Regio- and stereoselective access to highly substituted vinylphosphine oxides via metal-free electrophilic phosphonoiodination of alkynes.

In general, the P-centered ring-opening of quaternary phosphirenium salts (QPrS) predominantly leads to hydrophosphorylated products, while the C-centered ring-opening is primarily confined to intramolecular nucleophilic reactions, resulting in the formation of phosphorus-containing cyclization products instead of difunctionalized products generated through intermolecular nucleophilic processes. Here, through the promotion of ring-opening of three-member rings by iodine anions and the quenching of electronegative carbon atoms by iodine cations, we successfully synthesize ß-functionalized vinylphosphine oxides by the P-addition of QPrS intermediates generated in situ. Multiple ß-iodo-substituted vinylphosphine oxides can be obtained with exceptional regio- and stereo-selectivity by reacting secondary phosphine oxides with unactivated alkynes. In addition, a variety of ß-functionalized vinylphosphine oxides converted from C-I bonds, especially the rapid construction of benzo[b]phospholes oxides, demonstrates the significance of this strategy.

Reaction Rate and Stereoselectivity Enhancement in Glycosidations with O-Glycosyl Trihaloacetimidate Donors due to Catalysis by a Lewis Acid-Nitrile Cooperative Effect.

Activation of O-glycosyl trihaloacetimidate glycosyl donors with AuCl3 as a catalyst and pivalonitrile (tBuCN) as a ligand led to excellent glycosidation results in terms of yield and anomeric selectivity. In this way, various ß-d-gluco- and ß-d-galactopyranosides were obtained conveniently and efficiently. Experimental studies and density functional theory (DFT) calculations, in order to elucidate the reaction course, support formation of the tBuCN-AuCl2-OR(H)+ AuCl4- complex as a decisive intermediate in the glycosidation event. Proton transfer from this acceptor complex to the imidate nitrogen leads to donor activation. In this way, guided by the C-2 configuration of the glycosyl donor, the alignment of the acceptor complex enforces the stereoselective ß-glycoside formation in an intramolecular fashion, thus promoting also a fast reaction course. The high stereocontrol of this novel 'Lewis acid-nitrile cooperative effect' is independent of the glycosyl donor anomeric configuration and without the support of neighboring group or remote group participation. The power of the methodology is shown by a successful glycoalkaloid solamargine synthesis.

Dual Photoredox/Nickel-Catalyzed Dehydrative Difluoroalkylation of Benzyl Alcohols for the Synthesis of Allylic gem-Difluorides.

A photoredox/Lewis acid cooperative catalytic system has been developed for the construction of Cvinyl-CRf bonds through the dehydrative difluoroalkylation of benzyl alcohols. A variety of allylic gem-difluorides could be obtained in moderate yields with good to excellent E/Z selectivity. In addition, several control experiments have been explored, and a possible mechanism was proposed for this process.

Visible-light-induced selective defluoroalkylations of polyfluoroarenes with alcohols.

To provide α-polyfluoroarylalcohols, a novel protocol for the selective defluoroalkylation of polyfluoroarenes with easily accessible alcohols was reported via the cooperation of photoredox and hydrogen atom transfer (HAT) strategies with the assistance of Lewis acids under visible light irradiation. The protocol featured broad scope, excellent regioselectivity for both C-H and C-F bond cleavages, and mild conditions. Mechanistic studies suggested that the reaction occurred through Lewis acid-promoted HAT to provide an alkyl radical and sequential addition to polyfluoroarenes. Impressively, the regioselectivity for C-F cleavage was verified with the Fukui function. The feasibility and application of this protocol on fluoroarene synthesis were well illustrated by gram-scale synthesis under both batch and flow conditions, late-stage decoration of bioactive compounds, and further transformations of the fluoroarylalcohols.

Anticancer Effect of Chlorambucil Enhanced by Chiral Phthalidyl Promoiety.

Phthalidyl promoiety has been used in several drugs, but they were all marketed in racemic form. The pharmaceutical effects of each enantiomer have not been clearly demonstrated. In this project, an anticancer chemotherapy drug, chlorambucil, was modified as enantiopure phthalidyl prodrugs. The enantiomers, together with phthalidyl unit and their racemic mixture, were then subject to the in vivo bioactivity tests against B16F10 melanoma cells. It was found that proper chirality within the promoiety had noticeably better in vivo pharmacological effects than the parent drug, the enantiomer and racemic mixture. This merit perhaps could be extended from the phthalidyl prodrugs to other chirality containing prodrugs.

Rigid P-Chiral Phosphorus Ligands for Highly Selective Palladium-Catalyzed (4+2) and (4+4) Annulations.

We developed novel shackled P-chiral ligands based on 1-phosphanorbornenes and oxazolines. They were subsequently evaluated in palladium-catalyzed (4+2) annulations, producing enantioenriched tetrahydropyran scaffolds in good yields with high site selectivity and enantioselectivity. Moreover, chemoselective (4+4) products were also achieved by using acyclic imines. In addition, density functional theory calculations were performed to afford the energy profile of the Michael addition step and ring formation step. This demonstrated that the enantioselective (4+2) annulations and the chemoselective reaction between (4+2) and (4+4) products were mostly under thermodynamic control.

Metal Free Access to Polysubstituted Pyrimidines via Nitrile Activation and [2+2+2] Cycloaddition.

Tf2 O mediated intermolecular / intramolecular [2+2+2] cycloaddition between alkynes and nitriles has been developed for efficient construction of polysubstituted pyrimidines and bicyclopyrimidines. In presence of Tf2 O, aza-allene species were generated in situ through nitrile activation and subsequently participated in the [2+2+2] cycloaddition, which was fully supported by deuteration experiments. The reaction had good substrate extensibility with moderate to excellent yield including trimethylsilylalkynes. The method was utilized as a synthetic tool in the preparation of a luminescent metal complex.

Assembly of multicyclic isoquinoline scaffolds from pyridines: formal total synthesis of fredericamycin A.

The construction of an isoquinoline skeleton typically starts with benzene derivatives as substrates with the assistance of acids or transition metals. Disclosed here is a concise approach to prepare isoquinoline analogues by starting with pyridines to react with ß-ethoxy α,ß-unsaturated carbonyl compounds under basic conditions. Multiple substitution patterns and a relatively large number of functional groups (including those sensitive to acidic conditions) can be tolerated in our method. In particular, our protocol allows for efficient access to tricyclic isoquinolines found in hundreds of natural products with interesting bioactivities. The efficiency and operational simplicity of introducing structural complexity into the isoquinoline frameworks can likely enable the collective synthesis of a large set of natural products. Here we show that fredericamycin A could be obtained via a short route by using our isoquinoline synthesis as a key step.

Cu-Catalyzed Dehydrogenative Olefinsulfonation of Alkyl Arenes.

A copper-catalyzed reaction protocol for the dehydrogenation of ethylbenzenes into styrene derivatives has been developed. This reaction procedure proceeded well under mild reaction conditions, providing a practical and efficient strategy for the rapid assembly of biologically and pharmaceutically significant molecules, such as vinyl sulfone. Simple alkyl arenes were functionalized via consecutive ß-elimination in the presence of N-sulfonylbenzo[d]imidazole with broad substrate scope and good functional group tolerance.

Carbene-Catalyzed Dynamic Kinetic Resolution and Asymmetric Acylation of Hydroxyphthalides and Related Natural Products.

A catalytic dynamic kinetic resolution and asymmetric acylation reaction of hydroxyphthalides is developed. The reaction involves formation of a carbene catalyst derived chiral acyl azolium intermediate that effectively differentiates the two enantiomers of racemic hydroxyphthalides. The method allows quick access to enantiomerically enriched phthalidyl esters with proven applications in medicine. It also enables asymmetric modification of natural products and other functional molecules that contain acetal/ketal groups, such as corollosporine and fimbricalyxlactone C.

Carbene-Catalyzed Desymmetrization and Direct Construction of Arenes with All-Carbon Quaternary Chiral Center.

Multisubstituted arenes such as indanes with attached all-carbon quaternary centers are unique scaffolds in synthetic functional molecules and sophisticated natural products. A key challenge in preparing such molecules lies in the enantioselective installation of the quaternary carbon centers. Conventional methods in this direction include asymmetric substitution reactions and substrate-controlled cyclization reactions. These reactions lead to poor stereoselectivities and/or require long and tedious synthetic steps. Disclosed here is a one-step organic catalytic strategy for enantioselective access to this class of molecules. The reaction involves an N-heterocyclic carbene catalyzed process for direct benzene construction, indane formation, remote-carbon desymmetrization, and excellent chirality control. This approach will enable the concise synthesis of arene-containing molecules, including those with complex structures and challenging chiral centers.

Catalytic asymmetric acetalization of carboxylic acids for access to chiral phthalidyl ester prodrugs.

Carboxylic acids are common moieties in medicines. They can be converted to phthalidyl esters as prodrugs. Unfortunately, phthalidyl esters are now mostly prepared in racemic forms. This is not desirable because the two enantiomers of phthalidyl esters likely have different pharmacological effects. Here we address the synthetic challenges in enantioselective modification of carboxylic acids via asymmetric acetalizations. The key reaction step involves asymmetric addition of a carboxylic acid to the catalyst-bound intermediate. This addition step enantioselectively constructs a chiral acetal unit that lead to optically enriched phthalidyl esters. A broad range of carboxylic acids react effectively under mild and transition metal-free conditions. Preliminary bioactivity studies show that the two enantiomers of chlorambucil phthalidyl esters exhibit different anti-cancer activities to inhibit the growth of Hela cells. Our catalytic strategy of asymmetric acetalizations of carboxylic acids shall benefit future development of chiral phthalidyl ester prodrugs and related molecules.

Carbene and Acid Cooperative Catalytic Reactions of Aldehydes and o-Hydroxybenzhydryl Amines for Highly Enantioselective Access to Dihydrocoumarins.

A highly enantioselective method for quick access to dihydrocoumarins is reported. The reaction involves a cooperative catalytic process with carbene and in situ generated Brønsted acid as the catalysts. α-Chloro aldehyde and readily available and stable o-hydroxybenzhydryl amine substrates were used to generate reactive azolium ester enolate and ortho-quinone methide (o-QM) intermediates, respectively, to form dihydrocoumarins with exceptionally high diastereo- and enantioselectivities. The catalytic reaction products can be easily transformed to valuable pharmaceuticals and bioactive molecules.

Development of a hypoxia-triggered and hypoxic radiosensitized liposome as a doxorubicin carrier to promote synergetic chemo-/radio-therapy for glioma.

The treatment of malignant primary brain tumors is challenging. Concomitant radiochemotherapy has become the standard clinical treatment for malignant glioma, but there are two critical challenges to overcome in order to increase efficacy. First, glioma is known to have increased resistant to radiation due to its intra-tumoral hypoxia. In addition, the blood-brain barrier (BBB) restricts the distribution of the chemotherapeutic agent to the brain. Therefore, we developed a hypoxic radiosensitizer-prodrug liposome (MLP), in order to deliver DOX to the tumor and to overcome the above challenges, achieving a synergistic chemo-/radiotherapy treatment of malignant glioma. In this study, hypoxic radiosensitizer nitroimidazoles were conjugated with lipid molecules with a hydrolysable ester bond to form MDH. MDH was mixed together with DSPE-PEG2000 and cholesterol to make MLP liposomes, which were found to have strong radiosensitivity and to promote cargo release under hypoxic conditions, due to the properties of nitroimidazoles under hypoxic conditions. MLP/DOX was found to have distinct advantages, including precise and stealthy pharmacokinetics and efficient passive uptake by the tumor. Furthermore, the combination of MLP/DOX and radiotherapy (RT) significantly inhibited glioma growth as assessed by in vivo bioluminescence imaging. These findings suggest that MLP is a promising candidate as a DOX delivery system to enhance the antitumor treatment effects on glioma, owing to synergistic chemo-/radiotherapy.

Synthetic phenylethanoid glycoside derivatives as potent neuroprotective agents.

Several phenylethanoid glycoside derivatives were designed and synthesized. Most of the synthetic compounds showed significant neuroprotective effects, including antioxidative and anti-apoptotic properties. Specifically, target compounds displayed potent effects against various toxicities such as H2O2 and 6-hydroxydopamine (6-OHDA) in PC12 cells. Among the synthetic derivatives, three compounds (5, 6, 8) exhibited much superior activities to the marketed drug Edaravone. The compounds were able to prevent the 6-OHDA-induced damage in PC12 cells in a dose-dependent manner. The anti-apoptotic effects could be observed via cell morphological changes. Moreover, the compounds significantly reduced the intracellular ROS increase resulting from 6-OHDA treatment. The preliminary structure-activity relationships were also explored. Compounds 5, 6, 8 may hold the potential as promising neuroprotective agents and new lead compounds for the treatment of neurodegenerative diseases or cerebral ischemia.

Folic acid-conjugated glucose and dextran coated iron oxide nanoparticles as MRI contrast agents for diagnosis and treatment response of rheumatoid arthritis.

Coating superparamagnetic iron oxide (SPIO) with dextran increases the stability of the magnetic nanoparticles during blood circulation, yet this is accompanied by an increase in the particle size and the vascular permeability efficiency of the SPIO nanoparticles into the joints decreases. In our study, the thickness of the dextran coated onto SPIO (dex-SPIO) was optimized without affecting the magnetic quality of iron oxide by adding a suitable amount of glucose into the crystal growth process. To further improve the signal enhancement effect of this glucose and dextran coated SPIO (glu-dex-SPIO) for the detection of the inflammatory site of arthritis, folic acid (FA) was conjugated to glu-dex-SPIO. This FA glu-dex-SPIO was used as a negative contrast agent for MRI to visualize the antigen induce arthritis (AIA) model in rats using a 7 T MR scans. MR imaging revealed more significant differences between the synovium and surrounding tissues with FA glu-dex SPIO than when using the non-targeting glu-dex-SPIO over a long period of time (24 h) after intravenous injection. Moreover, the therapeutic efficacy of the cyclooxygenase 2 (COX-2) inhibitor treatment of the inflamed joints also could be confirmed by using FA glu-dex SPIO enhanced MRI, indicating that this type of nanoparticles could also have potential as a contrast agent for measuring the treatment response of rheumatoid arthritis.