and N₃) were investigated using the MP2 method at 6-311++G(2d,2p) basis set. Three different patterns including non-classical hydrogen bond (HB) H···C and classical HB H···X were found for complex formation between SY and HX molecules. Stability of the H···C type complexes are greater than H···X complexes. Quantum theories of atoms in molecules, natural bond orbitals, and energy decomposition analysis methods have been applied to analyze the intermolecular interactions. Good correlations have been found between the interaction energies (SE), the second-order perturbation energy E ⁽²⁾ and the charge transfer qCT in the studied systems.     

The complexity of catalysis: origins of enantio- and diastereocontrol in sulfur ylide mediated epoxidation reactions

The reaction of chiral sulfur ylides with aldehydes and ketones has emerged as a useful asymmetric process for the synthesis of epoxides. Processes employing either catalytic or stoichiometric amounts of sulfides have been developed. Although a large number of chiral sulfur ylides have been tested in the epoxidation process, only a few have delivered high diastereo- and enantio- selectivity. This review examines the factors that influence stereocontrol (steric hindrance of the sulfide, ylide conformation, ylide face selectivity, reversibility of betaine formation, solvent, and metal salts). This analysis leads to the conclusion that high reversibility in betaine formation leads to high diastereoselectivity but low enantioselectivity, and non-reversible betaine formation leads to low diastereoselectivity and high enantioselectivity (provided that other criteria are met). To achieve both high diastereoselectivity and high enantioselectivity simultaneously, requires non-reversible formation of the anti-betaine and reversible formation of the syn-betaine. Thus, factors that influence the degree of reversibility in betaine formation are critically important since with subtle changes in reaction conditions (solvent, temperature, metal ions) both high enantio- and diastereoselectivity can often be achieved.     

Computational investigations on the general reaction profile and diastereoselectivity in sulfur ylide promoted aziridination

Mechanism and diastereoselectivity of sulfur ylide promoted aziridination reactions were studied by density functional theory with inclusion of solvent effects through the continuum solvation model. The general reaction pathway was modeled for the addition of substituted sulfur ylides (Me(2)S(+)CH(-)R) to an aldimine ((E)-methyl ethylidenecarbamate, MeHC=NCO(2)Me). The nature of the substituents on the ylidic carbon atom substantially affects the reaction profile. The stabilized (R=COMe) and semistabilized (R=Ph) ylides follow a cisoid addition mode leading to trans aziridines via anti betaine intermediates. The simplest model ylide (unstabilized, R=H) underwent cisoid addition in a similar fashion. In the case of stabilized ylides product diastereoselectivity is controlled by the barriers of the elimination step leading to the 2,3-trans aziridine, whereas it is decided in the addition step in the case of semistabilized ylides. The importance of steric and electronic factors in diastereoselective addition (2 and 5) and elimination (5) transition states was established. Comparison of results obtained with the gas-phase optimized geometries and with the fully optimized solvent-phase geometries reveals that the inclusion of solvent effects does not bring about any dramatic changes in the reaction profiles for all three kinds of ylides. In particular, diastereoselectivity for both kinds of ylides was found to be nearly the same in both these approaches.     

Design of sulfides with a locked conformation as promoters of catalytic and asymmetric sulfonium ylide epoxidation

[reaction: see text] A new generation of 2,5-dimethylthiolanes with a locked conformation was developed to promote the asymmetric addition of chiral sulfonium ylides to aldehydes. The novel chiral sulfur derivative 4 succeeded the synthesis of trans-stilbene oxide derivatives with enantiomeric ratios ranging from 95:5 to 98:2. This user-friendly organocatalytic process proved to be efficient with 20-10% of sulfide 4 in 1 or 2 days of reaction. An insight into the ylide intermediate conformation is given on the basis of a computational ab initio study.     

Theoretical investigation on reaction pathways for ethylene epoxidation on Ti-decorated graphene

The activities of atomic Ti-decorated graphene (Ti/dG) for ethylene epoxidation and competitive paths for acetaldehyde (AA) formation are investigated by means of density functional theory together with the D3 dispersion correction (UM06-L-D3). Two reaction mechanisms for ethylene epoxidation, namely concerted and stepwise mechanisms, were considered. The computational results reveal that the electron transfer from graphene can effectively enhance the catalytic activity of Ti atom. Without graphene support, atomic Ti becomes an inert metal for this reaction. Strong adsorption and significant activation of the reactant O₂ molecule were observed on the Ti-decorated graphene material. Over the O₂-adsorbed Ti/dG, the direct attack of the olefin on an peroxo oxygen center is preferred. The activation for this step is 10.9 kcal mol^?1. After the reaction, an ethylene oxide is formed with one atomic oxygen on top of Ti. Consequently, a gaseous ethylene reacts with the remaining O atom of TiO moiety for the formation of the second ethylene oxide molecule. The formation of ethylene oxide over the TiO/dG involves a two-step process which is the formations of oxametallacycle intermediate and EO, respectively. The calculated barriers for these two steps are 9.9 and 18.9 kcal mol^?1, respectively. Furthermore, the Ti/dG showed a lower activation barrier toward EO formation than that of AA. Therefore, our theoretical study suggests that atomic Ti-decorated graphene could possess catalytic activity for ethylene epoxidation comparable to that of potential catalysts.     

Synthesis of quinine and quinidine using sulfur ylide-mediated asymmetric epoxidation as a key step

The epoxidation of meroquinene aldehyde with a chiral sulfur ylide as the key step in the synthesis of quinine and quinidine is described. The epoxidation reactions proceed under reagent control with high selectivity and good yield. The effect of sulfide and ylide substituents on the stereochemical outcome of the reaction is discussed.     

Theoretical investigation on chiral cinchona alkaloid salts‐catalyzed asymmetric epoxidation of cyclic enones

Chiral cinchona alkaloid salts‐catalyzed asymmetric epoxidation of 2‐cyclohexen‐1‐one with hydrogen peroxide (H₂O₂) has been investigated using density functional theory (DFT). The ring‐closure step is rate limiting in the catalytic reaction. The enantioselectivity‐determining step is initial nucleophilic addition involving two orientations of axial and equatorial. In (S)‐catalyst j ‐mediated process, axial pathway is favored over equatorial leading to the major epoxide [2S,3S]‐ 3 . An opposite enantiomer [2R,3R]‐ 3 is primarily generated in (R)‐catalyst k ‐assisted case preferring equatorial pathway. The results indicate that the enantioselectivity of epoxidation is dominated by central chirality of the bifunctional catalysts in the activation of enone by primary amine salt via iminium formation and of H₂O₂ by tertiary amine reacting as a general base. The substituent effect is also discussed to clarify a tendency existing in experiment. © 2010 Wiley Periodicals, Inc. Int J Quantum Chem, 2011     

Theoretical study of the mechanism generating azomethine ylide from formaldehyde and glycine

The mechanism to generate azomethine ylide from formaldehyde and glycine is systematically investigated. The density functional theory at the B3LYP/6-311++G(d,p) level is employed for both geometry optimization and single point energy calculation. Our results indicate that two possible pathways can lead to the generation of the carbinolamine intermediate with a favorable step-wise pathway. However, as for the step to form azomethine ylide, a concerted elimination of water and carbon dioxide is preferred. This calculation result is totally different from the widely accepted revised Rizzi mechanism.     

Novel chiral calix[4]arenes by direct asymmetric epoxidation reaction

We report the first asymmetric synthesis of trans optically active (+) C 2 1,3-bisarylepoxide of calix[4]arene in excellent chemical yield and >99% ee, and its enantiospecific conversion to the corresponding bis-dioxolane.     

Theoretical study of molecular interactions of sulfur ylide with HSX (X = F, Cl, and Br) molecules

The molecular interactions between sulfur ylide (SY) and HSX molecules (X = F, Cl and Br) were investigated using the MP2 method with the 6-311++G (2d, 2p) basis set. The SY (CH₂=SH₂) have two reactive sites: CH₂ (denoted as C-interaction) and SH₂ (S-interaction) that both could interact with three atoms of HSX molecules. The results show that S···C, X···C, and H···C interactions (C-interactions) is preference over the X···S, H···S, and H···X interactions. Quantum theories of atoms in molecules and natural bond orbitals methods have been applied to analyze the intermolecular interactions. Good correlations have been found between the interaction energies, the second-order perturbation energies E⁽²⁾, and the charge transfer qCT in the studied systems.     

Theoretical study of hydrogen abstraction and sulfur insertion in the reaction H2S + S

The reaction of H2S + S has been characterized at the multireference configuration interaction level with the geometries optimized using the aug-cc-pVTZ basis set and the single-point energy calculated using the aug-cc-pV(Q+d)Z basis set. As in the analogous reaction of H2 + S, the presence of an intersystem crossing enables products (SH + SH) to be formed on the singlet surface through S insertion, which bypasses the triplet barrier (19.1 kJ mol-1 relative to SH + SH) of the H abstraction route. This provides theoretical evidence for SH + SH formation without barrier beyond endothermicity at sufficiently low temperatures. The H abstraction route, however, is expected to be competitive at higher temperatures due to a much higher Arrhenius pre-exponential factor (6.9 x 10(14) cm3 mol-1 s-1 derived from TST calculation) than that of S insertion channel (3.7 x 10(13) cm3 mol-1 s-1, derived by a least-squares fit to the measurements). With a slightly higher transition-state barrier than that of the H abstraction channel, the production of S2 + H2 is less favored due to proceeding via intersystem crossing and insertion. While the formation of HSS + H is energetically unfavorable relative to SH + SH, recombination channels producing H2SS or the more stable HSSH are expected to occur under collisional stabilization conditions at high pressures.     

Efficient synthesis of the core structure of muraymycin and caprazamycin nucleoside antibiotics based on a stereochemically revised sulfur ylide reaction

The reaction of protected uridine 5′-aldehydes with sulfur ylides has been reinvestigated. Further transformation of the resulting epoxide product provided a compound of which a single crystal for X-ray diffraction was obtained. As a consequence from the elucidated structure, the stereochemical configuration of the epoxide furnished by the sulfur ylide reaction was revised. Based on these results, an efficient synthesis of the core structure of the naturally occurring muraymycin and caprazamycin nucleoside antibiotics was developed.     

Catalytic asymmetric epoxidation of cyclic enones

A highly enantioselective epoxidation of cyclic enones with hydrogen peroxide has been developed that is catalyzed by chiral primary amine salts.     

Theoretical study of the cycloaddition of nitrones to cinnamonitrile: effect of Lewis acid coordination on the selectivity of the reaction

A number of quantum chemical and density functional methods have been used to study the chemo- and regioselectivity of the uncatalysed and Lewis acid mediated cycloaddition of the nitrone PhCHN(Me)O with the CC or the CN bond of (E)-cinnamonitrile. In agreement with experimental evidence, Lewis acid coordination to the nitrile strongly promotes reaction at the CN bond over reaction at the alkene moiety. The main factors responsible for this inversion of the chemoselectivity were identified as the following: (i) the Lewis acid strongly stabilises the product of CN addition and the transition state leading to it, thus favouring this reaction both kinetically and thermodynamically. Addition across the CC bond, in contrast, only receives weak kinetic activation; (ii) the cycloaddition to the CC or CN bonds involves different molecular orbitals at the cinnamonitrile, and the Lewis acid influences the orbital involved in CN addition to a larger extent; (iii) the Lewis acid has a stronger effect on the electron distribution of the CN bond. As an overall result, the Lewis acid not only promotes the cycloaddition, but also alters the order of functional group reactivity and brings about a complete change in chemoselectivity.