通过自由基加成环化反应制备香豆素衍生物的研究进展

香豆素衍生物是一类重要的杂环内酯化合物,广泛应用于有机合成、生物医药及荧光材料等领域。开发新型简单高效的功能化香豆素合成策略一直受到人们的关注,通过苯丙炔酸酯与各类自由基前驱体的直接自由基加成环化反应为香豆素衍生物的功能化修饰提供了一条简单、清洁、高效的合成路线。本文综述了近年来基于自由基加成环化历程制备各类功能化香豆素衍生物的新进展。     

A stereoselective route to multi-substituted tetrahydropyrans by vinyl radical cyclization

The tin-mediated 6-exo-trig radical cyclization of the acetylenic β-alkoxy acrylates proceeded smoothly to give fully substituted tetrahydropyrans in good yields with high equatorial selectivity irrespective of the stereochemistry of the propargylic position.     

An easy access to pyrimidine-fused azocine derivatives by thiophenol-mediated radical cyclization via 8-endo-trig mode

An efficient route for the synthesis of eight-membered nitrogen heterocycles has been developed via a thiophenol-mediated intramolecular 8-endo-trig radical cyclization. The radical precursors were prepared using BF₃·Et₂O-catalyzed aza-Claisen rearrangement followed by the reaction with propargyl bromide. The alkenyl radicals are generated from thiophenol initiated by the benzoyl peroxide instead of commonly used AIBN for easy and facile isolation of the pure products.     

A new approach to fused furan ring systems and benzofurans: Intramolecular cyclization reactions of unsaturated acyloxy sulfone derivatives

Unsaturated acyloxy sulfones 3 undergo intramolecular cyclization upon deprotonation with LHMDS in THF. Dehydration and double bond isomerization of the products upon exposure to acid, gave the fused ring furans, 4, in good yields. This strategy could be readily adapted to prepare substituted benzofurans 12 from the cyclization reactions of acyloxy sulfones 11 prepared from phenols. Finally, this approach could be successfully modified to access dihydropyrans and benzopyrans.     

Synthesis of N-tosyl-3,3,4-trisubstituted pyrrolidine derivatives starting from the Baylis-Hillman adducts via radical cyclization

N-Tosyl-3,3-disubstituted-4-vinylpyrrolidine derivatives 3a-c were synthesized via radical cyclization from the modified Baylis-Hillman adducts 2. The required starting materials 2a-c were prepared in moderate yields from the Baylis-Hillman adducts in three steps: (i) acetylation of the Baylis-Hillman adducts, (ii) S_N2′ reaction with tosylamide to prepare 1, and (iii) alkylation with 1,4-dibromo-2-butene.     

An unusual stereochemical outcome of radical cyclization: synthesis of (+)-biotin

An enantioselective synthesis of (+)-biotin 1 starting from naturally available cysteine is described. The key steps are the unusual stereochemical outcome of radical cyclization of compound 10 to prepare 5,5-fused system 11, and the introduction of C4-sidechain at C₆ in 13 via a Grignard reaction.     

Thiophenol-catalyzed Claisen rearrangement and radical cyclization: formation of furo- and pyrano-coumarin derivatives

Regioselective synthesis of dihydrofurocoumarins and dihydropyranocoumarins in excellent yields from 4-prop-2-ynyloxy coumarin via a thiol mediated radical reaction is described. Alkenyl radicals are generated from easily available terminal alkynes and thiophenol. Thiophenol catalyzed the Claisen rearrangement of the 4-prop-2-ynyloxycoumarin ethers.     

Thiophenol mediated radical cyclization: an expedient approach to 2H-pyrrolo[3,2-d]pyrimidines (9-deazaxanthine analogs)

A new efficient route for the synthesis of substituted 2H-pyrrolopyrimidines (9-deazaxanthine analogs) via thiophenol mediated radical cyclization has been achieved. The stereochemistry of the newly synthesised compounds has been settled from NOE data.     

Convenient switching of 7-endo/6-exo radical cyclization

7-endo/6-exo Selectivity of radical cyclization to α,β-unsaturated amides was readily controlled by the presence or absence of a temporary substituent, a phenylthio or chlorine group, at the α-position of the acceptor.     

Synthesis of poly-substituted tetrahydropyridines from Baylis-Hillman adducts modified with N-allylamino group via radical cyclization

An expedient method was developed for the synthesis of 1,4,5,6-tetrahydropyridines by radical cyclization protocol involving consecutive 1,5-hydrogen transfer and double bond isomerization process starting from Baylis-Hillman adducts.     

Indium-mediated radical cyclization of iodoalkenes and iodoalkynes with and without allylic and propargylic leaving groups

Upon treatment with In and I₂, mono-substituted alkenes having an iodine substituent at the δ-position of the tether gave the corresponding iodinated cyclic compounds, whereas di- and tri-substituted alkenes gave the corresponding hydroxylated cyclic compounds. Alkenes bearing leaving groups at the allylic position were transformed only to the corresponding vinyl substituted cyclic compounds. On the other hand, alkynes bearing good leaving groups at the propargylic position gave allenic products selectively.     

Six-membered nitrogen ring formation by radical cyclization of trichloroacetamides with enones. A synthetic entry to cis-perhydroisoquinoline-3,6-diones

Intramolecular reactions between 1-(carbamoyl)dichloromethyl radicals and enones acting as radical acceptors are reported for the first time. The Bu₃SnH promoted 6-exo reaction of trichloroacetamides with enones, avoiding the 1,5-hydrogen transfer, constitutes a new synthetic entry to cis-perhydoisoquinoline-3,6-diones.     

Alkyl radical cyclization to vinylogous carbonates for the stereoselective synthesis of unsymmetrical dioxa-cage compounds: effect of conformation on the rate of cyclization versus reduction

An efficient strategy for the stereoselective construction of unsymmetrical dioxa-cage compounds containing ether linkages employing a 6-exo-trig alkyl radical cyclization to vinylogous carbonates is developed. The radical precursors are prepared from the diols obtained from the Diels-Alder adducts via iodoetherification followed by addition of the alcohol to the ethyl propiolate. The geometrical constrains play important role in deciding the outcome of the reaction as cyclization versus simple reduction. Formation of the mono-oxa-cage compounds via a 5-exo-trig intramolecular alkyl radical cyclization to olefin is also described. The dioxa-cages could also be assembled employing a tandem oxymercuration reduction-radical cyclization to vinylogous carbonates protocol with equal efficiency and with reduced number of steps.     

Synthesis and photoinitiated radical cyclization of allyl- and propynyloxymethyl substituted cyclopentanones to tetrahydrocyclopenta[c]furanols

Bicyclic cyclopentafuranols were formed by photoinitiated radical cyclization of allyl- and propinyloxymethyl substituted cyclopentanones with high regioselectivity. The irradiations were carried out at a wavelength of 300 nm in aprotic solvents such as benzene and acetonitrile. We could also show that reductive photoinduced electron transfer (PET) of the propynyloxymethyl substituted cyclopentanone 5 does not lead to any cyclization. The starting materials were synthesized in good yields following known procedures.     

天然产物合成中八元碳环的构建

总结归纳了近年来天然产物合成中八元碳环构建的主要方法:环合反应、裂解反应以及涉及环扩张/收缩的重排反应。     

Photochemical radical cyclization of γ,δ-unsaturated ketone oximes to 3,4-dihydro-2H-pyrroles

3,4-Dihydro-2H-pyrroles are synthesized from γ, δ-unsaturated oximes by photochemical radical cyclization with 1,5-dimethoxynaphthalene (DMN) as the sensitizer. The cyclization of alkyl ketone O-acetyloximes proceeds via photosensitized electron transfer in the presence of acetic acid, while conjugated oximes of aryl and α,β-unsaturated ketones are cyclized via energy transfer.     

A novel approach to functionalized (E)-1,4-diaryl-1-butenes by Heck reaction and their applications for the construction of dibenzylbutyrolactone lignan skeletons by radical cyclization

A highly regio- and stereoselective [Pd(allyl)Cl]₂ catalyzed Heck reaction of aryl iodides and electronically neutral terminal olefins generated in situ by fluoride induced protiodesilylation of alkenylsilanol derivatives under mild conditions has been developed. The products, viz. terminally substituted styrenes and (E)-1,4-diaryl-1-butenes were obtained in very good yields. The dibenzylbutyrolactone lignan skeletons have been prepared employing two regio- and stereoselective Bu₃SnH-mediated radical cyclization routes.     

A copper-catalyzed domino radical cyclization route to benzospiro-indolizidinepyrrolidinones

In this Letter the synthesis of benzospiro-indolizidinepyrrolidinones is described by a domino atom transfer radical cyclization reaction using a copper catalyst. The structure of one of the products was established by single crystal X-ray diffraction. The investigated precursors, bearing a homo allyl substituent on the N-indole, result in a 5-exo-trig, followed by a 6-endo-trig cyclization. When the N-indole is substituted with an allyl group, only the spiro-cyclization occurs.     

Development of a 5-exo, 6-exo tandem radical cyclization to access bisabosqual A

Substrates were designed to undergo tandem radical cyclizations to afford the cis, cis-fused hexahydrobenzofurobenzopyran ring system of the bisabosquals. Studies with these revealed that different initiating systems gave different yields and somewhat different diastereomeric ratios. A photocatalytic cyclization was also successful with the bisabosqual substrate.     

Regio- and stereoselective synthesis of methyl 5-methylenetetrahydropyran-3-carboxylates from Baylis-Hillman adducts via allyltributylstannane-mediated radical cyclization

Two types of regioisomeric methyl 5-methylenetetrahydropyran-3-carboxylate derivatives 3a-c and 6a-c were synthesized stereoselectively starting from the Baylis-Hillman adducts via the allyltributylstannane-mediated vinyl radical cyclization as the key step.