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Adverse drug reactions (ADRs) restrict the maximum doses applicable in chemotherapy, which leads to failure in cancer treatment. Various approaches, including nano-drug and prodrug strategies aimed at reducing ADRs, have been developed, but these strategies have their own pitfalls. A renovated strategy for ADR reduction is urgently needed. Here, we employ an enzymatic supramolecular self-assembly process to accumulate a bioorthogonal decaging reaction trigger inside targeted cancer cells, enabling spatiotemporally controlled, synergistic prodrug activation. The bioorthogonally activated prodrug exhibits significantly enhanced potency against cancer cells compared with normal cells. This prodrug activation strategy further demonstrates high tumour inhibition efficacy with satisfactory biocompatibility, pharmacokinetics, and safety in vivo. We envision that integration of enzymatic and bioorthogonal reactions will serve as a general small-molecule-based strategy for alleviation of ADRs in chemotherapy., The side effects of cancer drugs limit their utility. Here, the authors developed a method in which an inactive (prodrug) version of the cancer drug doxorubicin enters tumour cells and then gets activated inside the cells upon a trigger facilitated by enzyme-instructed supramolecular self-assembly.

Solid support-enabled site isolation has previously allowed to use paraldehyde as an acetaldehyde surrogate in aldol reactions. However, only electron-poor aldehydes were tolerated by the system. Herein, we show that the temporary conversion of benzaldehyde into η6-benzaldehyde Cr(CO)3 circumvents this limitation. Asymmetric synthesis of (R)-Phenoperidine, as well as formal syntheses of (R)-Fluoxetine and (R)-Atomoxetine, illustrate the benefits of this strategy.

Organocatalytic polymerization reactions have a number of advantages over their metal-catalyzed counterparts, including environmental friendliness, ease of catalyst synthesis and storage, and alternative reaction pathways. Here we introduce an organocatalytic polymerization method called benzylic chloromethyl-coupling polymerization (BCCP). BCCP is catalyzed by organocatalysts not previously employed in polymerization processes (sulfenate anions), which are generated from bench-stable sulfoxide precatalysts. The sulfenate anion promotes an umpolung polycondensation via step-growth propagation cycles involving sulfoxide intermediates. BCCP represents an example of an organocatalyst that links monomers by C=C double bond formation and offers transition metal-free access to a wide variety of polymers that cannot be synthesized by traditional precursor routes., Polymerization reactions are often catalysed by metal compounds and hence there are concerns surrounding toxicity, cost and environmental friendliness. Here the authors show sulfenate anions as organocatalysts for benzylic chloromethyl-coupling polymerization reactions to form poly(stilbene)s.

A novel carbanionic reactivity of imines mediated by photoredox catalysis is demonstrated. The umpolung imine reactivity is exemplified by proton abstraction from water as a key step in the reduction of benzophenone ketimines to amines (up to 98% yield). Deuterium is introduced into amines efficiently using D2O as an inexpensive deuterium source (≥95% D ratio). The mechanism of this unusual transformation is probed.

The science and art of preventing and managing disease and prolonging life is dependent on advances in medicine, biology, and biochemistry. Many of these advances will involve interactions of small molecules with biological entities. As such, they will rely on the efficient synthesis of active compounds with very high stereochemical purity. Although enantioselective reactions are important in this regard, most stereocenters in complex molecule synthesis are installed in diastereoselective reactions. Perhaps the most well-known diastereoselective C-C bond-forming reaction is the addition of nucleophiles to carbonyl groups with α- or β-stereogenic centers. Diastereoselective additions of organometallic reagents to protected chiral α- and β-hydroxy aldehydes and ketones are described by either Cram chelation or Felkin-Anh models, which are protecting group (PG)-dependent. Small PGs (X = OMOM, OBn, etc.) favor Cram chelation, wherein both the carbonyl group and the O-PG bind to the Lewis acidic metal, providing syn diol motifs. In contrast, silyl PGs, with the OSiR

A simple and effective one-pot cascade procedure to provide 2,4-disubstituted thiazoles and symmetrical dimeric thiazoles directly from commercially available acid chlorides and β-azido disulfides in moderate to high yields is described. This cascade transformation consists of disulfide cleavage, thiocarbonylation, phosphine-promoted intramolecular Staudinger/aza-Wittig reaction and dehydrogenation to form the corresponding thiazoles. The application of our methodology is demonstrated by the concise two-step synthesis of anticancer agent SMART and its O-linked dimer in 64% and 46% overall yields, respectively. This directed cascade reaction could be easily handled and scaled up under mild conditions, enabling the construction of focused thiazole derivatives for further pharmacological evaluation.

The interference from endogenous signaling enzymes represents a major hurdle for building orthogonal signaling cascade inside cells, particularly among the close related isoforms within an enzyme family. Here we employed the genetically-encoded chemical decaging strategy to build orthogonal-activated kinase isoforms, with the endogenous counterparts temporally disabled by an extracellular-delivered bacterial effector. This approach eliminated the potential interference from other kinase isoforms as well as the endogenous kinases, which allowed the specific, gain-of-function report of mitogen activated protein kinase kinase 1 (MEK1) activity as opposed to MEK2 with high temporal resolution. Our study dissected the distinct enzymatic activity, feedback regulation and signal outputs between these close related kinase isoforms.

Temporal and reversible control over protein and cell conjugations holds great potential for traceless release of antibody-drug conjugates (ADCs) on tumor sites as well as on-demand altering or removal of targeting elements on cell surface. We herein developed a bioorthogonal and traceless releasable reaction on proteins and intact cells to fulfill such purposes. A systematic survey of transition metals in catalyzing the bioorthogonal cleavage reactions revealed that copper complexes such as Cu(I)-BTTAA and dual-substituted propargyl (dsPra) or propargyloxycarbonyl (dsProc) moieties offered a bioorthogonal releasable pair for reversible blockage and rescue of primary amines and phenol alcohols on small molecule drugs, protein side chains, as well as intact cell surface. For proof-of-concept, we employed such Cu(I)-BTTAA/dsProc and Cu(I)-BTTAA/dsPra pairs as a "traceless linker" strategy to construct cleavable ADCs to unleash cytotoxic compounds on cancer cells in situ and as a "reversible modification" strategy for cell surface engineering. Furthermore, by coupling with the genetic code expansion strategy, we site-specifically modulated ligand-receptor interactions on live cell membranes. Together, our work expanded the transition-metal-mediated bioorthogonal cleavage tool kit from terminal decaging to internal-linker breakage, which offered a temporal and reversible conjugation strategy on therapeutic proteins and cells.

The inverse-electron-demand Diels-Alder (iDA) reaction has recently been repurposed as a bioorthogonal decaging reaction by accelerating the elimination process after an initial cycloaddition between trans-cyclooctene (TCO) and tetrazine (TZ). Herein, we systematically surveyed 3,6-substituted TZ derivatives by using a fluorogenic TCO-coumarin reporter followed by LC-MS analysis, which revealed that the initial iDA cycloaddition step was greatly accelerated by electron-withdrawing groups (EWGs) while the subsequent elimination step was strongly suppressed by EWGs. In addition, smaller substituents facilitated the decaging process. These findings promoted us to design and test unsymmetric TZs bearing an EWG group and a small non-EWG group at the 3- and 6-position, respectively. These TZs showed remarkably enhanced decaging rates, enabling rapid iDA-mediated protein activation in living cells.

Selective manipulation of protein kinases under living conditions is highly desirable yet extremely challenging, particularly in a gain-of-function fashion. Here we employ our recently developed bioorthogonal cleavage reaction as a general strategy for intracellular activation of individual kinases. Site-specific incorporation of trans-cyclooctene-caged lysine in place of the conserved catalytic lysine, in conjunction with the cleavage partner dimethyl-tetrazine, allowed efficient lysine decaging with the kinase activity chemically rescued in living systems., Site-specific incorporation of trans-cyclooctene-caged lysine in place of the catalytic lysine, followed by the bioorthogonal cleavage reaction, allowed efficient kinase activation in living systems.

The genetic code expansion strategy allowed incorporation of unnatural amino acids (UAAs) bearing diverse functional groups into proteins, providing a powerful toolkit for protein manipulation in living cells. We report a multifunctional UAA, Ne-p-azidobenzyloxycarbonyl lysine (PABK), that possesses a panel of unique properties capable of fulfilling various protein manipulation purposes. In addition to being used as a bioorthogonal ligation handle, an infrared probe and a photo-affinity reagent, PABK was shown to be chemically decaged by trans-cyclooctenols via a strain-promoted 1,3-dipolar cycloaddition, which provides a new bioorthogonal cleavage strategy for intracellular protein activation. The biocompatibility and efficiency of this method were demonstrated by decaging of a PABK-caged firefly luciferase under living conditions. We further extended this method to chemically rescue a bacterial toxin OspF inside mammalian host cells.

Light-mediated transformations with CO2 have recently attracted great attention, with the focus on CO2 incorporation into C–C double and triple bonds, organohalides and amines. Herein is demonstrated visible light -mediated umpolung imine reactivity capable of engaging CO2 to afford α-amino acid derivatives. By employing benzophenone ketimine derivatives, CO2 fixation by hydrocarboxylation of C=N double bonds is achieved. Good to excellent yields of a broad range of α,α–disubstituted α-amino acid derivatives are obtained under mild conditions (rt, atmospheric pressure of CO2, visible light). A procedure that avoids tedious chromatographic purification and uses sustainable sunlight is developed to highlight the simplicity of this method.

A novel carbanionic reactivity of imines mediated by photoredox catalysis is demonstrated. The umpolung imine reactivity is exemplified by proton abstraction from water as a key step in the reduction of benzophenone ketimines to amines (up to 98% yield). Deuterium is introduced into amines efficiently using D

We report the genetically encoded chemical decaging strategy for protein activation in living bacterial cells. In contrast to the metabolically labile photocaging groups inside Escherichia coli, our chemical decaging strategy that relies on the inverse electron-demand Diels–Alder (iDA) reaction is compatible with the intracellular environment of bacteria, which can be a general tool for gain-of-function study of a given protein in prokaryotic systems. By applying this strategy for in situ activation of the indole-producing enzyme TnaA, we built an orthogonal and chemically inducible indole production pathway inside E. coli cells, which revealed the role of indole in bacterial antibiotic tolerance.

Polystyrene-supported (PS) diarylprolinol catalysts 1a (Ar = phenyl) and 1b (Ar = 3,5-bis(trifluoromethyl)-phenyl) have been developed. Operating under site-isolation conditions, PS-1 a/1b worked compatibly with PS- bound sulfonic acid catalyst 2 to promote deoligomerization of paraldehyde and subsequent cross-aldol reactions of the resulting acetaldehyde in one pot, affording aldol products in high yields with excellent enantioselectivities. The effect of water on the performance of the catalytic system has been studied and its optimal amount (0.5 equiv) has been determined. The dual catalytic system (1/2) allows repeated recycling and reuse (10 cycles). The potential of this methodology is demonstrated by a two- step synthesis of a phenoperidine analogue (68 % overall yield ; 98 % ee) and by the preparation of highly enantioenriched 1,3-diols 4 and 3-methylamino-1-arylpropanols 5, key intermediates in the synthesis of a variety of druglike structures.

By using a novel, simple, and convenient synthetic route, enantiopure 6-ethynyl-BINOL (BINOL = 1,1-binaphthol) was synthesized and anchored to an azidomethylpolystyrene resin through a copper-catalyzed alkyne-azide cycloaddition (CuAAC) reaction. The polystyrene (PS)-supported BINOL ligand was converted into its diisopropoxytitanium derivative in situ and used as a heterogeneous catalyst in the asymmetric allylation of ketones. The catalyst showed good activity and excellent enantioselectivity, typically matching the results obtained in the corresponding homogeneous reaction. The allylation reaction mixture could be submitted to epoxidation by simple treatment with tert-butyl hydroperoxide (TBHP), and the tandem asymmetric allylation epoxidation process led to a highly enantioenriched epoxy alcohol with two adjacent quaternary centers as a single diastereomer. A tandem asymmetric allylation/Pauson-Khand reaction was also performed, involving simple treatment of the allylation reaction mixture with Co2(CO)8/N-methyl morpholine N-oxide. This cascade process resulted in the formation of two diastereomeric tricyclic enones in high yields and enantioselectivities.

Racemic β-hydroxy ketones were kinetically resoluted into the enantiopure isomers and (E)-α,β-unsaturated ketones using catalytic asymmetric intramolecular dehydration for the first time. Synthetic tetrapeptides were used to imitate fatty acid dehydratases to efficiently discriminate racemic β-hydroxy ketones, enantioselectively catalyze the intramolecular dehydration, and result in highly enantioenriched β-hydroxy and (E)-α,β-unsaturated ketones in the environmentally benign process. Mechanistically, the high discrimination of the racemic substrates and successive enantioselective dehydration are highly dependent on the cooperative catalysis of the NH2 and COOH groups of the peptide.

Polystyrene (PS)-supported diphenylprolinol silyl ethers have been developed as highly active catalysts for the enantioselective α-amination of aldehydes. Understanding the mechanism of catalyst deactivation has led to the development of reaction conditions notably extending catalyst life in repeated recycling (10 cycles; accumulated TON of 480) and has allowed the implementation of a continuous flow α-amination process (6 min residence time, 8 h operation).

A highly asymmetric catalytic addition of various aryl Grignard reagents to aldehydes is achieved at room temperature with (S)-H8-BINOL and inexpensive commercially available Ti(OiPr)4.

Two polymer supported materials are used as recyclable catalyst mixture for the aldol condensation of paraldehyde (I) with aromatic aldehyde.

The usability of the title complexes is shown in several asymmetric and mechanistically diverse reactions including Michael additions, aza-Michael additions, and direct Aldol reactions.

The title catalyst allows successful heterogeneous catalysis for the challenging asymmetric allylation of a diverse range of ketones.

Shibasaki's REMB catalysts (REMB; RE = Sc, Y, La-Lu; M = Li, Na, K; B = 1,1'-bi-2-naphtholate; RE/M/B = 1/3/3) are among the most enantioselective asymmetric catalysts across a broad range of mechanistically diverse reactions. However, their widespread use has been hampered by the challenges associated with their synthesis and manipulation. We report here the self-assembly of novel hydrogen-bonded rare earth metal BINOLate complexes that serve as bench-stable precatalysts for Shibasaki's REMB catalysts. Incorporation of hydrogen-bonded guanidinium cations in the secondary coordination sphere leads to unique properties, most notably, improved stability toward moisture in solution and in the solid state. We have exploited these properties to develop straightforward, high-yielding, and scalable open-air syntheses that provide rapid access to crystalline, nonhygroscopic complexes from inexpensive hydrated RE starting materials. These compounds can be used as precatalysts for Shibasaki's REMB frameworks, where we have demonstrated that our system performs with comparable or improved levels of stereoselectivity in several mechanistically diverse reactions including Michael additions, aza-Michael additions, and direct Aldol reactions.

The newly synthesized polystyrene supported diphenylprolinol silyl ether is used as a highly active catalyst for the enantioselective α-amination of aldehydes.

Enantiopure trans-triflate-silyloxypyrrolidine efficiently catalyzes the asymmetric α-aminoxylation of aldehydes (I) with nitrosobenzene (II).

A new type of extremely active, highly enantioselective organocatalysts for the anti-selective Mannich reactions of aldehydes and ketones is prepared.

Lighten the load! A family of enantiopure 4-oxy-substituted 3-aminopyrrolidines arising from the enantioselective ring-opening of meso-3-pyrroline oxide have been developed as catalysts for the asymmetric, anti-selective Mannich reaction (see scheme; PMP=p-methoxyphenyl; PG=protecting group). Very high catalytic activity (down to 0.01 mol % loading) and stereoselectivity have been recorded.

Because of the high reactivity of Grignard reagents, a direct, highly enantioselective Grignard reaction with aldehydes has rarely been disclosed. In this report, Grignard reagents were introduced with bis[2-(N,N′-dimethylamino)ethyl] ether (BDMAEE) to effectively deactivate their reactivity; thus, a highly enantioselective alkylation of aldehydes with Grignard reagents resulted from catalysis by (S)-BINOL-Ti(OiPr)2. It is thought that BDMAEE chelates the in situ generated salts MgBr2 from a Schlenk equilibrium of RMgBr and Mg(OiPr)Br from transmetalation of RMgBr with Ti(OiPr)4. The Mg salts can actively promote the undesired background reaction to give the racemate. The chelation definitely inhibits the catalytic activity of the Mg salts, suppresses the unwanted background reaction, and enables the highly enantioselective addition catalyzed by (S)-BINOL-Ti(OiPr)2. Consequently, the Mg salt byproducts were not removed, less Ti(OiPr)4 than RMgBr was used, and extremely low temperature was avoided in this ...

A highly asymmetric catalytic addition of various aryl Grignard reagents to aldehydes is achieved at room temperature with (S)-H8-BINOL and inexpensive commercially available Ti(OiPr)4.

Because of the high reactivity of Grignard reagents, a direct, highly enantioselective Grignard reaction with aldehydes has rarely been disclosed. In this report, Grignard reagents were introduced with bis[2-(N,N'-dimethylamino)ethyl] ether (BDMAEE) to effectively deactivate their reactivity; thus, a highly enantioselective alkylation of aldehydes with Grignard reagents resulted from catalysis by (S)-BINOL-Ti(O(i)Pr)(2). It is thought that BDMAEE chelates the in situ generated salts MgBr(2) from a Schlenk equilibrium of RMgBr and Mg(O(i)Pr)Br from transmetalation of RMgBr with Ti(O(i)Pr)(4). The Mg salts can actively promote the undesired background reaction to give the racemate. The chelation definitely inhibits the catalytic activity of the Mg salts, suppresses the unwanted background reaction, and enables the highly enantioselective addition catalyzed by (S)-BINOL-Ti(O(i)Pr)(2). Consequently, the Mg salt byproducts were not removed, less Ti(O(i)Pr)(4) than RMgBr was used, and extremely low temperature was avoided in this catalytic asymmetric reaction in comparison with the research disclosed before. Various alkyl Grignard reagents were investigated in the asymmetric addition, and (i)BuMgBr resulted in the highest enantioselectivity,99%. Furthermore, important intermediate secondary arylpropanols for chiral drug synthesis were effectively synthesized with high enantioselectivity, up to 97%, in one step.

Generally used and highly reactive RMgBr reagents were effectively deactivated by bis[2-(N,N-dimethylamino)ethyl] ether and then were employed in the highly enantioselective addition of Grignard reagents to aldehydes. The reaction was catalyzed by the complex of commercially available (S)-BINOL and Ti(Oi-Pr)4 under mild conditions. Compared with the other observed Grignard reagents, alkyl Grignard reagents showed higher enantioselectivity and they achieved >99% ee.

Generally used and highly reactive RMgBr reagents were effectively deactivated by bis[2-(N,N-dimethylamino)ethyl] ether and then were employed in the highly enantioselective addition of Grignard reagents to aldehydes. The reaction was catalyzed by the complex of commercially available (S)-BINOL and Ti(O(i-)Pr)(4) under mild conditions. Compared with the other observed Grignard reagents, alkyl Grignard reagents showed higher enantioselectivity and they achieved99% ee.

Multithreaded programming has been widely used nowadays, but developing mutlithreaded applications is still a tough task. To alleviate such kind of work we propose a new concept, Smart Active Object, an extension to the normal object in object-oriented technology. Smart Active Object runs concurrently with the main execution logic of the program, leveraging multithreading mechanisms and meanwhile leaves only sequential interfaces for programmers to insert application-specific parts, masking details of multithreading, which eventually enhances programming productivity. To support our claims, we design and implement a framework comprising a collection of cooperative Smart Active Objects for stateful applications, a typical problem in telecom world. Using this framework, we easily solve a toy problem, derived from the behavior of SIP stateful proxy servers within much shorter time than a conventional C version counterpart.