Atom Transfer Radical Cyclization Research Articles

Microwave-Assisted Atom Transfer Radical Cyclization in the Synthesis of 3,3-Dichloro-γ- and δ-Lactams from N-Alkenyl-Tethered Trichloroacetamides Catalyzed by RuCl2(PPh3)3 and Their Cytotoxic Evaluation.

An expeditious synthesis of γ- and δ-lactams from tethered alkenyl trichloroacetamides in the presence of 5% of RuCl2(PPh3)3 is reported. In this investigation we have demonstrated that microwave activation significantly enhances reaction rates, leading to the formation of the corresponding lactams in yields ranging from good to excellent. Thus, we have been able to prepare a wide range of lactams, including indole and morphan bicyclic scaffolds, where the corresponding reactions were completely diastereoselective. This process was successfully extended to α,α-dichloroamides without affecting either their yield or their diastereoselectivity. Some of the lactams prepared in this work were evaluated for their hemolytic and cytotoxic responses. All compounds were found to be non-hemolytic at the tested concentration, indicating their safety profile in terms of blood cell integrity. Meanwhile, they exhibited interesting cytotoxicity responses that depend on both their lactam structure and cell line. Among the molecules tested, γ-lactam 2a exhibited the lowest IC50 values (100-250 µg/mL) as a function of its cell line, with promising selectivity against squamous carcinoma cells (A431) in comparison with fibroblasts (3T3 cell line).

Iron-Mediated Hydrogen Atom Transfer Radical Cyclization of Alkenyl Indoles and Pyrroles Gives Their Fused Derivatives: Total Synthesis of Bruceolline E and H

Iron-Mediated Hydrogen Atom Transfer Radical Cyclization of Alkenyl Indoles and Pyrroles Gives Their Fused Derivatives: Total Synthesis of Bruceolline E and H

Comparison of the Catalytic Activity of Surface-Immobilized Copper Complexes with Phosphonate Anchoring Groups for Atom Transfer Radical Cyclizations and Additions

Comparison of the Catalytic Activity of Surface-Immobilized Copper Complexes with Phosphonate Anchoring Groups for Atom Transfer Radical Cyclizations and Additions

Copper-catalysed bromine atom transfer cyclisation in SDS micelles.

The atom transfer radical cyclisation (ATRC) of non-activated alkyl bromides was realized under blue light irradiation in carbonate-buffered aqueous SDS solution using a catalytic system of CuBr2, Me6-TREN and ascorbic acid. The beneficial effect of SDS micelles can be accounted for by the activation of the C-Br bond as well as by the suppression of competitive reductive cyclisation.

Photochemically Induced Hydrogen Atom Transfer and Intramolecular Radical Cyclization Reactions with Oxazolones.

Photochemically induced intramolecular hydrogen atom transfer in oxazolones is reported. An acetal or thioacetal function at the side chain acts as a hydrogen donor while the photochemical exited oxazolone is the acceptor. A one-step process─the electron and the proton are simultaneously transferred─is productive, while electron transfer followed by proton transfer is inefficient. Radical combination then takes place, leading to the formation of a C-C or C-N bond. The regioselectivity of the reaction is explained by the diradical/zwitterion dichotomy of radical intermediates at the singlet state. In the present case, the zwitterion structure plays a central role, and intramolecular electron transfer favors spin-orbit coupling and thus the intersystem crossing to the singlet state. The reaction of corresponding thioacetal derivatives is less efficient. In this case, photochemical electron transfer is competitive. The photoproducts resulting from C-C bond formation easily undergo stepwise thermal decarboxylation in which zwitterionic and polar transition states are involved. A computational study of this step has also been performed.

P450-catalyzed atom transfer radical cyclization.

Cytochromes P450 have been extensively studied for both fundamental enzymology and biotechnological applications. Over the past decade, by taking inspiration from synthetic organic chemistry, new classes of P450-catalyzed reactions that were not previously encountered in the biological world have been developed to address challenging problems in organic chemistry and asymmetric catalysis. In particular, by repurposing and evolving P450 enzymes, stereoselective biocatalytic atom transfer radical cyclization (ATRC) was developed as a new means to impose stereocontrol over transient free radical intermediates. In this chapter, we describe the detailed experimental protocol for the directed evolution of P450 atom transfer radical cyclases. We also delineate protocols for analytical and preparative scale biocatalytic atom transfer radical cyclization processes. These methods will find application in the development of new P450-catalyzed radical reactions, as well as other synthetically useful processes.

Copper-mediated bromine atom transfer radical cyclisation of unactivated alkyl bromides.

The atom transfer radical cyclisation of unactivated alkyl bromides was realized by using a catalytic system of CuBr and Me6-TREN. This protocol is applicable to the preparation of five-membered rings from unsaturated primary and secondary bromides.

Surface immobilized Cu-1,10-phenanthroline complexes with α-aminophosphonate groups in the 5-position as heterogenous catalysts for efficient atom-transfer radical cyclizations.

Many Cu catalyzed ATRC reactions suffer from low catalyst activity and stability. We have synthesized five 1,10-phenanthroline ligands substituted in the 5-position with α-aminophosphonate groups, through which the corresponding Cu complexes can be immobilized on Al2O3. These catalysts show similar activity and higher selectivity than the homogenous catalysts while being recyclable.

Superfast desulfurization for protein chemical synthesis and modification

Superfast desulfurization for protein chemical synthesis and modification

Cu- or Fe-catalyzed Atom-Transfer Radical Reactions in Cyclizations

Abstract Herein, we report an efficient method using transition metal catalysts for controlling atom-transfer radical cyclization elimination (ATRCE) and atom-transfer radical cyclization (ATRC) in the reaction of α-bromocarbonyls possessing a styrene moiety. An iron salt efficiently catalyzed the ATRCE to produce cyclic compounds possessing a C-C double bond. On the other hand, the copper catalyst produced halogenated cyclic compounds.

Rates and Yields of Unimolecular Reactions Producing Highly Oxidized Peroxy Radicals in the OH-Induced Autoxidation of α-Pinene, β-Pinene, and Limonene.

Recent ambient atmospheric measurements have detected highly oxygenated organic molecules (HOMs) at many sites and are a consequence of autoxidation processes occurring at ambient temperatures. Monoterpenes in particular have a propensity to autoxidize although they exhibit a wide range of HOM yields, which may be due to a variety of reasons including reactions with different oxidants like OH and O3, differing hydrogen (H) atom transfer or peroxy radical cyclization rates, numbers of available reaction pathways, and/or energy loss processes for activated HO-monoterpene or O3-monoterpene adducts. In this work, the autoxidation mechanisms of (+)-α-pinene, (+)-β-pinene, and (+)-limonene following initial OH oxidation and three successive O2 additions are examined using density functional theory (DFT) to understand what accounts for the disparity. Rates of different potential autoxidation pathways initiated by OH addition or abstraction reactions are quantified using transition-state theory (TST) and master equation approaches using the lowest-energy conformers. OH abstraction reactions do not appreciably influence HOM production in the pinenes and limit autoxidation for limonene because the subsequent autoxidation reactions are slow while OH addition reactions are found to be the main route to HOMs for all three monoterpenes. Generally, faster autoxidation rates are computed in later unimolecular reactions that produce RO7 radicals after OH addition (∼10 s-1 or greater) than rates for RO5 peroxy radical production (0.2-7 s-1). Mechanistic pathways that form RO7 peroxy radicals are similar for all three monoterpenes with a particular bicyclo RO7 radical involving a five-membered peroxide ring being favored for all three monoterpenes. The molar yields of RO7 radicals are 4.6% (+10.0/-2.4), 3.8% (+9.1/-2.6), and 7.6% (+13.1/-4.9) for α-pinene, β-pinene, and limonene, respectively, at 298 K and 1 ppb of NO and only significantly decline at NO concentrations exceeding 10 ppb. The higher yield for limonene relative to the pinenes is predominantly a consequence of the initial oxidation step: OH adducts of the bicyclic pinenes have to use the excess energy after OH addition to break one of the rings and make the molecule more flexible for autoxidation although this process is inefficient, while one of the prominent OH adducts for monocyclic limonene does not have to do this and may add O2 immediately before autoxidizing further. These insights may be used to guide a better representation of these processes in atmospheric models because they affect particulate matter (PM), NOx, and ozone concentrations via enhanced production of low-volatility species, less early-generation NOx cycling, and altered organic nitrate production.

Engineered myoglobin as a catalyst for atom transfer radical cyclisation.

Myoglobin was subjected to site-directed mutagenesis and transformed into a catalyst able to perform atom transfer radical cyclisation reactions, i.e. intramolecular atom transfer radical additions. Replacing the iron-coordinating histidine with serine, or introducing small changes inside or at the entrance of the active site, transformed the completely inactive wild-type myoglobin into an artificial metalloenzyme able to catalyse the 5-exo cyclisation of halogenated unsaturated compounds for the synthesis of γ-lactams. This new-to-nature activity was achieved not only with purified protein but also in crude cell lysate and in whole cells.

Stereodivergent atom-transfer radical cyclization by engineered cytochromes P450.

Naturally occurring enzymes can be a source of unnatural reactivity that can be molded by directed evolution to generate efficient biocatalysts with valuable activities. Owing to the lack of exploitable stereocontrol elements in synthetic systems, steering the absolute and relative stereochemistry of free-radical processes is notoriously difficult in asymmetric catalysis. Inspired by the innate redox properties of first-row transition-metal cofactors, we repurposed cytochromes P450 to catalyze stereoselective atom-transfer radical cyclization. A set of metalloenzymes was engineered to impose substantial stereocontrol over the radical addition step and the halogen rebound step in these unnatural processes, allowing enantio- and diastereodivergent radical catalysis. This evolvable metalloenzyme platform represents a promising solution to tame fleeting radical intermediates for asymmetric catalysis.

Tetrahydroxydiboron-Initiated Atom-Transfer Radical Cyclization

AbstractIn this work, the first diboron reagent initiated atom-transfer radical cyclization was reported, in which the boryl radicals were generated by the homolytic cleavage of a B–B single bond weakened by the coordination of Lewis base. To clarify the role of carbonate and DMF in the cleavage of B–B bond, we calculated the free energy diagram of two pathways by density functional theory (DFT) investigations. The DFT calculation showed that the presence of carbonate facilitates the B–B bond cleavage to form boron radicals, which can be further stabilized by DMF. Subsequent atom-transfer cyclization initiated by stabilized dihydroxyboron radical is also energetically favored.

Atom-transfer radical cyclization of α-bromocarboxamides under organophotocatalytic conditions

The atom-transfer radical cyclization (ATRC) reaction gives halogenated heterocycles from the corresponding halocarbonyls that possess a C–C double bond. In contrast, the reductive ATRC reaction gives non-halogenated heterocycles in the presence of a reductant. In this research, we successfully control the ATRC and reductive ATRC reactions of N-allyl-α-haloamides under visible-light irradiation in the presence/absence of the Hantzsch ester as a reductant.

Electro-Mechanochemical Atom Transfer Radical Cyclizations using Piezoelectric BaTiO3.

The formation and regeneration of active CuI species is a fundamental mechanistic step in copper‐catalyzed atom transfer radical cyclizations (ATRC). Typically, the presence of the catalytically active CuI species in the reaction mixture is secured by using high CuI catalyst loadings or the addition of complementary reducing agents. In this study it is demonstrated how the piezoelectric properties of barium titanate (BaTiO3) can be harnessed by mechanical ball milling to induce electrical polarization in the strained piezomaterial. This strategy enables the conversion of mechanical energy into electrical energy, leading to the reduction of a CuII precatalyst into the active CuI species in copper‐catalyzed mechanochemical solvent‐free ATRC reactions.

Electro‐Mechanochemical Atom Transfer Radical Cyclizations using Piezoelectric BaTiO3

AbstractThe formation and regeneration of active CuI species is a fundamental mechanistic step in copper‐catalyzed atom transfer radical cyclizations (ATRC). Typically, the presence of the catalytically active CuI species in the reaction mixture is secured by using high CuI catalyst loadings or the addition of complementary reducing agents. In this study it is demonstrated how the piezoelectric properties of barium titanate (BaTiO3) can be harnessed by mechanical ball milling to induce electrical polarization in the strained piezomaterial. This strategy enables the conversion of mechanical energy into electrical energy, leading to the reduction of a CuII precatalyst into the active CuI species in copper‐catalyzed mechanochemical solvent‐free ATRC reactions.

Synthesis of Chlorinated, Heteroatom‐Rich and Differently Fused Tricyclic β‐Lactams by Cu(I)‐Catalyzed Halogen Atom Transfer Radical Cyclization

AbstractThe application of Cu (I)‐catalyzed halogen atom transfer radical cyclization (ATRC) for the synthesis of two different series of chlorinated, heteroatom rich and differently fused tricyclic β‐lactams has been demonstrated. N‐substituted‐3,4‐dihydropyrimidine‐2(1H)‐thiones synthesized by Biginelli reaction were used as starting materials for this synthetic pathway which upon S‐allylation/alkylation furnished 2‐allylthio/alkylthio‐1,4‐dihydropyrimidines (cyclic imines). Staudinger reaction of these cyclic imines with dichloroketene was employed to obtain the bicyclic dichloro‐S‐allyl/N‐allyl‐β‐lactams, which upon subsequent Cu(I)‐catalyzed ATRC produced two different series of tricyclic β‐lactams. The difference in the relative behavior of N‐allyl bicyclic dichloro‐β‐lactams and S‐allyl bicyclic dichloro‐β‐lactams towards ATRC was also introspected in terms of their relative rates of cyclization, the amount of catalyst loading needed and the stabilities of tricyclic‐β‐lactams obtained after cyclization. To study the relative reactivity of N‐allyl group and S‐allyl group towards ATRC, the bicyclic dichloro‐β‐lactams having both S‐allyl and N‐allyl groups were synthesized. The intramolecular competitive experiments revealed the high reactivity of S‐allyl group towards ATRC than the N‐allyl group.

Harnessing Energy‐Transfer in N‐Centered Radical‐Mediated Synthesis of Pyrrolidines

Atom transfer radical addition (ATRA), cyclization (ATRC), and polymerization (ATRP) are valuable synthetic methods for the functionalization of olefins. With the advent of photoredox catalysis, visible‐light became a popular tool for the initiation of these reactions. We have developed a protocol that enables easy access to distally functionalized pyrrolidines employing blue‐light mediated atom transfer radical [3+2] cyclization. The reaction is scalable, proceeds at very mild conditions. tolerates various functional groups, and provides the corresponding products in good to excellent yields. If rigid olefins are utilized as the reaction partners, the products can be isolated as single diastereomers. The mechanistic investigations provide strong support for an energy‐transfer mechanism.

The Use of Copper and Vanadium Mineral Ores in Catalyzed Mechanochemical Carbon–Carbon Bond Formations

Under mechanochemical conditions in ball mills, copper- and vanadium-containing minerals initiate atom transfer radical cyclizations and oxidative couplings, respectively. Only catalytic quantities of the minerals are required, and the reactions proceed either under neat conditions or in the presence of a minimal amount of solvent.