Co-Catalyzed Asymmetric Hydrogenation. The Same Enantioselection Pattern for Different Mechanisms.

The mechanism of the recently reported catalyzed asymmetric hydrogenation of enyne 1 catalyzed by the Co-(R,R)-QuinoxP* complex was studied by DFT. Conceivable pathways for the Co(I)-Co(III) mechanism were computed together with a Co(0)-Co(II) catalytic cycle. It is commonly assumed that the exact nature of the chemical transformations taking place along the actually operating catalytic pathway determine the sense and level of enantioselection of the catalytic reaction. In this work, two chemically different mechanisms reproduced the experimentally observed perfect stereoselection of the same handedness. Moreover, the relative stabilities of the transition states of the stereo induction stages were controlled via exactly the same weak disperse interactions between the catalyst and the substrate.

The Reduction of Carbonyl Compounds with Dicyclopentylzinc: A New Example of Asymmetric Amplifying Autocatalysis.

A previously unknown reduction of carbonyl compounds with dicyclopentylzinc is reported. Aldehydes react in mild conditions yielding corresponding primary alcohols and cyclopentene. Although cyclohexanone and acetophenone are inert to dicyclopentylzinc, a variety of heterocyclic ketones reacted readily, yielding reasonable to high yields of corresponding secondary alcohols. When the reaction was catalyzed with (-)-(1R,2S)-ephedrine, 3-acetylpyridine (10) resulted in a high yield of (S)-1-(pyridin-3-yl)ethanol (19) with >99% ee. 5-Acetyl-2-bromopyridine (11) also provided the corresponding optically active alcohol 20, albeit with a much lower optical yield. When 10% of 19 with 92% ee was used as an autocatalyst, 55% yield of the same compound was obtained, with 95% ee and 96% ee in two independent experiments. A three-stage reaction sequence starting from "no chirality" reaction yielded 19 with 6% ee. Thus, amplifying autocatalysis was detected in the reaction of ketone 10 with dicylopentylzinc.

Global Search for Stable C4H5NO Compounds-Guinness Molecules and Stability Islands.

Global reaction route mapping (GRRM) analysis for compounds with the formula C4H5NO allowed for the detection of the corresponding "Guinness molecules" 000 and 001, as well as around 150 other stable minima of the same composition. The results suggest that compounds of similar functionality form a kind of "Stability Island" with their free energies of formation falling within s relatively limited range.

Nickel-Catalyzed Asymmetric Hydrogenation of α-Substituted Vinylphosphonates and Diarylvinylphosphine Oxides.

Chiral α-substituted ethylphosphonate and ethylphosphine oxide compounds are widely used in drugs, pesticides, and ligands. However, their catalytic asymmetric synthesis is still rare. Of the only asymmetric hydrogenation methods available at present, all cases use rare metal catalysts. Herein, we report an efficient earth-abundant transition-metal nickel catalyzed asymmetric hydrogenation affording the corresponding chiral ethylphosphine products with up to 99 % yield, 96 % ee (enantiomeric excess) (99 % ee, after recrystallization) and 1000 S/C (substrate/catalyst); this is also the first study on the asymmetric hydrogenation of terminal olefins using a nickel catalyst under a hydrogen atmosphere. The catalytic mechanism was investigated via deuterium-labelling experiments and calculations which indicate that the two added hydrogen atoms of the products come from hydrogen gas. Additionally, it is believed that the reaction involves a NiII rather than Ni0 cyclic process based on the weak attractive interactions between the Ni catalyst and terminal olefin substrate.

Asymmetric Hydroacylation Involving Alkene Isomerization for the Construction of C3 -Chirogenic Center.

A new transformation pattern for enantioselective intramolecular hydroacylation has been developed involving an alkene isomerization strategy. Proceeding through a five-membered rhodacycle intermediate, 3-enals were converted to C3 - or C3 ,C5 -chirogenic cyclopentanones with satisfactory yields, diastereoselectivities, and enantioselectivities. A catalytic cycle has been theoretically calculated and the origin of the stereoselection is rationally explained.

Nickel-Catalyzed Asymmetric Hydrogenation of 2-Amidoacrylates.

Earth-abundant nickel, coordinated with a suitable chiral bisphosphine ligand, was found to be an efficient catalyst for the asymmetric hydrogenation of 2-amidoacrylates, affording the chiral α-amino acid esters in quantitative yields and excellent enantioselectivity (up to 96 % ee). The active catalyst component was studied by NMR and HRMS, which helped us to realize high catalytic efficiency on a gram scale with a low catalyst loading (S/C=2000). The hydrogenated products could be simply converted into chiral α-amino acids, ß-amino alcohols, and their bioactive derivatives. Furthermore, the catalytic mechanism was investigated using deuterium-labeling experiments and computational calculations.

Methylene Group Transfer in Carbonyl Compounds Discovered in†silico and Detected Experimentally.

A previously unknown transformation of aldehydes, ketones, and carboxylic acid derivatives leads to the formation of substituted oxiranes, aziridines, and azirines as shown by DFT and MP2 computations. Formations of 2,2-dimethyloxirane-d8 from acetone-d6 , phenylazirine-d2 from benzonitrile and 2-methyl-2-(4-hydroxyphenyl)-oxirane from 4-hydroxyacetophenone were detected experimentally by electrospray ionization mass-spectrometry with a heated desolvating capillary. This reaction is a truly concerted process characterized by high activation barriers (activation enthalpies 320-480 kJ mol-1 ).

Nickel-Catalyzed Asymmetric Hydrogenation of N-Sulfonyl Imines.

An efficient nickel-catalyzed asymmetric hydrogenation of N-tBu-sulfonyl imines was developed with excellent yields and enantioselectivities using (R,R)-QuinoxP* as a chiral ligand. The use of a much lower catalyst loading (0.0095 mol %, S/C=10500) represents the highest catalytic activity for the Ni-catalyzed asymmetric hydrogenations reported so far. Mechanistic studies suggest that a coordination equilibrium exists between the nickel salt and its complex, and that excess nickel salt promotes the formation of the active Ni-complex, and therefore improved the efficiency of the hydrogenation. The catalytic cycle was also investigated by calculations to determine the origin of the enantioselectivity. An extensive network of numerous weak attractive interactions was found to exist between the catalyst and substrate in the transition state and may also contribute to the high catalytic activity.

Chemo- and Enantioselective Hydrogenation of α-Formyl Enamides: An Efficient Access to Chiral α-Amido Aldehydes.

In order to effectively synthesize chiral α-amino aldehydes, which have a wide range of potential applications in organic synthesis and medicinal chemistry, a highly chemo- and enantioselective hydrogenation of α-formyl enamides has been developed, catalyzed by a rhodium complex of a P-stereogenic bisphosphine ligand. Under different hydrogen pressures, the chiral α-amido aldehydes and ß-amido alcohols were obtained in high yields (97-99 %) and with excellent chemo- and enantioselectivities (up to >99.9 % ee). The hydrogenation can be carried out on a gram scale and with a high substrate/catalyst ratio (up to 20 000 S/C), and the hydrogenated products were further converted into several important chiral products. Computations of the catalytic cycle gave a clear description for the R/S pathways, provided a reasonable explanation for the enantioselectivity, and revealed several other specific features.

Cobalt-Catalyzed Asymmetric Hydrogenation of C=N Bonds Enabled by Assisted Coordination and Nonbonding Interactions.

An efficient cobalt-catalyzed asymmetric hydrogenation of C=N bonds has been realized. Chiral hydrazines were obtained in high yields and with excellent enantioselectivities (95-98 % ee). The hydrogenation went smoothly at up to 2000 substrate/catalyst and on a gram scale. The success of this reaction relies on the presence of an NHBz group in the substrates, with the reactivity and enantioselectivity improved by an assisted coordination to the cobalt atom and a nonbonding interaction with the ligand. Furthermore, this reaction has practical applications for the synthesis of several useful chiral nitrogen-containing compounds.

Mechanism of the asymmetric hydrogenation of exocyclic α,ß-unsaturated carbonyl compounds with an iridium/BiphPhox catalyst: NMR and DFT studies.

The mechanism of the asymmetric hydrogenation of exocyclic α,ß-unsaturated carbonyl compounds with the (aS)-Ir/iPr-BiphPhox catalyst was studied by NMR experiments and DFT computational analyses. Computed optical yields of the asymmetric hydrogenation proceeding by an iridium(I)/iridium(III) mechanism involving a transition state stabilized through two intramolecular hydrogen bonds are in good accordance with the experimental ee values.

Biomimetic total synthesis of cyanosporaside aglycons from a single enediyne precursor through site-selective p-benzyne hydrochlorination.

The cyanosporasides A-F are a collection of monochlorinated benzenoid derivatives isolated from the marine actinomycetes Salinispora and Streptomyces sp. All derivatives feature one of two types of cyanocyclopenta[a]indene frameworks, which are regioisomeric in the position of a single chlorine atom. It is proposed that these chloro-substituted benzenoids are formed biosynthetically through the cycloaromatization of a bicyclic nine-membered enediyne precursor. Herein, we report the synthesis of such a bicyclic precursor, its spontaneous transannulation into a p-benzyne, and its differential 1,4 hydrochlorination reactivity under either organochlorine or chloride-salt conditions. Our bioinspired approach culminated in the first regiodivergent total synthesis of the aglycons A/F and B/C, as well as cyanosporasides D and E. In addition, empirical insights into the site selectivity of a natural-like p-benzyne, calculated to be a ground-state triplet diradical, to hydrogen, chlorine, and chloride sources are revealed.

Palladium-catalyzed allylic alkylation of simple ketones with allylic alcohols and its mechanistic study.

Allylic alcohols were directly used in Pd-catalyzed allylic alkylations of simple ketones under mild reaction conditions. The reaction proceeded smoothly at 20 °C by the concerted action of a Pd catalyst, a pyrrolidine co-catalyst, and a hydrogen-bonding solvent, and does not require any additional reagents. A computational study suggested that methanol plays a crucial role in the formation of the π-allylpalladium complex by lowering the activation barrier.

Rigid P-chiral phosphine ligands with tert-butylmethylphosphino groups for rhodium-catalyzed asymmetric hydrogenation of functionalized alkenes.

Both enantiomers of 2,3-bis(tert-butylmethylphosphino)quinoxaline (QuinoxP*), 1,2-bis(tert-butylmethylphosphino)benzene (BenzP*), and 1,2-bis(tert-butylmethylphosphino)-4,5-(methylenedioxy)benzene (DioxyBenzP*) were prepared in short steps from enantiopure (S)- and (R)-tert-butylmethylphosphine-boranes as the key intermediates. All of these ligands were crystalline solids and were not readily oxidized on exposure to air. Their rhodium complexes exhibited excellent enantioselectivities and high catalytic activities in the asymmetric hydrogenation of functionalized alkenes, such as dehydroamino acid derivatives and enamides. The practical utility of these catalysts was demonstrated by the efficient preparation of several chiral pharmaceutical ingredients having an amino acid or a secondary amine component. A rhodium complex of the structurally simple ligand BenzP* was used for the mechanistic study of asymmetric hydrogenation. Low-temperature NMR studies together with DFT calculations using methyl α-acetamidocinnamate as the standard model substrate revealed new aspects of the reaction pathways and the enantioselection mechanism.

Nickel-catalysed asymmetric hydrogenation of oximes.

Chiral hydroxylamines are vital substances in bioscience and versatile subunits in the preparation of a variety of functional molecules. However, asymmetric and non-asymmetric synthetic approaches to these compounds are far from satisfactory. Although atom-economic metal-catalysed asymmetric hydrogenations have been studied for over 50 years, the asymmetric hydrogenation of oximes to the corresponding chiral hydroxylamines remains challenging because of the labile N-O bond and inert C=N bond. Here we report an environmentally friendly, earth-abundant, transition-metal nickel-catalysed asymmetric hydrogenation of oximes, affording the corresponding chiral hydroxylamines with up to 99% yield, 99% e.e. and with a substrate/catalyst ratio of 1,000. Computational results indicate that the weak interactions between the catalyst and substrate play crucial roles not only in the transition states, but also during the approach of the substrate to the catalyst, by selectively reducing the reaction barriers and thus improving the reaction efficiency and securing the generation of chirality.

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 ß-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 ß-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.

A method for the synthesis of substituted quinolines via electrophilic cyclization of 1-azido-2-(2-propynyl)benzene.

A new and efficient strategy for the synthesis of substituted quinolines via electrophilic cyclization is developed. The intramolecular cyclization of 1-azido-2-(2-propynyl)benzene 1 proceeds smoothly in the presence of electrophilic reagents (I(2), Br(2), ICl, NBS, NIS, and HNTf(2)) in CH(3)NO(2) at room temperature or in the presence of catalytic amounts of AuCl(3)/AgNTf(2) in THF at 100 degrees C to afford the corresponding quinolines 2 in good to high yields. In the case of the electrophilic reagents, E of 2 is either I, Br, or H, depending on the reagent type, while E of 2 is H in the case of the electrophilic catalyst.

Size is Important: Artificial Catalyst Mimics Behavior of Natural Enzymes.

Heavily substituted (R)-DTBM-SegPHOS is active in the asymmetric Pd(II)-catalyzed hydrogenation or C-O bond cleavage of α-pivaloyloxy-1-(2-furyl)ethanone, whereas (R)-SegPHOS fails to catalyze either of these transformations. An extensive network of C-H ··· H-C interactions provided by the heavily substituted phenyl rings of (R)-DTBM-SegPHOS leads to increased stabilities of all intermediates and transition states in the corresponding catalytic cycles compared with the unsubstituted analogues. Moreover, formation of the encounter complex and its rearrangement into the reactive species proceeds in a fashion similar to that seen in natural enzymatic reactions. Computations demonstrate that this feature is the origin of enantioselection in asymmetric hydrogenation, since the stable precursor is formed only when the catalyst is approached by one prochiral plane of the substrate.

Intermolecular Oxidative Friedel-Crafts Reaction Triggered Ring Expansion Affording 9,10-Diarylphenanthrenes.

A novel intermolecular tandem oxidative aromatic coupling between arylidene fluorenes and unfunctionalized aromatics mediated by a DDQ/TFA oxidation system has been developed for the construction of 9,10-diarylphenanthrenes (DAPs). The formation of a benzylic carbocation species possessing a quaternary sp3-carbon center on the fluorene moiety by an intermolecular oxidative Friedel-Crafts reaction of two different arenes successfully triggered the subsequent ring expansion to afford DAPs.

Ni-catalyzed asymmetric hydrogenation of N-aryl imino esters for the efficient synthesis of chiral α-aryl glycines.

Chiral α-aryl glycines play a key role in the preparation of some bioactive products, however, their catalytic asymmetric synthesis is far from being satisfactory. Herein, we report an efficient nickel-catalyzed asymmetric hydrogenation of N-aryl imino esters, affording chiral α-aryl glycines in high yields and enantioselectivities (up to 98% ee). The hydrogenation can be conducted on a gram scale with a substrate/catalyst ratio of up to 2000. The obtained chiral N-p-methoxyphenyl α-aryl glycine derivatives are not only directly useful chiral secondary amino acid esters but can also be easily deprotected by treatment with cerium ammonium nitrate for further transformations to several widely used molecules including drug intermediates and chiral ligands. Formation of a chiral Ni-H species in hydrogenation is detected by 1H NMR. Computational results indicate that the stereo selection is determined during the approach of the substrate to the catalyst.