NHC-Au-Catalyzed Isomerization of Propargylic B(MIDA)s to Allenes and Double Isomerization of Alkynes to 1,3-Dienes.

The synthesis of allenyl boronates is an important yet challenging topic in organic synthesis. Reported herein is an NHC-gold-catalyzed 1,3-H shift toward allenyl boronates synthesis from simple propargylic B(MIDA)s. Mechanistic studies suggest dual roles of the boryl moiety in the reaction: to activate the substrate for isomerization and at the same time, to prevent the allene product from further isomerization. These effects should be a result of α-anion stabilization and α-cation destabilization conferred by the B(MIDA) moiety, respectively. The NHC-Au catalyst, which is commercially available, is also found to be reactive in alkyne-to-1,3-diene isomerization reactions in an atom-economic and base-free manner.

Site-Specific Deaminative Trifluoromethylation of Aliphatic Primary Amines.

The introduction of trifluoromethyl groups into organic molecules is of paramount importance in modern synthetic chemistry and medicinal chemistry. While methods for constructing C(sp2 )-CF3 bonds have been well established, the advancement of practical and comprehensive approaches for forming C(sp3 )-CF3 bonds remains considerably restricted. In this work, we describe an efficient and site-specific deaminative trifluoromethylation reaction of aliphatic primary amines to afford the corresponding alkyl trifluoromethyl compounds. The reaction proceeds at room temperature with readily accessible N-anomeric amide (Levin's reagent) and bench-stable bpyCu(CF3 )3 (Grushin's reagent, bpy=2,2'-bipyridine) under blue light. The protocol features mild reaction conditions, good functional group tolerance, and moderate to good yields. Remarkably, the method can be applied to the direct, late-stage trifluoromethylation of natural products and bioactive molecules. Experimental mechanistic studies were conducted, and a radical mechanism is proposed, wherein the dual roles of Grushin's reagent have been elucidated.

Iodine(III)-Mediated Migratory gem-Difluorinations: Synthesis of ß Transformable Functionality Substituted gem-Difluoroalkanes.

Geminal-difluoroalkanes featuring intriguing steric and electronic properties are of great significance in medicinal chemistry, and great progresses have been achieved for their synthesis. In recent years, iodine(III) reagent-mediated migratory gem-difluorination of alkenes has proved to be an efficient and powerful strategy to access to diverse gem-difluoroalkanes, especially those bearing a readily transformable functionality (TF), which are important for rapid assembly of complex gem-difluorinated molecules in a modular and diverse manner. In this review, we systematically summarize the recent development of iodine(III)-mediated migratory gem-difluorination reactions for the synthesis of gem-difluoroalkanes bearing a synthetically versatile TF at the ß position. The reaction mechanism and the utilities of the products are also discussed. This review is presented and grouped basically according to the types of transformable functionalities within the products.

Regioselective Electrophilic Addition to Propargylic B(MIDA)s Enabled by ß-Boron Effect.

Electrophilic addition reaction to alkynes is of fundamental importance in organic chemistry, yet the regiocontrol when reacting with unsymmetrical 1,2-dialkyl substituted alkynes is often problematic. Herein, it is demonstrated that the rarely recognized ß-boron effect can confer a high level of site-selectivity in several alkyne electrophilic addition reactions. A broad range of highly functionalized and complex organoborons are thus formed under simple reaction conditions starting from propargylic MIDA (N-methyliminodiacetic acid) boronates. These products are demonstrated to be valuable building blocks in organic synthesis. In addition to the regiocontrol, this study also observes a drastic rate enhancement upon B(MIDA) substitution. Theoretical calculation reveals that the highest occupied molecular obital (HOMO) energy level of propargylic B(MIDA) is significantly raised by 0.3 eV, and the preferential electrophilic addition to the γ position is due to its higher HOMO orbital coefficient and more negative natural bond orbital (NBO) charge compared to the ß position. This study demonstrates the potential of utilizing the ß-boron effect in stereoelectronic control of chemical transformations, which can inspire further research in this area.

Nickel-Catalyzed Reductive Decarboxylative/Deaminative Glycosylation of Activated Aliphatic Acids and Primary Amines.

This study describes the nickel-catalyzed reductive decarboxylative/deaminative glycosylation of activated aliphatic acids/amines. Various alkyl C-glycosides were efficiently constructed under simple and mild reaction conditions. The reactions were high-yielding and exhibited a broad substrate scope, thereby enabling the transformation of some structurally complex natural products and late-stage modifications of drugs.

Divergent Fluorinations of Vinylcyclopropanes: Ring-Opening 1,5-Hydrofluorination and Ring-Retaining 1,2-Difluorination.

Organofluorine compounds have been widely used in pharmaceutical, agrochemical, and material sciences. Reported herein are divergent fluorination reactions of vinylcyclopropanes with different electrophiles, which allow the facile synthesis of homoallylic monofluorides and vicinal-difluorides through ring-opening 1,5-hydrofluorination and ring-retaining 1,2-difluorination, respectively. Both protocols feature mild conditions, simple operations, good functional group tolerance, and generally good yields. The practicality of these reactions is demonstrated by their scalability, as well as the successful conversion of the formed homoallylic monofluorides into other complex fluorinated molecules.

Stereoselective Synthesis of Amphoteric α-Haloalkenyl Boronates by Halogenative Semipinacol Rearrangement of B(MIDA)-Propargylic Alcohols.

The facile synthesis of stereo-defined and transformable functionality-enriched building blocks is of great importance in modern organic chemistry, as it allows the rapid and divergent assembly of complex molecules. Herein a halogen electrophile (N-bromosuccinimide and N-iodosuccinimide) initiated semipinacol rearrangement reaction of B(MIDA)-propargylic alcohols (MIDA=N-methyliminodiacetyl) by aryl migration towards the synthesis of amphoteric α-haloalkenyl boronates in moderate to good yields with excellent stereoselectivities is reported. The value of the products is evidenced by their ability to undergo divergent conversions to polysubstituted alkenes through manipulation of the C-B and C-X (X=Br, I) bonds and the carbonyl group.

Deaminative bromination, chlorination, and iodination of primary amines.

The primary amino group has been seldom utilized as a transformable functionality in organic synthesis. Reported herein is a deaminative halogenation of primary amines using N-anomeric amide as the nitrogen-deletion reagent. Both aliphatic and aromatic amines are competent substrates for direct halogenations. The mildness and robustness of the protocol are evidenced by the successful reactions of several complex- and functional group-enriched bioactive compounds or drugs. Elaboration of the resulting products provides interesting analogues of drug molecules.

ß-Boron Effect Enables Regioselective and Stereospecific Electrophilic Addition to Alkenes.

Electrophilic addition to alkenes is a textbook-taught reaction, yet it is not always possible to control the regioselectivity of addition to unsymmetrical 1,2-disubstituted substrates. We report the observation and applications of the ß-boron effect that accounts for high regioselectivity in electrophilic addition reactions to allylic MIDA (N-methyliminodiacetic acid) boronates. While the well-established ß-silicon effect bears partial resemblance to the observed reactivity, the silyl group is typically lost during functionalization. In contrast, the boryl moiety is retained in the product when B(MIDA) is used as the nucleophilic stabilizer. Mechanistic studies elucidate the origin of this effect and demonstrate how σ(C-B) hyperconjugation helps stabilize the incipient carbocation. This transformation represents a rare example of the stereospecific hydrohalogenation of secondary allyl MIDA-boronates that proceeds in a syn-fashion.

Synthesis of α-Boryl Ketones via Hydration or Oxidation of B(MIDA)-Decorated Alkynes.

α-Boryl ketones are traditionally challenging targets in organic synthesis. Reported herein is a mild and metal-free synthesis of α-boryl ketones via the hydration or oxidation of N-methyliminodiacetyl boronate (B(MIDA))-decorated alkynes. A new hydration system comprised of AcCl and H2O in HFIP allows the hydration of arylethynyl B(MIDA)s at room temperature with decent functional group tolerance. An oxidative carbon deletion process of propargylic B(MIDA)s is also developed for the synthesis of aliphatic α-boryl ketones. An intriguing ß-boron effect was observed to account for the unique site- and chemoselectivities. The application of the products in the synthesis of borylated heterocycles was demonstrated.

Discovery of a Novel G-Quadruplex and Histone Deacetylase (HDAC) Dual-Targeting Agent for the Treatment of Triple-Negative Breast Cancer.

The development of triple-negative breast cancer (TNBC) is highly associated with G-quadruplex (G4); thus, targeting G4 is a potential strategy for TNBC therapy. Because concomitant histone deacetylases (HDAC) inhibition could amplify the impact of G4-targeting compounds, we designed and synthesized two novel series of G4/HDAC dual-targeting compounds by connecting the zinc-binding pharmacophore of HDAC inhibitors to the G4-targeting isaindigotone scaffold (1). Among the new compounds, a6 with the potent HDAC inhibitory and G4 stabilizing activity could induce more DNA G4 formation than SAHA and 1 in TNBC cells. Remarkably, a6 caused more G4-related DNA damage and G4-related differentially expressed genes, consistent with its effect on disrupting the cell cycle, invasion, and glycolysis. Furthermore, a6 significantly suppresses the proliferation of various TNBC cells and the MDA-MB-231 xenograft model without evident toxicity. Our study suggests a novel strategy for TNBC therapeutics through dual-targeting HDAC and G4.

Design, Synthesis, and Evaluation of New Sugar-Substituted Imidazole Derivatives as Selective c-MYC Transcription Repressors Targeting the Promoter G-Quadruplex.

c-MYC is a key driver of tumorigenesis. Repressing the transcription of c-MYC by stabilizing the G-quadruplex (G4) structure with small molecules is a potential strategy for cancer therapy. Herein, we designed and synthesized 49 new derivatives by introducing carbohydrates to our previously developed c-MYC G4 ligand 1. Among these compounds, 19a coupled with a d-glucose 1,2-orthoester displayed better c-MYC G4 binding, stabilization, and protein binding disruption abilities than 1. Our further evaluation indicated that 19a blocked c-MYC transcription by targeting the promoter G4, leading to c-MYC-dependent cancer cell death in triple-negative breast cancer cell MDA-MB-231. Also, 19a significantly inhibited tumor growth in the MDA-MB-231 mouse xenograft model accompanied by c-MYC downregulation. Notably, the safety of 19a was dramatically improved compared to 1. Our findings indicated that 19a could become a promising anticancer candidate, which suggested that introducing carbohydrates to improve the G4-targeting and antitumor activity is a feasible option.

Cp*Ir(III) and Cp*Rh(III)-catalyzed annulation of salicylaldehydes with fluorinated vinyl tosylates.

A mild, selective and redox-neutral Cp*Ir(III)- and Cp*Rh(III)-catalyzed C-H activation/annulation of salicylaldehydes with fluorovinyl tosylates is reported. The use of monofluorovinyl tosylate favors the synthesis of C2- and C3-substitution-free chromones via C-H activation/ß-F elimination/annulation, whereas difluorovinyl tosylate leads to the construction of C2-fluoroalkoxy chromones. Mild reaction conditions and good functional-group tolerance were observed. Further functionalization of the resulting chromones via halogenation, alkynylation, alkylation and hydrocyanation was successfully realized.

Boryl-Dictated Site-Selective Intermolecular Allylic and Propargylic C-H Amination.

For internal alkenes possessing two or more sets of electronically and sterically similar allylic protons, the site-selectivity for allylic C-H functionalization is fundamentally challenging. Previously, the negative inductive effect from an electronegative atom has been demonstrated to be effective for several inspiring regioselective C-H functionalization reactions. Yet, the use of an electropositive atom for a similar purpose remains to be developed. α-Aminoboronic acids and their derivatives have found widespread applications. Their current syntheses rely heavily on functional group manipulations. Herein we report a boryl-directed intermolecular C-H amination of allyl N-methyliminodiacetyl boronates (B(MIDA)s) and propargylic B(MIDA)s to give α-amino boronates with an exceptionally high level of site-selectivities (up to 300:1). A wide variety of highly functionalized secondary and tertiary α-amino boronates are formed in generally good to excellent yields, thanks to the mildness of the reaction conditions. The unsaturated double and triple bonds within the product leave room for further decorations. Mechanistic studies reveal that the key stabilization effect of the B(MIDA) moiety on its adjacent developing positive charge is responsible for the high site-selectivity and that a closed transition state might be involved, as the reaction is fully stereoretentive. An activation effect of B(MIDA) is also found.

Regiocontrolled allylic functionalization of internal alkene via selenium-π-acid catalysis guided by boron substitution.

The selenium-π-acid-catalysis has received increasing attention as a powerful tool for olefin functionalization, but the regioselectivity is often problematic. Reported herein is a selenium-catalyzed regiocontrolled olefin transpositional chlorination and imidation reaction. The reaction outcome benefits from an allylic B(MIDA) substitution. And the stabilization of α-anion from a hemilabile B(MIDA) moiety was believed to be the key factor for selectivity. Broad substrate scope, good functional group tolerance and generally good yields were observed. The formed products were demonstrated to be valuable precursors for the synthesis of a wide variety of structurally complex organoborons.

Hypervalent iodine-mediated ß-difluoroalkylboron synthesis via an unusual 1,2-hydrogen shift enabled by boron substitution.

ß-Difluoroalkylborons, featuring functionally important CF2 moiety and synthetically valuable boron group, have great synthetic potential while remaining synthetically challenging. Herein we report a hypervalent iodine-mediated oxidative gem-difluorination strategy to realize the construction of gem-difluorinated alkylborons via an unusual 1,2-hydrogen migration event, in which the (N-methyliminodiacetyl) boronate (BMIDA) motif is responsible for the high regio- and chemoselectivity. The protocol provides facile access to a broad range of ß-difluoroalkylborons under rather mild conditions. The value of these products was demonstrated by further transformations of the boryl group into other valuable functional groups, providing a wide range of difluorine-containing molecules.

Oxidative Fluoroarylation of Benzylidenecyclopropanes with HF·Py and Aryl Iodides via Iodonio-[3,3]-Rearrangement.

Reported herein is an in situ-generated hypervalent iodine-incorporating fluoroarylation of benzylidenecyclopropanes using commercially available HF·Py and aryl iodides as fluorine and aryl sources, respectively. The reaction proceeds via regioselective 1,2-fluoroiodination of a double bond followed by an iodonio-[3,3]-rearrangement of the formed cyclopropyl-I(III) species. The protocol offers facile access to valuable monofluorinated 1,1-bis-benzyl-alkenes with mild reaction conditions and moderate to good yields. The synthetic utility of the products was demonstrated by further transformations. Preliminary mechanistic studies were conducted.

Design, synthesis, and evaluation of 9-(pyrimidin-2-yl)-9H-carbazole derivatives disrupting mitochondrial homeostasis in human lung adenocarcinoma.

Since more than 85% of lung cancer cases are non-small cell lung cancer (NSCLC), finding novel agents with anti-tumor activities is meaningful for NSCLC patients. Mitochondria is essential for cellular energy metabolism in cancer, and regulating mitochondrial bioenergetics is emerging as a practical approach for cancer treatment and prevention. The carbazole scaffold is an active structure showing anti-cancer biological activity, and the structural diversity has been expanded through the improvement and optimization of synthesizing methods. To find novel carbazole derivatives with great anti-tumor potential and explore structures variety, we designed and synthesized a series of 9-(pyrimidin-2-yl)-9H-carbazole derivatives based on the previously reported Cp∗Rh(III)/H+ tandem catalytic system. With thoroughly bioactivity exploration, we found benzo[d] [1,3]dioxol-5-yl(9-(pyrimidin-2-yl)-9H-carbazol-1-yl)methanone (compound 5n) showed notable activity in disrupting the mitochondrial homeostasis, induced cell cycle arrest and apoptosis in human adenocarcinoma cells, and finally showed anti-tumor activity in an NSCLC-xenograft mice model.

9-Bromo-2,3-diethylbenzo[de]chromene-7,8-dione (MSN54): A novel non-intercalative topoisomerase II catalytic inhibitor.

Novel mansonone F derivative MSN54 (9-bromo-2,3-diethylbenzo[de]chromene-7,8-dione) exhibited significant cytotoxicity against twelve human tumor cell lines in vitro, with particularly strong potency against HL-60/MX2 cell line resistant to Topo II poisons. MSN54 was found to have IC50 of 0.69 and 1.43 µM against HL-60 and HL-60/MX2 cells, respectively. The resistance index is 10 times lower than that of the positive control VP-16 (etoposide). Various biological assays confirmed that MSN54 acted as a Topo IIα specific non-intercalative catalytic inhibitor. Furthermore, MSN54 exhibited good antitumor efficacy and low toxicity at a dose of 5 mg/kg in A549 tumor xenograft models. Thus, compound MSN54 is a promising candidate for the development of novel antitumor agents.

Iodine(III)-Mediated Fluorination/Semipinacol Rearrangement Cascade of 2-Alkylidenecyclobutanol Derivatives: Access to ß-Monofluorinated Cyclopropanecarbaldehydes.

A hypervalent iodine(III)-mediated ring-contractive fluorination reaction of 2-alkylidenecyclobutanol derivatives is presented. The protocol allows the facile synthesis of ß-monofluorinated cyclopropanecarbaldehydes via a fluorination/semipinacol rearrangement cascade using nucleophilic Py·HF as the fluorine source. For challenging electron-rich arene substrates, the installation of a protecting group on the free alcohol is pivotal for maintaining the reaction efficiency. The synthetic utility was demonstrated by the scalability of this reaction and further transformations of the products.