Synthesis of α-Amino Tertiary Alkylperoxides by Lewis Acid-Catalyzed Peroxidation of 1,3,5-Triazines.

α-Substituted peroxides have been found in natural products and are widely used as anti-malarial agents. Zn(OTf)2 -catalyzed peroxidation of 1,3,5-triazines has been developed, accessing diversely substituted α-amino tertiary alkylperoxides with high efficiency. Mechanistic investigations and useful synthetic application of the products have also been presented.

Label-free fluorescence detection of circulating microRNAs based on duplex-specific nuclease-assisted target recycling coupled with rolling circle amplification.

A simpler, more rapid and selective biosensor has been developed for the sensitive detection of circulating miRNAs (c-miRNAs) based on duplex-specific nuclease (DSN)-assisted target recycling coupled with rolling circle amplification (RCA) using SYBR Gold Dye as a signal indicator. This biosensor exhibits a tremendously low detection limit of 0.3 fM of c-miRNAs and shows high selectivity for one-base mismatched c-miRNA. In addition, most importantly, the biosensor could accurately determine the amounts of target c-miRNA in total c-miRNAs isolated from human serums and human cancer cell lines, which confirms that the biosensor could be used to quantify c-miRNAs in complex biological samples and for the clinical early diagnosis of cancers based on c-miRNAs detection.

Development of a versatile DNMT and HDAC inhibitor C02S modulating multiple cancer hallmarks for breast cancer therapy.

DNMT and HDAC are closely related to each other and involved in various human diseases especially cancer. These two enzymes have been widely recognized as antitumor targets for drug discovery. Besides, research has indicated that combination therapy consisting of DNMT and HDAC inhibitors exhibited therapeutic advantages. We have reported a DNMT and HDAC dual inhibitor 15a of which the DNMT enzymatic inhibitory potency needs to be improved. Herein we reported the development of a novel dual DNMT and HDAC inhibitor C02S which showed potent enzymatic inhibitory activities against DNMT1, DNMT3A, DNMT3B and HDAC1 with IC50 values of 2.05, 0.93, 1.32, and 4.16 µM, respectively. Further evaluations indicated that C02S could inhibit DNMT and HDAC at cellular levels, thereby inversing mutated methylation and acetylation and increasing expression of tumor suppressor proteins. Moreover, C02S regulated multiple biological processes including inducing apoptosis and G0/G1 cell cycle arrest, inhibiting angiogenesis, blocking migration and invasion, and finally suppressing tumor cells proliferation in vitro and tumor growth in vivo.

Chiral Brønsted Acid Catalyzed Dynamic Kinetic Asymmetric Hydroamination of Racemic Allenes and Asymmetric Hydroamination of Dienes.

The first highly efficient and practical chiral Brønsted acid catalyzed dynamic kinetic asymmetric hydroamination (DyKAH) of racemic allenes and asymmetric hydroamination of unactivated dienes with both high E/Z selectivity and enantioselectivity are described herein. The transformation proceeds through a new catalytic asymmetric model involving a highly reactive π-allylic carbocationic intermediate, generated from racemic allenes or dienes through a proton transfer mediated by an activating/directing thiourea group. This method affords expedient access to structurally diverse enantioenriched, potentially bioactive alkenyl-containing aza-heterocycles and bicyclic aza-heterocycles.

Cu/Chiral Phosphoric Acid-Catalyzed Asymmetric Three-Component Radical-Initiated 1,2-Dicarbofunctionalization of Alkenes.

An asymmetric intermolecular, three-component radical-initiated dicarbofunctionalization of 1,1-diarylalkenes with diverse carbon-centered radical precursors and electron-rich heteroaromatics by a copper(I) and chiral phosphoric acid cooperative catalysis strategy has been developed, providing straightforward access to chiral triarylmethanes bearing quaternary all-carbon stereocenters with high efficiency as well as excellent chemo- and enantioselectivity. The key to success is not only the introduction of a sterically demanding chiral phosphoric acid to favor radical difunctionalization over the otherwise remarkable side reactions but also the in situ generation of carbocation intermediates from benzylic radical to realize asymmetric induction with the aid of a removable hydroxy directing group via cooperative interactions with chiral phosphate. Density functional theory calculations elucidated the critical chiral environment created by the hydrogen-bonding and ion-pair interactions between the chiral phosphoric acid catalyst and substrates, which leads to the enantioselective C-C bond formation.

Branched rolling circle amplification method for measuring serum circulating microRNA levels for early breast cancer detection.

Serum circulating microRNAs (c-miRNAs) are serving as useful biomarkers for cancer diagnosis. Here, we describe the development of a one-step branched rolling circle amplification (BRCA) method to measure serum c-miRNAs levels for early diagnosis of breast cancer. Four c-miRNAs, c-miRNA16 (c-miR-16), c-miRNA21 (c-miR-21), c-miRNA155 (c-miR-155), and c-miRNA195 (c-miR-195) were isolated from the serum of 49 breast cancer patients and 19 healthy controls. Among them, 45 breast cancer patients and 15 healthy controls were analyzed using one-step BRCA, 4 breast cancer patients and 4 healthy controls were analyzed by quantitative real-time PCR assay [corrected]. The serum levels of c-miR16, c-miR21, c-miR155, and c-miR195 were higher (P < 0.0001) in stage I breast cancer patients than healthy controls. These levels were also higher in several breast cancer molecular subtypes (HER-2 over-expression, Luminal A, Luminal B, and triple negative breast cancer) than in healthy control subjects. The diagnostic accuracy of c-miR16, c-miR21, c-miR155, and c-miR195 for early diagnosis of breast cancer was confirmed by receiver operating characteristic (ROC) curve assay. These results show that the BRCA method can be used to measure serum c-miRNAs levels, and that this method has high accuracy, sensitivity, and specificity. Moreover, both BRCA approach and quantitative real-time PCR (qRT-PCR) method show that the serum levels of c-miR16, c-miR21, c-miR155, and c-miR195 could be used as biomarkers to improve the early diagnosis of breast cancer, and distinguish different breast cancer molecular subtypes.

Transition-Metal-Free ß-C-H Bond Carbonylation of Enamides or Amides with a Trifluoromethyl Group as CO Surrogate for the Synthesis of 1,3-Oxazin-6-ones.

A cascade ß-C-H bond trifluoromethylation/C(sp3)-F bond activation/hydrolysis reaction of enamides with Togni's reagent has been disclosed. This formal C-H bond carbonylation reaction utilizes the CF3 group as a CO surrogate to provide an efficient approach to 1,3-oxazin-6-ones in satisfactory yields. Furthermore, CF3-containing 1,3-oxazin-6-ones could also be accessed using this method by using alkenyl N-ethylamides involving the functionalization of one Csp2-H, one Csp3-H, one Csp2-H, and three Csp3-F bonds. The broad substrate scope of this method enables access to synthetically or pharmaceutically important compounds, which are difficult to access by known methods.

Catalytic asymmetric radical aminoperfluoroalkylation and aminodifluoromethylation of alkenes to versatile enantioenriched-fluoroalkyl amines.

Although great success has been achieved in asymmetric fluoroalkylation reactions via nucleophilic or electrophilic processes, the development of asymmetric radical versions of this type of reactions remains a formidable challenge because of the involvement of highly reactive radical species. Here we report a catalytic asymmetric radical aminoperfluoroalkylation and aminodifluoromethylation of alkenes with commercially available fluoroalkylsulfonyl chlorides as the radical sources, providing a versatile platform to access four types of enantioenriched α-tertiary pyrrolidines bearing ß-perfluorobutanyl, trifluoromethyl, difluoroacetyl and even difluoromethyl groups in excellent yields and with excellent enantioselectivity. The key to success is not only the introduction of the CuBr/chiral phosphoric acid dual-catalytic system but also the use of silver carbonate to suppress strong background and side hydroamination reactions caused by a stoichiometric amount of the in situ generated HCl. Broad substrate scope, excellent functional group tolerance and versatile functionalization of the products make this approach very practical and attractive.

Stereoselective Radical Cyclization Cascades Triggered by Addition of Diverse Radicals to Alkynes To Construct 6(5)-6-5 Fused Rings.

Cascade radical cyclization of alkynyl ketones with various carbon- and heteroatom-centered radical precursors via a sequential radical addition/1,5-H radical shift/5-exo-trig/radical cyclization process was realized for the first time. This method provides a strategically novel and step-economical protocol for diversity-oriented synthesis of a wide range of carbocyclic and heterocyclic 6(5)-6-5 fused ring systems with three contiguous stereocenters, including a quaternary carbon in high yields with excellent chemo- and diastereoselectivity.

A Dual-Catalytic Strategy To Direct Asymmetric Radical Aminotrifluoromethylation of Alkenes.

A novel asymmetric radical aminotrifluoromethylation of alkenes has been developed for the first time, providing straightforward access to densely functionalized CF3-containing azaheterocycles bearing an α-tertiary stereocenter with excellent enantioselectivity. The key to success is not only the introduction of a Cu(I)/chiral phosphoric acid dual-catalytic system but also the use of urea with two acidic N-H as both the nucleophile and directing group. The utility of this method is illustrated by facile transformations of the products into other important compounds useful in organic synthesis and medicinal chemistry.

Brønsted Acid Catalyzed Asymmetric Hydroamination of Alkenes: Synthesis of Pyrrolidines Bearing a Tetrasubstituted Carbon Stereocenter.

The first highly enantioselective Brønsted acid catalyzed intramolecular hydroamination of alkenes enables the efficient construction of a series of chiral (spirocyclic) pyrrolidines with an α-tetrasubstituted carbon stereocenter with excellent functional group tolerance. A unique feature of this strategy is the use of a thiourea group acting as both the activating and the directing group through cooperative multiple hydrogen bonding with a Brønsted acid and the double bond. The utility of this method is highlighted by the facile construction of chiral synthetic intermediates and important structural motifs that are widely found in organic synthesis.

Enantioselective C-H bond functionalization triggered by radical trifluoromethylation of unactivated alkene.

An asymmetric unactivated alkene/C-H bond difunctionalization reaction for the concomitant construction of C-CF3 and C-O bonds was realized by using a Cu/Brønsted acid cooperative catalytic system, thus providing facile access to valuable chiral CF3-containing N,O-aminals with excellent regio-, chemo-, and enantioselectivity. Mechanistic studies revealed that this reaction may proceed by an unprecedented 1,5-hydride shift involving activation of unactivated alkenes and a radical trifluoromethylation to initiate subsequent enantioselective functionalization of C-H bonds. Control experiments also suggested that chiral Brønsted acid plays multiple roles and not only controls the stereoselectivity but also increases the reaction rate through activation of Togni's reagent.

Copper-catalyzed aminotrifluoromethylation of unactivated alkenes with (TMS)CF3: construction of trifluoromethylated azaheterocycles.

The first example of a copper(I)-catalyzed intramolecular aminotrifluoromethylation of unactivated alkenes using (TMS)CF3 (trimethyl(trifluoromethyl)silane) as the CF3 source is described. A broad range of electronically and structurally varied substrates undergo convenient and step-economical transformations for the concurrent construction of a five- or six-membered ring and a C-CF3 bond toward different types of trifluoromethyl azaheterocycles. The methodology not only circumvents use of expensive electrophilic CF3 reagents or the photoredox strategy but also expands the scope to substrates that are difficult to access by the existing methods. Mechanistic studies are conducted, and a plausible mechanism is proposed.

Efficient copper-catalyzed direct intramolecular aminotrifluoromethylation of unactivated alkenes with diverse nitrogen-based nucleophiles.

A mild, convenient, and step-economical intramolecular aminotrifluoromethylation of unactivated alkenes with a variety of electronically distinct, nitrogen-based nucleophiles in the presence of a simple copper salt catalyst, in the absence of extra ligands, is described. Many different nitrogen-based nucleophiles (e.g., basic primary aliphatic and aromatic amines, sulfonamides, carbamates, and ureas) can be employed in this new aminotrifluoromethylation reaction. The aminotrifluoromethylation process allows straightforward access to diversely substituted CF3-containing pyrrolidines or indolines, in good to excellent yields, through a direct difunctionalization strategy from the respective acyclic starting materials. Mechanistic studies were conducted and a plausible mechanism was proposed.