Atropisomeric Carboxylic Acids Synthesis via Nickel-Catalyzed Enantioconvergent Carboxylation of Aza-Biaryl Triflates with CO2.

Upgrading CO2 to value-added chiral molecules via catalytic asymmetric C-C bond formation is a highly important yet challenging task. Although great progress on the formation of centrally chiral carboxylic acids has been achieved, catalytic construction of axially chiral carboxylic acids with CO2 has never been reported to date. Herein, we report the first catalytic asymmetric synthesis of axially chiral carboxylic acids with CO2, which is enabled by nickel-catalyzed dynamic kinetic asymmetric reductive carboxylation of racemic aza-biaryl triflates. A variety of important axially chiral carboxylic acids, which are valuable but difficult to obtain via catalysis, are generated in an enantioconvergent version. This new methodology features good functional group tolerance, easy to scale-up, facile transformation and avoids cumbersome steps, handling organometallic reagents and using stoichiometric chiral materials. Mechanistic investigations indicate a dynamic kinetic asymmetric transformation process induced by chiral nickel catalysis.

Cu-Catalyzed Asymmetric Dicarboxylation of 1,3-Dienes with CO2.

Dicarboxylic acids and derivatives are important building blocks in organic synthesis, biochemistry, and the polymer industry. Although catalytic dicarboxylation with CO2 represents a straightforward and sustainable route to dicarboxylic acids, it is still highly challenging and limited to generation of achiral or racemic dicarboxylic acids. To date, catalytic asymmetric dicarboxylation with CO2 to give chiral dicarboxylic acids has not been reported. Herein, we report the first asymmetric dicarboxylation of 1,3-dienes with CO2 via Cu catalysis. This strategy provides an efficient and environmentally benign route to chiral dicarboxylic acids with high regio-, chemo-, and enantioselectivities. The copper self-relay catalysis, that is, Cu-catalyzed boracarboxylation of 1,3-dienes to give carboxylated allyl boronic ester intermediates and subsequent carboxylation of C-B bonds to give dicarboxylates, is key to the success of this dicarboxylation. Moreover, this protocol exhibits broad substrate scope, good functional group tolerance, easy product derivatizations, and facile synthesis of chiral liquid crystalline polyester and drug-like scaffolds.

Arylcarboxylation of unactivated alkenes with CO2 via visible-light photoredox catalysis.

Photocatalytic carboxylation of alkenes with CO2 is a promising and sustainable strategy to synthesize high value-added carboxylic acids. However, it is challenging and rarely investigated for unactivated alkenes due to their low reactivities. Herein, we report a visible-light photoredox-catalyzed arylcarboxylation of unactivated alkenes with CO2, delivering a variety of tetrahydronaphthalen-1-ylacetic acids, indan-1-ylacetic acids, indolin-3-ylacetic acids, chroman-4-ylacetic acids and thiochroman-4-ylacetic acids in moderate-to-good yields. This reaction features high chemo- and regio-selectivities, mild reaction conditions (1 atm, room temperature), broad substrate scope, good functional group compatibility, easy scalability and facile derivatization of products. Mechanistic studies indicate that in situ generation of carbon dioxide radical anion and following radical addition to unactivated alkenes might be involved in the process.

Electroreductive Dicarboxylation of Unactivated Skipped Dienes with CO2.

Carboxylation of easily available alkenes with CO2 is highly important to afford value-added carboxylic acids. Although dicarboxylation of activated alkenes, especially 1,3-dienes, has been widely investigated, the challenging dicarboxylation of unactivated 1,n-dienes (n>3) with CO2 remains unexplored. Herein, we report the first dicarboxylation of unactivated skipped dienes with CO2 via electrochemistry, affording valuable dicarboxylic acids. Control experiments and DFT calculations support the single electron transfer (SET) reduction of CO2 to its radical anion, which is followed by sluggish radical addition to unactivated alkenes, SET reduction of unstabilized alkyl radicals to carbanions and nucleophilic attack on CO2 to give desired products. This reaction features mild reaction conditions, broad substrate scope, facile derivations of products and promising application in polymer chemistry.

Photocatalytic Carboxylation of C-N Bonds in Cyclic Amines with CO2 by Consecutive Visible-Light-Induced Electron Transfer.

Visible-light photocatalytic carboxylation with CO2 is highly important. However, it still remains challenging for reluctant substrates with low reduction potentials. Herein, we report a novel photocatalytic carboxylation of C-N bonds in cyclic amines with CO2 via consecutive photo-induced electron transfer (ConPET). It is also the first photocatalytic reductive ring-opening reaction of azetidines, pyrrolidines and piperidines. This strategy is practical to transform a variety of easily available cyclic amines to valuable ß-, γ-, δ- and ϵ-amino acids in moderate-to-excellent yields. Moreover, the method also features mild and transition-metal-free conditions, high selectivity, good functional-group tolerance, facile scalability and product derivations. Mechanistic studies indicate that the ConPET might be the key to generating highly reactive photocatalysts, which enable the reductive activation of cyclic amines to generate carbon radicals and carbanions as the key intermediates.

Tumor Suppressor Role and Clinical Significance of the FEV Gene in Prostate Cancer.

Background: In our previous research, we developed a 32-gene risk index model that may be utilized as a robust prognostic method for predicting prostate cancer (PCa) recurrence after surgery. Among the 32 genes, the Fifth Ewing Variant (FEV) gene was one of the top downregulated genes in relapsed PCa. However, current understanding of the FEV gene and its involvement in PCa is limited. Methods: FEV mRNA expression was analyzed and correlated to clinical outcomes in PCa patients who underwent prostatectomy at the Massachusetts General Hospital. Specimens from tissue microarray (TMA) including 102 prostate cancer patients were analysis for the expression of FEV. Meanwhile, FEV expression profiles were also assessed in PCa cell lines and in BPH-1 prostate epithelial cells using western blotting and quantitative reverse transcription-PCR (qRT-PCR). Furthermore, we transfected LNCaP and PC-3 cells with either an empty vector or full-length FEV gene and performed in vitro cell functional assays. The part FEV plays in tumor xenograft growth was also assessed in vivo. Results: Of the 191 patients included in this study base on the DASL dataset, 77 (40.3%) and 24 (13.6%), respectively, developed prostate-specific antigen (PSA) relapse and metastasis postradical prostatectomy. Significant FEV downregulation was observed in PCa patients showing PSA failure and metastasis. The protein expression of FEV was significantly negatively correlated with the Gleason score and pathological stage in prostate cancer tissues. Similarly, FEV expression significantly decreased in all PCa cell lines relative to BPH-1 (all P < 0.05). Functional assays revealed that FEV expression markedly inhibited PCa cell growth, migration, and invasion, which in turn significantly repressed the growth of tumor xenografts in vivo. Conclusion: The results of this study suggest an association between downregulated FEV expression and PSA relapse in PCa patients. In addition, FEV may act as a tumor suppressor in PCa.

Photoredox-Catalyzed Defluorinative Functionalizations of Polyfluorinated Aliphatic Amides and Esters.

Selective C-F bond functionalization of perfluoalkyl units has huge potential towards accessing functionalized organofluorinated compounds, but remains challenging due to the high C-F bond strength and inherent selectivity challenges. We report a new catalytic approach to the selective functionalization of strong C-F bonds in polyfluorinated aliphatic esters and amides. This simple reaction proceeds in mild and operational fashion with divergent conversions, including hydrodefluorination, defluoroalkylation, and defluoroalkenylation, affording a diverse array of important partially fluorinated motifs. Straightforward downstream chemistry towards fluorinated alcohols, amines and drug derivatives highlights the potential of the protocol.

Radical Carboxylative Cyclizations and Carboxylations with CO2.

Carbon dioxide (CO2) is not only a greenhouse gas and a common waste product but also an inexpensive, readily available, and renewable carbon resource. It is an important one-carbon (C1) building block in organic synthesis for the construction of valuable compounds. However, its utilization is challenging owing to its thermodynamic stability and kinetic inertness. Although significant progress has been achieved, many limitations remain in this field with regard to the substrate scope, reaction system, and activation strategies.Since 2015, our group has focused on CO2 utilization in organic synthesis. We are also interested in the vast possibilities of radical chemistry, although the high reactivity of radicals presents challenges in controlling selectivity. We hope to develop highly useful CO2 transformations involving radicals by achieving a balance of reactivity and selectivity under mild reaction conditions. Over the past 6 years, we along with other experts have disclosed radical-type carboxylative cyclizations and carboxylations using CO2.We initiated our research by realizing the Cu-catalyzed radical-type oxytrifluoromethylation of allylamines and heteroaryl methylamines to generate valuable 2-oxazolidones with various radical precursors. Apart from Cu catalysis, visible-light photoredox catalysis is also a powerful method to achieve efficient carboxylative cyclization. In these cases, single-electron-oxidation-promoted C-O bond formation between benzylic radicals and carbamates is the key step.Since carboxylic acids exist widely in natural products and bioactive drugs and serve as important bulk chemicals in industry, we realized further visible-light-promoted carboxylations with CO2 to construct such chemicals. We have achieved the selective umpolung carboxylations of imines, enamides, tetraalkylammonium salts, and oxime esters by successive single-electron-transfer (SSET) reduction. Using this strategy, we have also realized the dearomative arylcarboxylation of indoles with CO2. In addition to the incorporation of 1 equiv of CO2 per substrate, we have recently developed a visible-light photoredox-catalyzed dicarboxylation of alkenes, allenes, and (hetero)arenes via SSET reduction, which allows the incorporation of two CO2 molecules into organic compounds to generate valuable diacids as polymer precursors.In addition to the two-electron activation of CO2, we sought to develop new strategies to realize efficient and selective transformations via single-electron activation of CO2. Inspired by the hypothetical electron-transfer mechanism of iron-sulfur proteins, we have realized the visible-light-driven thiocarboxylation of alkenes with CO2 using catalytic iron salts as promoters. The in-situ-generated Fe/S complexes are likely able to reduce CO2 to its radical anion, which could react with alkenes to give a stabilized carbon radical. Moreover, we have also disclosed charge-transfer complex (CTC) formation between thiolate and acrylate/styrene to realize the visible-light-driven hydrocarboxylation of alkenes with CO2 via generation of a CO2 or alkene radical anion. On the basis of this novel CTC, the visible-light-driven organocatalytic hydrocarboxylation of alkenes with CO2 has also been realized using a Hantzsch ester as an effective reductant.

Visible-Light-Induced Cycloaddition of α-Ketoacylsilanes with Imines: Facile Access to ß-Lactams.

We report the synthesis of ß-lactams from α-ketoacylsilanes and imines, which proceeds via a formal [2+2] photochemical cycloaddition with in situ generation of siloxyketene. This mild and operationally simple reaction proceeds in an atom-economic fashion with broad substrate scope, including aldimines, ketimines, hydrazones, and fused nitrogen heterocycles, affording a variety of important ß-lactams with satisfactory diastereoselectivities in most cases. This reaction also features good functional-group tolerance, facile scalability and product diversification. Experimental and computational studies suggest that α-ketoacylsilanes can serve as photochemical precursors by engaging in a 1,3 silicon shift to the distal carbonyl group.

Visible-Light Photoredox-Catalyzed Remote Difunctionalizing Carboxylation of Unactivated Alkenes with CO2.

Remote difunctionalization of unactivated alkenes is challenging but a highly attractive tactic to install two functional groups across long distances. Reported herein is the first remote difunctionalization of alkenes with CO2 . This visible-light photoredox catalysis strategy provides a facile method to synthesize a series of carboxylic acids bearing valuable fluorine- or phosphorus-containing functional groups. Moreover, this versatile protocol shows mild reaction conditions, broad substrate scope, and good functional-group tolerance. Based on DFT calculations, a radical adds to an unactivated alkene to smoothly form a new carbon radical, followed by a 1,5-hydrogen atom-transfer process, the rate-limiting step, generating a more stable benzylic radical. The reduction of the benzylic radicals by an IrII species generates the corresponding benzylic carbanions as the key intermediates, which further undergo nucleophilic attack with CO2 to generate carboxylates.

Visible-Light-Induced, Metal-Free Carbene Insertion into B-H Bonds between Acylsilanes and Pinacolborane.

Carbene insertion reactions with B-H bonds are a challenging but promising method for the synthesis of organoboranes. Herein, we report visible-light-induced B-H insertions of HBpin with acylsilane. This metal-free and operationally simple reaction proceeds in an atom-economical way with broad substrate scope under mild reaction conditions, affording a variety of important α-alkoxyorganoboronate esters in quantitative yields. Control experiments and density functional theory calculations suggest that the siloxycarbene generation from the T1 state of acylsilane and the carbene insertion into the B-H bond occurred in a concerted manner.

Transition metal-free phosphonocarboxylation of alkenes with carbon dioxide via visible-light photoredox catalysis.

Catalytic difunctionalization of alkenes has been an ideal strategy to generate structurally complex molecules with diverse substitution patterns. Although both phosphonyl and carboxyl groups are valuable functional groups, the simultaneous incorporation of them via catalytic difunctionalization of alkenes, ideally from abundant, inexpensive and easy-to-handle raw materials, has not been realized. Herein, we report the phosphonocarboxylation of alkenes with CO2 via visible-light photoredox catalysis. This strategy is sustainable, general and practical, providing facile access to important ß-phosphono carboxylic acids, including structurally complex unnatural α-amino acids. Diverse alkenes, including enamides, styrenes, enolsilanes and acrylates, undergo such reactions efficiently under mild reaction conditions. Moreover, this method represents a rare example of redox-neutral difunctionalization of alkenes with H-P(O) compounds, including diaryl- and dialkyl- phosphine oxides and phosphites. Importantly, these transition-metal-free reactions also feature low catalyst loading, high regio- and chemo-selectivities, good functional group tolerance, easy scalability and potential for product derivatization.

Correction to: MicroRNA-30d promotes angiogenesis and tumor growth via MYPT1/c-JUN/VEGFA pathway and predicts aggressive outcome in prostate cancer.

After publication of the article [1], the author reported that this article contained some errors.

Intermolecular, Branch-Selective, and Redox-Neutral Cp*IrIII -Catalyzed Allylic C-H Amidation.

Herein, we report the redox-neutral, intermolecular, and highly branch-selective amidation of allylic C-H bonds enabled by Cp*IrIII catalysis. A variety of readily available carboxylic acids were converted into the corresponding dioxazolones and efficiently coupled with terminal and internal olefins in high yields and selectivities. Mechanistic investigations support the formation of a nucleophilic IrIII -allyl intermediate rather than the direct insertion of an Ir-nitrenoid species into the allylic C-H bond.

Expression of PD-L1 in tumor-associated nerves correlates with reduced CD8+ tumor-associated lymphocytes and poor prognosis in prostate cancer.

To investigate immune profile consisting of stromal PD-L1 expression, inhibitory or non-T-cell inflamed tumor microenvironment that may predict response to anti-PD-L1/PD-1 immunotherapy in prostate cancer, we validated the specificity of a PD-L1 monoclonal antibody (E1L3N) and identified PD-L1 specific expression in prostatic stromal nerve cells. PD-L1 expression was analyzed in 73 primary prostate cancers and 7 castration-resistant prostate cancers (CRPC) by immunohistochemistry (IHC) and resulting data from primary prostate cancers were correlated with tumor-associated lymphocytes (TALs), clinicopathological characteristics and clinical outcome. PD-L1 was expressed in the tumor cells in only one primary prostate cancer case and none of the CRPC. However, PD-L1 was frequently observed in the nerve branches in the tumor-associated stroma (69 of 73 cases, 94.5%), supported by colocalization with axonal marker PGP9.5. FoxP3-, CD3- and CD8-positive T lymphocytes were observed in 74.6% (47/63), 98.4% (62/63) and 100% (61/61) of the cases, respectively. The density of PD-L1+ tumor-associated nerves (TANs) was inversely correlated with that of CD8+ TALs. Higher density of PD-L1+ TANs was significantly associated with biochemical recurrence (BCR) in Kaplan-Meier survival analysis (p = 0.016). In both univariate and multivariate Cox analysis, the density of PD-L1+ TANs was independently prognostic of BCR. In conclusion, PD-L1 expression is rare in prostate tumor cells but prevalent in TANs and negatively correlated with CD8+ TALs. Neuro-immunological interaction may be a contribution to immune-suppressive microenvironment. Combinatorial treatment regimen designs to neural PD-L1 and TALs should be warranted in future clinical application of anti-PD-L1/PD-1 immunotherapy in prostate cancer.

Visible-Light-Driven External-Reductant-Free Cross-Electrophile Couplings of Tetraalkyl Ammonium Salts.

Cross-electrophile couplings between two electrophiles are powerful and economic methods to generate C-C bonds in the presence of stoichiometric external reductants. Herein, we report a novel strategy to realize the first external-reductant-free cross-electrophile coupling via visible-light photoredox catalysis. A variety of tetraalkyl ammonium salts, bearing primary, secondary, and tertiary C-N bonds, undergo selective couplings with aldehydes/ketone and CO2. Notably, the in situ generated byproduct, trimethylamine, is efficiently utilized as the electron donor. Moreover, this protocol exhibits mild reaction conditions, low catalyst loading, broad substrate scope, good functional group tolerance, and facile scalability. Mechanistic studies indicate that benzyl radicals and anions might be generated as the key intermediates via photocatalysis, providing a new direction for cross-electrophile couplings.

Selective and Catalytic Hydrocarboxylation of Enamides and Imines with CO2 to Generate α,α-Disubstituted α-Amino Acids.

The first catalytic hydrocarboxylation of enamides and imines with CO2 to generate valuable α,α-disubstituted α-amino acids is reported. Notably, excellent chemo- and regio-selectivity are achieved, significantly different from previous reports on ß-carboxylation of enamides, homocoupling or reduction of imines. Moreover, this transition-metal-free procedure exhibits low loading of an inexpensive catalyst, easily available substrates, mild reaction conditions, high efficiency, facile scalability and easy product derivatization, providing great potential for application in organic synthesis, pharmaceutical chemistry, and biochemistry.

Synthesis of Oxazolidin-2-ones from Unsaturated Amines with CO2 by Using Homogeneous Catalysis.

Carbon dioxide (CO2 ), a well-known greenhouse gas, is also a nontoxic, readily accessible, and renewable one-carbon (C1) source. However, owing to its thermodynamic stability and kinetic inertness, the efficient utilization of CO2 is challenging. Much effort has been devoted to achieving efficient and selective organic transformations of CO2 . Recently, the synthesis of important oxazolidin-2-ones from unsaturated amines by using CO2 has attracted much attention and been heavily studied. This Focus Review presents recent advances in this area by using homogenous catalysis. The cyclization of amines that contain alkynes, alkenes, and allenes with CO2 is discussed, and possible reaction mechanisms and applications of these transformations are also described.