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COAP-Pd-catalyzed asymmetric cascade formal [4 + 1] annulation was developed between racemic vinyl benzoxazinones and N-tosylhydrazone sodium salts, affording trans-2,3-disubstituted indolines in good yields with high stereoselectivity.

The chiral oxamide–phosphine (COAP) ligands were developed for the palladium-catalyzed asymmetric allylic amination of vinyl benzoxazinones with alkylamines, affording a series of optically active diamines in good yields with high enantioselectivity.

An asymmetric linear selective allylic alkylation of vinylaziridines with 3-aryl oxindoles has been developed by using a chiral oxamide-phosphine (COAP-Bn-OMe

An asymmetric [3 + 2] cycloaddition of vinyl ethylenecarbonates (VECs) and (E)-3-arylvinyl substituted benzo[d] isothiazole 1,1-dioxides has been developed using the Pd complex of a bidentate phosphoramidite (Me-BIPAM) as the catalyst, providing a wide variety of chiral multistereogenic vinyltetrahydrofurans in good yields with excellent diastereo- and enantioselectivities (up to >20:1 dr, 99% ee).

Enantioselective copper-catalyzed cascade inter- and intramolecular amidation was achieved between ethynyl benzoxazinanones and α-halohydroxamates in the presence of an indapybox ligand. The one-pot cascade transformation was triggered by the attack of hydroxamates to dipolar copper–allenylidene intermediates, followed by a nucleophilic annulation reaction. Thus, a series of exo-methylene 3-aminoindoline derivatives were obtained in good yields with high enantioselectivities under mild reaction conditions.

The combination of chiral binaphthyl box-copper(II) with triflimide (Tf2NH) was identified as an efficient catalytic system for the asymmetric Michael/ketalization of (E)-2-hydroxyaryl-2-oxobut-3-e...

Enantioselective copper-catalyzed cascade inter- and intramolecular amidation was achieved between ethynyl benzoxazinanones and α-halohydroxamates in the presence of an indapybox ligand. The one-pot cascade transformation was triggered by the attack of hydroxamates to dipolar copper-allenylidene intermediates, followed by a nucleophilic annulation reaction. Thus, a series of

The chiral bis-oxalamides (CBOA), readily derived from optically pure 1,2-diphenylethylenediamine (DPEN), were proven to be a class of efficient C2-symmetric chiral ligands for copper(II)-catalyzed...

A bifunctional organocatalyst catalyzed tandem annulation reaction between β,γ-unsaturated α-ketoesters with α-arylidene pyrazolinones was reported. The tandem Michael–aldol process allows access to optically active bi-spirocyclic pyrazolone and oxindole compounds in high yields with good to excellent enantioselectivity and diastereoselectivity. The resulting bi-spirocyclic compounds possess highly dense functionalized substituents, two all-carbon spiro quaternary stereocenters and one hemiketal stereogenic centers.

A chiral N-heterocyclic-carbene-catalyzed cascade asymmetric desymmetrization reaction of cyclopentenediones with enals has been successfully initiated, followed with tandem aldol annulation, aromatization, as well as sequential methylation. The reactions proceeded well under mild reaction conditions, with broad substrate scope and good functional group tolerance, providing a rapid access to highly functionalized chiral 2,2-disubstituted 1,3-indandione derivatives containing an all-carbon quaternary stereogenic center in moderate to good yields with high enantioselectivities.

The synthesis and characterization of the chiral bifunctional NHC ligands based on the imidazo[1,5-a]pyridine (ImPy) scaffold are described. These ligands possess a fluxional biaryl axis and a chiral center. The configurational stability of the biaryl axis in their gold(I) complexes is investigated. The application of these axially chiral ImPy-based AuCl complexes in a series of gold catalysis is explored, and varying degrees of asymmetric induction are observed. In most cases, the ligand (aS,R)-L8-H with its cyclohexyl group pointing to the reaction site and hence exerting asymmetric steric influence is more effective in asymmetric induction.

In this paper, a pybox-copper catalyzed enantioselective decarboxylative [4+2] cycloaddition reaction of ethynyl benzoxazinanones with azlactones has been developed, which provides optically active 3,4-dihydroquinolin-2-ones in high yields with good enantioselectivities and diastereoselectivities. In this transformation, the chiral dipolar copper–allenylidene intermediates are kinetically generated via decarboxylative ethynyl benzoxazinanones, followed by the attack of the enolate azlactones to form enantiomerically enriched 3,4-dihydroquinolin-2-one structures.

Background Despite the growing number of studies on the coronavirus disease-19 (COVID-19), little is known about the association of menopausal status with COVID-19 outcomes. Materials and methods In this retrospective study, we included 336 COVID-19 inpatients between February 15, 2020 and April 30, 2020 at the Taikang Tongji Hospital (Wuhan), China. Electronic medical records including patient demographics, laboratory results, and chest computed tomography (CT) images were reviewed. Results In total, 300 patients with complete clinical outcomes were included for analysis. The mean age was 65.3 years, and most patients were women (n = 167, 55.7%). Over 50% of patients presented with comorbidities, with hypertension (63.5%) being the most common comorbidity. After propensity score matching, results showed that men had significantly higher odds than premenopausal women for developing severe disease type (23.7% vs. 0%, OR 17.12, 95% CI 1.00–293.60; p = 0.003) and bilateral lung infiltration (86.1% vs. 64.7%, OR 3.39, 95% CI 1.08–10.64; p = 0.04), but not for mortality (2.0% vs. 0%, OR 0.88, 95% CI 0.04–19.12, p = 1.00). However, non-significant difference was observed among men and postmenopausal women in the percentage of severe disease type (32.7% vs. 41.7%, OR 0.68, 95% CI 0.37–1.24, p = 0.21), bilateral lung infiltration (86.1% vs. 91.7%, OR 0.56, 95% CI 0.22–1.47, p = 0.24), and mortality (2.0% vs. 6.0%, OR 0.32, 95% CI 0.06–1.69, p = 0.25). Conclusions Men had higher disease severity than premenopausal women, while the differences disappeared between postmenopausal women and men. These findings support aggressive treatment for the poor prognosis of postmenopausal women in clinical practice.

Background: Despite the growing number of studies on the Coronavirus Disease-19 (COVID-19), little is known about the association of menopausal status with COVID-19 outcomes.Materials and methods: In this retrospective study, we included 336 COVID-19 in-patients between February 15, 2020 and April 30, 2020 at the Taikang Tongji Hospital (Wuhan), China. Electronic medical records, including patient demographics, laboratory results, and chest computed tomography (CT) images were reviewed. Results: In total, 300 patients with complete clinical outcomes were included for analysis. The mean age was 65.3 years and most patients were women (n=167, 55.7%). Over 50% of patients presented with comorbidities, with hypertension (63.5%) being the most common comorbidity. After propensity-score matching, results showed that men had significantly higher odds than premenopausal women for developing severe disease type (23.7% vs. 0%, OR 17.12, 95% CI 1.00–293.60; p=0.003) and bilateral lung infiltration (86.1% vs. 64.7%, OR 3.39, 95% CI 1.08–10.64; p= 0.04), but not for mortality (2.0% vs. 0%, OR 0.88, 95% CI 0.04–19.12, p=1.00). However, non-significant difference was observed among men and post-menopause women in the percentage of severe disease type (32.7% vs. 41.7%, OR 0.68, 95% CI 0.37–1.24, p=0.21) and bilateral lung infiltration (86.1% vs. 91.7%, OR 0.56, 95% CI 0.22–1.47, p=0.24), mortality (2.0% vs. 6.0%, OR 0.32, 95% CI 0.06–1.69, p=0.25).Conclusions: Men had higher disease severity than premenopausal women, while the differences disappeared between postmenopausal women and men. These findings support aggressive treatment for the poor-prognosis of postmenopausal women in clinical practice.

We have reported the 1,4-diazabicyclo[2.2.2]octane (DABCO)-catalyzed [3 + 3] cycloaddition reaction of α-arylidene pyrazolinones and 2-benzylidenemalononitriles under mild reaction conditions, which afforded the spirocyclohexadiene-pyrazolones in good yields with moderate to good diastereoselectivities. By the use of a cinchona alkaloid derived bifunctional squaramide-tertiary amine catalyst, an asymmetric variant of this [3 + 3] cycloaddition reaction has also been developed to provide optically active spirocyclohexadiene-pyrazolones bearing an all-carbon quaternary chiral center in good yields with excellent enantioselectivities and moderate diastereoselectivities.

A combination of metal- and organo-catalysts sequentially catalyzing the Friedel-Crafts/aldol tandem reaction between 3-pyrrolyl-oxindoles and isatin-derived β,γ-unsaturated α-ketoesters has been reported, which leads to two types of diastereomeric enantio-enriched bispirooxindoles with three quaternary stereocentres and synthetically valuable functional groups in high yields with excellent enantioselectivity and diastereoselectivity.

A cascade asymmetric Michael–intramolecular aldol-lactonization of enals with oxindolyl β,γ-unsaturated α-keto esters was developed. An optically pure aminoindanol-derived triazolium-based N-heterocyclic carbene was used as the catalyst. The corresponding desired β-propiolactone-fused spiro[cyclopentane-oxindoles] were obtained in moderate yields with excellent diastereoselectivities and enantioselectivities. Notably, the obtained enantio-enriched highly functionalized complex molecules contain four contiguous stereocenters, including a spiro all-carbon center and a quaternary carbon center.

Several chiral BINOL-derived bisoxazoline (BOX)/copper(II) complexes were synthesized and evaluated as catalysts for the Friedel–Crafts reaction of indoles with isatin-derived β,γ-unsaturated α-keto esters. The resulting bis-indole products bearing a quaternary stereocenter were obtained in excellent yields and enantioselectivities. Additionally, the desired products were practically transformed to α-amino esters, α-hydroxy esters and α-keto amides. It is noteworthy that this catalytic procedure was conducted with a catalyst loading of 0.5 mol% without any discernible decrease in the reactivity or enantioselectivity.

One peculiar type of aza-hetero-imidazolidinyl spirooxindole derivatives was efficiently constructed by the three-component [2+2+1] cascade reaction of 1,4-oxazepines with diazo-oxindoles. Iron(II) trifluoromethanesulfonate [Fe(OTf)2] or p-toluenesulfonic acid monohydrate (p-TsOH⋅H2O) proved to be optimal catalysts for this transformation, providing the desired products in high yields (up to 94 %) with excellent diastereoselectivity (up to 99:1 dr). Experimental studies showed that the reaction rate of Bronsted acid catalysis was faster than that of Lewis acids. Furthermore, the mechanism was theoretically investigated for Bronsted acid as the catalyst and a reaction pathway was proposed. DFT calculations suggested that the diazo-oxindole can act as a 1,3-dipole to add to a C=N double bond of 1,4-oxazepine, which forms a 4,5-dihydro-1H-1,2,3-triazole intermediate. Subsequently, the releasing of N2 is the rate-limiting step of the whole catalytic cycle.

The asymmetric amination of anilines to 3-bromooxindoles was developed in the presence of a bis(oxazoline)-Ni(dppp)Cl2 complex, to provide enantiomerically enriched 3-amino-2-oxindoles with quaternary stereocenters in up to 90% yield with 92:8 er. Simultaneously, direct stereoselective amination of α-amino-acid methyl esters to 3-bromooxindoles was also accomplished without any catalysts, which furnished the 3-amino-2-oxindole derivatives in high yields with moderate diastereoselectivities.

A series of enantiomerically enriched 3,4-dihydrocoumarins containing contiguous quaternary and tertiary stereogenic centers has been efficiently constructed via domino asymmetric Michael addition/transesterification reactions of azlactones with o-hydroxychalcones using a quinine-derived thiourea as bifunctional organocatalyst. Under mild reaction conditions, the optically active 3,4-dihydrocoumarins were generally obtained in 63–96% yields with >20:1 dr and 81–96% ee.

Based on oxindole-derived diketones as the substrates, asymmetric desymmetrizing intramolecular aldol or aldol condensation reactions are reported, which are catalyzed by a Trost bis-ProPhenol dinuclear zinc complex. The corresponding spiro[cyclohexanone-oxindole] derivatives were obtained in good yields with moderate to good enantioselectivities.

The enantioselective formal [3 + 3] annulation reaction of isatin-derived β,γ-unsaturated α-ketoesters with 3-hydroxy-4H-chromen-4-ones or 2-hydroxy-1,4-naphthoquinone was successfully implemented under catalysis of quinine-derived bifunctional tertiary amine-thiourea catalysts. The efficient tandem Michael-cyclization has provided facile access to optically active spiro[oxindole-pyrano[3,2-b]chromenone] and spiro[oxindole-benzo[g]chromene-dione] derivatives in high yields with excellent diastereo- and enantioselectivities.

An enantioselective formal thio[3 + 3] spiroannulation reaction of indoline-2-thiones to 1-azadienes has been developed by the use of a quinine-derived bifunctional tertiary amine-thiourea catalyst, which furnished a series of optically active spiro[thiopyranoindole-benzoisothiazole] heterocycles with a spiro quaternary C-N/C-S stereogenic centers in high yields with good to excellent diastereo- and enantioselectivities.

The regioselective and enantioselective Michael addition between azlactones and o-hydroxy chalcone derivatives is reported. Enantiomerically enriched N,O-aminals with two continuous stereogenic centers are exclusively obtained in moderate to good yields with excellent diastereoselectivities and good to excellent enantioselectivities. The experimental results show that an o-hydroxy group on the cinnamenyl motif of chalcone derivatives plays a crucial role at the reaction sites for the regioselective Michael addition. In addition, circular dichroism (CD) spectroscopy and density functional theory (DFT) are used to investigate the absolute configuration of N,O-aminals and the corresponding transition-state structures.

Computational studies have been performed to elucidate the activation mechanism of the Michael addition reactions containing bifunctional tertiary amine–thioureas and isatylidene malononitriles by density functional theory (DFT) calculations at the B3LYP/6-311++G(d,p)//B3LYP/6-31G(d) level of theory. Results showed a difference of 6.47 kcal mol−1 between M1-O and M1-N, which suggest that it is the carbonyl group, instead of the malononitrile moiety of isatylidene malononitriles, that plays a dominating role in the activation of the electrophile by the catalysts. The predicted mechanism also successfully explains the experimentally observed enantioselectivity.

A Michael–hemiketalization–oxa-Pictet–Spengler cyclization has been developed for the construction of chiral bridged and spiro heterocyclic skeletons with one spiro stereogenic carbon center and two bridgehead carbon centers, utilizing cooperative catalysts of a Takemoto thiourea catalyst and a triflimide. In particular, an oxocarbenium ion acts as a key intermediate for this cyclization reaction. Additionally, biological evaluation of this type of novel structure has revealed obvious antiproliferative activity against some cancer cell lines.

A formal thio [3 + 3]-cyclization catalyzed by a DPEN-derived chiral thiourea has been reported for the construction of optically active thiopyrano-indole annulated heterocyclic compounds in high yields with excellent enantioselectivities. The high reactivity between indoline-2-thione (keto-S) and 2-benzylidenemalononitrile has also been supported by density functional theory (DFT) calculations.

The tandem oxo-Michael-IED/HDA and oxo-Michael-IED/HDA-Michael-Aldol condensation transformations between (E)-2-hydroxyaryl-2-oxobut-3-enoate derivatives with enals have been developed in the presence of (S)-diphenylprolinol trimethylsilyl ether as an organocatalyst. Two types of tricyclic chroman derivatives were, respectively, obtained, by adjusting the reactant ratio and reaction temperature, in good yields (up to 96%) with excellent enantioselectivities (up to >99%) and good diastereoselectivities (up to >30/1). It should be noted that the divergent chiral chroman derivatives were obtained by successive reaction of (E)-2-hydroxyaryl-2-oxobut-3-enoate derivatives with two different enal substrates in highly catalytic results.

Enantioselective phosphination and hydrophosphonylation reactions between azomethine imines and diarylphosphine oxides or dialkyl phosphites were respectively developed by the use of a chiral squaramide as the hydrogen bonding organocatalyst, which afforded two types of phosphorus containing product in high yields with good to excellent enantioselectivities.

Chiral molecules containing sulfonyl and 1,5-diol moieties are useful synthetic blocks for various asymmetric transformations. A protocol has been developed for the enantioselective synthesis of optically active bis(β-hydroxy) sulfones catalyzed by a chiral cationic ruthenium diamine catalyst. A series of bis(β-hydroxy) sulfones have been obtained in excellent yields (up to 99%) with excellent enantioselectivities (up to 99%) as well as good diastereoselectivities (up to 99:1).

Pyranonaphthoquinone units are common in molecular structures with significant biological and pharmaceutical activities. Herein, the organocatalytic asymmetric cascade Michael cyclization reaction of 2-hydroxynaphthalene-1,4-diones to isatylidene malononitriles has been developed, which provided the desired spiro[4H-benzo[g]chromene-indoline] derivatives in up to 99% yield with up to 99% ee. To illustrate the potential utility of these products, a further transformation was conducted to give a spiropoly­heterocyclic compound in moderate yield without loss of enantioselectivity (>99% ee). Biological evaluation of these spiro[benzo[g]chromene-indoline] derivatives has revealed excellent antiproliferative activity against a number of cancer cell lines, with a high inhibition rate ranging from 93% to 99% at a concentration of 50 μM.

The enantioselective Michael addition of dialkyl phosphites to N-unprotected isatylidene malononitriles has been established for the first time by using a simple bifunctional tertiary amine–thiourea catalyst. The corresponding adducts, 3-phospho-2-oxindoles, containing a chiral quaternary carbon center at the 3-position of the oxindole, were obtained in good to excellent yields (up to 98%) with moderate to excellent enantioselectivities (up to 95% ee). In addition, optically active 3,3′-disubstituted oxindoles bearing carboxylate and phosphonate groups were facilely obtained by the oxidative degradation of the Michael adducts.

Given the importance of indane derivatives in both organic and medicinal chemistry, the development of an effective synthetic protocol for the preparation of multifunctionalized 1,2,3-trisubstituted indane derivatives is of considerable interest. In this paper, we developed a cascade regio- and enantioselective double Michael addition to construct challenging multifunctionalized chiral indane derivatives in the presence of a bifunctional acid–base organocatalyst. The resulting optically active indane derivatives with three alternating trans stereocenters were produced in moderate to good yields with excellent diastereoselectivities and excellent enantioselectivities. Remarkably, the resulting products were facilely converted into multifunctionalized optically active (1-indanylmethyl)amine and tetrahydroindeno[2,1-b]pyrrole derivatives.

The synthesis of organophosphorus compounds is of great importance to industrial, agricultural, and pharmaceutical chemistry. In this paper, we have reported the synthesis of highly substituted pyrazole derivatives through P–C bond formation under catalyst-free conditions. On the other hand, the first catalytic asymmetric version of this reaction has also been developed under catalysis by an isosteviol derived thiourea organocatalyst. The optically active phosphorus-containing compounds have been obtained in good chemical yields with moderate enantioselectivities.

The highly efficient asymmetric reduction of title compounds (I), (III), and (V) using a phosphine-free chiral Ru-complex furnishing corresponding β-hydroxy sulfonamides and -sulfones (II), (IV), and (VI), resp., is described.

Pyrazoles are an important class of molecular structures with significant biological and pharmaceutical activities. Herein, heterocyclic compounds containing both a pyrazole motif and a masked amino acid structure are synthesized through the asymmetric Michael/aromatization of azlactones to α,β-unsaturated pyrazolones by using isosteviol-derived amine thiourea as the organocatalyst. The products are obtained in good yields (up to 93 %) with good diastereoselectivities and good enantioselectivities (up to >10:1 dr, 97 % ee).

The origin of the enantio- and regioselectivity of ring-opening reaction of oxabicyclic alkenes catalyzed by rhodium/Josiphos has been examined using M06-2X density functional theory(DFT). DFT calculations predict a 98% ee for the enantioselectivity and only the 1,2-trans product as one regio- and diastereomer, in excellent agreement with experimental results. The solvent tetrahydrofuran(THF) plays a key role in assisting nucleophilic attack. Orbital composition analysis of the LUMO and the NPA atomic charge calculations were conducted to probe the origins of the regioselectivity. The orbital composition analysis reveals two potential electrophilic sites of the Rh–π-allyl intermediate M3 and the NPA atomic charges demonstrate that Cα carries more positive charges than Cγ, which suggests that Cα is the electrophilic site.

The spirocyclic pyrazolones are an important class of molecular structures with significant biological and pharmaceutical activities. Herein, we demonstrate that the combination of a Cinchona-based chiral primary amine and an ortho-fluorobenzoic acid is an efficient catalyst system for the double Michael addition of arylidenepyrazolones with α,β-unsaturated ketones, providing chiral unsymmetrical 6,10-diaryl-substituted spiro[cyclohexanone-pyrazolone] derivatives in high yields (up to 98%) with good diastereoselectivities and excellent enantioselectivities (up to 88:12 dr, 99% ee).