Sense Of Enantioselectivity Research Articles

Highly enantioselective catalytic Friedel–Crafts reactions of cyclic α-alkylidene β-oxo imides

Highly enantioselective catalytic Friedel–Crafts reactions of cyclic α-alkylidene β-oxo imides with indole, pyrrole, and furan derivatives at relatively low temperatures are described. The X-ray crystallographic analysis of the product revealed that the sense of enantioselectivity of the Friedel–Crafts reactions could be well explained by the proposed chelate model. The model was stabilized by an intramolecular hydrogen bond, wherein the cyclic α-alkylidene β-oxo imide coordinates with Cu(II) through the two imide carbonyls.

Enantioselective carbolithiation of S-alkenyl-N-aryl thiocarbamates: kinetic and thermodynamic control.

The addition of n-butyllithium to alkenylthiocarbamates in the presence of (-)-sparteine or the (+)-sparteine surrogate leads to asymmetric carbolithiation, and returns enantiomerically enriched thiocarbamate derivatives of secondary thiols. In THF, with the (+)-sparteine surrogate, in situ aryl migration leads to an enantiomerically enriched tertiary thiol derivative. Remarkably, the two pseudoenantiomeric chiral ligands do not always give enantiomeric products, probably as a result of a complex interplay of kinetic and thermodynamic control. In situ IR and NMR studies of a stable, hindered lithiated thiocarbamate demonstrated its chemical and configurational stability over a period of hours at 0 °C.

Rationalization of an Unusual Solvent‐Induced Inversion of Enantiomeric Excess in Organocatalytic Selenylation of Aldehydes

AbstractAn unusual solvent‐induced inversion of the sense of enantioselectivity observed in the α‐selenylation of aldehydes catalyzed by a diphenylprolinol silyl ether catalyst is correlated to the presence of intermediates formed subsequent to the highly selective CSe bond‐forming step in the catalytic cycle. This work provides support for a mechanistic concept for enamine catalysis and includes a general role for “downstream intermediates” in selectivity outcomes in organocatalysis.

Rationalization of an unusual solvent-induced inversion of enantiomeric excess in organocatalytic selenylation of aldehydes.

An unusual solvent-induced inversion of the sense of enantioselectivity observed in the α-selenylation of aldehydes catalyzed by a diphenylprolinol silyl ether catalyst is correlated to the presence of intermediates formed subsequent to the highly selective C-Se bond-forming step in the catalytic cycle. This work provides support for a mechanistic concept for enamine catalysis and includes a general role for "downstream intermediates" in selectivity outcomes in organocatalysis.

Amine‐Tunable Ruthenium Catalysts for Asymmetric Reduction of Ketones

AbstractA series of efficient ruthenium catalysts has been developed for the asymmetric hydrogenation and transfer hydrogenation of ketones with high reactivities and selectivities. The new chiral bisdihydrobenzooxaphosphole (BIBOP)/diamine‐ruthenium complexes catalyzed the enantioselective hydrogenation of substrates such as aryl and heteroaryl cyclic and alkyl ketones with substrate/catalyst (S/C) ratios of up to 100,000. The opposite sense of enantioselectivity can be obtained by proper selection of a diamine with a given chirality of the phosphine. The usefulness of the new system has been demonstrated in the asymmetric hydrogenation of a complex synthetic intermediate towards cholesteryl ester transfer protein (CETP) inhibitors at S/C 20,000 on large‐scale operation.magnified image

Biomimetic Superhelical Conducting Microfibers with Homochirality for Enantioselective Sensing

Chiral amplification and discrimination are great challenges in both scientific and technological research fields such as chemical synthesis, chiral catalysis, and biomedicine. By mimicking protein superstructures in nature, chiral conducting polyaniline (PANI) molecules induced by chiral dopants were self-assembled to ultra-ordered superhelical microfibers. The induced homochirality is observed to be amplified into different hierarchies, from chiral molecules to helical nanostructures, and to superhelical microstructures. Furthermore, both experimental and theoretical results indicated that the gas sensor made from a single PANI helical microfiber showed enantioselective discrimination to chiral aminohexane, giving it great potential for applications in online chiral discrimination.

Z- and Enantioselective Ring-Opening/Cross-Metathesis with Enol Ethers Catalyzed by Stereogenic-at-Ru Carbenes: Reactivity, Selectivity, and Curtin–Hammett Kinetics

The first instances of Z- and enantioselective Ru-catalyzed olefin metathesis are presented. Ring-opening/cross-metathesis (ROCM) reactions of oxabicyclic alkenes and enol ethers and a phenyl vinyl sulfide are promoted by 0.5-5.0 mol % of enantiomerically pure stereogenic-at-Ru complexes with an aryloxy chelate tethered to the N-heterocyclic carbene. Products are formed efficiently and with exceptional enantioselectivity (>98:2 enantiomer ratio). Surprisingly, the enantioselective ROCM reactions proceed with high Z selectivity (up to 98% Z). Moreover, reactions proceed with the opposite sense of enantioselectivity versus aryl olefins, which afford E isomers exclusively. Preliminary DFT calculations in support of Curtin-Hammett kinetics as well as initial models that account for the stereoselectivity levels and trends are provided.

Enantioselective Sensing by Luminescence from Cyclometalated Iridium(III) Complexes Adsorbed on a Colloidal Saponite Clay

Abstract Emission from a cationic cyclometalated iridium(III) complex, Δ- or Λ-[Ir(ppy)2(dmbpy)]+ (Hppy: 2-phenylpyridine and dmbpy: 4,4′-dimethyl-2,2′-bipyridine), adsorbed on a colloidal saponite clay was quenched stereoselectively by chiral [Ru(acac)3] (acac: acetylacetonato) in a solution at the overall selectivity factor of KSVo(Δ–Δ or Λ–Λ)/KSVo(Δ–Λ) = 1.84 in favor of the pseudo-enantiomeric pair between the emitter and the quencher.

New Umpolung Catalysts: Reactivity and Selectivity of Terpenol‐Based Lithium Phosphonates in Enantioselective Benzoin‐Type Couplings

AbstractTwo new classes of terpenol‐based lithium phosphonates, i.e. phenylfenchyl phosphonates and 2,2′‐biphenyldiylbis(terpenyl) phosphonates, are employed as umpolung catalysts for the enantioselective cross benzoin coupling. The structural characteristics of the phosphonates were investigated by means of X‐ray, 31P‐NMR analyses as well as DFT computations. The chiral lithium phosphonates were found to catalyze the cross benzoin coupling with enantioselectivities up to 54 % ee. For the phenylfenchyl phosphonates, the catalyst reactivities highly depend on the substituents in benzylic position. Modification of benzylic >CH2 to >C(CF3)2 significantly increases the yield from 19 to 92 %. For phenylfenchyl phosphonate pre‐catalysts, substitution of the benzylic >CH2 group by >C(CF3)2 changes the sense of enantioselectivity from S‐ to the R‐configured benzoin product.

Mechanism of Enantioselective C−C Bond Formation with Bifunctional Chiral Ru Catalysts: NMR and DFT Study

The mechanism of Michael addition reactions of 1,3-dicarbonyl compounds to cyclic enones catalyzed by bifunctional Ru catalysts bearing N-sulfonylated (R,R)-DPEN ligands (DPEN = (R,R)-1,2-diphenylethylenediamine) was studied by NMR and DFT computational analyses. NMR investigation of the stoichiometric reactions of chiral amido Ru complexes, Ru(N-sulfonylated dpen)(η(6)-arene) 1a-c, with dimethyl malonate 2 and β-keto ester 3 revealed that at decreased temperatures deprotonation proceeds in a stereoselective manner to provide amine complexes. The reaction with malonic ester 2 provided exclusively C-bound amino Ru complexes 6a,c, while the reaction of β-keto ester 3 gave an equilibrium mixture of rapidly interconverting C- and O-bound complexes. The structures of C-bound Ru complex 6c and O-bound Ru complex 9c were determined by single crystal X-ray analysis. A computational study showed that the enatioselective C-C bond formation proceeds through intermediate formation of chelating ion pairs that coordinate a molecule of enone via the Ru metal center producing a highly organized environment for the C-C bond formation, yielding selectively only one enantiomer of the product. Systematic study of a series of the catalyst-substrate combinations revealed that the experimentally observed sense of enantioselection was consistently explained by computational analysis. The tendency of increasing ee with the bulk of the coordinated arene in Ru complex is reproduced computationally by changes in the difference of either ZPPE-corrected energies or Gibbs free energies for S- and R-pathways.

Enantioselective Alcoholysis of meso‐Glutaric Anhydrides Catalyzed by Cinchona‐Based Sulfonamide Catalysts

AbstractThe bifunctional Cinchona‐based sulfonamide catalysts showed the highest levels of enantioselectivity reported to date in the alcoholytic desymmetrization of meso‐glutaric anhydrides. Density functional theory (DFT) computational studies provide detailed insight into the observed sense of enantioselectivity. Moreover, detailed experimental studies and single crystal X‐ray analysis confirmed that these bifunctional organocatalysts 3 do not form H‐bonded self‐aggregates in both solution and solid state. The synthetic utility of this methodology was also demonstrated in the synthesis of pharmaceutically important γ‐amino acids, such as (S)‐pregabalin. Of the many asymmetric syntheses of enantiomerically pure (S)‐pregabalin reported to date, our synthesis requires the least number of and the simplest steps.

Synthesis of Chiral Bulky Monophosphite Ligands and Their Application in Cu-Catalyzed Asymmetric Conjugate Addition of Diethylzinc to Cyclic Enones

A series of new bulky monophosphite ligands were synthesized from axially chiral BINOL and highly sterically hindered adamantanecarbonyl chloride. These ligands were applied to the Cu-catalyzed asymmetric 1,4-conjugate addition of diethylzinc to cyclic enones and were found to have moderate enantioselectivities (up to 61% ee). The stereochemically matched combination of (S)-BINOL in ligand (S)-(2-(adamantane-1-carboxylic acid)-1,1′-binapthalen-2′-yl)-((S)-1,1′-binaphthalen-2,2′-yl)phosphite induces a moderate enantioselectivity. The sense of enantioselectivity is mainly controlled by the configuration of the 2,2′-o, o-(1,1′-binaphthyl)-dioxo-phosphite moiety of the ligands.

Resolving Isotopically Chiral Alcohols

Autocatalytic reactions, which are accelerated by their own product, can amplify small imbalances in the chiral distribution of starting materials. A particularly effective system is the alkylation of certain aldehydes by diisopropyl zinc, which becomes increasingly stereoselective as the chiral alkoxide product coordinates to unreacted zinc centers. Kawasaki et al. (p. [492][1], published online 26 March) show that the sense of enantioselection in this system can be influenced by a factor as subtle as chirality in an alcohol that arises only because two positions differ in having 12C and 13C atoms. Isotopically chiral ligands were carefully prepared by using methods that would avoid chiral contaminants, and each led to a distinct enantiomer with enantiomeric excesses exceeding 90%. [1]: /lookup/doi/10.1126/science.1170322

Chiral diphosphinites derived from 2,2-biphosphole as a new class of stereodynamic ligands for enantioselective hydrogenation

New stereodynamic diphosphinites derived from 2,2'-biphosphole, were synthesised by introduction of a linker obtained from chiral diols between the two phosphorus atoms and used for catalytic hydrogenation through a dual chirality control induced by Rh-coordination. The application of these ligands in hydrogenation of dimethyl itaconate shows that the enantioselectivity strongly depends on steric and electronic properties of the chiral linker whereas the sense of enantioselection is determined by the configuration of these stereocentres. These stereodynamic diphosphinites induce higher enantioselectivities than the analogous stereodynamic diphosphanes derived from 2,2-biphosphole.

Homo- vs. heterometallic organoaluminum fencholates: Structures and selectivities

Homo (Al)- and heterometallic (Al, Li)-fencholates and TADDOLates ( 5– 12) yield in methylations of benzaldehyde 1-phenylethanol with up to 90% ee. Surprisingly, the new BISFOL-based (Al, Li)-heterometallic fencholate ( 11) shows an strong increase and a change of the sense of enantioselectivity from 19% ee ( S) to 62% ee ( R) in comparison to its (Al)-homometallic fencholate ( 7). Despite of the presence of nucleophilic methylide groups, the O-BIFOL-based (Al, Li)-heterometallic fencholate ( 10) yields a stable complex with benzaldehyde, a lithium ion binds the carbonyl group.

Asymmetric Hydrogenation Catalyzed by a Rhodium Complex of (R)-(tert-Butylmethylphosphino)(di-tert-butylphosphino)methane: Scope of Enantioselectivity and Mechanistic Study

The rhodium complex of (R)-(tert-butylmethylphosphino)(di-tert-butylphosphino)methane used in Rh-catalyzed asymmetric hydrogenation of representative substrates 3-14 demonstrated high catalytic activity coupled with wide scope and nearly perfect enantioselectivity. Mechanistic studies (NMR and DFT computations) were carried out in order to investigate the mechanism of the enantioselection in the asymmetric hydrogenation of (Z)-alpha-acetamidocinnamate (3). Although catalyst-substrate complexes 15a,b with the double bond coordinated near the non-"chiral" phosphorus atom were formed as kinetic products upon the addition of 3 to solvate complex 2 at -100 degrees C, they rapidly rearranged to more stable isomers 15c,d with the double bond coordinated near the "chiral" phosphorus atom. The thermodynamic and kinetic parameters of the interconversion between 15c and 15d were determined by NMR; mainly, the interconversion occurred intramolecularly via nonchelating catalyst-substrate complexes 16. The equilibrium between 15d and 16d was directly observed from NMR line shape changes at temperatures ranging from -100 to -40 degrees C, whereas no such equilibrium was observed for 15c. This result was accounted for computationally by determining the corresponding transition states for the methanol insertion into 15c,d. Three sets of experiments of the low-temperature hydrogenation of different catalyst-substrate complexes gave the same order and sense of enantioselectivity (97% ee (R)) even in the case when 15c, having Re-coordinated double bond, was hydrogenated under the conditions precluding its isomerization to 15d. It was concluded that the hydrogenation of 15c,d does not occur directly, but is preceded by the dissociation of the double bond to result in the more reactive species 16. This indicates that enantioselection must occur at a later step of the catalytic cycle. DFT computations of association and migratory insertion steps suggest that enantioselection takes place during the association step when chelating dihydride 19d.MeOH is formed from nonchelating dihydride 18d.

Chiral Phosphoric Acid Catalyzed Enantioselective Aza‐Friedel—Crafts Reaction of Indoles.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Chiral Phosphoric Acid‐Catalyzed Enantioselective Aza‐Friedel–Crafts Reaction of Indoles

AbstractA highly enantioselective 1,2‐aza‐Friedel–Crafts reaction of N‐tert‐butyldimethylsilylindole with N‐tert‐butoxycarbonyl aromatic imines is demonstrated using a BINOL‐derived monophosphoric acid catalyst. The present approach provides efficient access to 3‐indolylmethaneamines with aryl substituents in excellent enantioselectivities (up to 98 % ee). An inversion in the sense of enantioselection was found between monophosphoric acid catalysts bearing different substituents introduced at the 3,3′‐position of binaphthyl backbone. We also calculated the three‐dimensional structure of the monophosphoric acid catalysts to speculate on the inversion of the stereochemical outcome.

Asymmetric Hydroformylation of Styrene Catalyzed by Pyranoside Diphosphite-Rh(I) Complexes

Abstract Several chiral aryl diphosphite ligands derived from pyranoside backbones of glucose and galactose were applied in Rh-catalyzed asymmetric hydroformylation of styrene. A synergistic effect between the chiralities of glucose and the binaphthyl moieties was observed. The sense of enantioselectivity is mainly controlled by the binaphthyl moieties, and the chirality of the sugar moiety can also affect the enantioselectivity of the reactions. In the case of the matching combination of phenyl-3,6-anhydro- β -D-glucopyranoside and binaphthyl moiety, 4-bis{[( S )-1,1′-binaphthyl-2,2′-diyl]-phosphite}-phenyl-3,6-anhydro- β -D-glucopyranoside (L 4 ), 41% ee, and 74:26 of branch-to-normal ratio were obtained.

Controlling the Sense of Enantioselection on Surfaces by Conformational Changes of Adsorbed Modifiers

Gestaltwandler: Die Richtung der Enantioselektivität bei der asymmetrischen Hydrierung von aktivierten Ketonen auf einer modifizierten Platinoberfläche hängt von dem Chinaalkaloid ab, das zur Modifizierung verwendet wurde (z. B. O-Phenylcinchonidin im Bild). Spektroskopiestudien und Rechnungen zeigen, dass eine Konformationsänderung der modifizierenden Substanz die chirale Umgebung beeinflusst.