The chemistry of quinone methides formed in situ has been flourishing in recent years. In sharp contrast, the development and utilization of biphenyl quinone methides are rare. In this study, we achieved a remote stereocontrolled 1,12-conjugate addition of biphenyl quinone methides formed in situ for the first time. In the presence of a suitable chiral phosphoric acid, alkynyl biphenyl quinone methides were generated from α-[4-(4-hydroxyphenyl)phenyl]propargyl alcohols, followed by enantioselective 1,12-conjugate addition with indole-2-carboxylates. The strategy enabled the alcohols to serve as efficient allenylation reagents, providing practical access to a broad range of axially chiral allenes bearing a (1,1'-biphenyl)-4-ol unit, which were previously less accessible. Combined with control experiments, density functional theory calculations shed light on the reaction mechanism, indicating that enantioselectivity originates from the nucleophilic addition of alkynyl biphenyl quinone methides. Notably, not only the presence of biphenyl quinone methides as versatile intermediates was confirmed but also organocatalytic enantioselective 1,12-addition was established.
The 3d transition metal-catalyzed enantioconvergent radical cross-coupling provides a powerful tool for chiral molecule synthesis. In the classic mechanism, the bond formation relies on the interaction between nucleophile-sequestered metal complexes and radicals, limiting the nucleophile scope to sterically uncongested ones. The coupling of sterically congested nucleophiles poses a significant challenge due to difficulties in transmetalation, restricting the reaction generality. Here, we describe a probable outer-sphere nucleophilic attack mechanism that circumvents the challenging transmetalation associated with sterically congested nucleophiles. This strategy enables a general copper-catalyzed enantioconvergent radical N-alkylation of aromatic amines with secondary/tertiary alkyl halides and exhibits catalyst-controlled stereoselectivity. It accommodates diverse aromatic amines, especially bulky secondary and primary ones to deliver value-added chiral amines (>110 examples). It is expected to inspire the coupling of more nucleophiles, particularly challenging sterically congested ones, and accelerate reaction generality.
Poly(disulfide)s are an emerging class of sulfur-containing polymers with applications in medicine, energy, and functional materials. However, the constituent dynamic covalent S-S bond is highly reactive in the presence of the sulfide (RS-) anion, imposing a persistent challenge to control the polymerization. Here, we report an anion-binding approach to arrest the high reactivity of the RS- chain end to control the synthesis of linear poly(disulfide)s, realizing a rapid, living ring-opening polymerization of 1,2-dithiolanes with narrow dispersity and high regioselectivity (Mw/Mn â¼ 1.1, Ps â¼ 0.85). Mechanistic studies support the formation of a thiourea-base-sulfide ternary complex as the catalytically active species during the chain propagation. Theoretical analyses reveal a synergistic catalytic model where the catalyst preorganizes the protonated base and anionic chain end to establish spatial confinement over the bound monomer, effecting the observed regioselectivity. The catalytic system is amenable to monomers with various functional groups, and semicrystalline polymers are also obtained from lipoic acid derivatives by enhancing the regioselectivity.
Catalytic enantioselective construction of optically active tetraarylmethanes remains a challenging issue in the field of asymmetric synthesis because of the overwhelming steric hindrance and formidable stereocontrol that existed in construction of the all-aryl-substituted quaternary carbon stereocenter. Here, we reported an organocatalytic asymmetric synthesis of chiral tetraarylmethanes from racemic tertiary alcohols. With the aid of a chiral phosphoric acid catalyst, 6-methylenenaphthalen-2(6H)-ones were generated in situ from 6-(hydroxydiarylmethyl)naphthalen-2-ols, followed by stereoselective 1,8-conjugate addition to afford the corresponding tetraarylmethanes in high to excellent yields with high enantioselectivities. Furthermore, the scope of tertiary alcohols has been successfully enlarged to 6-(hydroxydiphenylmethyl)naphthalen-2-amines. Notably, it is the first time to use 2-naphthol/naphthalen-2-amine unit as the auxiliary group to in situ generate α,ß,γ,δ,ε,ζ-conjugate systems, which have been successfully involved in organocatalytic remote stereocontrolled 1,8-conjugate addition reactions. Particularly, organocatalytic stereoconvergent formal nucleophilic substitution reaction of triarylmethanols has been achieved for the asymmetric construction of chiral tetraarylmethanes. In addition, DFT calculations have been applied to provide guidance for the design of additional tertiary alcohols and understand the origin of stereoselectivity.
An asymmetric organocatalytic remote 1,10-addition of alkynyl indole imine methides generated in situ from α-(6-indolyl) propargylic alcohols with thiazolones has been developed for the first time, affording axially chiral tetrasubstituted allenes featuring vicinal sulfur-containing quaternary carbon stereocenters in high yields with excellent stereoselectivities. The representative scale-up reaction and transformations of the 1,10-adduct were examined. The reaction mechanism was expounded by control experiments and DFT calculations.
Optically pure pseudo-natural products (PNPs), particularly exemplified by azabicyclo[3.3.1]nonane molecules and their analogs provide an attractive platform for structure-activity relationship studies, and also lead new compound discovery in drug development. However, there are currently no examples of guiding catalytic asymmetric strategies available to construct such important PN-scaffolds, thus limiting their broad use. Here, we report a general and modular method for constructing these pseudo-natural N-bridged [3.3.1] ring systems via cascade process by bifunctional phosphonium salt/Lewis acid relay catalysis. A wide variety of substrates bearing an assortment of functional groups (59 examples) are compatible with this protocol. Other features include a [3 + 2] cyclization/ring-opening/Friedel-Crafts cascade pathway, excellent reactivities and stereoselectivities, easily available starting materials, step economy and scalability. The obtained enantioenriched products showed potential of preliminary anticancer activities. Insights gained from our studies are expected to advance general efforts towards the catalytic synthesis of challenging even unprecedented chiral PNPs, offering new opportunities for bioactive small-molecule discovery.
The installation of (benzo)thiophene-containing biaryls via coupling reactions has become a staple in designing photoelectric materials. Undeniably, C-H/C-H cross-coupling reactions between two (hetero)aromatics would be a shortcut toward these structural fragments. While more reliable cross-coupling technologies are well-established to provide C2-arylated (benzo)thiophenes, efficient methods that arylate the C3-position remain underdeveloped. Herein we provide insight into the factors that determine regioselectivity switching for these cross-coupling reactions. X-ray crystallographic analysis gives solid evidence for the key roles of triflate in regioselective dearomatization and acetate in base-assisted anti-ß-deprotonated rearomatization. The first isolation and X-ray characterization of a medium-sized dearomatized cyclometalated adduct involving both substrates provide extra insight into aerobic oxidative Ar-H/Ar-H cross-coupling reactions. The mechanistic breakthrough incubates the first example, enabling C-H/C-H-type C3-arylation of benzothiophenes. Finally, this chemistry is used to design blue-emitting thermally activated delayed fluorescence (TADF) materials with a helicene conformation that exhibit a high maximum external quantum efficiency of 25.4% in OLED.
Terminal alkynes have become one of the most versatile building blocks for C-C bond construction in the past few decades, and they are usually considered to convert to acetylides before further transformations. In this study, a novel direct nucleophilic addition mode for Cu(I)-catalyzed cross-coupling of terminal alkynes and N-tosylhydrazones to synthesize chiral allenes is proposed, and it was investigated by density functional theory with the M11-L density functional. Three different reaction pathways were considered and investigated. The computational results show that the proposed reaction pathway, which includes direct nucleophilic attack of protonated acetylene, deprotonation of the vinyl cation, and catalyst regeneration, is the most favorable pathway. Another possible deprotonation-carbenation-insertion pathway is shown to be unfavorable. The direct nucleophilic addition step is the rate- and enantioselectivity-determining step in the catalytic cycle. Noncovalent interaction analysis shows that the steric effect between the methyl group of the carbene moiety and the naphthalyl group of the bisoxazoline ligand is important to control the enantioselectivity. In addition, calculation of a series of chiral bisoxazoline ligands shows that a bulky group on the oxazoline ring is favorable for high enantioselectivity, which agrees with experimental observations. Moreover, copper acetylides are stable, and their generation is a favorable pathway in the absence of chiral bisoxazoline ligands.
OBJECTIVE: To investigate the association between preoperative plasma fibrinogen level and overall survival (OS) in a cohort of Chinese gastric cancer patients who underwent gastrectomy. METHODS: A retrospective cohort study was conducted among 1090 gastric cancer patients treated between January 2003 and December 2011 who were eligible for inclusion criteria. Plasma fibrinogen level was routinely measured before surgeries. The optional cut-off value for fibrinogen level was estimated by receiver operating characteristic (ROC) curve analysis. OS was evaluated using Kaplan-Meier curve. Univariate and multivariate Cox regression models were performed to determine correlations between preoperative plasma fibrinogen level and OS. RESULTS: Enrolled subjects who returned for at least one follow-up visit had been followed for a median of 44.0 months (interquartile range, 62.0 months). An optimal cut-off value of 3.9g/L was determined for preoperative plasma fibrinogen level. Lymph node dissection method, tumor location, invasion depth, lymph node metastasis, differentiation, distant metastasis, CA199 and plasma fibrinogen level remained statistically significant with OS in multivariate analysis. Plasma fibrinogen level was significantly associated with age, tumor size, lymph node dissection method, invasion depth, lymph node metastasis, TNM stage and CEA. CONCLUSIONS: Elevated preoperative plasma fibrinogen was independently associated with poor prognosis and may serve as a clinically useful biomarker for risk assessment and treatment choice in Chinese gastric cancer patients.
Fibrinogen/metabolism , Stomach Neoplasms/blood , Adult , Aged , Asian People , Female , Humans , Male , Middle Aged , Prognosis , Retrospective Studies , Risk Assessment , Stomach Neoplasms/mortality , Stomach Neoplasms/pathology , Survival Analysis
