Alkene Trifluoromethylation-Initiated Remote α‑Azidation of Carbonyl Compounds toward Trifluoromethyl γ‑Lactam and Spirobenzofuranone-Lactam

The first unprecedented one-pot domino strategy toward diverse CF₃-containing γ-lactam and spirobenzofuranone-lactam scaffolds of antibacterial armeniaspirole from readily available acyclic precursors was developed. The key point of this transformation was the concurrent incorporation of CF₃ and azide into the alkene and remote carbonyl α-C–H position via carbonyl-stabilized radical intermediate triggered by alkene trifluoromethylation via a 1,5-H shift in a highly controlled site-selective manner. Furthermore, gram-scale synthesis and synthetic applicability of these compounds proved suitable

Activated Yki promotes fat storage and rescues the reduction of lipid content caused by ectopic Hpo in expression <i>Drosophila melanogaster</i>.

<p>(a–b) Gain-of-function of Yki elevates triglyceride content of larvae. Triglyceride content of male (a) and female (b) third instar larvae was examined. Note that activated Yki (Yki(S168A)) dramatically increased larval fat storage. (c–d) Gain-of-function of Yki elevates triglyceride content of adult flies. Triglyceride content of five to seven-day old male (a) and female (b) flies was quantified. Note the increase in fat content when ectopic Yki(S168A) is expressed. (e) Activating Yki suppresses the effect of Hpo on fat storage. Triglyceride content of five to seven-day old male flies expressing the indicated transgenes was analyzed. Note that overexpression of Hpo specifically in the fat body reduced fat storage, while coexpressing Yki(S168A) rescued this phenotype. Data were illustrated as mean ± SEM from three independent experiment. *p<0.05, n>6 for each genotype. (f) Ectopic Yki(S168A) promotes fly survival under starvation conditions. Adult flies expressing the indicated <i>Dcg-Gal4</i>-driven transgenes were starved, and the survival rate was examined. Note that expression of Yki(S168A) extended the survival time of flies. In addition, Yki(S168A) could reverse the pro-death effect of Hpo.</p

Activating Hpo inhibits fat accumulation in <i>Drosophila melanogaster</i>.

<p>(a) Ectopic Hpo reduces larval body size and fat body reporter signal. Larvae carrying a fat body GFP reporter (Dcg-GFP) expressing either control or Hpo transgene driven by <i>Dcg-Gal4</i> in fat body were photographed under bright field (left) or GFP fluorescence (right) microscopy. Note that body size and GFP fluorescence signal were decreased by Hpo overexpression. (b) Ectopic Hpo results in decrement of larval triglyceride content. Triglyceride content of third instar larvae expressing either control or Hpo transgene driven by <i>Dcg-Gal4</i> was quantified (data were expressed as mean ± SEM from three independent experiments. *p<0.05, n>6 for each genotype). (c) Ectopic Hpo expression results in small body size in adult flies. The photograph was taken from well-fed female adults expressing control or Hpo transgene under the control of <i>Dcg-Gal4</i>. (d) Ectopic Hpo reduces adult body weight. Body weights of five to seven-day-old adults expressing control or Hpo transgene were examined. Data were expressed as mean ± SEM from three independent experiment. *p<0.05 **p<0.01, n>20 for each genotype. (e) Ectopic Hpo causes decrement of triglyceride content in adult flies. Triglycerides of five to seven-day-old adults were quantified. Note that overexpression of Hpo significantly inhibits fat storage in adult male flies. (f) Ectopic Hpo leads to early death in starved flies. Five to seven-day-old male adults were deprived of food and their survival rate was plotted. Note that gain-of-function of Hpo led to more rapid death compared to the control group.</p

Inactivation of Hpo promotes fat storage in <i>Drosophila melanogaster</i>.

<p>(a) Compromised Hpo expression elevates larval body size and fat body reporter signal. Third instar larvae carrying a fat body GFP reporter (Dcg-GFP) expressing either control or <i>Hpo-RNAi</i> transgene driven by <i>Dcg-Gal4</i> in fat body were photographed under bright field (left) or GFP fluorescence (right) microscopy. Note that body size and GFP fluorescence were increased by knockdown of Hpo. (b–c) Inactivation of Hpo in the fat body produces obesity in adult flies. The body weight (b) and triglyceride content (c) of adult flies expressing either control or <i>Hpo-RNAi</i> transgene were quantified. Note that both body weight and fat content were increased by restricting Hpo expression. Data were illustrated as mean ± SEM from three independent experiments. *p<0.05, n>20 (b) and n>6 (c) for each genotype. (d) Knockdown of Hpo extends survival rate of starved flies. Five to seven-day-old male adults expressing control or <i>Hpo-RNAi</i> were deprived of food, and a survival curve was drawn by calculating number of the deaths every eight hours.</p

Hpo controls fat cell number to affect fat storage.

<p>(a–b) Ectopic Hpo decreases fat cell number. Hpo or control transgenes were expressed in the fat body by crossing with a fat body specific driver, <i>Dcg-Gal4</i>. To quantify fat cells, the genomic DNA of third instar larvae was extracted and quantified. Note that DNA content of both male (a) and female (b) larvae was reduced upon overexpression of Hpo. (c–d) Knockout of Hpo promotes fat cell proliferation. Mosaic analysis with a repressible cell marker (MARCM) technology was utilized to generate clones in fat body. Note that clones lacking Hpo grew larger than control clones. (e) Quantification of clone size. The number of GFP positive cells within one clone was counted. More than 20 independent microscopic fields from more than six larval fat bodies of each genotype were counted. The data were calculated as follows: the number of GFP positive cells within one clone divided by the total number of GFP positive cells in one independent microscopic field. The data were expressed as mean ± SEM, *p<0.05.</p

Metal-Free Direct 1,6- and 1,2-Difunctionalization Triggered by Radical Trifluoromethylation of Alkenes

A metal-free direct remote C–H functionalization triggered by radical trifluoromethylation of alkenes was explored, realizing highly selective 1,6-difunctionalization of alkenes toward valuable trifluoromethyl α-hydroxycarbonyl compounds. Furthermore, a metal-free direct intermolecular regioselective 1,2-oxytrifluoromethylation of alkenes is also disclosed. With Togni’s reagent as both the CF₃ source and oxidant, the reaction exhibits a broad substrate scope with excellent functionality tolerance under mild metal-free conditions, thus showing great potential for synthetic utility

Metal-Free Direct 1,6- and 1,2-Difunctionalization Triggered by Radical Trifluoromethylation of Alkenes

A metal-free direct remote C–H functionalization triggered by radical trifluoromethylation of alkenes was explored, realizing highly selective 1,6-difunctionalization of alkenes toward valuable trifluoromethyl α-hydroxycarbonyl compounds. Furthermore, a metal-free direct intermolecular regioselective 1,2-oxytrifluoromethylation of alkenes is also disclosed. With Togni’s reagent as both the CF₃ source and oxidant, the reaction exhibits a broad substrate scope with excellent functionality tolerance under mild metal-free conditions, thus showing great potential for synthetic utility

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

Transition-Metal-Free β‑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 β-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 <i>N</i>-ethylamides involving the functionalization of one C_sp2–H, one C_sp3–H, one C_sp2–H, and three C_sp3–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

Nickel(0)-Catalyzed Denitrogenative Transannulation of Benzotriazinones with Alkynes: Mechanistic Insights of Chemical Reactivity and Regio- and Enantioselectivity from Density Functional Theory and Experiment

The mechanism of Ni(0)-catalyzed denitrogenative transannulation of 1,2,3-benzotriazin-4­(<i>3H</i>)-ones with alkynes to access isoquinolones has been comprehensively studied by a density functional theory (DFT) calculation and control experimental investigation. The results indicate that the transformations proceed via a sequential nitrogen extrusion, carbometalation, Ni–C bond insertion, and reductive elimination process. A frontier molecular orbital (FMO) theory and natural bond orbital (NBO) analysis reveals that the advantages of substituents on chemical reactivity and regioselectivity exist for multiple reasons: (1) Phenyl groups on the N atom of benzotriazinone and/or unsymmetrical alkynes mainly account for the high reactivity and regioselectivity via its electronic effect. (2) The π···π interaction between the phenyl substituent on the alkyne and triazole ring might partially contribute to the high regioselectivity when unsymmetrical alkynes were employed as the substrates. Furthermore, DFT calculations successfully explain the origin of enantioselectivity and discrepancy of reactivities between different <i>N</i>-substituted benzotriazinones for the asymmetric construction of axially chiral isoquinolones in an atroposelective manner. The calculated results indicate that high enantioselectivity is mainly determined by the structural difference between these two transition states of the key annulation step, which lies in the orientation of the naphthyl substituent relative to the chiral ligand