Catalytic Synthesis of Trifluoromethyl Cyclopropenes and Oligo-Cyclopropenes.

The synthesis of trifluoromethylated cyclopropenes is often associated with important applications in drug discovery and functional materials. In this report, we describe the use of readily available chiral rhodium(II) catalysts for a highly efficient asymmetric cyclopropenation reaction of fluorinated donor-acceptor diazoalkanes with a broad variety of aliphatic and aromatic alkynes. Further studies highlight the unique reactivity of fluorinated donor-acceptor diazoalkanes in the synthesis of oligo-cyclopropenes. Subsequent C-H functionalization of trifluoromethyl cyclopropenes furnishes densely substituted cyclopropene frameworks and also allows the alternative synthesis of bis-cyclopropenes.

Tryptamine Synthesis by Iron Porphyrin Catalyzed C-H Functionalization of Indoles with Diazoacetonitrile.

The functionalization of C-H bonds with non-precious metal catalysts is an important research area for the development of efficient and sustainable processes. Herein, we describe the development of iron porphyrin catalyzed reactions of diazoacetonitrile with N-heterocycles yielding important precursors of tryptamines, along with experimental mechanistic studies and proof-of-concept studies of an enzymatic process with YfeX enzyme. By using readily available FeTPPCl, we achieved the highly efficient C-H functionalization of indole and indazole heterocycles. These transformations feature mild reaction conditions, excellent yields with broad functional group tolerance, can be conducted on gram scale, and thus provide a unique streamlined access to tryptamines.

The Generation of Diazo Compounds in Continuous-Flow.

Toxic, cancerogenic and explosive-these attributes are typically associated with diazo compounds. Nonetheless, diazo compounds are nowadays a highly demanded class of reagents for organic synthesis, yet the concerns with regards to safe and scalable transformations of these compounds are still exceptionally high. Lately, the research area of the continuous-flow synthesis of diazo compounds attracted significant interest and a whole variety of protocols for their "on-demand" preparation have been realized to date. This concept article focuses on the recent developments using continuous-flow technologies to access diazo compounds; thus minimizing risks and hazards when working with this particular class of compounds. In this article we discuss these concepts and highlight different pre-requisites to access and to perform downstream functionalization reaction.

Iron-catalysed carbene-transfer reactions of diazo acetonitrile.

A continuous-flow protocol for the synthesis of diazo acetonitrile was developed. It was further applied in iron-catalysed insertion reactions of diazo acetonitrile into N-H and S-H bonds to yield valuable α-substituted acetonitrile, including gram-scale synthesis.

Corey-Chaykovsky Reactions of Nitro Styrenes Enable cis-Configured Trifluoromethyl Cyclopropanes.

Trifluoromethyl-substituted cyclopropanes are an attractive family of building blocks for the construction of pharmaceutical and agrochemical agents. This work demonstrated the utilization of fluorinated sulfur ylides as versatile reagents for Corey-Chaykovsky cyclopropanation reactions of nitro styrenes. This protocol favored the synthesis of cis-configured trifluoromethyl cyclopropanes for a broad range of substrates with excellent yields and good diastereoselectivities.

Enantioselective [2,3]-Sigmatropic Rearrangements: Metal-Bound or Free Ylides as Reaction Intermediates?

Out of bounds: Enantioselective rearrangement reactions are a long-standing challenge in organic synthesis. Recent advances are highlighted that led to the development of the first enantioselective Doyle-Kirmse reaction and enantioselective rearrangement reactions of iodonium ylides.

Fluoroalkyl-Substituted Diazomethanes and Their Application in a General Synthesis of Pyrazoles and Pyrazolines.

A novel continuous-flow approach for the synthesis of fluoroalkyl-substituted diazomethanes has been developed. Utilizing a cheap, self-made microreactor fluoroalkyl-substituted amines were transformed into the corresponding diazomethanes using tert-butyl nitrite and acetic acid as catalyst. These diazomethanes were employed in [2+3] cycloaddition reactions with olefins and alkynes, yielding valuable pyrazolines and pyrazoles in good to excellent yields.

Structural Modifications Yield Novel Insights Into the Intriguing Pharmacodynamic Potential of Anti-inflammatory Nitro-Fatty Acids.

Endogenous nitro-fatty acids (NFA) are potent electrophilic lipid mediators that exert biological effects in vitro and in vivo via selective covalent modification of thiol-containing target proteins. The cytoprotective, anti-inflammatory, and anti-tumorigenic effects of NFA in animal models of disease caused by targeted protein nitroalkylation are a valuable basis for the development of future anti-phlogistic and anti-neoplastic drugs. Considering the complexity of diseases and accompanying comorbidities there is an urgent need for clinically effective multifunctional drugs. NFA are composed of a fatty acid backbone containing a nitroalkene moiety triggering Michael addition reactions. However, less is known about the target-specific structure-activity relationships and selectivities comparing different NFA targets. Therefore, we analyzed 15 NFA derivatives and compared them with the lead structure 9-nitro-oleic acid (9NOA) in terms of their effect on NF-κB (nuclear factor kappa B) signaling inhibition, induction of Nrf-2 (nuclear factor erythroid 2-related factor 2) gene expression, sEH (soluble epoxide hydrolase), LO (lipoxygenase), and COX-2 (cyclooxygenase-2) inhibition, and their cytotoxic effects on colorectal cancer cells. Minor modifications of the Michael acceptor position and variation of the chain length led to drugs showing increased target preference or enhanced multi-targeting, partly with higher potency than 9NOA. This study is a significant step forward to better understanding the biology of NFA and their enormous potential as scaffolds for designing future anti-inflammatory drugs.

Dealkylative intercepted rearrangement reactions of sulfur ylides.

Sulfur ylides are well-known to undergo sigmatropic rearrangement reaction. Herein, we describe a novel reactivity of sulfur ylides, which provides access to the product of a formal functional group metathesis upon dealkylative interception of the rearrangement process. Using a simple iron catalyst and in situ generated diazoalkanes this method provides access to α-mercaptoacetonitrile derivatives.

Nickel-catalyzed C-N bond activation: activated primary amines as alkylating reagents in reductive cross-coupling.

Nickel-catalyzed reductive cross coupling of activated primary amines with aryl halides under mild reaction conditions has been achieved for the first time. Due to the avoidance of stoichiometric organometallic reagents and external bases, the scope regarding both coupling partners is broad. Thus, a wide range of substrates, natural products and drugs with diverse functional groups are tolerated. Moreover, experimental mechanistic investigations and density functional theory (DFT) calculations in combination with wavefunction analysis have been performed to understand the catalytic cycle in more detail.

Cyanomethyl anion transfer reagents for diastereoselective Corey-Chaykovsky cyclopropanation reactions.

A readily available and bench-stable cyanomethyl sulfonium salt was used in highly diastereoselective Corey-Chaykovsky cyclopropanation reactions of electron-poor olefins. This efficient method provides a rapid route to access densely functionalized cyclopropyl nitriles.

Anti-inflammatory nitro-fatty acids suppress tumor growth by triggering mitochondrial dysfunction and activation of the intrinsic apoptotic pathway in colorectal cancer cells.

Nitro-fatty acids (NFAs) are endogenously occurring lipid mediators exerting strong anti-inflammatory effects and acting as anti-oxidants in a number of animal models of inflammation. These NFA effects are mediated by targeting important regulatory proteins involved in inflammatory processes, such as 5-lipoxygenase, soluble epoxide hydrolase, or NF-κB. In the present study, we investigated the anti-tumorigenic effects of NFAs on colorectal cancer (CRC) cells in cell culture-based experiments and in a murine xenograft model of human CRC. We could show that 9-NOA suppresses the viability of CRC cells (HCT-116 and HT-29) by inducing a caspase-dependent apoptosis via the intrinsic apoptotic pathway. Co-treatment with the pan-caspase inhibitor Q-VD-OPH counteracted the NFA-mediated apoptosis in both cell lines. Furthermore, NFAs affected the cell cycle transition and reduced the oxygen consumption rate (OCR) immediately. On the contrary to their well-known anti-oxidative properties, NFAs mediated the generation of mitochondrial oxidative stress in human CRC cells. Additionally, similar to the cytostatic drug mitomycin, 9-NOA significantly reduced tumor growth in a murine xenograft model of human colorectal cancer. In contrast to the established cytostatic drug, 9-NOA treatment was well tolerated by mice. This study delivers a novel mechanistic approach for nitro-fatty acid-induced inhibition of CRC cell growth by targeting mitochondrial functions such as the mitochondrial membrane potential and mitochondrial respiration. We suggest these naturally occurring lipid mediators as a new class of well tolerated chemotherapeutic drug candidates for treatment of CRC or potentially other inflammation-driven cancer types.

Enabling iron catalyzed Doyle-Kirmse rearrangement reactions with in situ generated diazo compounds.

Slow addition of sodium nitrite allows the in situ preparation of highly explosive diazo compounds and enables their safe and scalable application in iron catalyzed rearrangement reactions of allylic and propargylic sulfides. With catalyst loadings as low as 0.1 mol% an effective entry into α-mercapto-nitriles, α-mercapto-esters and α-trifluoromethyl-sulfides on a gram-scale is achieved.

Rhodium catalyzed synthesis of difluoromethyl cyclopropanes.

Difluoromethyl-substituted cyclopropanes still remain one of the most challenging class of substrates. Despite significant progress in modern chemistry, an atom-economic and concise synthesis has not been described to date. Herein, we describe the first method for their catalytic, one-step synthesis using difluoromethyl diazomethane and a rhodium(ii) catalyst.