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The regio- and enantioselective functionalization of 1,3-dienes has become a powerful tool for the synthesis of allylic compounds, yet it remains a challenge for aliphatic dienes. Herein, we report...

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.

The enantioselective addition of potent nucleophilic reagents to ketene compounds poses challenges due to the presence of significant background reactions, along with simultaneous stereoselectivity and enantioselectivity issues in the reaction process. We present a method for enantioselective amination of ketenes employing α-aryl-α-diazoketones as ketene precursors and phosphoric acids as catalysts. Upon exposure to visible light, diazoketones undergo Wolff rearrangement to gradually generate ketenes. Subsequently, the phosphoric acid not only accelerates capture of ketenes by amines, forming a singular configuration of aminoenol intermediates, but also promotes the enantioselective proton transfer of the intermediates to yield product. Mechanism studies elucidate the reaction pathways and explain how the catalysts expedite this transformation and control enantioselectivity.

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.

Chiral benzylic amines are privileged motifs in pharmacologically active molecules. Intramolecular enantioselective radical C(sp3)H functionalization by a hydrogen-atom transfer (HAT) process has emerged as a straightforward and powerful tool for the synthesis of chiral amines, while intermolecular enantioselective C(sp3)H amination remains elusive. In this article, we report a cationic copper catalytic system for intermolecular enantioselective benzylic C(sp3)H amination with peroxide as oxidant. This mild yet straightforward method transforms an array of feedstock alkylarenes and amides into chiral amines with high enantioselectivities. The protocol has good functional group tolerance and broad substrate scope. More importantly, the method can be applied to synthesizing bioactive molecules and chiral drugs. Preliminary mechanistic studies indicate that benzylic radicals resulting from the HAT process are involved in the amination reaction.

Summary Transfer functionalization has emerged as an efficient strategy for the synthesis of organic functional compounds. This article reports a new cleavage model of functional radicals, which enables transfer hydrocyanation of alkenes, dienes, and alkynes. By introducing readily available, low-toxic azobisisobutyronitrile (AIBN) as a hydrocyanation reagent, we have developed a practical and economic method for the preparation of nitrile compounds. Mechanistic studies showed that the hydrocyanation proceeds through a relay transfer of the cyano group and the hydrogen atom of cyanoisopropyl radicals generated by pyrolysis of AIBN. The reaction represents the first example of group transfer of α-functional radicals.

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., An iridium catalyzed asymmetric hydrogenation of exocyclic γ,δ-unsaturated β-ketoesters via dynamic kinetic resolution was developed, providing efficient protocol for enantioselective synthesis of functionalized chiral allylic alcohols.

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.

Background Evidence suggests that glucocorticoids are important in the treatment of sudden hearing loss (SHL) and Meniere’s disease (MD). However, different glucocorticoid administration methods may have a significant impact on treatment outcomes. Objective This study aimed to investigate effects of different glucocorticoid administration methods on sudden hearing loss and Meniere’s disease. Methods In this study, glucocorticoids were administered orally in 18 patients, by retroauricular injection in 15 patients and by intratympanic injection in 15 patients. White blood cell (WBC) count, serum K+, fasting plasma glucose (FPG), body temperature, heart rate and blood pressure were used to evaluate effects of glucocorticoids on patients with hearing loss. Visual analog scale (VAS) of pain and sleep disorders were also surveyed, and pure tone audiometry (PTA) results were compared among groups to evaluate efficacy of different glucocorticoids administration methods. Result WBC count, heart rate and blood pressure were higher in patients taking oral glucocorticoids, while body temperature, serum K+ and FPG levels did not change in all three groups. However, patients who received intratympanic injection of glucocorticoids experienced more pain, while those taking oral glucocorticoids reported more sleep impairment. Treatment efficacy on hearing loss was not significantly different among the three groups. Conclusion These findings suggest that systemic glucocorticoid administration can result in greater whole body responses than local administration, but with similar hearing treatment efficacy.

An enantioselective total synthesis of the alleged structure of (+)-fimbricalyxoid A is reported. The synthetic strategy features a pyridine

A three-step process for the enantioselective assembly of

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(sp2)-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.

Although the transition metal-catalyzed asymmetric hydrogenation of aromatic ketones has been extensively explored, the enantioselective hydrogenation of aliphatic ketones remains a challenge becau...

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.

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.

An efficient asymmetric hydrogenation of racemic α-aryl-s-ethoxycarbonyl cyclopentanones via dynamic kinetic resolution is reported. Via catalysis by a chiral iridium Ir-SpiroPAP catalyst, a range of racemic α-aryl-s-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 I³-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 Bronsted 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 tag team approach to forming C–N bonds Many pharmaceutical compounds contain carbon-nitrogen (C–N) bonds in just one of two mirror-image orientations. Forging these bonds with electron-rich nitrogen reactants is challenging because the nitrogen groups can coordinate with, and thus interfere with, the catalyst. Li et al. report a cooperative approach to overcoming this obstacle (see the Perspective by Ovian and Jacobsen). They used a copper catalyst to activate the carbon reactant and then a hydrogen-bonding thiourea catalyst to set the product geometry with high selectivity. The reaction is compatible with a broad range of diazo ester and amine coupling partners. Science , this issue p. 990 ; see also p. 948

This study was designed to determine whether plasma CXCL12 levels in postmenopausal osteoporosis (PMOP) patients are related to disease severity. A total of 91 PMOP females were recruited, and 88 postmenopausal non-osteoporotic (PMNOP) women and 90 healthy females were incorporated as controls. Dual-energy X-ray absorptiometry was utilised to explore bone-mineral density (BMD). The Genant semi-quantitative grading scale was used for vertebral fractures, and plasma CXCL12/SDF-1 levels were investigated by ELISA. Plasma TNF-α and C-telopeptide cross-linked collagen type 1 (CTX-1) were also tested. The Oswestry Disability Index (ODI) and a visual analogue scale (VAS) were completed in order to assess clinical severity. Plasma CXCL12 levels were considerably elevated in PMOP females compared to PMNOP women and healthy controls. Plasma CXCL12 concentrations were positively correlated with the Genant grading system. We observed significant and negative correlations of plasma CXCL12 levels with lumbar spine, femoral neck and total hip BMD. Moreover, plasma CXCL12 concentrations were positively correlated to VAS and ODI, as well as plasma TNF-α and CTX-1 levels. In conclusion, elevated plasma CXCL12 levels are correlated with disease severity in PMOP females.

We report an enantioselective hydroarylation reaction of styrenes and 1,3-dienes with arylboronic acids catalyzed by nickel complexes bearing chiral spiro aminophosphine ligands. The reaction serve...

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., Stereospecific [1,3]-rearrangements are rarely reported method to efficiently build complex organic architectures. Here, the authors describe a metal-free intramolecular hydroalkoxylation/[1,3]-rearrangement sequence affording medium-sized lactams with wide scope, also in an asymmetric fashion.

Asymmetric Friedel–Crafts conjugate addition reactions that generate an α-chiral center are challenging because the configuration-determining step is a proton-transfer reaction of a highly active e...