Lewis Base-Catalyzed Dynamic Kinetic Asymmetric Transformation of Racemic Chlorosilanes en Route to Si-Stereogenic Silylethers.

Enantiopure Si-stereogenic organosilanes are highly valued in the fields of organic synthesis, development of advanced materials, and drug discovery. However, they are not naturally occurring, and their synthesis has been largely confined to resolution of racemic silanes or desymmetrization of symmetric silanes. In contrast, the dynamic kinetic asymmetric transformation (DYKAT) of racemic organosilanes offers a mechanistically distinct approach and would broaden the accessibility of Si-stereogenic silanes in an enantioconvergent manner. In this study, we report a Lewis base-catalyzed DYKAT of racemic chlorosilanes. The chiral isothiourea catalyst, (S)-benzotetramisole, facilitates silyletherification with phenols, yielding (R)-silylethers in good yields with high enantioselectivity (27 examples, up to 86% yield, up to 98:2 er). Kinetic analysis, control experiments, and DFT calculations suggest that a two-catalyst-bound pentacoordinate silicate is responsible for the Si-configurational epimerization of the ion-paired tetracoordinated silicon intermediates.

Elucidating Mechanism and Selectivity in Pyridine Functionalization Through Silylium Catalysis.

The functionalization of aromatic N-heterocycles through silylium activation demonstrates exceptional selectivity and efficiency. Density functional theory (DFT) calculations unveil the detailed silylium catalysis mechanism and elucidate the origins of selectivity in this reaction. The phosphoramidimidate sulfonamide (PADI) precatalyst orchestrates of the catalytic cycle via three elementary steps. The Brønsted acidity of precatalyst significantly influences both the formation of silylium-based Lewis acid active species and the silylium activation of pyridine. Unlike disulfonimide (DSI)-type precatalysts, both Tf2NH and PADI precatalysts with strong acidities can easily promote the generation of activated silylium pyridine species. A semi-enclosed 'rigid' electronegative cavity in PADI-type anions constructs a well-defined recognition site, facilitating engagement with the positively charged silylium pyridine species. Due to the high electrophilicity and less steric demand at the C4-position of the pyridine substrate, the product with C4-regioselectivity was predominantly generated.

Redox-neutral depolymerization of lignin-derived aryl ethers catalyzed by Rh(III)-complexes: a mechanistic insight.

Density functional theory (DFT) calculations at the TPSSh-D3(BJ)/def2-TZVP (SMD, water) level of theory were performed to understand the mechanism of redox-neutral depolymerization of four types of lignin-derived aryl ether dimers catalyzed by rhodium-terpyridine ([Rh]) and a binuclear Rh complex ([2Rh]). The cleavage of the Cß-O bond in the ß-O-4 model compound was initiated by the dehydrogenation of the alcohol moiety into a ketone intermediate, followed by the reductive cleavage of the ether bond, producing phenol and aromatic ketone products. The [Rh]-OH intermediate, generated by the interaction between the Rh-complex and NaOH, facilitated the transformation of the alcohol group to a CO group in the lignin model compound and subsequent H-transfer, selectively forming rhodium-H active species and the ketone intermediate. The [2Rh]-H complex exhibited high reactivity, with energy barriers for a rate-determining Cß-O bond breakage of 35.3 kcal mol-1. In contrast to 1-phenylethan-1-ol and H2, lignin itself acted as a good hydrogen source to generate [Rh]-H species. The transformation of ß-O-4 model compounds with the γ-OH group occurred via the elimination of the γ-OH group, reduction of the CC bond, and Cß-O bond cleavage steps. However, since lignin itself was unable to supply enough hydrogen to form [Rh]-H species, the aromatic products were obtained in low yields, as observed in the experiment.

Oxidative Upcycling of Polyethylene to Long Chain Diacid over Co-MCM-41 Catalyst.

Plastic pollution is an emerging global threat due to lack of effective methods for transforming waste plastics into useful resources. Here, we demonstrate a direct oxidative upcycling of polyethylene into high-value and high-volume saturated dicarboxylic acids in high carbon yield of 85.9 % in which the carbon yield of long chain dicarboxylic (C10-C20) acids can reach 58.9% over cobalt-doped MCM-41 molecular sieves, in the absence of any solvent or precious metal catalyst. The distribution of the dicarboxylic acids can be controllably adjusted from short-chain (C4-C10) to long-chain ones (C10-C20) through changing cobalt loading of MCM-41 under nanoconfinement. Highly and sparsely dispersed cobalt along with confined space of mesoporous structure enables complete degradation of polyethylene and high selectivity of dicarboxylic acid in mild condition. So far, this is the first report on highly selective one-step preparation of long chain dicarboxylic acids. The approach provides an attractive solution to tackle plastic pollution and a promising alternative route to long chain diacids.

Novel Stereo-Induction Pattern in Pudovik Addition/Phospha-Brook Rearrangement Towards Chiral Trisubstituted Allenes.

Despite the significance of chiral allene skeletons in catalysis, organic synthesis and medicinal chemistry et al., there is a scarcity of reports on axially chiral allenyl phosphorus compounds. Here, we disclosed an efficient and straightforward cascade reaction between ethynyl ketones and phosphine oxides, resulting in a broad array of trisubstituted allenes incorporating a phosphorus moiety in high yields with excellent stereoselectivities facilitated by peptide-mimic phosphonium salt (PPS) catalysis, Additionally, comprehensive series of mechanistic experiments have been conducted to elucidate that this cascade reaction proceeds via an asymmetric Pudovik addition reaction followed by a subsequent phospha-Brook rearrangement that occurs concomitantly with kinetic resolution, representing a stereospecific rearrangement and protonation process facilitating central-to-axial chirality transfer in a cascade manner. We anticipate that our research will pave the way for a promising exploration of novel stereo-induction pattern in the Pudovik addition/phospha-Brook rearrangement cascade reaction.

Theoretical Study on Cooperation Catalysis of Chiral Guanidine/ Copper(I) in Asymmetric Azide-Alkyne Cycloaddition/[2 + 2] Cascade Reaction.

Density functional theory (DFT) calculations with BP86-D3(BJ) functionals were employed to reveal the mechanism and stereoselectivity of chiral guanidine/copper(I) salt-catalyzed stereoselective three-component reaction among N-sulfonyl azide, terminal alkyne, and isatin-imine for spiroazetidinimines that was first reported by Feng and Liu (Angew. Chem. Int. Ed. 2018, 57, 16852-16856). For the noncatalytic cascade reaction, the denitrogenation to generate ketenimine species was the rate-determining step, with an activation barrier of 25.8-34.8 kcal mol-1. Chiral guanidine-amide promoted the deprotonation of phenylacetylene, generating guanidine-Cu(I) acetylide complexes as active species. In azide-alkyne cycloaddition, copper acetylene coordinated to the O atom of the amide moiety in guanidium, and TsN3 was activated by hydrogen bonding, affording the Cu(I)-ketenimine species with an energy barrier of 3.5∼9.4 kcal mol-1. The optically active spiroazetidinimine oxindole was constructed via a stepwise four-membered ring formation, followed by deprotonation of guanidium moieties for C-H bonding in a stereoselective way. The steric effect of the bulky CHPh2 group and chiral backbone in the guanidine, combined with the coordination between the Boc group in isatin-imine with a copper center, played important roles in controlling the stereoselectivity of the reaction. The major spiroazetidinimine oxindole product with an SS configuration was formed in a kinetically more favored way, which was consistent with the experimental observation.

Organocatalytic Dynamic Kinetic Resolution Enabled Asymmetric Synthesis of Phosphorus-Containing Chiral Helicenes.

The catalytic asymmetric synthesis of phosphorus-containing helicenes remains a formidable challenge, presumably due to the lack of rational design of substrates, right choice of reactions together with highly effective catalysis systems. Herein, we disclosed an efficient and practical DKR-involving (dynamic kinetic resolution) cascade strategy toward synthesizing a novel family of phosphorus-installing helicenes by peptide-mimic phosphonium salt (PPS) catalysis. The sequential process of PPS-catalyzed phospha-Michael attack and copper salt-facilitated aromatization led to the formation of unprecedented phosphorus-containing oxa[5]helicene scaffolds. A wide variety of substrates bearing an assortment of functional groups were compatible with this protocol, furnishing the expected helical compounds in high yields and excellent stereoselectivities. Additionally, the helical products could be conveniently elaborated to promising phosphine ligands with perfectly retained helical chirality, which turned out to be highly efficient chiral ligands in transition metal-catalyzed reactions. These findings not only expand the current library of phosphorus-containing helicenes but also offer insights to explore other challenging scaffolds with molecular chirality.

Sterically Hindered and Deconjugative α-Regioselective Asymmetric Mannich Reaction of Meinwald Rearrangement-Intermediate.

Compared to γ-addition, the α-addition of α-branched ß,γ-unsaturated aldehydes faces larger steric hindrance and disrupts the π-π conjugation, which might be why very few examples are reported. In this article, a highly diastereo- and enantioselective α-regioselective Mannich reaction of isatin-derived ketimines with α-, ß- or γ-branched ß,γ-unsaturated aldehydes, generated in situ from Meinwald rearrangement of vinyl epoxides, is realized by using chiral N,N'-dioxide/ScIII catalysts. A series of chiral α-quaternary allyl aldehydes and homoallylic alcohols with vicinal multisubstituted stereocenters are constructed in excellent yields, good d.r. and excellent ee values. Experimental studies and DFT (density functional theory) calculations reveal that the large steric hindrance of the ligand and the Boc (tButyloxy carbonyl) protecting group of imines are critical factors for the α-regioselectivity.

Towards Axially Chiral Pyrazole-Based Phosphorus Scaffolds by Dipeptide-Phosphonium Salt Catalysis.

Given the comparatively lower rotational barriers, the catalytic asymmetric construction of axially chiral biaryl structures, especially those containing a five-membered heterocycle, still remains a challenge. Herein, we described a general and modular protocol to access atropisomeric arylpyrazole scaffolds containing a phosphorus unit by a dipeptide phosphonium salt catalyzed reaction involving an oxidative central-to-axial chirality conversion. This reaction features excellent yields and enantioselectivities, broad substrate scope, and a low catalyst loading, delivering axially chiral phosphine compounds.

Mechanistic Study of Asymmetric Alkynylation of Isatin-Derived Ketimine Mediated by a Copper/Guanidine Catalyst.

In this work, we performed a mechanistic study of asymmetric alkynylation of isatin-derived N-Boc ketimine that was first reported by Feng, Liu, and co-workers (Chem. Commun. 2018, 54, 678-681). Guanidine-amide promoted the formation of highly nucleophilic copper acetylene species by abstracting the terminal proton of phenylacetylene with an imine moiety. The guanidinium salt-Cu(I) complex was the most active species in the addition of the C═N bond, in which copper acetylene coordinated to the O atom of the amide moiety, and the isatin-derived ketimine substrate was activated by hydrogen bonding as well as tert-butoxycarbonyl···Cu(I) coordination. Due to weak interaction between Cu(I) and the Ph group in the amide of guanidine, as well as the repulsion between the tert-butyl group in ketimine and the cyclohexyl group in guanidine, the copper acetylene preferred to attack isatin-derived ketimine from the re-face, leading to the S-configuration product with excellent stereoselectivity. The affinity of the counterion for the Cu(I) center in the copper salt affected the deprotonation of phenylacetylene and the formation of guanidinium salt active species. In contrast to CuBr and CuCl, the combination of CuI with aniline-derived guanidine-amide exhibited high catalytic activity and a chiral induction effect, contributing to a high turnover frequency (9.70 × 10-4 s-1) in catalysis and ee%.

Remarkable enantioselectivity enhancement of the extractors with nonaxial chirality in liquid-liquid extraction of underivatized amino acids by introducing t-butyl group.

A class of carbonyl extractors, (R)-3, (R)-4, and (R)-5, with nonaxial chirality containing asymmetric carbons has been synthesized and studied for their efficiencies in enantioselective liquid-liquid extraction for underivatized amino acids. The bulky t-butyl ketone extractors, (R)-4 and (R)-5, showed the stereoselectivities ranging 5.4-9.4 of l/d ratio much better than those of the aldehyde extractor, (R)-3, ranging 2.4-5.2. The imine formation rates and yields of the t-butyl ketones were not significantly affected by their bulkiness and even in the absence of resonance-assisted hydrogen bond. This work confirms that a bulky t-butyl ketone can be a good choice in the development of an extractor not only with axial chirality but also with nonaxial chirality for the enantioselective extraction of unprotected amino acids.

Enantioselective Synthesis of Atropisomeric Biaryl Phosphorus Compounds by Chiral-Phosphonium-Salt-Enabled Cascade Arene Formation.

Axially chiral biaryl monophosphorus molecules, exemplified by atropisomeric 1,1'-biaryl aminophosphines, are significant motifs in numerous chiral ligands/catalysts. Developing efficient methods for preparing phosphorus compounds with these privileged motifs is an important endeavor in synthetic chemistry. Herein, we develop an effective, modular method by a chiral-phosphonium-salt-catalyzed novel cascade between phosphorus-containing nitroolefins and α,α-dicyanoolefins, leading to a great diversity of atropisomeric biaryls bearing phosphorus groups in high yields with excellent stereoselectivities. The reaction features include a Thorpe-type cycloaddition/oxidative hydroxylation/aromatization cascade pathway with a central-to-axial chirality transfer process. Insight gained from our studies is expected to advance general efforts towards the catalytic synthesis of atropisomeric biaryl phosphorus compounds, offering a platform for developing new efficient chiral ligands and catalysts.

[3,3]-Sigmatropic Rearrangements of Naphthyl 1-Propargyl Ethers: para-Propargylation and Catalytic Asymmetric Dearomatization.

The para-Claisen rearrangement of aryl 1-propargyl ethers involves two-step [3,3]-sigmatropic rearrangements and dearomatization process, which has high activation barriers and is of challenge. Here we discovered thermal para-Claisen rearrangement of naphthyl 1-propargyl ethers, and it enabled the formation of formal para-C-H propargylation products upon rearomatization. Chirality transfer occurred if optically active propargyl ethers were employed, leading to the construction of aryl/propargyl-containing stereogenic centers. Moreover, catalytic asymmetric dearomatization of naphthyl 1-propargyl ethers with different substitution at para-position gave access to benzocyclohexenones bearing all-carbon quaternary stereocenters. The reaction was accelerated by a chiral N,N'-dioxide/Co(OTf)2 complex catalyst to achieve high yields (up to 98 %) and high enantioselectivities (up to 93 % ee). The DFT calculations and experimental results provided important clues to clarify the para-Claisen rearrangement process as well as the chiral induction and remote delivery.

Modular Construction of Unnatural α-Tertiary Amino Acid Derivatives by Multicomponent Radical Cross-Couplings.

Although the synthesis of α-tertiary amino acids (ATAAs) has been extensively studied, the development of an inexpensive and facile methodology to incorporate multifunctionality on ATAAs remains challenging. In this article, we present a single-step radical approach for the modular synthesis of functionally diverse ATAAs. This synthesis takes place under mild conditions with an absence of metals, photocatalysts, and all other additives. We demonstrate the broad applications of this approach on a variety of aliphatic and aromatic carboxylic acids, alkenes, 1,3-enynes, and oxazolones. The results prove that our method provides excellent functional group tolerance and late-stage applicability, as well as gram-scale synthesis via flow chemistry. Additionally, we include mechanistic studies which reveal that the excited state of oxazolone enolate upon light excitation is a key intermediate that acts as a radical precursor and an efficient reductant.

Synergistic Catalysis between a Dipeptide Phosphonium Salt and a Metal-Based Lewis Acid for Asymmetric Synthesis of N-Bridged [3.2.1] Ring Systems.

We present an unprecedented synergic catalytic route for the asymmetric construction of fluorinated N-bridged [3.2.1] cyclic members of tropane family via a bifunctional phosphonium salt/silver co-catalyzed cyclization process. A broad variety of substrates bearing an assortment of functional groups are compatible with this method, providing targeted compounds bearing seven-membered ring and four contiguous stereocenters in high yields with excellent stereoselectivities. The gram-scale preparations, facile elaborations and preliminary biological activities of the products demonstrate the application potential. Moreover, both experimental and computational mechanistic studies revealed that the cyclization proceeded via a "sandwich" reaction model with multiple weak-bond cooperative activations. Insights gained from our studies are expected to advance general efforts towards the catalytic synthesis of challenging chiral heterocyclic molecules.

Dibenzo[b,f][1,4,5]chalcogenadiazepine Photoswitches: Conversion of Excitation Energy into Ring Strain.

Tetra-ortho-substituted, heteroaryl and cyclic azobenzenes have emerged as three key strategies on morphology design of photoswitch to diversify controllability. Cyclic azobenzene is of particular utilization in photo-energy conversion due to rigid and ring-strain structure. Despite the well-recognized diazocine, the photo-switching properties of seven-membered cyclic azobenzenes (diazepines) have yet been exploited. Herein, we report a family of dibenzo[b,f][1,4,5]chalcogenadiazepines (DBChDs) and their T-type photo-switching nature with tunable relaxation rate. Based on experiments together with DFT calculations, we found that an unsymmetric 2-bithiophenyl-dibenzo[b,f][1,4,5]thiadiazepine exhibited an efficient response to 445 nm laser stimulation (quantum efficiency, ΦZ→E =0.71) with millisecond relaxation half-life (t1/2 =40 ms). Photo-energy transduction efficiency was also exceptionally high with 29.1 % converted into ring-strain energy mainly loaded on azo π-bond.

Mechanism and Selectivity of Cyclopropanation of 3-Alkenyl-oxindoles with Sulfoxonium Ylides Catalyzed by a Chiral N,N'-Dioxide-Mg(II) Complex.

The mechanism and stereoselectivity of an asymmetric cyclopropanation reaction between 3-alkenyl-oxindole and sulfoxonium ylide catalyzed by a chiral N,N'-dioxide-Mg(II) complex were explored using the B3LYP-D3(BJ) functional and the def2-TZVP basis set. The noncatalytic reaction occurred via a stepwise mechanism, with activation barriers of 21.6-23.5 kcal mol-1. The C2-Cα bond formed followed by the carbanion SN2 substitution, constructing a three-membered ring in spiro-cyclopropyl oxindoles, accompanied by the release of dimethylsulfoxide. The electron-withdrawing N-protecting t-butyloxy carbonyl (Boc) and acetyl (Ac) groups in isatin enhanced the local electrophilicity of the C2 atom and the repulsion between the two COPh groups in the reactants, contributing to high reactivity as well as good diastereoselectivity results. The N-Boc-3-phenacylideneoxindole coordinated to the chiral ligand (L-PiPr2) in a bidentate fashion, forming a hexacoordinate-Mg(II) complex as the reactive species. The origin of enantioselectivity was from the shielding effect of 2,6-diisopropylphenyl groups in the ligand toward the si-face of oxindole. The repulsion between the SO(CH3)2 and COPh groups in 3-alkenyl-oxindole and the neighboring ortho-iPr group in the ligand directed the re-face of ylide to attack the re-face of oxindole preferably, contributing to the high diastereoselectivity of the product. A metal-ion-ligand matching relationship was important for a good asymmetric induction effect of the chiral N,N'-dioxide-metal catalyst. A large chiral cavity in the Zn(II) catalyst weakened the shielding effect of 2,6-diisopropylphenyl groups in the ligand toward the prochiral face of oxindole, leading to inferior enantioselectivity observed in the experiment.

Guanidine-Amide-Catalyzed Aza-Henry Reaction of Isatin-Derived Ketimines: Origin of Selectivity and New Catalyst Design.

Density functional theory (DFT) calculations were performed to investigate the mechanism and the enantioselectivity of the aza-Henry reaction of isatin-derived ketimine catalyzed by chiral guanidine-amide catalysts at the M06-2X-D3/6-311+G(d,p)//M06-2X-D3/6-31G(d,p) (toluene, SMD) theoretical level. The catalytic reaction occurred via a three-step mechanism: (i) the deprotonation of nitromethane by a chiral guanidine-amide catalyst; (ii) formation of C-C bonds; (iii) H-transfer from guanidine to ketimine, accompanied with the regeneration of the catalyst. A dual activation model was proposed, in which the protonated guanidine activated the nitronate, and the amide moiety simultaneously interacted with the ketimine substrate by intermolecular hydrogen bonding. The repulsion of CPh3 group in guanidine as well as N-Boc group in ketimine raised the Pauli repulsion energy (∆EPauli) and the strain energy (∆Estrain) of reacting species in the unfavorable si-face pathway, contributing to a high level of stereoselectivity. A new catalyst with cyclopropenimine and 1,2-diphenylethylcarbamoyl as well as sulfonamide substituent was designed. The strong basicity of cyclopropenimine moiety accelerated the activation of CH3NO2 by decreasing the energy barrier in the deprotonation step. The repulsion between the N-Boc group in ketimine and cyclohexyl group as well as chiral backbone in the new catalyst raised the energy barrier in C-C bond formation along the si-face attack pathway, leading to the formation of R-configuration product. A possible synthetic route for the new catalyst is also suggested.

Regio- and Stereoselective Cascade of ß,γ-Unsaturated Ketones by Dipeptided Phosphonium Salt Catalysis: Stereospecific Construction of Dihydrofuro-Fused [2,3-b] Skeletons.

Chiral (dihydro)furo-fused heterocycles are significant structural motifs in numerous natural products, functional materials and pharmaceuticals. Therefore, developing efficient methods for preparing compounds with these privileged scaffolds is an important endeavor in synthetic chemistry. Herein, we develop an effective, modular method by a dipeptide-phosphonium salt-catalyzed regio- and stereoselective cascade reaction of readily available linear ß,γ-unsaturated ketones with aromatic alkenes, affording a wide variety of structurally fused heterocyclic molecules in high yields with excellent stereoselectivities. Moreover, mechanistic investigations revealed that the bifunctional phosphonium salt controlled the regio- and stereoselectivities of this cascade reaction, particularly proceeding through the initial ketone α-addition followed by O-participated substitution; and the multiple hydrogen-bonding interactions between Brønsted acid moieties of catalyst and nitro group of aromatic alkene were crucial in asymmetric induction. Given the generality, versatility, and high efficiency of this method, we anticipate that it will have broad synthetic utilities.

Diversified Transformations of Tetrahydroindolizines to Construct Chiral 3-Arylindolizines and Dicarbofunctionalized 1,5-Diketones.

Enantioselective diverse synthesis of a small-molecule collection with structural and functional similarities or differences in an efficient manner is an appealing but formidable challenge. Asymmetric preparation and branching transformations of tetrahydroindolizines in succession present a useful approach to the construction of N-heterocycle-containing scaffolds with functional group, and stereochemical diversity. Herein, we report a breakthrough toward this end via an initial diastereo- and enantioselective [3 + 2] cycloaddition between pyridinium ylides and enones, following diversified sequential transformations. Chiral N,N'-dioxide-earth metal complexes enable the generation of optically active tetrahydroindolizines in situ, across the strong background reaction for racemate-formation. In connection with deliberate sequential transformations, involving convenient rearomatic oxidation, and light-active aza-Norrish II rearrangement, the tetrahydroindolizine intermediates were converted into the final library including 3-arylindolizine derivatives and dicarbofunctionalized 1,5-dicarbonyl compounds. More importantly, the stereochemistry of four-stereogenic centered tetrahydroindolizine intermediates could be efficiently transferred into axial chirality in 3-arylindolizines and vicinal pyridyl and aryl substituted 1,5-diketones. In addition, densely functionalized cyclopropanes and bridged cyclic compounds were also discovered depending on the nature of the pyridinium ylides. Mechanism studies were involved to explain the stereochemistry during the reaction processes.