molecules Review Thiyl Radicals: Versatile Reactive Intermediates for Cyclization of Unsaturated Substrates Dylan M. Lynch and Eoin M. Scanlan * School of Chemistry and Trinity Biomedical Sciences Institute (TBSI), Trinity College Dublin, The University of Dublin, Dublin 2, Ireland; [email protected] * Correspondence: [email protected] Academic Editor: John C. Walton Received: 15 June 2020; Accepted: 2 July 2020; Published: 7 July 2020 Abstract: Sulfur centered radicals are widely employed in chemical synthesis, in particular for alkene and alkyne hydrothiolation towards thioether bioconjugates. The steadfast radical chain process that enables efficient hydrothiolation has been explored in the context of cascade reactions to furnish complex molecular architectures. The use of thiyl radicals offers a much cheaper and less toxic alternative to the archetypal organotin-based radical methods. This review outlines the development of thiyl radicals as reactive intermediates for initiating carbocyclization cascades. Key developments in cascade cyclization methodology are presented and applications for natural product synthesis are discussed. The review provides a chronological account of the field, beginning in the early seventies up to very recent examples; a span of almost 50 years. Keywords: radical; cyclisation; thiyl radicals; sulfur; carbocyclization 1. Introduction Since the turn of the millennium, organosulfur compounds have garnered substantial interest in the fields of medicinal chemistry, chemical biology and material science [1–7]. Of the diverse biochemical processes involving free radicals, many are thiyl radical mediated, highlighting the chemoselectivity, efficiency and biocompatibility of these reactive intermediates [8]. Sulfur-centered radicals have been broadly utilized in a wide range of synthetic applications over the past three decades. While their general utility has been previously reviewed [9–17], this account seeks to update the reader specifically on the application of thiyl radicals (RS•), in the carbocyclizations of unsaturated moieties, and the scope and limitations of these reactions in natural product synthesis. Sulfur, in its 2 oxidation state, can act as either a nucleophile or as a radical. The S-H bond is − generally considered relatively weak, with a bond dissociation energy (BDE) of 365 kJ/mol [18], and as such, both alkyl thiols and thiocarboxylic acids (thioacids) are precursors to thiyl/acyl thiyl radicals through facile homolytic cleavage. Thiyl radicals may be generated by homolytic bond breakage, and by one-electron redox processes. In the former process, a carbon centered radical (for example, from the radical initiator azobisisobutyronitrile (AIBN)) will abstract a hydrogen atom from the thiol. 8 1 1 Rate constants for this homolytic breakdown are of the magnitude 10 M− s− , which is below the diffusion limit for this reaction [19]. In the case of redox processes, single electron oxidants such as Mn (III) complexes or other metal sources can be used to accomplish radical formation [20–22]. Both radiolysis and direct photolysis of the S-H bond under UV irradiation are also valuable pathways to thiyl radical formation [23,24]. Thiyl radicals are well known to react efficiently at sites of unsaturation, through the thiol-ene and thiol-yne reactions. A full analysis of the utility of these reactions is beyond the scope of this review, and readers are directed to the reviews already present in the literature [6,24–29]. This account will Molecules 2020, 25, 3094; doi:10.3390/molecules25133094 www.mdpi.com/journal/molecules Molecules 20202020,, 2525,, xx FORFOR PEERPEER REVIEWREVIEW 22 ofof 4242 Molecules 2020, 25, 3094 2 of 40 will focus exclusively on the intramolecular trapping of the nascent carbon radical formed via thiyl radicalfocusradical exclusively addition,addition, andand on the howhow intramolecular thesethese radicalsradicals trapping formform ringsrings of the andand nascent productsproducts carbon inin cascadecascade radical reactions.reactions. formed via thiyl radical addition, and how these radicals form rings and products in cascade reactions. 2. Dienes and Diynes 2. Dienes and Diynes 2.1. Origin 2.1. Origin For the purpose of this review, ‘homogenous’ infersfers thethe samesame degreedegree ofof unsaturationunsaturation forfor allall reactivereactiveFor sitessites the purpose inin thethe substratesubstrate of this review, oror substrates;substrates; ‘homogenous’ i.e.,i.e., dienes, infers diynes, the same trienes, degree etc. of Possibly unsaturation the earliest for all examplereactive sitesof a incyclization the substrate cascade or substrates;on a homogenous i.e., dienes, substrate diynes, was trienes, published etc. Possiblyby Kuehne the et earliest al. in 1977.[30]example The of a account cyclization details cascade thethe cyclizationcyclization on a homogenous ofof selectedselectedsubstrate dienesdienes wiwi wasthth aa rangerange published ofof thiylthiyl by radicalradical Kuehne precursors,precursors, et al. in relying1977relying [30 ].uponupon The accountradicalradical detailsinitiationinitiation the cyclizationviavia photolysis of selected of diphen dienesyl withdisulfide a range or of thermolysis thiyl radical of precursors, benzoyl peroxide.relying upon Kuehne radical and initiation co-workers via photolysis sought ofto diphenyl compare disulfide the cyclizations or thermolysis effected of benzoyl by a range peroxide. of representativeKuehnerepresentative and co-workers thiylthiyl radicalradical sought species,species, to compare andand thusthus the cyclizationsexexperimented eff ectedwith bythe a initiator range of representativeitself, and thermal thiyl versusradical photoinitiation. species, and thus While experimented they obtained with a the nu initiatormber of itself,acyclic and adducts thermal and versus complex photoinitiation. mixtures of stereoisomers,Whilestereoisomers, they obtained aa numbernumber a number ofof cyclizedcyclized of acyclic productsproducts adducts werewere and complexalsoalso identified.identified. mixtures TheThe of stereoisomers,representativerepresentative aexampleexample number in ofin Schemecyclized 1 products shows the were cyclization also identified. of dimethyl The representativediallylmalonate example 1 under in a Schemenumber1 ofshows reaction the cyclizationconditions, theofthe dimethyl bestbest ofof whichwhich diallylmalonate employedemployed thethe1 under photolysisphotolysis a number ofof diphendiphen of reactionylsulfide conditions, in benzene the to best generate of which the employed thiyl radical the ofphotolysis ethanethiol. of diphenylsulfide These conditions in benzene resulted to in generate the formation the thiyl of radical over 90% of ethanethiol. cyclized product These conditions2,, andand sixsix minorresulted acyclic in the adducts. formation However, of over the 90% formation cyclized of product any six-membered2, and six minor cyclization acyclic products adducts. was However, ruled outthe formationsystematically. of any six-membered cyclization products was ruled out systematically. SchemeScheme 1.1. CyclizationCyclization ofof dimethyldimethyl diallylmalonatediallylmalonate byby ethanethiylethanethiyl radical.radical. XX == H or SCH 22CHCH33.. Kuehne and co-workers applied these findings findings to the analogous cyclization of of αα-acoradiene-acoradiene 44,,, which proceededproceeded almostalmost quantitatively.quantitatively. Desulfurization Desulfurization with with Raney Raney nickel nickel yielded yielded dihydrocedrene dihydrocedrene6, 6the,, thethe hydrogenated hydrogenatedhydrogenated form formform of a of sesquiterpeneof aa sesquiterpenesesquiterpene found foundfound in the in essentialin thethe essentialessential oil of cedar oiloil ofof (Scheme cedarcedar 2(Scheme(Scheme). This approach 2).2). ThisThis approachwas later appliedwas later to theapplied cyclization to the ofcyclization geranyl acetate, of geranyl but the acetate, acyclic but monoadducts the acyclic ofmonoadducts geranyl acetate of geranyland the acetate thiyl radical and the source thiyl were radical mostly source obtained. were mostly obtained. Scheme 2. CyclizationCyclization of α-Acoradiene-Acoradiene 44 byby Kuehne Kuehne et et al al.al.. These results results were were greatly greatly expanded expanded upon upon in inwork work published published by Padwa by Padwa et al. et in al. 1985.[31] in 1985 Using [31]. thioaceticUsingthioacetic thioacetic acidacid andand acid AIBN,AIBN, and PadwaPadwa AIBN, andand Padwa co-workersco-workers and co-workers werewere ableable were toto cyclizecyclize able aa to relativelyrelatively cyclizea simplesimple relatively tosylaminetosylamine simple 7tosylamine withwith twotwo allyl7allylwith substituents,substituents, two allyl substituents, inin aa 55-exo-trig-exo-trig in aprocess. 5-exo-trig Additionprocess. of Addition the thiyll of radical,radical, the thiyl formedformed radical, indirectlyindirectly formed byindirectly thermolysis by thermolysis of AIBN, and of AIBN, intramolecular and intramolecular cyclizationization cyclization ofof thethe nascentnascent of the carbon-centeredcarbon-centered nascent carbon-centered radicalradical 8 immediatelyradicalimmediately8 immediately provedproved thethe proved utilityutility the ofof utility thisthis reactionreaction of this reactionasas aa viableviable as arouteroute viable toto routeheterocyclesheterocycles to heterocycles (Scheme(Scheme (Scheme 3A).3A). ItIt may3mayA). Molecules 2020, 25, 3094 3 of 40 Molecules 2020, 25, x FOR PEER REVIEW 3 of 42 beIt