Desymmetric Hydrogenation of meso-Dicarboxylic Acids.

Efficient transformation of platform chemicals into key intermediates has been increasingly important for the pharmaceutical industry. The development of the catalytic reduction of abundant carboxylic acids with molecular hydrogen has been of both practical and theoretical value. We herein report the homogeneous hydrogenation of dicarboxylic acids with the strategy of desymmetrization. Using a rhodium/bisphosphine catalyst, one carboxyl group of meso-diacids was selectively reduced to yield chiral lactones with satisfactory enantioselectivity. This method provides a straightforward approach to produce chiral lactone intermediates for the manufacture of biotin, telaprevir, and other antivirus drugs. Both experimental and computational investigations were carried out, revealing a novel neighboring group coordination mechanism in the catalytic cycle.

Rhodium-Catalyzed Asymmetric Hydrogenation and Transfer Hydrogenation of 1,3-Dipolar Nitrones.

Owing to their distinctive 1,3-dipolar structure, the catalytic asymmetric hydrogenation of nitrones to hydroxylamines has been a formidable and longstanding challenge, characterized by intricate enantiocontrol and susceptibility to N-O bond cleavage. In this study, the asymmetric hydrogenation and transfer hydrogenation of nitrones were accomplished with a tethered TsDPEN-derived cyclopentadienyl rhodium(III) catalyst (TsDPEN: p-toluenesulfonyl-1,2-diphenylethylene-1,2-diamine), the reaction proceeds via a novel 7-membered cyclic transition state, producing chiral hydroxylamines with up to 99 % yield and >99 % ee. The practical viability of this methodology was underscored by gram-scale catalytic reactions and subsequent transformations. Furthermore, mechanistic investigations and DFT calculations were also conducted to elucidate the origin of enantioselectivity.

Site-Selective sp2 C-H Cyanation of Allenes via Copper-Catalyzed Radical Relay.

Compared with the extensively reported hydrogen atom transfer (HAT) at sp3 C-H, abstraction of hydrogen atoms at the sp2 carbon is extremely rare. Here, we communicate the site-selective cyanation of the sp2 C-H bond of allenes using the strategy of copper-catalyzed radical relay. The reactions afford various allenyl nitriles directly from simple allenes with a broad substrate scope and a remarkable functional group compatibility under mild conditions. These reactions exhibit excellent site-selectivity toward sp2 C-H, which can be attributed to the unique pocket created by the Cu-bound nitrogen-centered radical. The favorable HAT on sp2 C-H is due to crucial hydrogen bonding between the fluoride bonded to the Cu(II) center and the hydrogen atom at the allylic position. These features enable the late-stage functionalization of druglike bioactive molecules containing an allene motif.

Regio- and enantioselective remote dioxygenation of internal alkenes.

Methods for the enantioselective direct oxygenation of internal alkenes have provided chemists with versatile and powerful toolboxes for the synthesis of optically pure alcohols, one of the most privileged structural motifs. Regioselectivity, however, remains a formidable challenge in the functionalization of internal alkenes. Here we report a palladium-catalysed highly regio- and enantioselective remote 1,n-dioxygenation (n ≥ 4) of internal alkenes with engineered pyridine-oxazoline (Pyox) ligands. The reactions proceed efficiently and exhibit a broad substrate scope with excellent regio- and enantioselectivity, affording optically pure 1,n-diol acetates as the key synthons for important bioactive molecules. Experimental studies and density functional theory calculations provide evidence that the regioselectivity is governed by the reactivity disparity of two allylic C-H bonds, where the oxypalladation is reversible and the first palladium migration step proves to be the regioselectivity-determining step, enabled by the modified phenyl-substituted Pyox ligands.

Understanding the Organometallic Step: SO2 Insertion into Bi(III)-C(Ph) Bond.

Heavier main-group element-catalyzed reactions provide an increasingly attractive tool to perform transformations mimicking the behaviors of transition metal catalysts. Recently, Magre and Cornella reported a Bi-catalyzed synthesis of aryl sulfonyl fluorides, which involves a fundamental organometallic step of SO2 insertion into the Bi-Ph bond. Our theoretical studies reveal that i) the ability of hypervalent coordination of the Bi(III) center allows facile coordination sphere expansion for the SO2 coordination via one oxygen atom; and ii) the high polarity of the Bi-Ph bond makes the Ph migration from the Bi(III) center feasible. These features enable the heavier main group element to resemble the transition metal having flexibility for ligand association and dissociation. Furthermore, iii) the available π electron pair of the migrating Ph group stabilizes the SO2 insertion transition state by maintaining interaction with the Bi(III) center during migration. The insight helps us better understand the heavier main-group catalysis.

Reactivity of Unsupported Transition Metal-Aluminyl Complexes: A Nucleophilic TM-Al Bond.

Despite the long history of research in transition metal (TM) complexes, the study of TM-aluminyl complexes is still in its early stage of development. It is expected that the presence of an electropositive Al donor atom would open up new possibilities in TM complex reactivity, and indeed TM-aluminyl has shown an early sign of success in small-molecule activation. On the other hand, the existing reports on TM-aluminyl reactivity are often explained to readers with different understanding on individual cases, and a general picture of TM-aluminyl reactivity is still not available. In this work, we have attempted to provide a systematic picture to explain some early explorations in this field, specifically a series of recently reported heteroallene insertion reactions involving unsupported TM-aluminyl complexes. Through density functional theory calculations of a number of TM-aluminyl complexes, covering both Au and Cu centers, we found that their reactivity against heteroallenes (including CO2 and carbodiimides) is mostly based on the strong nucleophilicity of the TM-Al σ-bond.

Ir/f-Ampha complex catalyzed asymmetric sequential hydrogenation of enones: a general access to chiral alcohols with two contiguous chiral centers.

A general and highly efficient method for asymmetric sequential hydrogenation of α,ß-unsaturated ketones has been developed by using an iridium/f-Ampha complex as the catalyst, furnishing corresponding chiral alcohols with two contiguous stereocenters in high yields with excellent diastereo- and enantioselectivities (up to 99% yield, >20 : 1 dr and >99% ee). Control experiments indicated that the C[double bond, length as m-dash]C and C[double bond, length as m-dash]O bonds of the enones were hydrogenated sequentially, and the final stereoselectivities were determined by the dynamic kinetic resolution of ketones. Moreover, DFT calculations revealed that an outer sphere pathway was involved in both reduction of C[double bond, length as m-dash]C and C[double bond, length as m-dash]O bonds of enones. The synthetic utility of this method was demonstrated by a gram-scale reaction with very low catalyst loading (S/C = 20 000) and a concise synthetic route to key chiral intermediates of the antiasthmatic drug CP-199,330.

Gold-Catalyzed Desymmetric Lactonization of Alkynylmalonic Acids Enabled by Chiral Bifunctional P,N ligands.

Due to the linear coordination nature of gold(I) catalysts, achieving high enantiocontrol in asymmetric gold catalysis is a great challenge. To improve the enantiocontrol of gold catalysis, an ion-pairing strategy was therefore proposed. A series of bifunctional P,N ligands based on chiral spirocyclic and biaryl scaffolds were synthesized and applied in the gold(I)-catalyzed desymmetric lactonization of alkynylmalonic acids. A wide range of chiral lactones containing an α-position quaternary stereocenter were synthesized with high yields, excellent regioselectivity and enantioselectivity under mild reaction conditions. The synthetic utilities of the current reaction were demonstrated by gram-scale synthesis and transformations of chiral lactones. The origin of enantioselectivity and the role of the alcohol additive were elucidated via control experiments and DFT calculations.

Enantioselective Copper-Catalyzed Radical Cyanation of Propargylic C-H Bonds: Easy Access to Chiral Allenyl Nitriles.

The first enantioselective copper-catalyzed cyanation of propargylic C-H bonds via radical relay was established using novel BoxOTMS ligands, providing an efficient and straightforward tool for the construction of structurally diverse chiral allenyl nitriles in good yields with excellent enantioselectivities. This reaction features high functional group tolerance and mild conditions. In addition, the chiral allene products can be readily converted to other chiral compounds via axis-to-center chirality transfer.

Priority of Mixed Diamine Ligands in Cobalt Dithiolene Complex-Catalyzed H2 Evolution: A Theoretical Study.

Redox non-innocent metal dithiolene or diamine complexes are potential alternative catalysts in hydrogen evolution reaction and have been incorporated into 2D metal-organic frameworks to obtain unexpected electrocatalytic activity. According to an experimental study, Co-bis(dithiolene), Co-bis(diamine), and Co-dithiolene-diamine portions are considered as active sites where the generation of H2 occurs and a diamine ligand is necessary for high catalytic efficiency. We are interested in the difference between these catalytic active sites, and mechanistic studies on extracted Co-bis(dithiolene), Co-bis(diamine), and Co-dithiolene-diamine complex-catalyzed hydrogen evolution reactions are carried out by using density functional methods. Our calculated results indicate that the priority of ligand mixed complexes resulted from the readily occurring protonation of diamine ligands and large electron affinity of dithiolene ligands as well as the lowest overall barrier for H2 evolution.

Asymmetric Transfer Hydrogenation of α-Substituted-ß-Keto Carbonitriles via Dynamic Kinetic Resolution.

A catalytic protocol for the enantio- and diastereoselective reduction of α-substituted-ß-keto carbonitriles is described. The reaction involves a DKR-ATH process with the simultaneous construction of ß-hydroxy carbonitrile scaffolds with two contiguous stereogenic centers. A wide range of α-substituted-ß-keto carbonitriles were obtained in high yields (94%-98%) and excellent enantio- and diastereoselectivities (up to >99% ee, up to >99:1 dr). The origin of the diastereoselectivity was also rationalized by DFT calculations. Furthermore, this methodology offers rapid access to the pharmaceutical intermediates of Ipenoxazone and Tapentadol.

Fate characterization of bound residues of 14C-Pyraoxystrobin in soils.

Formation of bound residues (BR) has generally been considered as a detoxification process for organic contaminants. BR is an indispensable component for risk assessment of pesticides. In this study, BR of 14C-pyraoxystrobin in three soils cultivated for 100 days were characterized in light fraction (LF), loosely combined humus (LCH), stably combined humus (SCH), humic acid (HA), fulvic acid (FA), and humin. Isotope labeling technique was used to detect the distribution of BR of 14C-pyraoxystrobin in the six fractions of soil organic matter (SOM). The results showed that the amount of total BR was positively correlated with the SOM content (p < 0.05). The BR of 14C-pyraoxystrobin in cambisol soil was largest at 31.26 ± 0.04% of the induced radioactivity. During the whole incubation period, the BR of pyraoxystrobin in LCH of the three soils were consistently higher than that in SCH, and the amount of BR in FA was consistently greater than that in HA. The BR of 14C-pyraoxystrobin bound with humin increased over time. In addition, a degradation product 3-(4-chlorophenyl)-1-methyl-1H-pyrazol-5-ol (M1) from the hydrolysis of pyraoxystrobin was detected in cambisol soil, indicating the bonding of M1 with the HA separated from LCH (HALCH) via ester or ether linkages. The results provide new insights into the fate of BR of pyraoxystrobin in soils and may help to develop an understanding for the risk assessment of pyraoxystrobin and other strobilurin fungicides.

Chiral Electron-Rich PNP Ligand with a Phospholane Motif: Structural Features and Application in Asymmetric Hydrogenation.

Despite the remarkable reactivity that was achieved by a series of transition-metal catalysts with a PNP type ligand, the electron-rich chiral PNP ligands have still been rarely reported because of the difficulties in synthesis and the nature of air-sensitivity. Herein, we report a novel chiral PNP ligand (Heng-PNP) with both a rigid backbone and a bulky tert-butyl group on the phospholane motif. We successfully obtained its divalent iron complex. The chiral environment of its Ir(III) complex was also discussed with quadrant analysis. This tridentate ligand was applied in iridium-catalyzed asymmetric hydrogenation of challenging diaryl ketones: up to 98% ee and 500 TON are achieved. Computational study showed that the twist of conjugate aryl group in the substrate (induced by the special chiral pocket of Ir/Heng-PNP complex) leads to the energy difference in the enantiodetermining step.

Understanding the Diverse Reactivity of Pentaphenylborole toward Epoxides.

Density functional theory calculations have been performed to study the diverse reactivity of pentaphenylborole toward different epoxides. We systematically investigated the effect of substituents on epoxides for the preference/competition of three experimentally observed pathways, that is, intramolecular proton transfer, direct ring expansion via insertion of one epoxide molecule, and ring expansion via insertion of two epoxide molecules. Our calculations also predicted a high competitivity between the proton transfer and direct ring expansion pathways for the epoxide containing both alkyl and aryl substituents.

A Green and Wide-Scope Approach for Chiroptical Sensing of Organic Molecules through Biomimetic Recognition in Water.

Optical chirality sensing has attracted a lot of interest due to its potential in high-throughput screening in chirality analysis. A molecular sensor is required to convert the chirality of analytes into optical signals. Although many molecular sensors have been reported, sensors with wide substrate scope remain to be developed. Herein, we report that the amide naphthotube-based chirality sensors have an unprecedented wide scope for chiroptical sensing of organic molecules. The substrates include, but are not limited to common organic products in asymmetric catalysis, chiral molecules with inert groups or remote functional groups from their chiral centers, natural products and their derivatives, and chiral drugs. The effective chirality sensing is based on biomimetic recognition in water and on effective chirality transfer through guest-induced formation of a chiral conformation of the sensors. Furthermore, the sensors can be used in real-time monitoring on reaction kinetics in water and in determining absolute configurations and ee values of the products in asymmetric catalysis.

Author Correction: Directed self-assembly of herbal small molecules into sustained release hydrogels for treating neural inflammation.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Asymmetric Hydrogenation of Cationic Intermediates for the Synthesis of Chiral N,O-Acetals.

For over half a century, transition-metal-catalyzed homogeneous hydrogenation has been mainly focused on neutral and readily prepared unsaturated substrates. Although the addition of molecular hydrogen to C=C, C=N, and C=O bonds represents a well-studied paradigm, the asymmetric hydrogenation of cationic species remains an underdeveloped area. In this study, we were seeking a breakthrough in asymmetric hydrogenation, with cationic intermediates as targets, and thereby anticipating applying this powerful tool to the construction of challenging chiral molecules. Under acidic conditions, both N- or O-acetylsalicylamides underwent cyclization to generate cationic intermediates, which were subsequently reduced by an iridium or rhodium hydride complex. The resulting N,O-acetals were synthesized with remarkably high enantioselectivity. This catalytic strategy exhibited high efficiency (turnover number of up to 4400) and high chemoselectivity. Mechanistic studies supported the hypothesis that a cationic intermediate was formed in situ and hydrogenated afterwards. A catalytic cycle has been proposed with hydride transfer from the iridium complex to the cationic sp2 carbon atom being the rate-determining step. A steric map of the catalyst has been created to illustrate the chiral environment, and a quantitative structure-selectivity relationship analysis showed how enantiomeric induction was achieved in this chemical transformation.

Iridium-Catalyzed Enantioselective Hydrogenation of Oxocarbenium Ions: A Case of Ionic Hydrogenation.

Ionic hydrogenation has not been extensively explored, but is advantageous for challenging substrates such as unsaturated intermediates. Reported here is an iridium-catalyzed hydrogenation of oxocarbenium ions to afford chiral isochromans with high enantioselectivities. A variety of functionalities are compatible with this catalytic system. In the presence of a catalytic amount of the Brønsted acid HCl, an α-chloroether is generated in situ and subsequentially reduced. Kinetic studies suggest first-order kinetics in the substrate and half-order kinetics in the catalyst. A positive nonlinear effect, together with the half kinetic order, revealed a dimerization of the catalyst. Possible reaction pathways based on the monomeric iridium catalyst were proposed and DFT computational studies revealed an ionic hydrogenation pathway. Chloride abstraction and the cleavage of dihydrogen occur in the same step.

Homogeneous Hydrogenation with a Cobalt/Tetraphosphine Catalyst: A Superior Hydride Donor for Polar Double Bonds and N-Heteroarenes.

The development of catalysts based on earth abundant metals in place of noble metals is becoming a central topic of catalysis. We herein report a cobalt/tetraphosphine complex-catalyzed homogeneous hydrogenation of polar unsaturated compounds using an air- and moisture-stable and scalable precatalyst. By activation with potassium hydroxide, this cobalt system shows both high efficiency (up to 24 000 TON and 12 000 h-1 TOF) and excellent chemoselectivities with various aldehydes, ketones, imines, and even N-heteroarenes. The preference for 1,2-reduction over 1,4-reduction makes this method an efficient way to prepare allylic alcohols and amines. Meanwhile, efficient hydrogenation of the challenging N-heteroarenes is also furnished with excellent functional group tolerance. Mechanistic studies and control experiments demonstrated that a CoIH complex functions as a strong hydride donor in the catalytic cycle. Each cobalt intermediate on the catalytic cycle was characterized, and a plausible outer-sphere mechanism was proposed. Noteworthy, external inorganic base plays multiple roles in this reaction and functions in almost every step of the catalytic cycle.

Directed self-assembly of herbal small molecules into sustained release hydrogels for treating neural inflammation.

Self-assembling natural drug hydrogels formed without structural modification and able to act as carriers are of interest for biomedical applications. A lack of knowledge about natural drug gels limits there current application. Here, we report on rhein, a herbal natural product, which is directly self-assembled into hydrogels through noncovalent interactions. This hydrogel shows excellent stability, sustained release and reversible stimuli-responses. The hydrogel consists of a three-dimensional nanofiber network that prevents premature degradation. Moreover, it easily enters cells and binds to toll-like receptor 4. This enables rhein hydrogels to significantly dephosphorylate IκBα, inhibiting the nuclear translocation of p65 at the NFκB signalling pathway in lipopolysaccharide-induced BV2 microglia. Subsequently, rhein hydrogels alleviate neuroinflammation with a long-lasting effect and little cytotoxicity compared to the equivalent free-drug in vitro. This study highlights a direct self-assembly hydrogel from natural small molecule as a promising neuroinflammatory therapy.