Stereoselective Radical Cyclization Research Articles

Enzyme-controlled stereoselective radical cyclization to arenes enabled by metalloredox biocatalysis.

The effective induction of high levels of stereocontrol for free radical-mediated transformations represents a notorious challenge in asymmetric catalysis. Herein, we describe a novel metalloredox biocatalysis strategy to repurpose natural cytochromes P450 to catalyse asymmetric radical cyclisation to arenes through an unnatural electron transfer mechanism. Empowered by directed evolution, engineered P450s allowed diverse radical cyclisation selectivities to be accomplished in a catalyst-controlled fashion: P450arc1 and P450arc2 facilitated enantioconvergent transformations of racemic substrates, giving rise to either enantiomer of the product with excellent total turnover numbers (up to 12,000). In addition to these enantioconvergent variants, another engineered radical cyclase, P450arc3, permitted efficient kinetic resolution of racemic chloride substrates (S factor = 18). Furthermore, computational studies revealed a proton-coupled electron transfer (PCET) mechanism for the radical-polar crossover step, suggesting the potential role of the haem carboxylate as a base catalyst. Collectively, the excellent tunability of this metalloenzyme family provides an exciting platform for harnessing free radical intermediates for asymmetric catalysis.

Total synthesis of (±)-vinoxine: construction of the bridged pyrido[1,2-a]indole skeleton via Tf2O-mediated Bischler-Napieralski reaction and stereoselective radical cyclization.

The total synthesis of (±)-vinoxine was achieved featuring the assembly of a multi-substituted tetrahydropyrido[1,2-a]indole skeleton through the Tf2O-mediated Bischler-Napieralski reaction. The characteristic diazabicyclo[3.3.1]nonane skeleton was stereoselectively constructed via radical cyclization based on the one stereochemistry of the C3 position. The established methodology provides new options for the synthesis of natural products and pharmaceuticals containing the multi-substituted pyrido[1,2-a]indole skeleton.

Tin-mediated Radical Cyclization Reactions

Radical chemistry is known for two centuries. Due to the fascinating nature of the radical-mediated processes, these reactions have attracted the attention of organic chemists to prepare new compounds with diverse stereochemistry. Radical-induced methods mostly follow atom economical principles. Tin-based radical annulation method is the most common and widely used procedure for the synthesis of a wide range of organic compounds with medicinal significance. In this review, we report recent stereoselective tin-mediated radical cyclization reactions. The versatility of tinbased reagents in the cyclization process as reported herein will encourage chemists to construct many other molecules of interest following the principles involved in these reactions.

Synthesis of (+)-Tacamonine via Stereoselective Radical Cyclization.

A concise, asymmetric synthesis of the indole alkaloid (+)-tacamonine is reported involving a stereoselective radical cyclization of a 1-phenylsulfanyl tetrahydro-β-carboline bearing a pendant enoate ester side chain as a key step. In this process, a single stereocenter in the side chain allows for the formation of two stereocenters of the natural product in a highly diastereoselective fashion. Computational investigations of this key cyclization support the experimentally observed outcome and shed light on the factors impacting its stereoselectivity.

Synthesis of the ABCD fragment of gymnocin-B

A convergent synthesis of the ABCD fragment of gymnocin-B was accomplished. The tetracyclic ether ring system was synthesized by the construction of the BC ring system via the oxiranyl anion alkylation and ring expansion reaction, followed by the formation of the five-membered A-ring via a stereoselective radical cyclization reaction of a neopentyl-type iodide.

Stereoselective Radical Cyclization by Photoexcited Flavoenzymes

Key words alkenes - hydroalkylation - photocatalysis - flavoenzymes

Synthesis of the Methyl Analog of 2'-O,4'-C-Ethylene-Bridged 5-Methyluridine via Intramolecular Radical Cyclization and Properties of Modified Oligonucleotides.

The synthesis of 6'S-Me-2'-O,4'-C-ethylene-bridged 5-methyluridine (6'S-Me-ENA-T) was achieved using visible light-mediated stereoselective radical cyclization as a key step. This is the first example of a method for constructing a 2',4'-bridged structure from a 4'-carbon radical intermediate. The 6'S-Me-ENA-T monomer was successfully incorporated into oligonucleotides, and their properties were examined. The oligonucleotides containing 6'S-Me-ENA-T exhibited a highly selective hybridization affinity toward single-stranded RNA and an excellent enzymatic stability, compared to the corresponding LNA- and ENA-modified oligonucleotides.

Vanadium-Promoted Stereoselective Radical Cyclizations to Tetrahydrofurans

Vanadium-Promoted Stereoselective Radical Cyclizations to Tetrahydrofurans

The Computational Examination of the Stereoselective Radical Cyclization of the Complex Molecules

The Computational Examination of the Stereoselective Radical Cyclization of the Complex Molecules

Synthesis of C2-Symmetric gem-Difluoromethylenated Angular Triquinanes.

A synthesis of symmetrical gem-difluoromethylenated angular triquinanes is described. The synthetic strategy involved sequential fluoride-catalyzed nucleophilic addition of PhSCF2SiMe3 (1) to 2,2-diallylated or 2,2-dipropargylated indane-1,3-diones 2 followed by stereoselective radical cyclization of the resulting adducts 3 to provide the cyclized gem-difluoromethylenated diquinanes 4 as a mixture of stereoisomers. Repeated addition of 1 to 4 followed by cyclization resulted in the stereoselective synthesis of the desired C2-symmetric gem-difluoromethylenated angular triquinanes 6 in good yields with high stereoselectivity.

Synthesis of ferrocene substituted dihydrofuran derivatives via manganese(III) acetate mediated radical addition-cyclization reactions

In this study, the manganese(III) acetate mediated radical addition-cyclization reactions of ferrocene substituted alkenes and active methylene compounds were carried out. The regio- and stereoselective radical cyclization reactions of (E)-styrylferrocene (1a) and active methylene compounds (2a-g) gave trans-5-ferrocenyl-4-phenyl-4,5-dihydrofuran compounds as the sole products. The reactions of 1-ferrocenyl-1-aryl(heteroaryl)ethenes (1b-e) and active methylene compounds (2a-f) via Mn(OAc)3 led to furan and benzofuran derivatives (10–33) in mid-good yields (up to 75%). Surprisingly, ferrocene substituted allylidene derivatives were obtained from the Mn(OAc)3 mediated reactions of 1-aryl-1-ferrocenylethene (1b-d) and 1,3-dimethylbarbituric acid (2g). The uses of ferrocene substituted alkenes in manganese(III) acetate mediated radical reactions is the first example in this field as far as we know.

Stereoselective Radical Cyclization Cascades Triggered by Addition of Diverse Radicals to Alkynes To Construct 6(5)-6-5 Fused Rings.

Cascade radical cyclization of alkynyl ketones with various carbon- and heteroatom-centered radical precursors via a sequential radical addition/1,5-H radical shift/5-exo-trig/radical cyclization process was realized for the first time. This method provides a strategically novel and step-economical protocol for diversity-oriented synthesis of a wide range of carbocyclic and heterocyclic 6(5)-6-5 fused ring systems with three contiguous stereocenters, including a quaternary carbon in high yields with excellent chemo- and diastereoselectivity.

ChemInform Abstract: Total Synthesis and Absolute Configuration Determination of (+)‐Subincanadine F.

The first asymmetric synthesis of indole alkaloid (+)-subincanadine F was successfully accomplished with the uncommon 7-endo-trig stereoselective radical cyclization as the key step and its absolute configuration was thus assigned.

Synthetic studies on cytotoxic macrolides cruentarens A and B: stereoselective synthesis of the C 8–C 19 segment of cruentarens A and B

A stereoselective synthesis of the C 8–C 19 segment of cruentarens A and B, cytotoxic natural products, has been accomplished. The key steps involve a stereoselective radical cyclization, stereospecific methylation of a γ, δ-epoxy acrylate, nucleophilic epoxide ring opening and a cis-Wittig olefination.

ChemInform Abstract: Intramolecular Cyclization of 1-Nitroalkenyl Radicals Generated by One-Electron Oxidation of aci-Nitro Anions with CAN: Stereoselective Formation of 3,4-Functionalized Tetrahydrofurans.

Upon one-electron oxidation by ammonium hexanitratocerate(IV) (CAN), aci-nitro anions 3a-d resulting from oxa-Michael addition of allylic alcohol to α,β-disubstituted nitroalkenes 1a-d undergo stereoselective radical cyclization into 3-nitro-4-nitrooxymethyltetrahydrofurans 6a-d and 3-nitro-4-hydroxymethyltetrahydrofurans 7,8a-d.

Total synthesis and absolute configuration determination of (+)-subincanadine F

The first asymmetric synthesis of indole alkaloid (+)-subincanadine F was successfully accomplished with the uncommon 7-endo-trig stereoselective radical cyclization as the key step and its absolute configuration was thus assigned.

Stereoselective Radical Cyclizations of N‐(2‐Halobenzoyl)‐cyclic Ketene‐N,X (X; O, S)‐acetals.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Synthesis of 4,8-anhydro- d- glycero- d- ido-nonanitol 1,6,7-trisphosphate as a novel IP 3 receptor ligand using a stereoselective radical cyclization reaction based on a conformational restriction strategy

4,8-Anhydro- d- glycero- d- ido-nonanitol 1,6,7-trisphosphate ( 9 ), designed as a novel IP 3 receptor ligand having an α- C-glycosidic structure, was synthesized via a radical cyclization reaction with a temporary connecting allylsilyl group as the key-step. Phenyl 2- O-allyldimethylsilyl-3,4-bis- O-TBS-1-seleno-β- d-glucopyranoside ( 10a ), conformationally restricted in the unusual 1C 4-conformation, was treated with Bu 3SnH/AIBN to form the desired α-cyclization product 16a almost quantitatively. On the other hand, when a conformationally unrestricted O-benzyl-protected 2- O-allyldimethylsilyl -1-selenoglucoside 15 was used as the substrate, the radical reaction was not stereoselective and gave a mixture of the α-and β-products. From 16a , the target C-glucoside trisphosphate 9 was synthesized via phosphorylation of the hydroxyls by the phosphoramidite method. During the synthetic study, an efficient procedure for the oxidative C–Si bond cleavage, via a nucleophilic substitution at the silicon with p-MeOPhLi followed by Fleming oxidation, was developed. The C-glycoside 9 was found to be a full agonist for Ca 2+ mobilization, although its activity was weaker than that of the natural ligand IP 3. Thus, the α- C-glucosidic structure was shown to be a useful mimic of the myo-inositol backbone of IP 3.

Synthesis of (.+‐.)‐ and (‐)‐Botryodiplodin Using Stereoselective Radical Cyclizations of Acyclic Esters and Acetals.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Synthesis of (±)- and (−)-botryodiplodin using stereoselective radical cyclizations of acyclic esters and acetals

Three different routes for the stereoselective synthesis of botryodiplodin have been investigated. The intramolecular allylation of acetals proved to be unsatisfactory due to unstable intermediates and poor stereocontrol. Zard intramolecular radical allylation of a 2-iodopropionate derivative allows the development of an expeditious synthesis of racemic botryodiplodin. The relative configuration within the final product was corrected by a deprotonation–reprotonation step. The cyclization of allenyl bromoacetals was investigated next and proved to be satisfactory for the synthesis of racemic and enantiomerically pure botryodiplodin. Good stereocontrol was achieved by cyclizing a gem-dibromide followed by the stereoselective reduction of the thus formed cyclic monobromide.