Stereodivergent synthesis ofα-fluoroα-azaarylγ-butyrolactones via cooperative copper and iridium catalysis

The development of stereodivergent synthetic methods to access all four stereoisomers of biologically importantα-fluoroγ-butyrolactones containing vicinal stereocenters is of great importance and poses a formidable challenge owing to ring strain and steric hindrance.Herein,a novel asymmetric[3+2]annulation ofα-fluoroα-azaaryl acetates with vinylethylene carbonate was successfully developed through Cu/Ir-catalyzed cascade allylic alkylation/lactonization,affording a variety of enantioenrichedα-fluoroγ-butyrolactones bearing vicinal stereogenic centers with high reaction efficiency and excellent levels of both stereoselectivity and regioselectivity(up to 98%yield,generally>20:1 dr and>99%ee).Notably,all four stereoisomers of these pharmaceutically valuable molecules could be accessed individually via simple permutations of two enantiomeric catalysts.In addition,other azaaryl acetates bearingα-methyl,α-chlorine orα-phenyl group were tolerated well in this transformation.Reaction mechanistic investigations were conducted to explore the process of this bimetallic catalysis based on the results of reaction intermediates,isotopic labelling experiments,and kinetic studies.

Copper-catalyzed asymmetric 1,3-dipolar cycloaddition of azomethine ylides withβ-trifluoromethyl-substituted alkenyl heteroarenes

Copper-catalyzed asymmetric 1,3-dipolar cycloaddition of azomethine ylides andβ-trifluoromethyl-substituted alkenyl heteroarenes was developed for the first time.A wide range of enantioenriched pyrrolidines containing both heteroarenes and trifluoromethyl group with multiple stereogenic centers could be readily accessible by this method with good to high yields and excellent levels of both stereo-and regioselectivity(up to 99%yield,>20:1 rr,>20:1 dr,and up to 95%ee).Notably,substratecontrolled umpolung-type dipolar cycloaddition was also disclosed in this protocol to achieve regiodivergent synthesis withα-aryl substituted aldimine esters as the dipole precursors.Systematic DFT studies were conducted to explore the origin of the stereo-and regioselectivity of this 1,3-dipolar cycloaddition,and suggest that copper(Ⅱ)salt utilized in this catalytic system could be reduced in-situ to the active copper(Ⅰ)species and might be responsible for the observed high stereo-and regioselectivity.

Ir-Catalyzed Asymmetric Hydrogenation of Unprotected Indoles:Scope Investigations and Mechanistic Studies

Transition metal-catalyzed asymmetric hydrogenation(AH)of unprotected indoles has mainly been applied to alkyl substituted unprotected indoles.However,the challenging aryl substituted unprotected indoles with poor reactivity and enantioselectivity(≤42%ee)could not be hydrogenated well.In this work,a highly efficient Ir/bisphosphine-thiourea ligand ZhaoPhos catalytic system for the AH of challenging aryl substituted unprotected indoles has been successfully developed for the first time with high reactivity and excellent stereoselective control.Moreover,a series of 2-alkyl-substituted and 2,3-disubstituted unprotected indoles were also well tolerated in this catalytic system.A wide variety of chiral indoline derivatives were obtained in good to high yields with excellent stereoselectivities(75–99%yields,>20:1 dr,and 86–99%ee).The anion-binding activation strategy played an important role in accessing both high reactivity and excellent stereoselectivity,which was formed between the catalyst and unprotected indoles in situ-generating iminium ion with the assistance of Brønsted acid.A possible catalytic mechanism was proposed for this Ir-catalyzed AH according to density functional theory calculations and control experiment results.Readily available substrates,a broad range of substrate tolerance,an efficient chiral catalytic system,and a gram-scale protocol further demonstrated the potential practicality of this methodology.

Secukinumab demonstrates high efficacy and a favorable safety profile over 52 weeks in Chinese patients with moderate to severe plaque psoriasis

Background:Psoriasis is a chronic inflammatory skin disease,affecting about 0.6%of the Chinese population.Many patients are not well controlled by conventional treatments,thus there is need for new treatment regimens.In this study,we assessed the efficacy and safety of secukinumab in Chinese patients with moderate to severe plaque psoriasis.Methods:This study was a 52-week,multicentre,randomized,double-blind,placebo-controlled,parallel-group,Phase 3 trial.A sub-population of study participants(≥18 years)of Chinese ethnicity were randomized to receive subcutaneous injections of 300 or 150 mg secukinumab,or placebo.The co-primary endpoints were psoriasis area severity index(PASI)75 and Investigator’s Global Assessment(IGA)0/1 at Week 12.Results:A total of 441 Chinese patients were enrolled in this study.Co-primary outcomes were achieved;300 and 150 mg secukinumab were superior to placebo as shown in the proportion of patients that achieved PASI 75(97.7%and 87.2%vs.3.7%,respectively;P<0.001),and IGA 0/1(82.3%and 69.7%vs.2.7%;P<0.001)at Week 12.Treatment efficacy was maintained until Week 52.There was no increase in overall adverse events with secukinumab relative to placebo throughout the 52-week period.Conclusion:Secukinumab is highly effective and well tolerated in Chinese patients with moderate to severe plaque psoriasis.

具有完美水平取向的红光型热活化延迟荧光材料

如何实现发光材料跃迁偶极矩取向的调控一直是有机发光二极管(OLEDs)领域的巨大挑战之一.本文中,我们基于双位点长轴延伸策略,设计合成了一种线型的热活化延迟荧光(TADF)分子,PhNAI-PMSBA,实现了对跃迁偶极矩取向的选择性调控.由于PhNAI-PMSBA具有显著的水平分子取向,且其分子长轴与跃迁偶极矩取向高度统一,PhNAI-PMSBA在掺杂发光薄膜中获得的跃迁偶极矩水平取向度高达95%,远高于各向同性发光分子67%的跃迁偶极矩水平取向度.因此,基于PhNAI-PMSBA的红光OLED的光耦合输出效率可达43.2%,最大外量子效率达到22.3%,其CIE1931色坐标位于(0.60,0.40).

Stereodivergent Synthesis of Carbocyclic Quaternary α-Amino Acid Derivatives Containing Two Contiguous Stereocenters

A novel approach to stereodivergent synthesis of carbocyclicα-quaternary amino acid derivatives,bearing two contiguous stereocenters,is proposed through sequential dual Cu/Ir-catalyzed asymmetric allylation and ring-closing metathesis.A variety of five and six-membered carbocyclicα-quaternary amino acid derivatives could be readily achieved in good to high yields with exclusive regioselectivities,excellent diastereoselectivities(13:1->20:1 dr)and enantioselectivities(generally>99%ee).Of particular note is that the current protocol is also a versatile synthetic tool for the stereodivergent construction of the challenging seven and eight-membered carbocyclicα-amino acid derivatives.All four stereoisomers of these important molecules could be precisely synthesized through the permutation of chiral Cu/Ir catalytic system.The power of this strategy has been demonstrated for the facile access to some biologically active chiral molecules,such as spiro-hydantoins.

Cu-catalyzed endo-selective asymmetric 1,3-dipolar cycloaddition of azomethine ylides with ethenesulfonyl fluorides: Efficient access to chiral pyrrolidine-3-sulfonyl fluorides

Cu-catalyzed endo-selective asymmetric 1,3-dipolar cycloaddition of azomethine ylides with ethenesulfonyl fluorides(ESFs) was successfully developed, this protocol provided an efficient and facile method to a wide range of chiral pyrrolidine-3-sulfonyl fluorides with good to excellent results(up to 87% yield,>20:1 dr, 94% ee). Some other chiral sulfonyl derivatives, such as sulfonamide and sulfonate, were easily accessible through simple transformations with high yields, which demonstrated that the cycloaddition products could be synthetically useful in the sulfur(VI) fluoride exchange(Su FEx) chemistry.

Design, Synthesis and Application of Multifunctional Chiral Aminophosphine Catalyst for Asymmetric Intermolecular Cross Rauhut-Currier Reaction

A series of structurally novel multifunctional chiral aminophosphine catalysts were developed through a concise synthetic strategy from easily available starting materials.The highly enantioselective intermolecular cross Rauhut-Currier reactions of vinyl ketones with 3-acyl acrylates and 2-ene-1,4-diones catalyzed by(S,S)-5a were well realized,generating a wide range of the structurally important chiral multicarbonyl products in good to excellent yields with high stereocontrol(up to 97%yield,99%ee).In addition,a series of 31P NMR experiments were carried out to further investigate the catalytic process.

Facile access to chiral 1-pyrrolines through Rh-catalyzed enantioselective partial hydrogenation of unprotected simple pyrroles

Highly enantioselective Rh-catalyzed partial hydrogenation of unprotected simple 2-alkyl-5-aryl-disubstituted pyrroles has been successfully developed,generating a series of chiral 1-pyrroline derivatives generally with excellent results(95%-99%yields,91%-96%ee).Moreover,2,5-aryl-1H-pyrroles were hydrogenated well in high yields and good enantioselectivities.This efficient protocol features easily accessible substrates,wide substrate scope,well functional group compatibility,commercially available rhodium precursor and chiral ligand.It provides a versatile route to access chiral 1-pyrroline derivatives that are of great importance in organic synthesis and pharmaceutical chemistry.

A Computational Study of Asymmetric Hydrogenation of 2-Phenyl Acrylic Acids Catalyzed by a Rh(l) Catalyst with Ferrocenyl Chiral Bisphosphorus Ligand: The Role of Ion-Pair Interaction

Asymmetric hydrogenation reaction is one of the most efficient synthetic methods to form useful chiral compounds for synthetic chemistry,medicinal chemistry and material chemistry.Generally,the enantioselectivity of many hydrogenation reactions is controlled by steric hindrance between the chiral ligand and substrate.Recently,Zhang group developed a highly asymmetric hydrogenation of 2-aryl and 2-alkyl acrylic acids catalyzed by a Rh(l)catalyst with a chiral Wudaphos ligand.The excellent enantioselectivity of this asymmetric reaction was proposed to be controlled by ion-pair interaction between the substrate and chiral ligand.In this study,a systematic density functional theory study has been carried out to investigate the reaction mechanism and origin of the enantioselectivity.Our computational results suggest that this reaction follows the classic mechanism involving oxidative addition of H_(2),migratory insertion and reductive elimination.Different from the C=C coordination to the metal in the common oxidative addition step,our study found that the chelation of the carboxyl group of the substrate to the cationic Rh(l)metal is more favorable in this oxidative addition step.The high enantioselectivity is proposed to be dictated by a better catalyst/substrate geometric complementarity in the major pathway to have less distortion of the catalyst for a strong ion-pair interaction.

Facile access to chiral 4-substituted chromanes through Rh-catalyzed asymmetric hydrogenation

Rh/ZhaoPhos-catalyzed asymmetric hydroge nation of a series of(E)-2-(chro man-4-ylidene)acetates was successfully developed to prepare various chiral 4-substituted chromanes with high yields and excellent enantioselectivities(up to 99%yield,98%ee).Moreover,the gram-scale hydrogenation could be performed well in the presence of 0.02 mol%catalyst loading(TON=5000),the hydrogenation product was easily converted to access other important compounds,which demonstrated the synthetic utility of this asymmetric catalytic methodology.

Sequential Ir-Catalyzed Allylation/2-aza-Cope Rearrangement Strategy for the Construction of Chiral Homoallylic Amines

Sequential Ir-catalyzed asymmetric allylation/2-aza-Cope rearrangement of arylidene aminomalonates with allylic carbonates was successfully developed,and a variety of enantioenriched homoallylic amine derivatives were obtained in high yields with good chirality transfer and excellent E/Z-geometry control(up to 99%yield,96%ee).Compared with previous dual catalytic system established for this transformation,the current mono metal catalytic system provides a simpler and more practical protocol employing the readily available starting materials.