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.

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.

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, Nε-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.

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.

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.

Abstract Polystyrene-supported (PS) diarylprolinol catalysts 1?a (Ar=phenyl) and 1?b (Ar=3,5-bis(trifluoromethyl)phenyl) have been developed. Operating under site-isolation conditions, PS-1?a/1?b 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.

Heterobimetallic Lewis acid catalysts are broadly useful and methods to recycle them have immediate applications. However, their immobilization through covalent binding can be challenging. Non-covalent immobilization of supported asymmetric catalysts is attractive due to ease of preparation and potential for reversible binding. We report a novel non-covalent binding strategy for Shibasaki's REMB framework {RE=rare earth metal; M=Li, Na, K; B=BINOL; RE:M:B=1:3:3, [M-3(sol)(n)][(BINOLate)(3)RE]} and explore the reactivity of the supported catalyst.

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.

Enantiopure trans-3-trifluoromethylsulfonylamino-4-silyloxypyrrolidines efficiently catalyse the asymmetric alpha-aminoxylation of aldehydes. At 1% catalyst loading (solvent-free conditions) or at 2% catalyst loading (acetonitrile solution) aldehydes are completely converted in short reaction times leading to alpha-aminoxylation products with very high (96-99%) enantioselectivity.

Polystyrene (PS)-supported diphenylprolinol silyl ethers have been developed as highly active catalysts for the enantioselective a-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 alpha-amination process (6 min residence time, 8 h operation).

Because of the high reactivity of Grignard reagents a direct highly enantioselective Grignard reaction with aldehydes has lately been disclosed In this report. Grignard leagents were: introduced with bis[2-(N,N'-dimethylamino)ethyl) ether (BDMAEF) to effectively deactivate then reactivity thus a highly enantioselective alkylation of aldehydes with Grignard reagents resulted from catalysis by (S)-BINOL-Ti(O'Pt)(2). It is thought that BDMAEE chelates the in situ generated salts MgBt(2) from Schlenk equilibrium of RMgBr and Mg(O'Pt)Br from transmetalation of RMgBt with Ti(O'Pt). The Mg salt can actively promote the undesired background reaction to give the racemate I he 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'Pt)(2) Consequently, the Mg salt byproducts were not removed. less Ti(O'Pt)(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 leagents were investigated in the asymmetric addition and '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