Intramolecular Free Radical Cyclization Research Articles

Imidoyl Radicals for the Synthesis of Chromenoquinolines and Naphthyridines

The stability of imidoyl radicals prepared from 2-(2-alkenyloxy)-phenyl selenoimidates and 2-(2-allylamino)-phenyl selenoimidates and their intramolecular free radical cyclization through the slow addition of tri-N-butyltin hydride and AIBN to obtain 4-chromanones and 4-quinolones were studied. The extension of the methodology to N-phenyl substituted imidoyl selenoates produced tandem cyclizations of the imidoyl radical with the allyl substituent, followed for a second cyclization of the intermediate radical with the aromatic substituent to produce dihydro-chromenoquinolines or tetrahy-dro-dibenzonaphtyridines. Further oxidation with DDQ produced: 6H-chromeno [4,3,b] quinoline and 7-methyl-6H-chromenoquinoline from 2-alkenylamino-phenylbenzamide and 5,6-dihydro-dibenzo [b,h][1,6] naphthyridine and 5,6-dihydro-7-methyl-dibenzo [b,h][1,6] naphthyridine from 2-2-(alkylamino)-N-phenylbenzamides. The cyclization of 2-(N,N-di-prop-2.enylamino)-N-phenylnicotinamide selenoate obtained from 2-aminonicotinic acid, produced 5,6-dihidro-benzo[b]pyrido2,3-h] [1,6] naphthyridine.

An intramolecular para-phenolic allylation free radical cyclization strategy for the synthesis of alkaloids and terpenes with spiro[4.5]decane architectures

A Tsuji-Trost variant of the Winstein-Masamune reaction has been investigated for the synthesis of the AC spirocyclic ring system 9 bearing a quaternary carbon found in the fawcettimine type Lycopodium alkaloids magellanine 1 and lycojaponicumin B 2 and cyclopiane diterpenes such as conidiogenone 3. Annulation of the B ring for the synthesis of tricyclic ABC cores was demonstrated utilizing a 5-exo-trig free radical cyclization of a primary carbon radical onto a cyclohexadienone generated with tri-n-butylgermanium hydride (9→11).

ChemInform Abstract: Intramolecular Free‐Radical Cyclization Reactions on Pentose Sugars for the Synthesis of Carba‐LNA and Carba‐ENA and the Application of Their Modified Oligonucleotides as Potential RNA Targeted Therapeutics

AbstractReview: 107 refs.

Steric Effects in the Tuning of the Diastereoselectivity of the Intramolecular Free-Radical Cyclization to an Olefin As Exemplified through the Synthesis of a Carba-Pentofuranose Scaffold

Two free-radical cyclization reactions with the radical at the chiral C4 of the pentose sugar and the intramolecularly C1-tethered olefin (on radical precursors 8 and 17) gave a new diastereospecific C4-C8 bond in dimethylbicyclo[2.2.1]heptane 9, whereas the new C4-C7 bond in 7-methyl-2-oxabicyclo[2.2.1]heptanes 18a/18b gave trans and cis diastereomers, in which the chirality of the C4 center is fully retained as that of the starting material. It has been shown how the chemical nature of the fused carba-pentofuranose scaffolds, dimethylbicyclo[2.2.1]heptane 9 vis-a-vis 7-methyl-2-oxabicyclo[2.2.1]heptanes 18a/18b (C7-Me in the former versus 2-O- in the latter), dictates the stereochemical outcome both at the Grignard reaction step as well as in the free-radical ring-closure reaction. The formation of pure 1,8-trans-bicyclo[2.2.1]heptane 9 from 8 suggests that the boat-like transition state is favored due to the absence of steric clash of the bulky 1(S)-O-p-methoxybenzyl (PMB) and 7(R)-Me substituents (both in the α-face) with that of the 8(R)-CH(2)(•) radical in the β-face. The conversion of 17 → 18a-7(S) and 18b-7(R) in 6:4 ratio shows that the participation of both the chair- and the boat-like transition states is likely.

Intramolecular Free-Radical Cyclization Reactions on Pentose Sugars for the Synthesis of Carba-LNA and Carba-ENA and the Application of Their Modified Oligonucleotides as Potential RNA Targeted Therapeutics

Intramolecular Free-Radical Cyclization Reactions on Pentose Sugars for the Synthesis of Carba-LNA and Carba-ENA and the Application of Their Modified Oligonucleotides as Potential RNA Targeted Therapeutics

ChemInform Abstract: The Study of Intramolecular Free Radical Cyclizations of α- Sulfonyl and α-Sulfinyl Radicals.

ChemInform Abstract: The Study of Intramolecular Free Radical Cyclizations of α- Sulfonyl and α-Sulfinyl Radicals.

ChemInform Abstract: Free Radical Reactions for Heterocycle Synthesis: Formation of Tri- and Tetracyclic Isoindolinones.

Abstract A general method for synthesis of tri- and tetracyclic isoindolinones is achieved by intramolecular free radical cyclization.

The synthesis of carbohydrate-derived acylsilanes and their intramolecular free radical cyclizations with the formation of polyoxygenated cyclopentanes

A convenient way for the synthesis of acylsilanes from arabinose, lyxose, and ribose is developed. All the chiral centers of the carbohydrate templates are conserved, and only the reducing end is transformed into the acylsilane functional group. The non-reducing end of the templates can be converted into a bromide. These bromo acylsilanes undergo efficient intramolecular radical cyclizations to give polyoxygenated cyclopentanes.

Stereocontrolled Synthesis of the Sterically Encumbered F Ring of Lancifodilactone G

A stereochemically linear strategy has been developed to prepare the heavily congested F-ring sector of lancifodilactone G (1) from commercially inexpensive (R)-carvone. Prominent operations in our synthesis include Negishi-type sp2-sp3 cross-coupling and intramolecular free-radical cyclization for the purpose of appending the sidearm links of the D and H rings onto the F platform.

Titanium(III)-induced intramolecular radical cyclization of epoxyallene ethers: an efficient method for synthesis of multifunctional tetrahydrofurans

Ti(III)-mediated intramolecular free radical cyclization of epoxyallene ethers in an exo-mode was studied. The reaction afforded an efficient and highly regioselective method of synthetically important 3-vinyl-4-hydroxymethyl tetrahydrofurans.

Stereoselective Entry to Bicyclic β‐Lactams via Free Radical Cyclization of 2‐Azetidinone‐Tethered Bromohomoallylic Alcohols.

AbstractFor Abstract see ChemInform Abstract in Full Text.

A concise synthesis of denbinobin

A concise synthesis of denbinobin is described via an intramolecular free radical cyclization and Fremy’s salt mediated oxidation as a key reactions. A seven-step process starting from commercially available 3,5-dimethoxybenzyl bromide ( 6 ) and 2-bromoisovanillin ( 5 ) effectively constructs the natural product denbinobin ( 1 ).

Synthesis of small cyclic peptides constrained with 3-(3-aminomethylphenyl)propionic acid linkers using free radical-mediated macrocyclization

In this letter, we report that small peptides (di- and tri-) having a 3-bromobenzyl group at the C-termini and an acryloyl group at the N-termini undergo an efficient Bu 3SnH–AIBN mediated intramolecular free radical cyclization to afford cyclic peptides in good yields. We also propose that these cyclizations are occurring via a pre-organized acyclic structure dictated by a reverse turn (γ/β-turn).

Stereoselective Entry to Bicyclic β-Lactams via Free Radical Cyclization of 2-Azetidinone-Tethered Bromohomoallylic Alcohols

Triphenyltin hydride-promoted reaction of β-lactam-tethered bromodienes gave six-, seven-, or eight-membered bicyclic ring structures through intramolecular free radical cyclization. The cyclization precursors were synthesized by stereoselective tin-mediated carbonyl bromoallylation of4-oxoazetidine-2-carbaldehydes in an aqueous environment.

Total Syntheses of Iso‐, Neuro‐ and Phytoprostanes: New Insight in Lipid Chemistry

AbstractFor Abstract see ChemInform Abstract in Full Text.

Synthesis of Novel Polycyclic β-Lactams fromd-Glucose via Unusual ­Substrate-Controlled Radical Cyclization

A highly stereoselective and substrate-controlled synthesis of polycyclic β-lactams from d-glucose derived chiral template via intramolecular free radical cyclization is described. The cyclization is highly substrate dependant, proceeding via 6-exo and 7-endo heptynyl type radical cyclization with the radical acceptor at N-1 and the radical progenitor on a sugar moiety, anchored to the β-lactam ring at C-4.

Free radical reactions for heterocycle synthesis: formation of keto spiro-γ-lactones and keto spiro-γ«ctams

A new method for the synthesis of keto spiro-γ-lactones and keto spiro-γ-lactams by intramolecular free radical cyclization is described.

Free radical reactions for heterocycle synthesis: formation of tri- and tetracyclic isoindolinones

A general method for synthesis of tri- and tetracyclic isoindolinones is achieved by intramolecular free radical cyclization.

Applications of Free Radicals in Organic Synthesis

AbstractA summary of studies on the generation of acyl radicals and their subsequent use in intermolecular, intramolecular, macrocyclization, and tandem alkene addition reactions is provided. Similarly, the use of intramolecular free radical cyclization reactions in the total synthesis of (+)‐CC‐1065 and a series of structurally related analogs is summarized.

Synthesis of 2′,3′- cis-fused pyrrolidino-β-D-nucleosides and their conformational analysis by 500 MHz 1H-NMR

The unique “off-template” stereoselectivity in the intramolecular free radical cyclization of 3-aza-5-hexenyl endocyclic radical has been demonstrated for the first time through the synthesis of 2′,3′- cis-fused pyrrolidino-β-D-nucleosides, 19a, 20a, 21a, 22a, 23a, 35a, 36a, 37a and 38a, which are not hithertofore available by any known procedures. The 2′-linked chiral carbon (C c) in 19a, 20a, 21a and 22a has shown 25:1 to 10:1 stereoselectivity depending upon the bulk of its substituent. The 3′-linked chiral carbon (C c) in 35a, 36a and 37a, on the other hand, has shown only 4:1 to 2:1 stereoselectivity. Finally, a full conformational analysis of 2′,3′-cis-fused pyrrolidino-β-D-nucleosides 19a, 20a, 21a, 22a, 23a, 35a, 36a, 37a and 38a is reported using 1H-NMR at 500 MHz. The solution geometry of the furanose and the pyrrolidine rings were studied on the basis of vicinal proton-proton coupling constants using the concept of pseudorotation. The furanose rings in 19a – 23a have a geometry biased toward a South-type conformation [70 – 81 % S, 126° < P S < 131° (C1′-exo-C2′-endo), 28° < Ψ m < 32°, rms error ±0.05]. In compounds 35a – 38a, the riboses have a conformation biased toward the North-type [∼90 % N, 20° < P N < 38° (C3′-endo) and 27°< Ψ m < 30°, rms error ±0.05]. In compounds 19a – 22a, the pyrrolidine geometry is biased toward the North-type conformation (C2′-exo), with a phase angle of pseudorotation Q N ≈ −28° and a puckering amplitude Ψ * m ≈ 40° (rms error ±0.5). In compounds 35a – 37a, the pyrrolidine has a geometry biased toward a South-type conformation (C2′-endo), with Q S ≈ 175° and Ψ * m ≈ 39° (rms error ±0.8). The furanose and the pyrrolidine rings share the C2′C3′ bond and have correlated conformations. The pyrrolidine adopts a North-type conformation in 19a – 22a when the ribose is in a South-type conformation. In contrast, the pyrrolidine ring adopts a South-type conformation when the ribose is in a North-type conformation (in 35a – 37a). Compounds 19a – 23a and 35a – 38a show a preference for the γ + conformation (∼70%). The glycosyl conformation for all pyrrolidine-fused systems was found to be anti.