Discovery and Optimization of Novel Biphenyl Derivatives Bearing Cyclopropyl Linkage as Potent Programmed Cell Death-1/Programmed Cell Death-Ligand 1 Inhibitors.

A series of novel compounds bearing a cyclopropyl linkage were designed, synthesized, and evaluated as programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) inhibitors. An optimized compound (1S,2S)-A25 showed potent inhibitory activity against the PD-1/PD-L1 interaction (IC50 = 0.029 µM) with a selected binding affinity with PD-L1 (KD = 1.554 × 10-1 µM). Additionally, under the co-culture with H460/Jurkat cells, (1S,2S)-A25 can reduce the survival of H460 cells in a concentration-dependent way. A liver microsomal assay revealed that (1S,2S)-A25 had favorable metabolic stability. Furthermore, (1S,2S)-A25 displayed favorable pharmacokinetic properties (oral bioavailability of 21.58%) and potent antitumor potency in a LLC1 lung carcinoma model without observable side effects. Data from the flow cytometry and enzyme-linked immunosorbent assays demonstrated that (1S,2S)-A25 suppressed the tumor growth by activating the immune microenvironment. Our study suggests that (1S,2S)-A25 is a promising lead compound for the further development of PD-1/PD-L1 inhibitors.

Functionalization of DNA-Tagged Alkenes with Diazo Compounds via Photocatalysis.

To explore potential chemical space using DNA-encoded library (DEL) technology, the development of various types of robust DNA-compatible reactions is urgently needed. Diazo compounds, which serve as valuable building blocks and important synthons in synthetic chemistry, have been rarely applied in DEL synthesis, probably because of their potential modifications of the bases and phosphate backbone of DNA. Herein we report two cases of DNA-compatible reactions with alkenes and diazo compounds, providing corresponding hydroalkylation and cyclopropanation products in moderate to excellent yields. Notably, these transformations not only provide new access to C(sp3)-C(sp3) bond formation in DELs with excellent functional group tolerance but also represent practical ligation methods to introduce functionalized molecules into DNA.

Enantioselective Propargylation of Oxonium Ylide with α-Propargylic-3-Indolymethanol: Access to Chiral Propargylic Indoles.

An enantioselective three-component reaction of α-propargylic-3-indolymethanol with diazoindolinone and alcohol under cocatalysis of Rh(II) and chiral phosphoric acid (CPA) has been reported. It proceeds through the regio- and enantiospecific addition of the in situ formed oxonium ylide to the α-propargylic indole iminium ion that is generated from 3-indolyl propargylic alcohol with CPA. This work features an asymmetric counteranion-directed propargylation of oxonium ylide, and provides an efficient access to chiral propargylic indole derivatives with high yields and enantioselectivities.

Ternary Catalysis Enabled Three-Component Asymmetric Allylic Alkylation as a Concise Track to Chiral α,α-Disubstituted Ketones.

Multicomponent reactions that involve interception of onium ylides through Aldol, Mannich, and Michael addition with corresponding bench-stable acceptors have demonstrated broad applications in synthetic chemistry. However, because of the high reactivity and transient survival of these in situ generated intermediates, the substitution-type interception process, especially the asymmetric catalytic version, remains hitherto unknown. Herein, a three-component asymmetric allylation of α-diazo carbonyl compounds with alcohols and allyl carbonates is disclosed by employing a ternary cooperative catalysis of achiral Pd-complex, Rh2(OAc)4, and chiral phosphoric acid CPA. This method represents the first example of three-component asymmetric allylic alkylation through an SN1-type trapping process, which involves a convergent assembly of two active intermediates, Pd-allyl species, and enol derived from onium ylides, providing an expeditious access to chiral α,α-disubstituted ketones in good to high yields with high to excellent enantioselectivity. Combined experimental and computational studies have shed light on the mechanism of this novel three-component reaction, including the critical role of Xantphos ligand and the origin of enantioselectivity.

Dual Functional Pd-Catalyzed Multicomponent Reaction by Umpolung Chemistry of the Oxygen Atom in Electrophiles.

A Pd-catalyzed multicomponent reaction was developed by trapping oxomium ylide with nitrosobenzene via Pd-promoted umpolung chemistry. The Pd catalyst plays two important roles: diazo compound decomposed catalyst and Lewis acid for the activation of nitrosobenzene. This strategy provides some insight into a new way for discovery of multicomponent methodology to construct complex molecules. The developed method also provides rapid access to a series of O-(2-oxy) hydroxylamine derivatives, which exhibit good anticancer activity in osteosarcoma cells.

A metal-free photocatalyst for highly efficient hydrogen peroxide photoproduction in real seawater.

Artificial photosynthesis of H2O2 from H2O and O2, as a spotless method, has aroused widespread interest. Up to date, most photocatalysts still suffer from serious salt-deactivated effects with huge consumption of photogenerated charges, which severely limit their wide application. Herein, by using a phenolic condensation approach, carbon dots, organic dye molecule procyanidins and 4-methoxybenzaldehyde are composed into a metal-free photocatalyst for the photosynthetic production of H2O2 in seawater. This catalyst exhibits high photocatalytic ability to produce H2O2 with the yield of 1776 µmol g-1h-1 (λ ≥ 420 nm; 34.8 mW cm-2) in real seawater, about 4.8 times higher than the pure polymer. Combining with in-situ photoelectrochemical and transient photovoltage analysis, the active site and the catalytic mechanism of this composite catalyst in seawater are also clearly clarified. This work opens up an avenue for a highly efficient and practical, available catalyst for H2O2 photoproduction in real seawater.

Rh(II)/Ag(I)-Cocatalyzed Three-Component Reaction via SN1/SN1'-Type Trapping of Oxonium Ylide with the Nicholas Intermediate.

A Rh(II)/Ag(I)-cocatalyzed three-component reaction of propargylic alcohol-Co2(CO)6 complexes with diazo compounds and benzyl alcohols is described, which represents the first trapping process of oxonium ylides with carbocations via the SN1/SN1'-type pathway. This transformation provides an efficient approach for construction of dicobalt hexacarbonyl-complexed 3,3-disubstituted oxindoles. Further derivatization of the product, initiated by the deprivation of the dicobalt species, gives the 3,3-disubstituted oxindoles with the ene alkynyl group and the privileged spirooxindole-vinyldihydropyran structure.

A Rh-catalyzed three-component reaction for the diastereoselective synthesis of pyrazolone derivatives with contiguous quaternary stereocenters.

A diastereoselective three-component reaction of diazo compounds with alcohols and pyrazolinone ketimines by utilizing rhodium(ii) catalysis via interception of transient oxonium ylides is reported. The reaction provides an efficient approach for the facile construction of polyfunctionalized pyrazolone derivatives bearing two contiguous quaternary stereocenters in good yields with high regioselectivities and excellent diastereoselectivities.

Iron-catalyzed [3 + 2]-cycloaddition of in situ generated N-ylides with alkynes or olefins: access to multi-substituted/polycyclic pyrrole derivatives.

An iron-catalyzed one-pot three-component reaction of 1-substituted benzimidazoles with diazoacetates and electron-deficient alkynes or alkenes has been reported. Mechanistically, the reaction goes through a 1,3-dipolar cycloaddition of catalytically generated benzimidazolium N-ylides with various activated alkynes or alkenes, leading to multi-substituted and polycyclic fused pyrrole derivatives, respectively.

Privilege-Structure-Oriented Three-Component Asymmetric Aminomethylation: Assembly of Chiral 3-Aminomethyl Indolones.

The asymmetric aminomethylation reaction of 3-diazooxindoles with electronic-rich arenes and N,O-acetals cooperatively catalyzed by achiral dirhodium complex and chiral phosphoric acid is reported. The reaction provides a novel method for the facile synthesis of chiral 3-aminomethyl oxindoles with an all-carbon quaternary center in good yields (82-98%) with high to excellent enantioselectivities (up to 97% ee). The transformation proceeds through a convergent addition of a reactive zwitterionic intermediate with a chiral methylene iminium generated in situ via asymmetric counteranion-directed catalysis (ACDC). This work represents the first asymmetric aminomethylation method of mixed 3,3'-bisindoles with structural diversity.

A rhodium-catalysed three-component reaction to access C1-substituted tetrahydroisoquinolines.

A rhodium-catalyzed three-component reaction of diazo compounds, anilines and C,N-cyclic azomethine imines via trapping of transient ammonium ylides was developed. This reaction provided a simple and convenient approach for the synthesis of pharmaceutically intriguing tetrahydroisoquinoline derivatives in moderate to good yields (36-85%) with good diastereoselectivities (up to 95 : 5 dr) under mild reaction conditions.

Metal-Dependent Umpolung Reactivity of Carbenes Derived from Cyclopropenes.

Metal carbenes, divalent carbon species, are versatile intermediates that enable novel synthetic pathways. These species exhibit either electrophilic or nucleophilic character, depending on the carbene and metal fragments. Although the metal carbene reactivity is regulated by the metal, the umpolung of carbene reactivity by changing metal remains challenging. Here, we report a unique metal-induced de novo umpolung of carbene reactivity, wherein a carbene precursor can be transformed into either an electrophilic carbene or a nucleophilic carbenoid, depending on the metal promoters. Thus, a chemodivergent reaction of isatins and cyclopropenes is developed. Under the promotion of Zn2+ halides, a nucleophilic zinc carbenoid is formed and trapped by isatins to produce oxindole derivatives containing an alkenyl halide moiety. Using Rh2(esp)2 as a catalyst, the reaction delivers oxindoles carrying a dihydrofuran unit. This work provides a facile approach to harness the metal carbene reactivity and is critical for the development of diversity-oriented synthesis.

Asymmetric Counter-Anion-Directed Aminomethylation: Synthesis of Chiral ß-Amino Acids via Trapping of an Enol Intermediate.

A novel enantioselective aminomethylation reaction of diazo compound, alcohol and α-aminomethyl ether enabled by asymmetric counteranion-directed catalysis is disclosed that offers an efficient and convenient access to furnish optically active α-hydroxyl-ß-amino acids in high yield with high to excellent enantioselectivities. Control experiments and DFT calculations indicate that the transformation proceeds through trapping the in situ generated enol intermediate with methylene iminium ion, and the asymmetric induction was enabled by chiral pentacarboxycyclopentadiene anion via H-bonding and electrostatic interaction.

Diastereoselective synthesis of isochromans via the Cu(ii)-catalysed intramolecular Michael-type trapping of oxonium ylides.

A highly diastereoselective approach for the rapid construction of an isochroman skeleton was achieved by the copper(ii)-catalyzed transformation of alcohol-tethered enones and diazo compounds. This transformation was proposed to proceed through the intramolecular Michael-type trapping of an in situ generated oxonium ylide intermediate. The copper(ii) catalyst may play a dual role in catalyzing diazo decomposition as well as activating the enone unit. With this method, a series of 3,4-substituted isochromans were obtained with excellent diastereoselectivities under very mild reaction conditions.

Cu(I)-Catalyzed Three-Component Reaction of Diazo Compound with Terminal Alkyne and Nitrosobenzene for the Synthesis of Trifluoromethyl Dihydroisoxazoles.

A Cu(I)-catalyzed three-component reaction of terminal alkynes, trifluoromethyl diazo compounds, and nitrosoarenes was developed. With this method, a series of trifluoromethyl-substituted dihydroisoxazoles were effectively synthesized in high yields under mild reaction conditions. This transformation is proposed to proceed through an electrophilic trapping of the copper carbene species generated from terminal alkynes and diazo compounds by nitrosobenzenes.

Enantioselective Trapping of Oxonium Ylides by 3-Hydroxyisoindolinones via a Formal SN1 Pathway for Construction of Contiguous Quaternary Stereocenters.

An enantioselective Rh(II)/chiral phosphoric acid co-catalyzed three-component reaction via trapping of oxonium ylides with 3-hydroxyisoindolinones by a formal SN1 pathway is described. This reaction allows for the efficient synthesis of isoindolinone derivatives with two contiguous quaternary stereogenic centers in high yields (up to 93%) with excellent enantioselectivities and moderate diastereoselectivities under mild reaction conditions.

Regio- and Diastereoselective Three-Component Reactions via Trapping of Ammonium Ylides with N-Alkylquinolinium Salts: Synthesis of Multisubstituted Tetra- and Dihydroquinoline Derivatives.

Pd(II)-catalyzed three-component reactions via trapping of ammonium ylides with N-alkylquinolinium salts are reported. These reactions provided polyfunctional polycyclic tetrahydroquinolines or 4-substituted 1,4-dihydroquinolines in excellent yields (89-99% and 89-98%, respectively) with high regioselectivities and moderate to good diastereoselectivities (up to 95:5 dr) under mild reaction conditions.

Trapping of Transient Zwitterionic Intermediates by N-Acylpyridinium Salts: A Palladium-Catalyzed Diastereoselective Three-Component Reaction.

We developed a palladium-catalyzed diastereoselective three-component reaction of N-aryl diazoamides, pyridine, and chloroformate, which proceeded through trapping of transient zwitterionic intermediates by in situ formed N-acylpyridinium salts in a regioselective 1,4-addition fashion. This reaction can rapidly provide a library of biologically relevant 4-(2-oxoindolin-3-yl)-1,4-dihydropyridine derivatives in high yields (up to 98%) with moderate to excellent diastereoselectivities (up to >95:5 dr) under mild reaction conditions.

Bond cleavage, fragment modification and reassembly in enantioselective three-component reactions.

Chemical bond cleavage and reconstruction are common processes in traditional rearrangement reactions. In contrast, the process that involves bond cleavage, fragment modification and then reconstruction of the modified fragment provides an efficient way to build structurally diversified molecules. Here, we report a palladium(II)/chiral phosphoric acid catalysed three-component reaction of aryldiazoacetates, enamines and imines to afford α-amino-δ-oxo pentanoic acid derivatives in good yields with excellent diastereoselectivities and high enantioselectivities. The stereoselective reaction went through a unique process that involves cleavage of a C-N bond, modification of the resulting amino fragment and selective reassembly of the modified fragment. This innovative multi-component process represents a highly efficient way to build structurally diversified polyfunctional molecules in an atom and step economic fashion. A keto-iminium is proposed as a key intermediate and a chiral palladium/phosphate complex is proposed as an active catalyst.