Enantioselective Radical Reactions Using Chiral Catalysts.

Benefiting from the impressive increase in fundamental knowledge, the last 20 years have shown a continuous burst of new ideas and consequently a plethora of new catalytic methods for enantioselective radical reactions. This review aims to provide a complete survey of progress achieved over this latter period. The first part of this review focuses on the use of chiral organocatalysts, and these include catalysts covalently linked to the substrate and those that interact with the substrate by weaker interactions like hydrogen bonds. The second part of the review is devoted to transition-metal redox catalysis which is organized according to increasing atomic number for the first-row transition metals (Ti, Cr, Fe, Mn, Co, Ni, Cu). Bioinspired manganese- and iron-mediated hydroxylations and oxidations are also discussed. A specific section is dedicated to the reactivity of Ru, Rh, and Ir complexes as Lewis acids with a special focus on complexes chiral at metal. Absorption of photons result in different events such as energy transfer, single-electron transfer, and hydrogen-atom transfer facilitating the formation of radicals. Organocatalysis has been successfully combined with photocatalysts, a reactivity which has opened new pathways enlarging the number of radical precursors available. The merger of photocatalysis with organo- or metalla-photocatalysis has brought novelty and allowed for the discovery of a large number of original transformations. The use of enzyme-catalyzed reactions involving radical intermediates which also largely benefit from visible-light irradiation are included in the review. This review provides a comprehensive inventory of progress in enantioselective radical reactions with a goal of detailing the reaction mechanisms involved in these transformations such that any nonspecialist could find their own creativity to invent yet unknown applications.

One-pot Sonogashira coupling-cyclization toward regioselective synthesis of benzosultams.

A one-pot method for the Sonogashira coupling and cyclization of 2-bromobenzenesulfonamides and terminal alkynes is presented. This method allows access to a variety of substituted benzosultams regioselectively in excellent yields. The reasons for regioselectivity are interpreted through density functional theory (DFT) studies.

1,n-Hydrogen-atom transfer (HAT) reactions in which n≠5: an updated inventory.

Hydrogen-atom transfer (HAT) counts amongst the most widely investigated routes to carbon-centered radicals. Intramolecular processes involving 1,5-HAT are widespread to promote regioselective radical "CH activation". The aim of this review is to draw up a comprehensive inventory of the less commonly encountered 1,n-radical translocations (n≠5) with the aim to update this topic with the most recent relevant data.

Theoretical study to explain how chirality is stored and evolves throughout the radical cascade rearrangement of enyne-allenes.

This article reports a theoretical study to explain how the intrinsic property of chirality is retained throughout the radical cascade rearrangement of an enantiopure chiral enyne-allene (bearing one stereogenic center) selected as a model for this family of reactions. Calculations at the MRPT2/6-31G(d)//CASSCF(10,10)/6-31G(d) level of theory were used to determine the entire reaction pathway which includes singlet state diradicals and closed-shell species. The cascade process involves three elementary steps, i.e., by chronological order: Myers-Saito cycloaromatization (M-S), intramolecular hydrogen atom transfer (HAT), and recombination of the resulting biradical. The enantiospecificity of the reaction results from a double transmission of the stereochemical information, from the original center to an axis and eventually from this axis to the final center. The first two steps lead to a transient diradical intermediate which retains the chirality via the conversion of the original static chirogenic element into a dynamic one, i.e., a center into an axis. The only available routes to the final closed-shell tetracyclic product imply rotations around two σ bonds (σ(C-C) and σ(C-N), bonds ß and α respectively). The theoretical calculations confirmed that the formation of the enantiomerically pure product proceeds via the nonracemizing rotation around the σ(C-C) pivot. They ruled out any rotation around the second σ(C-N) pivot. The high level of configurational memory in this rearrangement relies on the steric impediment to the rotation around the C-N bond in the chiral native conformation of the diradical intermediate produced from tandem M-S/1,5-HAT.

Cooperative use of VCD and XRD for the determination of tetrahydrobenzoisoquinolines absolute configuration: a reliable proof of memory of chirality and retention of configuration in enediyne rearrangements.

The absolute configurations (AC) of azaheterocylic compounds resulting from the cascade rearrangement of enediynes involving only light atoms were unambiguously assigned by the joint use of vibrational circular dichroism (VCD) and copper radiation single crystal X-ray diffraction (XRD). These AC determinations proved that the rearrangements of enediynes proceeded with memory of chirality and retention of configuration.

Mechanistic investigation of enediyne-connected amino ester rearrangement. Theoretical rationale for the exclusive preference for 1,6- or 1,5-hydrogen atom transfer depending on the substrate. A potential route to chiral naphthoazepines.

Memory of chirality (MOC) and deuterium-labeling studies were used to demonstrate that the cascade rearrangement of enediyne-connected amino esters 1a and 1b evolved through exclusive 1,5- or 1,6-hydrogen atom transfer, subsequent to 1,3-proton shift and Saito-Myers cyclization, depending on the structure of the starting material. These results were independently confirmed by DFT theoretical calculations performed on model monoradicals. These calculations clearly demonstrate that in the alanine series, 1,5-hydrogen shift is kinetically favored over 1,6-hydrogen shift because of its greater exergonicity. In the valine series, the bulk of the substituent at the nitrogen atom has a major influence on the fate of the reaction. N-Tosylation increases the barrier to 1,5-hydrogen shift to the benefit of 1,6-hydrogen shift. The ready availability of 1,6-hydrogen atom transfer was explored as a potential route for the enantioselective synthesis of naphthoazepines.

Quinolone-fused cyclic sulfonamide as a novel benign antifilarial agent.

Search of potent antifilarial drugs has been a major thrust area in tropical medicine research over the decades. Herein, we report 4,7-dimethyl-3,4,7,8-tetrahydro-3λ6-[1,2]thiazino[4,3-f]quinoline-3,3,8-trione (8l) as a new class of antifilarial agent which is extremely potent, with lethality against all the developmental stages (oocyte, microfilaria and adult) of the filarial parasite Setaria cervi. Molecular investigation on its mode of action revealed that 8l is a typical inducer of reactive oxygen species that triggers oxidative stress inside the filarid and further signals induction of apoptosis by activating both intrinsic and extrinsic pathways. Moreover, 8l is also active against Wolbachia, the essential endosymbiont of several human infectious filarids. Selective toxicity against filarial parasites and non-toxic nature in rat model were found as unique traits of 8l to be a future medicine. Taken en masse, this maiden report on a novel quinolone fused cyclic sulfonamide presents a promising therapeutic lead for lymphatic filariasis in future.

Enediynes bearing polyfluoroaryl sulfoxide as new antiproliferative agents with dual targeting of microtubules and DNA.

A novel series of enediynes possessing pentafluorophenylsulfoxide have been developed. The innovative compounds possess antiproliferative activity against a broad panel of human cancer cells originating from breast, blood, lung, kidney, colon, prostate, pancreas or skin with IC50 ranging from 0.6 to 3.4 µM. The antiproliferative activity of enediynes in darkness is associated to their ability to compromise microtubule network. In addition, exposure to UV leads to double-stranded DNA cleavage caused by the newly synthesized molecules reducing further their IC50 in nanomolar range against human tumor cells, including chemo-resistant pancreatic cancer cells. Taken together, the examined data demonstrate that enediynes possessing pentafluorosulfoxide are promising molecules in the cancer therapy.

Spectroscopic, electrochemical and molecular docking study of the binding interaction of a small molecule 5H-naptho[2,1-f][1,2] oxathieaphine 2,2-dioxide with calf thymus DNA.

The interaction of 5H-naptho[2,1-f][1,2]oxathieaphine2,2-dioxide (NOTD) with calf thymus DNA in Tris-HCl buffer at physiological pH was investigated with the help of various spectroscopic and electrochemical methods along with molecular docking study. Studying the non-covalent binding interaction of a neutral fluorophore with ctDNA has become an active field of research at the interface between medicinal chemistry and biological science. NOTD is known for its various toxicological, skin sensitization, and antiviral properties. Still, to date, its interaction style with ctDNA is not well elucidated. UV-vis absorption, fluorescence emission and circular dichroism spectroscopy (CD) suggest the complex formation between NOTD and ctDNA with binding constant value in the order of 3.12-4.1(×104)M-1. Binding nature of NOTD with ctDNA is affirmed from the DNA helix melting experiment, comparative displacement assay using known DNA intercalator, cyclic voltammetry and finally molecular docking study. It was evident from experimental result that the probe NOTD binds with ctDNA in groove binding mode as manifested by a decrease in iodide quenching effect, spectral change in CD, a substantial increase in denaturing temperature in DNA and change in potential value. Furthermore, the molecular docking study insisted the above mentioned experimental result in a very affectionate way.

Photoactivated cyclization of aryl-containing enediynes coated gold nanoparticles: enhancement of the DNA cleavage ability of enediynes.

Two novel enediynes containing an aromatic ring and substituted by two thiol functions as end-groups were designed and studied as functionalizing agent of gold nanoparticles. Phototriggered cyclization of the capping agent under UV-visible irradiation was investigated. Interestingly, the length of the thiol-substituted chain was shown to influence significantly the cyclization rate. Depending on the length of the spacer, either polymerization or simple cyclization of the coating agent was evidenced. The present study underscores the possibility of finely controlling the fate of the coating agent (polymerization/cyclization). Nanocomposites were characterized by UV-visible absorption spectroscopy, dynamic light scattering (DLS) technique and transmission electron microscopy (TEM) measurements. Finally, the ability of the colloidal solutions to induce photoinitiated damages to PcDNA3 supercoiled DNA was evaluated. Interestingly, an increase as high as 50% of the DNA cleavage could be registered when adding enediynes-capped gold nanoparticles to solutions of enediynes. In particular, the enhancement of DNA scission was observed in both thermal and photochemical activation modes.

One-pot Crabbé homologation-radical cascade cyclisation with memory of chirality.

The tandem Crabbé homologation-radical rearrangement of terminal enediynes leads, in a one-pot procedure, to the enantioselective synthesis of six- and seven-membered ring α-aminoesters bearing a quaternary stereocenter based on the phenomenon of memory of chirality.