Radical Cascade Cyclization Research Articles

Polycyclic systems with the pyridopyrimidine and pteridine nuclei

The literary sources relating to the methods for obtaining polycyclic compounds with pyridopyrimidine and pteridine subunits have been systematized and analyzed. The synthetic potential of two main approaches to the processes of formation of these types of structures has been revealed: 1) annelation of the fused pyrimidine rings to the pyridine or diazine nuclei; 2) cyclization based on functional derivatives of fused pyrimidines. It has been shown that the core structures for implementation of the first approach are usually amino(iso)nicotinic acids, heteroaromatic halogen acids, isotiocyanatopyridine carboxylates, 1H-pyrido[2,3-d][1,3]oxazine-2,4-diones and 2-amino derivatives of pyridines or diazines. The convenient tools for formation of a fused pyrimidine ring such as the cross-coupling reaction by Buchwald-Hartwig through amination of haloarenes, the radical cascade cyclization of N-acylcyanamides and the intramolecular reaction of aza-Wittig have been described. The second approach focuses on the cycle formation processes involving hydrazinopyrimidines, 2-aminopyridopyrimidines and 2-thioxopyridopyrimidones. It has been noted that the electrophilic intramolecular cyclization under the action of halogenarylchalcogenides and mineral acids is an important factor for the directed synthesis of polycyclic systems based on alkenyl fused pyridopyrimidones or pteridones. In this review a considerable attention is paid to structures that exhibit pronounced biological effects.

Radical-Radical Cyclization Cascades of Barbiturates Triggered by Electron-Transfer Reduction of Amide-Type Carbonyls.

Radical-radical cyclization cascades, triggered by single-electron transfer to amide-type carbonyls by SmI2-H2O, convert simple achiral barbiturates in one step to hemiaminal- or enamine-containing tricyclic scaffolds containing up to five contiguous stereocenters (including quaternary stereocenters). Furthermore, we describe the surprising beneficial effect of LiBr on the most challenging of the radical-radical cyclization cascades. An alternative fragmentation-radical cyclization sequence of related substrates allows access to bicyclic uracil derivatives. The radical-radical cyclization process constitutes the first example of a radical cascade involving ET reduction of the amide carbonyl. Products of the cascade can be readily manipulated to give highly unusual and medicinally relevant bi- and tricyclic barbiturates.

ChemInform Abstract: Synthesis of Gem‐Difluorinated Fused Quinolines via Visible Light‐Mediated Cascade Radical Cyclization.

AbstractThe title compounds are prepared by reaction of functionalized difluoromethyl chlorides with alkenes.

ChemInform Abstract: Copper‐Catalyzed Double Additions and Radical Cyclization Cascades in the Re‐Engineering of the Antibacterial Pleuromutilin.

AbstractA general synthetic strategy to access novel tricyclic scaffolds inspired by the antibacterial pleuromutilin is developed.

Preparation of the Core Structure of Aspidosperma and Strychnos Alkaloids from Aryl Azides by a Cascade Radical Cyclization.

A novel approach to prepare the core structure of Aspidosperma and Strychnos alkaloids is described. The strategy is based on a cyclization cascade involving the formation of quaternary carbon center followed by trapping of the radical intermediate by an aryl azide to build the 5-membered ring of the pyrrolocarbazole system. This reaction is run with triethylborane without the need for any hydrogen atom donor such as a tin hydride or tris(trimethylsilyl)silane, and it furnishes the tetracyclic framework as a single diastereomer. The influence of different N-protecting groups on the starting iodoacetamide has been examined.

Synthesis of Gem-Difluorinated Fused Quinolines via Visible Light-Mediated Cascade Radical Cyclization.

A facile synthesis of gem-difluorinated fused quinolines via visible light-mediated cascade radical cyclization between functionalized difluoromethyl chlorides and alkenes was developed. Various highly functionalized fused quinolines were assembled in moderate to good yields under very mild reaction conditions. The reaction extends the applications of chlorodifluoroacetic acid as the gem-difluoromethylenated building block by simple derivatization, especially in the synthesis of gem-difluorinated fused heterocyclic rings, which are difficult to access with existing methods.

Silver-Catalyzed Cascade Radical Cyclization: A Direct Approach to 3,4-Disubstituted Dihydroquinolin-2(1H)-ones through Activation of the P-H Bond and Functionalization of the C(sp(2))-H Bond.

A silver-catalyzed cascade cyclization of cinnamamides with diphenylphosphine oxide was developed, in which activation of the P-H bond and functionalization of the C(sp(2))-H bond occurred. A direct method for the synthesis of 3,4-disubstituted dihydroquinolin-2(1H)-ones was developed.

Synthesis of Neurotrophic Seco-prezizaane Sesquiterpenes (1R,10S)-2-Oxo-3,4-dehydroneomajucin, (2S)-Hydroxy-3,4-dehydroneomajucin, and (-)-Jiadifenin.

An asymmetric approach to the synthesis of neurotrophic seco-prezizaane sesquiterpenes is described that is based on the strategic application of a hydroxyl-directed metallacycle-mediated [2 + 2 + 2] annulation and an intramolecular radical cyclization cascade. Targets prepared are among the most potent members of the natural product class and include (1R,10S)-2-oxo-3,4-dehydroneomajucin, (2S)-hydroxy-3,4-dehydroneomajucin, and (-)-jiadifenin. In addition to representing the first application of the alkoxide-directed metallacycle-mediated hydrindane-forming annulation reaction in natural product synthesis and the first total synthesis of (2S)-hydroxy-3,4-dehydroneomajucin, these pursuits have resulted in the elucidation of a complex radical cascade process for installation of the C5 quaternary center common to the natural product class.

Direct synthesis of sulfonated dihydroisoquinolinones from N-allylbenzamide and arylsulfinic acids via TBHP-promoted cascade radical addition and cyclization.

A novel synthesis of sulfonated dihydroisoquinolinones via cascade radical addition and cyclization was developed in the presence of tert-butyl hydroperoxide (TBHP). The reactions generated the desired sulfonated dihydroisoquinolinones in good yields from readily available arylsulfinic acids and N-allylbenzamides under metal-free conditions.

Copper-Catalyzed Double Additions and Radical Cyclization Cascades in the Re-Engineering of the Antibacterial Pleuromutilin.

A general synthetic sequence involving simply prepared starting materials provides rapid access to diverse, novel tricyclic architectures inspired by pleuromutilin. SmII‐mediated radical cyclization cascades of dialdehydes, prepared using a new, one‐pot, copper‐catalyzed double organomagnesium addition to β‐chlorocyclohexenone, proceed with complete sequence selectivity and typically with high diastereocontrol to give analogues of the target core. Our expedient approach (ca. 7 steps) allows non‐traditional, de novo synthetic access to analogues of the important antibacterial that can′t be prepared from the natural product by semisynthesis.

Organic Photocatalytic Cyclization of Polyenes: A Visible-Light-Mediated Radical Cascade Approach.

A visible-light-mediated, organic photocatalytic stereoselective radical cascade cyclization of polyprenoids is described. The desired cascade cyclization products are achieved in good yields and high stereoselectivities with eosin Y as photocatalyst in hexafluoro-2-propanol. The catalyst system is also suitable for 1,3-dicarbonyl compounds, which require only catalytic amounts of LiBr to promote the formation of the corresponding enols.

ChemInform Abstract: Copper‐Catalyzed Radical Cascade Cyclization for the Synthesis of Phosphorated Indolines.

AbstractTitle compounds (III) and (V) are prepared by a Cu‐catalyzed amino‐phosphorous difunctionalization via cascade cyclization.

Synthesis of Fused Indoles and Pyridin-2-ones by Radical Cyclization Cascades

Synthesis of Fused Indoles and Pyridin-2-ones by Radical Cyclization Cascades

Synthesis of (±)-aureol by bioinspired rearrangements.

A bioinspired and sustainable procedure for the straightforward synthesis of (±)-aureol has been achieved in eight steps (14% overall yield) from epoxyfarnesol. The key steps are the titanocene(III)-catalyzed radical cascade cyclization of an epoxyfarnesol derivative and a biosynthetically inspired sequence of 1,2-hydride and methyl shifts.

Enantioselective synthesis of dioxatriquinane structural motifs for HIV-1 protease inhibitors using a cascade radical cyclization

Synthesis of novel HIV-1 protease inhibitors incorporating dioxatriquinane-derived P2-ligands is described. The tricyclic ligand alcohol contains five contiguous chiral centers. The ligand alcohols were prepared in optically active form by an enzymatic asymmetrization of mesodiacetate, cascade radical cyclization, and Lewis acid catalyzed reduction as the key steps. Inhibitors with dioxatriquinane-derived P2-ligands exhibited low nanomolar HIV-1 protease activity.

Copper-catalyzed radical cascade cyclization for the synthesis of phosphorated indolines.

A novel and convenient approach to the synthesis of various phosphorated indolines via a copper-catalyzed radical cascade cyclization reaction has been developed. The reaction employs cheap copper as the catalyst and K2S2O8 as the oxidant under mild conditions. Various alkenes and P-radical precursors are compatible with this transformation. Preliminary mechanistic studies reveal that the addition of the P-radical may initiate the reaction, and then oxidative cyclization may be achieved to afford the desired product.

Asymmetric synthesis of gem-difluoromethylenated linear triquinanes via cascade gem-difluoroalkyl radical cyclization.

An asymmetric synthesis of gem-difluoromethylenated linear triquinanes is described exploiting the synthetic utilities of PhSCF2TMS (5) as a "(•)CF2(-)'' building block. The strategy involves fluoride-catalyzed nucleophilic addition of PhSCF2TMS (5) to chiral ketocyclopentenes 6 to provide silylated adducts 9 or alcohol derivatives 10 and 11. Subsequent cascade radical cyclization of the gem-difluoroalkyl radical generated from silylated adducts 9 or alcohols 10 and 11 afforded gem-difluoromethylenated linear triquinanes 16 as an approximate 1:1 mixture of two diastereomers (16A and 16B). Alternatively, a convenient asymmetric synthesis of gem-difluoromethylenated linear triquinanes 16A can be accomplished by oxidation of 16a (R = H) to provide ketotriquinane 17 followed by a highly stereoselective nucleophilic addition to 17 employing DIBAL, NaBH4, and various Grignard reagents.

ChemInform Abstract: A Free Radical Cascade Cyclization of Isocyanides with Simple Alkanes and Alcohols.

AbstractThe copper‐catalyzed process allows the selective access to various phenanthridine derivatives bearing an alkyl or alcohol substituent at position 6.

Synthesis of the Sesquiterpenes Albicanol, Drimanol, and Drimanic Acid, and the Marine Sesquiterpene Hydroquinone Deoxyspongiaquinol

AbstractA TiIII‐mediated radical cyclization cascade has been used for the synthesis of the sesquiterpenes (+)‐albicanol, (+)‐drimanol, and (+)‐drimanic acid. Starting from all‐trans‐farnesol, (+)‐albicanol could be prepared in seven steps in an overall yield of 14.9 %. Furthermore, a highly diastereoselective hydrogenation of (+)‐albicanol to give (+)‐drimanol has been developed. We used the synthesized (+)‐drimanic acid to achieve the first synthesis of the marine sesquiterpene hydroquinone deoxyspongiaquinol and the quinone deoxyspongiaquinone. Thus, this synthetic strategy gave access to five natural products.

Cascade cyclization of 1-(2-yl-3-phenylprop-2-enyl)-6-oxo-1,6-dihydropyridine-2-carbonitrile radical: Mechanistic insights from DFT study

Hybrid DFT calculations of mechanism of the titled reaction have been carried out by employing the BHandHLYP method combined with the 6-311++G(d,p), 6-311G(d,p), 3-21G, and LANL2DZ basis sets. The calculated results indicated that the radical precursor (Z)-1-(2-iodo-3-phenylprop-2-enyl)-6-oxo-1,6-dihydropyridine-2-carbonitrile prefers to undergo a deiodination to provide the titled free radical, followed by a tandem radical cyclization to construct several tetracyclic radical intermediates. The mechanism of the cascade radical cyclization was evaluated by the computed activation Gibbs free energies, intrinsic reaction barriers, attack angles, and orbital interaction energies. Further, we also explored the H-abstraction oxidations of the formed tetracyclic radicals by different abstractors. An excellent agreement with the available experiment was observed. The present investigation of reaction mechanism would be helpful not only for understanding the nature of radical chemistry but also for further experimental explorations.