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Stereoconvergent reactions enable the transformation of mixed stereoisomers into well-defined, chiral products─a crucial strategy for handling Z / E -mixed olefins, which are common but challenging substrates in organic synthesis. Herein, we report a stereoconvergent and highly enantioselective method for synthesizing Z -homoallylic alcohols via the nickel-catalyzed reductive coupling of Z / E -mixed 1,3-dienes with aldehydes. This process is enabled by an N -heterocyclic carbene ligand characterized by C 2 -symmetric backbone chirality and bulky 2,6-diisopropyl N -aryl substituents. Our method achieves excellent stereocontrol over both enantioselectivity and Z -selectivity in a single step, producing chiral Z -homoallylic alcohols that are valuable in natural products and pharmaceuticals.

Chiral amides are important structure in many natural products and pharmaceuticals, yet their efficient synthesis from simple amide feedstock remains challenge due to its weak Lewis basicity. Herein, we describe our study of the enantioselective synthesis of chiral amides by N-alkylation of primary amides taking advantage of an achiral rhodium and chiral squaramide co-catalyzed carbene N-H insertion reaction. This method features mild condition, rapid reaction rate (in all cases 1 min) and a wide substrate scope with high yield and excellent enantioselectivity. Further product transformations show the synthetic potential of this reaction. Mechanistic studies reveal that the non-covalent interactions between the catalyst and reaction intermediate play a critical role in enantiocontrol., (© 2024. The Author(s).)

Unactivated aliphatic alkenes are particularly desirable as starting materials because they are readily accessible in large quantities, but the enantioselective intermolecular reductive coupling of unactivated alkenes with imines is challenging. In this paper, we report a method for nickel-catalyzed intermolecular reductive coupling reactions between aliphatic alkenes and imines to yield chiral amines with excellent enantioselectivities and good linear selectivities. The reaction conditions are compatible with a broad range of aliphatic alkenes, including those derived from bioactive molecules. The success of this method can be attributed to the use of newly developed monodentate chiral spiro phosphine ligands.

We developed a method for the enantioselective synthesis of germanium-stereogenic compounds by the desymmetric carbene insertion of dihydrogermanes. A chiral rhodium phosphate catalyst decomposes diaryldiazo-methanes to generate rhodium carbenes that insert enantioselectively into one of the two Ge-H bonds of dihydrogermanes to form germanium-stereogenic compounds under mild reaction conditions. By this method, a variety of chiral germanes with germanium-stereogenic centers were synthesized in high yields and excellent enantioselectivities. Kinetic studies of the reaction showed that the diazo decomposition process was the rate-determining step. The remaining Ge-H bond of the chiral germane products provides a possibility for preparing chiral tetra-substituted germanium-stereogenic compounds.

Ligand modulation of transition-metal catalysts to achieve optimal reactivity and selectivity in alkene hydrofunctionalization is a fundamental challenge in synthetic organic chemistry. Hydroaminoalkylation, an atom-economical approach for alkylating amines using alkenes, is particularly significant for amine synthesis in the pharmaceutical, agrochemical, and fine chemical industries. However, the existing methods usually require specific substrate combinations to achieve precise regio- and stereoselectivity, which limits their practical utility. Protocols allowing for regiodivergent hydroaminoalkylation from the same starting materials, controlling both regiochemical and stereochemical outcomes, are currently absent. Herein, we report a ligand-controlled, regiodivergent nickel-catalyzed hydroaminoalkylation of unactivated alkenes with N -sulfonyl amines. The reaction initiates with amine dehydrogenation and involves aza-nickelacycle intermediates. Tri tert -butylphosphine promotes branched regioselectivity and syn diastereoselectivity, whereas ethyldiphenylphosphine enables linear selectivity, yielding regioisomers with inverse orientation. Systematic evaluation of diverse monodentate phosphine ligands reveals distinct regioselectivity cliffs, and % V bur ( min ), a ligand steric descriptor, was established as a predictive parameter correlating ligand structure to regioselectivity. Computational investigations supported experimental findings, offering mechanistic insights into the origins of regioselectivity. Our method provides an efficient and predictable route for amine synthesis, demonstrating broad substrate scope, excellent tolerance toward various functional groups, and practical advantages. These include the use of readily available starting materials and cost-effective nickel(II) salts as precatalysts.

Cyclopamine is a teratogenic steroidal alkaloid, which inhibits the Hedgehog (Hh) signaling pathway by targeting the Smoothened (Smo) receptor. Suppression of Hh signaling with synthetic small molecules has been pursued as a therapeutic approach for the treatment of cancer. We report herein the asymmetric synthesis of cyclopamine based on a two-stage relay strategy. Stage-I : total synthesis of veratramine through a convergent approach, wherein a crucial photoinduced excited-state Nazarov reaction was applied to construct the basic [6-6-5-6] skeleton of C- nor -D- homo -steroid. Stage-II : conversion of veratramine to cyclopamine was achieved through a sequence of chemo- selective redox manipulations.

The enantioselective addition of potent nucleophiles to ketenes poses challenges due to competing background reactions and poor stereocontrol. Herein, we present a method for enantioselective phosphoric acid catalyzed amination of ketenes generated from α-aryl-α-diazoketones. Upon exposure to visible light, the diazoketones undergo Wolff rearrangement to generate ketenes. The phosphoric acid not only accelerates ketene capture by amines to form a single configuration of aminoenol intermediates but also promotes an enantioselective proton-transfer reaction of the intermediates to yield the products. Mechanistic studies elucidated the reaction pathway and explained how the catalyst expedited the transformation and controlled the enantioselectivity., (© 2023 Wiley-VCH GmbH.)

We present the first enantioselective nickel-catalyzed borylative coupling of 1,3-dienes with aldehydes, providing an efficient route to highly valuable homoallylic alcohols in a single step. The reaction involves the 1,4-carboboration of dienes, leading to the formation of C-C and C-B bonds accompanied by the construction of two continuous stereogenic centers. Enabled by a chiral spiro phosphine-oxazoline nickel complex, this transformation yields products with exceptional diastereoselectivity, E -selectivity, and enantioselectivity. The diastereoselectivity of the reaction can be controlled by employing either ( Z )-1,3-dienes or ( E )-1,3-dienes.

Molecules with an allylic amine motif provide access to important building blocks and versatile applications of biologically relevant chemical space. The need for diverse allylic amines requires the development of increasingly general and modular multicomponent reactions for allylic amine synthesis. Herein, we report an efficient catalytic multicomponent coupling reaction of simple alkenes, aldehydes, and amides by combining nickel catalysis and Lewis acid catalysis, thus providing a practical, environmentally friendly, and modular protocol to build architecturally complex and functionally diverse allylic amines in a single step. The method is remarkably simple, shows broad functional-group tolerance, and facilitates the synthesis of drug-like allylic amines that are not readily accessible by other methods. The utilization of accessible starting materials and inexpensive Ni(ii) salt as the alternative precatalyst offers a significant practical advantage. In addition, the practicality of the process was also demonstrated in an efficient, gram-scale preparation of the prostaglandin agonist., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Chiral benzylic amines are privileged motifs in pharmacologically active molecules. Intramolecular enantioselective radical C(sp 3 )-H functionalization by hydrogen-atom transfer has emerged as a straightforward, powerful tool for the synthesis of chiral amines, but methods for intermolecular enantioselective C(sp 3 )-H amination remain elusive. Herein, we report a cationic copper catalytic system for intermolecular enantioselective benzylic C(sp 3 )-H amination with peroxide as an oxidant. This mild, straightforward method can be used to transform an array of feedstock alkylarenes and amides into chiral amines with high enantioselectivities, and it has good functional group tolerance and broad substrate scope. More importantly, it can be used to synthesize bioactive molecules, including chiral drugs. Preliminary mechanistic studies indicate that the amination reaction involves benzylic radicals generated by hydrogen-atom transfer., (© 2023 Wiley-VCH GmbH.)

Control of the regioselectivity of α-alkylation of carbonyl compounds is a longstanding topic of research in organic chemistry. By using stoichiometric bulky strong bases and carefully adjusting the reaction conditions, selective alkylation of unsymmetrical ketones at less-hindered α-sites has been achieved. In contrast, selective alkylation of such ketones at more-hindered α-sites remains a persistent challenge. Here we report a nickel-catalysed alkylation of unsymmetrical ketones at the more-hindered α-sites with allylic alcohols. Our results indicate that the space-constrained nickel catalyst bearing a bulky biphenyl diphosphine ligand enables the preferential alkylation of the more-substituted enolate over the less-substituted enolate and reverses the conventional regioselectivity of ketone α-alkylation. The reactions proceed under neutral conditions in the absence of additives, and water is the only byproduct. The method has a broad substrate scope and permits late-stage modification of ketone-containing natural products and bioactive compounds., (© 2023. The Author(s).)

Free carbene readily causes multiple side reactions due to its high energy, thus its asymmetric transformation is very difficult. We present here our findings of high-pK a Brønsted acid catalysts that enable free carbene insertion into N-H bonds of amines to prepare chiral α-amino acid derivatives with high enantioselectivity. Under irradiation with visible light, diazo compounds produce high-energy free carbenes that are captured by amines to form free ylide intermediates, and then the newly designed high-pK a Brønsted acids, chiral spiro phosphamides, promote the proton transfer of ylides to afford the products. Computational and kinetic studies uncover the principle for the rational design of proton-transfer catalysts and explain how the catalysts accelerate this transformation and provide stereocontrol., (© 2023 Wiley-VCH GmbH.)

Background: Extensive knowledge of allergic multimorbidities is required to improve the management of allergic diseases with the industrialization of China. However, the demography and allergen distribution patterns of allergic multimorbidities in China remain unclear, despite the increasing prevalence of allergies., Methods: This was a real-world, cross-sectional study of 1273 outpatients diagnosed with one or more allergic diseases in Guangzhou, the most populated city of southern China, with leading industrial and commercial centers, between April 2021 and March 2022. Seven allergic diseases (allergic rhinitis (AR), asthma (AS)/cough variant asthma (CVA), atopic dermatitis (AD)/eczema, food allergy (FA), allergic conjunctivitis (AC), drug allergy (DA), and anaphylaxis) were assessed. Positive rates of sensitization to different allergens were measured using an allergen detection system of the UniCAP (Pharmacia Diagnostics, Sweden) instrument platform to compare the groups of allergic multimorbidities against a single entity., Results: There were 659 (51.8%) males and 614 (48.2%) females aged from 4 months to 74 years included in the analysis. The study participants who were diagnosed with allergic diseases had an average of 1.6 diagnoses. Overall, 46.5% (592 of 1273) of the patients had more than one allergic condition, and allergic rhinitis was the most common type of multimorbidity. Women were more likely to suffer from an allergic disease alone, whereas allergic multimorbidities were more likely to be diagnosed in men ( p = 0.005). In addition, allergic multimorbidities were common in all age groups, with an incidence ranging from 37.1% to 57.4%, in which children and adolescents were more frequently diagnosed with allergic multimorbidities than adults (18-60 years old) (all p < 0.05). Allergic multimorbidity was observed throughout the year. A difference in the positive rate of allergens sensitization and total immunoglobulin E (tIgE) levels between different allergic multimorbidities was observed., Conclusions: Allergic multimorbidities were very commonly found in nearly half of all patients with allergies. The proportion of allergic multimorbidities varied with the type of disease, sex, age, and allergen distribution pattern. These findings may help clinicians to develop "One health" strategies for the clinical management of allergic diseases.

ConspectusCatalytic asymmetric hydrogenation is one of the most reliable, powerful, and environmentally benign methods for the synthesis of chiral molecules with high atom economy and has been successfully applied in the industrial production of pharmaceuticals, agrochemicals, and fragrances. The key to achieving highly efficient and highly enantioselective hydrogenation reactions is the design and synthesis of chiral catalysts.Our recent studies involving iridium complexes of bidentate chiral spiro aminophosphine ligands (Ir-SpiroAP) have revealed that adding another coordinating group on the nitrogen atom to form a tridentate ligand can provide catalysts with markedly higher stability, enantioselectivity, and efficiency. Specifically, chiral Ir-SpiroAP catalysts bearing an added pyridine group (designated Ir-SpiroPAP) exhibit high activity and excellent enantioselectivity in the asymmetric hydrogenation of a wide range of carbonyl compounds, including aryl ketones, β- and δ-ketoesters, α,β-unsaturated ketones and esters, and racemic α-substituted lactones, as well as highly electron-deficient alkenes such as α,β-unsaturated malonates and analogues. The efficiency of the Ir-SpiroPAP catalysts is extremely high: in the hydrogenation of aryl ketones, turnover numbers reach 4.5 million, which is the highest value reported to date for a molecular catalyst. Moreover, when a thioether or a bulky triarylphosphine group is added to afford tridentate ligands designated SpiroSAP and SpiroPNP, respectively, the resulting iridium catalysts show high efficiency and enantioselectivity for asymmetric hydrogenation of β-alkyl-β-ketoesters and dialkyl ketones, which are challenging substrates. Furthermore, chiral spiro catalysts containing an added oxazoline moiety (Ir-SpiroOAP) show high enantioselectivity for asymmetric hydrogenation of α-keto amides and racemic α-aryloxy lactones. The above-described catalysts have been used for enantioselective synthesis of chiral pharmaceuticals and other bioactive compounds.We have shown that chiral spiro ligands that combine a rigid skeleton with tridentate coordination stabilize iridium catalysts. The careful tailoring of the substituents on the ligand creates a chiral environment around the active metal center of the catalyst that can precisely discriminate between the two faces of a substrate carbonyl group. These factors are key for controlling the activity, enantioselectivity, and turnover numbers of asymmetric hydrogenation catalysts. We expect that catalysts based on iridium, and other transition metals, coordinated by tridentate chiral ligands with a rigid skeleton will find more applications in asymmetric hydrogenation and other asymmetric transformations.

Herein, we report the first enantioselective total synthesis of the highly complex hamigeran diterpenoid (-)-hamigeran F and its rearrangement product. The synthetic strategy features key steps of asymmetric hydrogenation, Horner-Wadsworth-Emmons olefination, and intramolecular Friedel-Crafts acylation to construct the [6,6,5]-tricyclic skeleton bearing three consecutive stereocenters, a sequence of steps involving Rosenmund reduction, Wittig reaction, dihydroxylation to assemble the α-acetoxy ketone group, and an intramolecular aldol reaction to build the tetracyclic core structure.

An enantioselective total synthesis of the alleged structure of (+)-fimbricalyxoid A is reported. The synthetic strategy features a pyridine- N -oxidate-mediated S N 2' reaction to introduce an oxygen functionality at position C3 of the A-ring and a sequential three-step process via the cleavage of the C-O bonds and hemiketalization to form the 3,20-oxybridge. With this strategy, the target molecule was synthesized in 19% overall yield and 12 steps from our previously synthesized cis -fused octahydrophenanthrene (+)- 6 .

Herein, we describe a novel protocol for visible-light-induced α,γ-C(sp 3 )-H difunctionalization of piperidines. This redox-neutral, atom-economical protocol, which exhibits a broad substrate scope and good functional group compatibility, constitutes a concise, practical method for constructing piperidine-containing bridged-ring molecules. Preliminary mechanistic studies indicated that highly regioselective activation of the inert γ-C(sp 3 )-H bond of piperidines was achieved through a 1,5-hydrogen atom transfer reaction of a nitrogen radical generated in situ.

A three-step process for the enantioselective assembly of cis -fused octahydrophenanthrenes with a quaternary stereocenter is reported. This synthetic strategy relies on a regioselective γ-alkylation, a one-pot sequence of asymmetric hydrogenation and oxidation, and an intramolecular enolate arylation to facilitate the rapid and enantioselective construction of cis -fused octahydrophenanthrene scaffolds with an arylated all-carbon quaternary stereocenter concisely and efficiently.

We have developed a nickel-catalyzed desymmetric reductive cyclization/coupling of 1,6-dienes. The reaction provides an efficient method for constructing a chiral tertiary alcohol and a quaternary stereocenter by a single operation. The method has excellent diastereoselectivity and high enantioselectivity, a broad substrate scope, as well as good tolerance of functional groups. Preliminary mechanism studies show that alkyl nickel(I) species are involved in the reaction., (© 2022 Wiley-VCH GmbH.)

Introduction: Enhanced recovery after surgery (ERAS) protocols are a series of perioperative care to optimize preoperative preparation, prevent postoperative complications, minimize stress, and speedup recovery. Tympanoplasty and mastoidectomy are common surgical procedures for chronic suppurative otitis media., Objective: To compare the efficacy and safety between ERAS and conventional recovery after surgery in the perioperative period of chronic suppurative otitis media., Methods: From April 2018 to February 2019, a total of 84 patients scheduled for tympanoplasty and/or mastoidectomy due to chronic suppurative otitis media were involved and randomly divided into the ERAS group and the control group. The patients' preoperative anxiety, postoperative pain, and comfort level were determined by comparing the results of Self-Rating Anxiety Scale (SAS), Visual Analog Scale (VAS) and General Comfort Questionnaire (GCQ). The postoperative complications, postoperative hospital stay, and hospitalization cost were calculated., Results: The ERAS group showed a lower SAS score (30 [28-31.5] vs 35 [30-43], P < .05], a higher GCQ score (88 [84-100] vs 83 [78.25-92.25], P < .05), and a lower VAS score (0 [0-0] vs 1 [0-2], P < .05] after surgery. No significant difference ( P > .05) was observed between the ERAS group and the control group in postoperative complications, postoperative hospitalization time, and hospitalization cost, respectively., Conclusion: Enhanced recovery after surgery can reduce pain and improve comfort in the perioperative period of chronic suppurative otitis media.

An efficient asymmetric hydrogenation of racemic α-aryl-β-ethoxycarbonyl cyclopentanones via dynamic kinetic resolution is reported. Via catalysis by a chiral iridium Ir-SpiroPAP catalyst, a range of racemic α-aryl-β-ethoxycarbonyl cyclopentanones were hydrogenated to the corresponding ester-functionalized chiral 2-arylcyclopentanols with three contiguous stereocenters in high yields with excellent enantio- and diastereoselectivities. This method was successfully applied in the enantioselective synthesis of cyclopentane-based γ-amino ester/alcohol derivatives and phenylpropanoid (+)-burmaniol A.

A ligand-enabled nickel-catalyzed intramolecular hydroalkenylation of imines with unactivated alkenes has been developed. A variety of five- and six-membered cyclic allylic amines were synthesized in high yields. The use of both wide-bite-angle diphosphine ligand and Brønsted acid is crucial for realizing the reaction. Preliminary investigation of the asymmetric intramolecular hydroalkenylation of imines shows promising potential for the application of the method in the synthesis of enantio-enriched cyclic allylic amines.

A highly enantioselective Si-H bond insertion reaction of α-aryldiazoacetates catalyzed by chiral spiro dirhodium tetraphosphate was developed. Various chiral α-silyl esters were prepared with high yield (up to 92%) and excellent enantioselectivity (up to >99% ee) through this protocol. It is noteworthy that the 2-substituted aryl diazoacetates, which are challenging substrates for other chiral dirhodium catalysts, also exhibited good results in this reaction. This work represents one of the few successful applications of chiral dirhodium phosphates in asymmetric catalysis.

An efficient asymmetric hydrogenation of racemic γ-substituted cyclic β-ketoesters via dynamic kinetic resolution to provide chiral cyclic β-hydroxy esters with three contiguous stereocenters is reported. Using a chiral spiro iridium catalyst ( R )- 5 (Ir-SpiroSAP), a series of racemic γ-aryl/alkyl substituted cyclic β-ketoesters were hydrogenated to the corresponding chiral cyclic β-hydroxy esters in high yields (84-97%) with good to excellent enantioselectivities (69->99% ee) and cis , cis -selectivities (up to >99:1).

A highly enantioselective and diastereoselective nickel-catalyzed desymmetrizing cyclization of 1,6-dienes was developed by using chiral spiro phosphoramidite ligands. The reaction provides a new atom- and step-economical approach to chiral spiro lactones and analogues bearing a quaternary stereocenter.

The Nazarov electrocyclization reaction is a convenient, widely used method for construction of cyclopentenones. In the past few decades, catalytic asymmetric versions of the reaction have been extensively studied, but the strategies used to control the position of the double bond limit the substituent pattern of the products and thus the synthetic applications of the reaction. Herein, we report highly enantioselective silicon-directed Nazarov reactions which were cooperatively catalyzed by a Lewis acid and a chiral Brønsted acid. The chiral cyclopentenones we synthesized using this method generally cannot be obtained by means of other catalytic enantioselective reactions, including previously reported methods for enantioselective Nazarov cyclization. The silicon group in the dienone substrate stabilized the β-carbocation of the intermediate, thereby determining the position of the double bond in the product. Mechanistic studies suggested that the combination of Lewis and Brønsted acids synergistically activated the dienone substrate and that the enantioselectivity of the reaction originated from a chiral Brønsted acid promoted proton transfer reaction of the enol intermediate.

A protocol of iridium catalyzed asymmetric hydrogenation of 4-alkyl substituted 3-ethoxycarbonyl quinolin-2-ones and coumarins has been reported, providing a wide range of chiral dihydroquinolin-2-ones and dihydrocoumarins in high yields with excellent enantioselectivities (up to 99% ee) and high turnover numbers (up to 28 000). This efficient protocol was successfully applied for the synthesis of MPR3160 and the key chiral intermediate of R-106578.

Chiral propargylsilanes and chiral allenylsilanes have emerged as versatile building blocks for organic synthesis. However, efficient methods for preparing these organosilicon compounds are lacking. We herein report a highly enantioselective method for synthesis of chiral propargylsilanes and chiral allenylsilanes from readily available alkynyl sulfonylhydrazones. Specifically, chiral spiro phosphate dirhodium complexes were used to catalyze asymmetric insertion of alkynyl carbenes into the Si-H bonds of silanes to afford a variety of chiral propargylsilanes with excellent enantioselectivity. Subsequently, a platinum catalyst was used for stereospecific isomerization of the chiral propargylsilanes to the corresponding chiral allenylsilanes.

An iridium catalyzed asymmetric hydrogenation of racemic exocyclic γ,δ-unsaturated β-ketoesters via dynamic kinetic resolution to functionalized chiral allylic alcohols was developed. With the chiral spiro iridium catalysts Ir-SpiroPAP, a series of racemic exocyclic γ,δ-unsaturated β-ketoesters bearing a five-, six-, or seven-membered ring were hydrogenated to the corresponding functionalized chiral allylic alcohols in high yields with good to excellent enantioselectivities (87 to >99% ee) and cis -selectivities (93 : 7 to >99 : 1). The origin of the excellent stereoselectivity was also rationalized by density functional theory calculations. Furthermore, this protocol could be performed on gram scale and at a lower catalyst loading (0.002 mol%) without the loss of reactivity and enantioselectivity, and has been successfully applied in the enantioselective synthesis of chiral carbocyclic δ-amino esters and the β-galactosidase inhibitor isogalactofagomine., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

A rhodium-catalyzed hydroformylation of alkynes with formic acid was developed. The method provides α,β-unsaturated aldehydes in high yield and E -selectivity without the need to handle toxic CO gas.

Herein, we report a practical method for efficient asymmetric hydrogenation of β-aryl alkylidene malonates. With a site-specifically tailored chiral spiro iridium catalyst, a series of β-aryl alkylidene malonate esters were hydrogenated to afford chiral malonate esters with good to excellent enantioselectivities (up to 99% ee) and high turnover numbers (up to 19000). The results showed that installing an ester group in α,β-unsaturated carboxylic esters significantly increased the efficiency of their asymmetric hydrogenation reactions.

A ruthenium-catalyzed asymmetric hydrogenation method for the synthesis of functionalized β-aryl cyclohexanols is described. With chiral spiro ruthenium catalyst ( R a , S , S )- 5c , a series of racemic α-aryl cyclohexanones bearing a β-monoethylene ketal group were hydrogenated to the corresponding functionalized β-aryl cyclohexanols in high yields with enantioselectivity of up to 99% ee via a dynamic kinetic resolution. This protocol can be conducted on a decagram scale and provide potential approaches for the synthesis of optically active and densely functionalized aryl cyclohexanols.

A highly enantio- and regioselective hydrosulfonylation of 1,3-dienes with sulfonyl hydrazides has been realized by using a palladium catalyst containing a monodentate chiral spiro phosphoramidite ligand. The reaction provided an efficient approach to synthetically useful chiral allylic sulfones. Mechanistic studies suggest that the reaction proceeds through the formation of an allyl hydrazine intermediate and subsequent rearrangement to the chiral allylic sulfone product. The transformation of the allyl hydrazine intermediate to the product is the enantioselectivity-determining step., (© 2020 Wiley-VCH GmbH.)

We have developed a protocol for insertion of alkylidene carbenes into the B-H bonds of amine-borane adducts, enabling, for the first time, the construction of C(sp 2 )-B bonds by means of carbene-insertion reactions. Various acyclic and cyclic alkenyl borane-amine adducts were prepared from readily accessible starting materials in good to high yields and were subsequently subjected to a diverse array of functional group transformations. The unprecedented spiro B-N heterocycles prepared in this study have potential utility as building blocks for the synthesis of pharmaceuticals. Preliminary mechanistic studies suggest that insertion of the alkylidene carbenes into the B-H bonds of the amine-borane adducts proceeds via a concerted process involving a three-membered-ring transition state.

Herein we report the first enantioselective total syntheses of pentacyclic homoproaporphine alkaloids by means of a route, which includes a tandem retro-oxa-Michael addition and nucleophilic substitution to generate the oxa-benzobicyclco[3.3.1]nonane core structure, a Pictet-Spengler cyclization to construct the fused B and C rings, and sequential Baeyer-Villiger oxidation and pinacol-type cyclization to install the hydroxyl-lactol moiety of D ring. With this unified route, six pentacyclic homoproaporphine alkaloids have been synthesized enantioselectively.

Catalytic enantioselection usually depends on differences in steric interactions between prochiral substrates and a chiral catalyst. We have discovered a carbene Si-H insertion in which the enantioselectivity depends primarily on the electronic characteristics of the carbene substrate, and the log(er) values are linearly related to Hammett parameters. A new class of chiral tetraphosphate dirhodium catalysts was developed; it shows excellent activity and enantioselectivity for the insertion of diarylcarbenes into the Si-H bond of silanes. Computational and mechanistic studies show how the electronic differences between the two aryls of the carbene lead to differences in energies of the diastereomeric transition states. This study provides a new strategy for asymmetric catalysis exploiting the electronic properties of the substrates.

Catalytic asymmetric reactions in which water is a substrate are rare. Enantioselective transition-metal-catalyzed insertion of carbenes into the O-H bond of water can be used to incorporate water into the stereogenic center, but the reported chiral catalysts give good results only when α-aryl-α-diazoesters are used as the carbene precursors. Herein we report the first highly enantioselective O-H bond insertion reactions between water and α-alkyl- and α-alkenyl-α-diazoesters as carbene precursors, with catalysis by a combination of achiral dirhodium complexes and chiral phosphoric acids or chiral phosphoramides. Participation of the phosphoric acids or phosphoramides in the carbene transfer reaction markedly suppressed competing side reactions, such as β-H migration, carbene dimerization, and olefin isomerization, and thus ensured good yields of the desired products. Fine-tuning of the ester moiety facilitated enantiocontrol of the proton transfer reactions of the enol intermediates and resulted in excellent enantioselectivity. This protocol represents an efficient new method for preparation of multifunctionalized chiral α-alkyl and α-alkenyl hydroxyl esters, which readily undergo various transformations and can thus be used for the synthesis of bioactive compounds. Mechanistic studies revealed that the phosphoric acids and phosphoramides promoted highly enantioselective [1,2]- and [1,3]-proton transfer reactions of the enol intermediates. Maximization of molecular orbital overlap in the transition states of the proton transfer reactions was the original driving force to involve the proton shuttle catalysts in this process.

A highly efficient asymmetric hydrogenation of γ- and δ-ketoacids was developed by using a chiral spiro iridium catalyst ( S )- 1a , affording the optically active γ- and δ-hydroxy acids/lactones in high yields with excellent enantioselectivities (up to >99% ee) and turnover numbers (TON up to 100000). This protocol provides an efficient and practical method for enantioselective synthesis of Ezetimibe.

Background: Not all adults with chronic insomnia respond to the recommended therapeutic options of cognitive behavioral therapy and approved hypnotic drugs. Transcranial alternating current stimulation (tACS) may offer a novel potential treatment modality for insomnia., Objectives: This study aimed to examine the efficacy and safety of tACS for treating adult patients with chronic insomnia., Methods: Sixty-two participants with chronic primary insomnia received 20 daily 40-min, 77.5-Hz, 15-mA sessions of active or sham tACS targeting the forehead and both mastoid areas in the laboratory on weekdays for 4 consecutive weeks, followed by a 4-week follow-up period. The primary outcome was response rate measured by the Pittsburgh Sleep Quality Index (PSQI) at week 8. Secondary outcomes were remission rate, insomnia severity, sleep onset latency (SOL), total sleep time (TST), sleep efficiency, sleep quality, daily disturbances, and adverse events at the end of the 4-week intervention and at the 4-week follow-up., Results: Of 62 randomized patients, 60 completed the trial. During the 4-week intervention, 1 subject per group withdrew due to loss of interest and time restriction, respectively. Based on PSQI, at 4-week follow-up, the active group had a higher response rate compared to the sham group (53.4% [16/30] vs. 16.7% [5/30], p = 0.009), but remission rates were not different between groups. At the end of the 4-week intervention, the active group had higher response and remission rates than the sham group (p < 0.001 and p = 0.026, respectively). During the trial, compared with the sham group, the active group showed a statistically significant decrease in PSQI total score, a shortened SOL, an increased TST, improved sleep efficiency, and improved sleep quality (p < 0.05 or p < 0.001). Post hoc analysis revealed that, in comparison with the sham group, the active group had improved symptoms, except for daily disturbances, at the end of the 4-week intervention, and significant improvements in all symptoms at the 4-week follow-up. No adverse events or serious adverse responses occurred during the study., Conclusion: The findings show that the tACS applied in the present study has potential as an effective and safe intervention for chronic insomnia within 8 weeks., (© 2019 S. Karger AG, Basel.)

A highly efficient asymmetric Michael addition of thiols to exocyclic enones was achieved by using chiral spiro phosphoramide catalysts. The precisely chiral control in the protonation of the enol intermediate ensured high enantioselectivity. The reaction features high activity (yields up to 99%, turnover numbers up to 8400) and high enantioselectivity (up to 97% ee) with a broad substrate scope, and it has the potential for wide application in the synthesis of chiral sulfides.

Aliphatic amines strongly coordinate, and therefore easily inhibit, the activity of transition-metal catalysts, posing a marked challenge to nitrogen-hydrogen (N-H) insertion reactions. Here, we report highly enantioselective carbene insertion into N-H bonds of aliphatic amines using two catalysts in tandem: an achiral copper complex and chiral amino-thiourea. Coordination by a homoscorpionate ligand protects the copper center that activates the carbene precursor. The chiral amino-thiourea catalyst then promotes enantioselective proton transfer to generate the stereocenter of the insertion product. This reaction couples a wide variety of diazo esters and amines to produce chiral α-alkyl α-amino acid derivatives., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Transition-metal-catalyzed hydrofunctionalization of 1,3-dienes is a useful and atom-economical method for constructing allylic compounds. Although substantial progress on hydroalkylation of dienes with stabilized carbon nucleophiles has been made, hydroalkylation of dienes with unstabilized carbon nucleophiles has remained a challenge. In this article, we report a protocol for nickel-catalyzed hydroalkylation of dienes with hydrazones, which serve as equivalents of alkyl carbon nucleophiles. In addition, we developed a protocol for hydroalkenylation of dienes with α,β-unsaturated hydrazones, providing a new method for the synthesis of 1,4-dienes. These hydroalkylation and hydroalkenylation reactions feature mild conditions and a wide substrate scope, and the utility of the reaction products is demonstrated by the preparation of an activator of soluble guanylate cyclase., (This journal is © The Royal Society of Chemistry 2019.)

Rearrangement reactions have attracted considerable interest over the past decades due to their high bond-forming efficiency and atom economy in the construction of complex organic architectures. In contrast to the well-established [3,3]-rearrangement, [1,3] O-to-C rearrangement has been far less vigorously investigated, and stereospecific [1,3]-rearrangement is extremely rare. Here, we report a metal-free intramolecular hydroalkoxylation/[1,3]-rearrangement, leading to the practical and atom-economical assembly of various valuable medium-sized lactams with wide substrate scope and excellent diastereoselectivity. Moreover, such an asymmetric cascade cyclization has also been realized by chiral Brønsted acid-catalyzed kinetic resolution. In addition, biological tests reveal that some of these medium-sized lactams displayed their bioactivity as antitumor agents against melanoma cells, esophageal cancer cells and breast cancer cells. A mechanistic rationale for the reaction is further supported by control experiments and theoretical calculations.

A protocol for highly enantioselective hydrogenation of racemic α-arylamino lactones with catalysis by site-specifically modified chiral spiro iridium complexes has been developed. With the optimized catalyst, racemic α-arylamino-γ-lactones and α-arylamino-δ-lactones could be hydrogenated to the corresponding chiral 2-amino diols with good to excellent enantioselectivities.

An iterative protocol was developed for highly diastereo- and enantioselective construction of high-order 1,3-polyols via iridium-catalyzed asymmetric hydrogenation of β-alkyl-β-keto esters. The protocol involves four operations-asymmetric hydrogenation, hydroxy protection, ester hydrolysis, and C-acylation-and the catalyst loading can be as low as 0.005 mol %. The configurations of all stereogenic centers of 1,3-polyols are controlled by the catalyst. By the use of this protocol, a formal total synthesis of the polyketide cyanolide A was achieved with high diastereoselectivity and enantioselectivity.

A functional group exchange reaction between allylamines and alkenes via nickel-catalyzed C-C bond cleavage and formation was developed. This reaction provides a novel protocol, which does not require the use of unstable imine substrates, for the synthesis of allylamines, which are widely used in the production of fine chemicals, pharmaceuticals, and agrochemicals.

A scalable enantioselective total synthesis of (-)-goniomitine has been developed by using an iridium-catalyzed asymmetric hydrogenation of an exocyclic enone ester to control the configuration of the molecule. The synthesis begins from commercially available starting materials, and proceeds through an integrated asymmetric ketone hydrogenation, Johnson-Claisen rearrangement, and one-pot oxidation/deprotection/cyclization process. With this highly efficient and scalable strategy, (-)-goniomitine was synthesized in eleven steps with 27 % overall yield, and formal enantioselective syntheses of (+)-1,2-dehydroaspidospermidine, (+)-aspidospermidine, and (+)-vincadifformine were also achieved., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

We developed a highly regioselective addition of 1,3-dienes with simple ketones by nickel-hydride catalyst bearing DTBM-SegPhos ligand. A wide range of aromatic and aliphatic ketones directly coupled with 1,3-dienes, providing synthetically useful γ,δ-unsaturated ketones in high yield and regioselectivity. The asymmetric version of the reaction was also realized in high enantioselectivity by using novel chiral ligand DTBM-HO-BIPHEP. The utility of this hydroalkylation was demonstrated by facile product modification and enantioselective synthesis of ( R)-flobufen.

Although transition-metal-catalyzed B-H bond insertion of carbenes into stable borane adducts has emerged as a promising method for organoborane synthesis, all the diazo compounds used to date as carbene precursors have had an electron-withdrawing group to stabilize them. Herein, we report a protocol for rhodium-catalyzed B-H bond insertion reactions of unstabilized diazo compounds generated in situ from tosylhydrazones. In addition, by using chiral dirhodium catalysts, we also achieved an asymmetric version of the reaction with good to excellent enantioselectivities (up to 98:2 e.r.). This is the first enantioselective heteroatom-hydrogen bond insertion reaction to use unstabilized diazo compounds as carbene precursors. The protocol exhibited good functional group tolerance and could be carried out on a gram scale. It also enabled one-pot transformation of a carbonyl group to a boryl group enantioselectively. The B-H bond insertion products could be easily transformed into chiral alcohols and other widely used organoboron reagents with enantiomeric fidelity.