Gold-Catalyzed Addition of Carboxylic Acids to Alkynes and Allenes

Home , Acyl group, Allenes, BINAP, Lactone, Thiocarboxylic acid

Review catalysts Gold-Catalyzed Addition of Carboxylic Acids to ReviewAlkynes and Allenes: Valuable Tools for Organic Gold-CatalyzedSynthesis Addition of Carboxylic Acids to Alkynes and Allenes: Valuable Tools for OrganicVictorio Cadierno Synthesis * Laboratorio de Compuestos Organometálicos y Catálisis (Unidad Asociada al CSIC), Departamento de VictorioQuímica Cadierno Orgánica e Inorgánica, Facultad de Química, Universidad de Oviedo, Julián Clavería 8, E-33006 Oviedo, Spain; [email protected]; Tel.: +34-985-103453 Laboratorio de Compuestos Organometálicos y Catálisis (Unidad Asociada al CSIC), Departamento de Química OrgReceived:ánica e29 Inorg Septemberánica, Facultad 2020; Accepted: de Química, 16 October Universidad 2020; Published: de Oviedo, date Juliá n Clavería 8, E-33006 Oviedo, Spain; [email protected]; Tel.: +34-985-103453 Abstract: In this contribution, the application of gold-based catalysts in the hydrofunctionalization Received:reactions 29of Septemberalkynes and 2020; allenes Accepted: with 16carboxylic October 2020; acids Published: is comprehensively 18 October 2020 reviewed. Both intra- and Abstract:intermolecularIn this processes, contribution, leading the respectively application ofto gold-basedlactones and catalysts linear unsaturated in the hydrofunctionalization esters, are covered. reactionsIn addition, of alkynescascade andtransformations allenes with carboxylicinvolving the acids initial is comprehensively cycloisomerization reviewed. of an alkynoic Both intra- acid and are intermolecularalso discussed. processes, leading respectively to lactones and linear unsaturated esters, are covered. In addition, cascade transformations involving the initial cycloisomerization of an alkynoic acid are Keywords: gold catalysts; addition reactions; hydrofunctionalization; alkynes; allenes; esters; also discussed. lactones Keywords: gold catalysts; addition reactions; hydrofunctionalization; alkynes; allenes; esters; lactones

1. Introduction 1. Introduction The catalytic hydrofunctionalization of alkynes provides convenient routes of access to a wide varietyThe of catalytic functionalized hydrofunctionalization olefins that address of alkynes the providescurrent need convenient for atom-economic, routes of access green to awide and varietysustainable of functionalized processes [1–7]. olefins In that this address regard, the coun currenttlessneed catalytic for atom-economic, systems capable green of andpromoting sustainable the processesaddition of [1 –different7]. In this heteroatom- regard, countless (e.g., O, catalytic N, S, P, systems B, Se, Si, capable P or halogens) of promoting and carbon-hydrogen the addition of di ffbondserent heteroatom-to alkyne molecules, (e.g., O,N, with S,P, high B, Se, levels Si, P of or efficiency halogens) and carbon-hydrogenselectivity, can be bonds found to in alkyne the literature. molecules, A withrelevant high example levels of of effi thisciency type and of selectivity,transformation can be is foundthe hydro-oxycarbonylation in the literature. A relevant of alkynes example with of thiscarboxylic type of acids transformation [2–4,8–13]. is Thus, the hydro-oxycarbonylation as shown in Scheme 1, ofthe alkynes intramolecular with carboxylic version acids of the [2 –process,4,8–13]. Thus,i.e., the as cycloisomerization shown in Scheme 1of, thealkynoic intramolecular acids, allows version the rapid of the assembly process, of i.e., unsaturated the cycloisomerization lactone rings ofwhich alkynoic are structural acids, allows units the present rapid assemblyin a huge of number unsaturated of biologically lactone rings active which molecules are structural and natural units presentproducts in [14–16]. a huge numberOf interest of biologically also, are the active intermolecular molecules andadditions natural of productscarboxylic [14 acids–16]. to Of alkynes, interest also,since arethe the resulting intermolecular enol ester additions products of carboxylicare relevant acids intermediates to alkynes, sincefor synthetic the resulting chemistry enol esterand productspolymerization are relevant reactions intermediates [8,13,17]. for synthetic chemistry and polymerization reactions [8,13,17].

Scheme 1. The intra- and intermolecularintermolecular additions of carboxylic acids to alkynes.

CatalystsSeveral 2020, 10 transition, x; doi: FOR metals PEER REVIEW have been employed to promote the hydrofunctionalizationwww.mdpi.com/journ ofal/catalysts alkynes, among which gold has gained prominence, given its outstanding eﬀectiveness for the π-electrophilic

Catalysts 2020, 10, 1206; doi:10.3390/catal10101206 www.mdpi.com/journal/catalysts Catalysts 2020, 10, 1206 2 of 36 activation of unsaturated carbon-carbon bonds towards nucleophiles [18–25]. In addition, the fact that the properties of both Au(I) and Au(III) complexes can be easily modulated by the surrounding ligands has been extensively exploited for the fine tuning of the activity and/or selectivity of the catalytic processes in which gold is involved [26]. Regarding the addition reactions of carboxylic acids to alkynes, the use of gold catalysts has made it possible to overcome some of the limitations found with other metals—for example, the hydro-oxycarbonylation of internal alkynes for which ruthenium, one of the most frequently employed metals, is ineffective. The marked preference of π-alkyne-gold complexes to undergo the addition of nucleophiles in an anti fashion is also beneficial in these reactions, since it limits the number of isomers that can be formed. To a lesser extent, gold-based catalysts have also been applied in recent years in the hydrofunctionalization of allenes, molecules of special relevance because their axial chirality can be exploited in asymmetric synthesis. Intramolecular hydroamination and hydroalkoxylation processes are by far the most documented [20,23,27,28], but some examples of both intra- and intermolecular hydro-oxycarbonylation reactions of allenes catalyzed by gold complexes are also known. In addition to the classical chemoselectivity, regioselectivity and stereoselectivity issues, positional selectivity is an extra problem associated to the nucleophilic additions to allenes [29]. In general, the regioselectivity of the addition process, i.e., attack of the heteroatom on the sp or the sp2 carbons, is strongly dependent on the substitution pattern of the substrates, and in the case of intramolecular processes, also on the length of the tether connecting the allenic unit and the nucleophile. In that regard, the exquisite selectivity found in all the gold-catalyzed hydro-oxycarbonylation reactions described to date in the literature is noteworthy. The aim of the present review article is to provide a comprehensive overview of the developments achieved in this particular research area.

2. Additions of Carboxylic Acids to Alkynes

2.1. Cycloisomerization of Alkynoic Acids The utility of gold catalysts in the cyclization of acetylenic acids was evidenced for the first time by Michelet and co-workers in 2006 [30]. As shown in Scheme2, they found that in the presence of catalytic amounts of AuCl (5 mol%), a large variety of terminal γ-alkynoic acids 1 are rapidly converted into the corresponding 5-alkylidene-butyrolactones 2, in high yields and in a complete regioselective manner, by performing the reactions in acetonitrile at room temperature. The process was also operative with γ-alkynoic acids containing internal alkyne units, such as the aromatic derivatives 3 or the aliphatic one 5 [30,31]. In the case of 3, regardless of the electronic properties of the aryl substituent, a selective 5-exo-dig cyclization was again observed. In addition, the corresponding five-membered ring enol-lactones 4 featured in all the cases (Z) stereochemistry for the exocyclic C=C bond. This last point implies that the reactions proceed through the intramolecular anti-addition of the carboxylic acid to the Au(I)-coordinated alkyne moiety (see the mechanistic proposal in Scheme3). The same stereochemistry was found in the butyrolactone 6 generated from the ethyl-substituted γ-alkynoic acid 5, although in this case the major reaction product was the 6-membered ring lactone 7 resulting from a 6-endo-dig cyclization. Almost simultaneously with Michelet’s work, Pale and co-workers reported the AuCl-catalyzed cyclization of different γ, δ and ε-alkynoic acids lacking substituents in α-position with respect to the carboxylic acid group (Scheme4)[ 32]. Unlike the previous examples, this type of substrate does not benefit from the Thorpe–Ingold effect and the reactions required of a higher metal loading (10 mol%) and the assistance of a base (K2CO3) to facilitate the generation of the nucleophilic carboxylate anion. Regardless of the length of the hydrocarbon chain and the nature of the alkyne terminus, the selective formation of the exo-dig cyclization products was observed, with generally high yields ( 60%), except ≥ for the case of hept-6-ynoic acid—which delivered the corresponding 7-membered ring enol-lactone in only 25% yield after 48 h of stirring in acetonitrile at r.t. (the rest of examples required only two Catalysts 2020, 10, 1206 3 of 36 hours of reaction). For those substrates featuring an internal C C bond, the anti-addition products ≡ were again exclusively generated, although in some cases the (Z) isomers initially formed partially isomerized in solution into the corresponding (E) ones [32,33]. Of note is the fact that the process was completely inoperative when silyl-protected alkynes were employed as substrates due to the strong withdrawing effect of the SiR3 group, which drastically reduces the electron density of the C C bond, Catalysts 2020, 10, x FOR PEER REVIEW ≡ 3 of 37 Catalyststhereby 2020 making, 10, x FOR its coordination PEER REVIEW to the gold center less favorable [32,33]. 3 of 37

Scheme 2. AuCl-catalyzed cycloisomerization of γ-alkynoic acids. Scheme 2. AuCl-catalyzed cycloisomerization of γ-alkynoic acids.

Scheme 3. Proposed mechanism for the AuCl-c AuCl-catalyzedatalyzed cycloisomerization of γ-alkynoic acids.acids. Scheme 3. Proposed mechanism for the AuCl-catalyzed cycloisomerization of γ-alkynoic acids. Almost simultaneously with Michelet's work, Pale and co-workers reported the AuCl-catalyzed Almost simultaneously with Michelet's work, Pale and co-workers reported the AuCl-catalyzed cyclization of different γ, δ and ε-alkynoic acids lacking substituents in α-position with respect to the cyclization of different γ, δ and ε-alkynoic acids lacking substituents in α-position with respect to the carboxylic acid group (Scheme 4) [32]. Unlike the previous examples, this type of substrate does not carboxylic acid group (Scheme 4) [32]. Unlike the previous examples, this type of substrate does not benefit from the Thorpe–Ingold effect and the reactions required of a higher metal loading (10 mol%) benefit from the Thorpe–Ingold effect and the reactions required of a higher metal loading (10 mol%) and the assistance of a base (K2CO3) to facilitate the generation of the nucleophilic carboxylate anion. and the assistance of a base (K2CO3) to facilitate the generation of the nucleophilic carboxylate anion. Regardless of the length of the hydrocarbon chain and the nature of the alkyne terminus, the selective Regardless of the length of the hydrocarbon chain and the nature of the alkyne terminus, the selective formation of the exo-dig cyclization products was observed, with generally high yields (≥ 60%), except formation of the exo-dig cyclization products was observed, with generally high yields (≥ 60%), except for the case of hept-6-ynoic acid—which delivered the corresponding 7-membered ring enol-lactone for the case of hept-6-ynoic acid—which delivered the corresponding 7-membered ring enol-lactone in only 25% yield after 48 h of stirring in acetonitrile at r.t. (the rest of examples required only two in only 25% yield after 48 h of stirring in acetonitrile at r.t. (the rest of examples required only two hours of reaction). For those substrates featuring an internal C≡C bond, the anti-addition products hours of reaction). For those substrates featuring an internal C≡C bond, the anti-addition products were again exclusively generated, although in some cases the (Z) isomers initially formed partially were again exclusively generated, although in some cases the (Z) isomers initially formed partially isomerized in solution into the corresponding (E) ones [32,33]. Of note is the fact that the process was isomerized in solution into the corresponding (E) ones [32,33]. Of note is the fact that the process was completely inoperative when silyl-protected alkynes were employed as substrates due to the strong completely inoperative when silyl-protected alkynes were employed as substrates due to the strong withdrawing effect of the SiR3 group, which drastically reduces the electron density of the C≡C bond, withdrawing effect of the SiR3 group, which drastically reduces the electron density of the C≡C bond, thereby making its coordination to the gold center less favorable [32,33]. thereby making its coordination to the gold center less favorable [32,33].

Catalysts 2020, 10, 1206 4 of 36 Catalysts 2020, 10, x FOR PEER REVIEW 4 of 37

Scheme 4. Base-assisted AuCl-catalyzed cycloisomerization of alkynoic acids.

PalePale´s´s group also explored the catalytic behavior of AuCl 3 inin these these cycloisomerization cycloisomerization processes, processes, observing for the three model alkynoic acids testedtested the unexpected formation of the dimeric methylene-lactone derivatives 8 (Scheme 55))[ [33].33]. These species were generated in a stereoselectivestereoselective manner as the corresponding (E,E) isomers,isomers, and werewere isolatedisolated inin lowlow yields.yields. A reaction pathway involving thethe homocouplinghomocoupling of of the the organogold organogold intermediates intermediatesA Agenerated generated during during the theexo exocyclization cyclization of theof the substrates substrates was was proposed proposed by by the the authors authors to to explain explain the the formation formation of of compounds compounds8 8.. TheThe reductive elimination of the resulting diorganogold speciesspecies BB would give dimers 8 with liberation of Au(I). This last point could be responsible forfor the low yields observed, sincesince halfhalf of the catalyst is consumed. The involvement of the diynyldiacids 9, which could potentially be generatedgenerated in the reaction mediummedium through a Glaser-typeGlaser-type homocoupling, was totally ruled out, sincesince thethe gold-catalyzedgold-catalyzed cyclization of these species leads to the formation of the compounds 8 with an opposite stereochemistry on the two CC=C=C bonds, bonds, i.e., i.e., as as ( (Z,ZZ,Z)) isomers isomers (see (see Scheme Scheme 55).).

Scheme 5. Gold-catalyzed synthesis of dimeric methylene-lactones from alkynoic acids.

Applying Pale´s conditions, i.e., using the AuCl/K2CO3 combination, van de Weghe and co-workers Applying Pale´s conditions, i.e., using the AuCl/K2CO3 combination, van de Weghe and co- 10 studiedworkers the studied cycloisomerization the cycloisomerization of the 2-alkynyl-substituted of the 2-alkynyl-substituted phenylacetic phenylacetic acids , thereby acids observing 10, thereby the 11 exo dig formationobserving ofthe reaction formation mixtures of reaction containing mixtures the respectivecontaining 1-alkylidene-isochroman-3-one the respective 1-alkylidene-isochroman-3-(6- - one 11 (6-exo-dig cyclization) and benzo[d]oxepin-2(1H)-one 12 (7-endo-dig cyclization), with the former being the major component in almost all the cases (except for R = nPr; see Scheme 6) [34].

Catalysts 2020, 10, 1206 5 of 36

Catalysts 2020, 10, x FOR PEER REVIEW 5 of 37 cyclization)Catalysts 2020, 10 and, x FOR benzo[ PEERd]oxepin-2(1 REVIEW H)-one 12 (7-endo-dig cyclization), with the former being the major5 of 37 Relatedcomponent reactions in almost employing all the cases as (exceptsubstrates for R2-alkynyl-substituted= nPr; see Scheme6)[ 34benzoic]. Related acids reactions 13 also employing afforded mixturesasRelated substrates reactionsof the 2-alkynyl-substituted regioisomers employing 14 as and substrates benzoic 15; the acidsexo 2-alkynyl-substituted-dig13 modealso a ofﬀorded cyclization mixtures benzoic predominated of theacids regioisomers 13 againalso afforded[34,35].14 and 15mixtures; the exo of-dig themode regioisomers of cyclization 14 and predominated 15; the exo-dig again mode [34 of,35 cyclization]. predominated again [34,35].

Scheme 6. AuCl-catalyzed cycloisomerization of 2-alkynyl-substituted phenylacetic and benzoic acids.Scheme 6.6. AuCl-catalyzedAuCl-catalyzed cycloisomerization cycloisomerization of 2-alkynyl-substitutedof 2-alkynyl-substituted phenylacetic phenylacetic and benzoicand benzoic acids. acids. Much more selectiveselective transformationstransformations were were described described by by Est Estévezévez and and co-workers, co-workers, starting starting from from the therelated relatedMuch 2-[(2-nitrophenyl)ethynyl]phenylacetic more2-[(2-nitrophenyl) selective transformationsethynyl]phenylacetic were acids descri16, acidsbedsince by16, lactones Estévezsince 17lactones and, resulting co-workers, 17, from resulting astarting regiospeciﬁc from from a regiospecific6-theexo related-dig cyclization, 2-[(2-nitrophenyl)6-exo-dig were cyclization, exclusivelyethynyl]phenylacetic were obtained exclusively (Scheme acids obtained7)[ 16,36 ]. since According(Scheme lactones 7) to [36]. the17, authors, Accordingresulting the from strongto the a authors,resonanceregiospecific the eﬀ strong ect6-exo of- thedigresonance nitrocyclization, group effect was wereof the probably exclusivelynitro group behind obtainedwas the probably exquisite (Scheme behind selectivity 7) the[36]. observedexquisite According withselectivity to these the particularobservedauthors, the with substrates. strong these resonance particular effect substrates. of the nitro group was probably behind the exquisite selectivity observed with these particular substrates.

Scheme 7. AuCl-catalyzedAuCl-catalyzed cycloisomerization cycloisomerization of 2-[(2 2-[(2-nitrophenyl)ethynyl]phenylacetic-nitrophenyl)ethynyl]phenylacetic acids 16. Scheme 7. AuCl-catalyzed cycloisomerization of 2-[(2-nitrophenyl)ethynyl]phenylacetic acids 16. Employing the AuCl/K AuCl/K2CO3 combinationcombination too, too, Testero Testero and and co-wor co-workerskers reported reported the the regioselective regioselective and stereoselectiveEmploying stereoselective the conversionAuCl/K conversion2CO of3 ofcombination th thee amino amino acid-derived too, acid-derived Testero andalkynoic alkynoic co-wor acidskers acids 18 reported into18 theinto the respective the regioselective respective enol- lactonesenol-lactonesand stereoselective 19 (Scheme19 (Scheme conversion 8) [37].8)[ Remarkably,37 of]. Remarkably,the amino secondary acid-derived secondary products productsalkynoic derived acids derived from 18 the frominto addition the the respective addition of the of N–Henol- the N–H unit to the C C bond were in no case observed, despite them easily occurring when the CO H unitlactones to the 19 C (Scheme≡C bond≡ 8) were [37]. in Remarkably, no case observed, secondary despite products them easily derived occurring from the when addition the CO of2 Hthe group N–H2 wasgroupunit replacedto wasthe C replaced≡ byC bond the byester were the one esterin noCO onecase2Me. CO observed, 2Me. despite them easily occurring when the CO2H group was replacedOn the by other the ester hand, one CO Perumal2Me. and co-workers described the synthesis of several pyrano[3,4-b]indol-1(9H)-ones 21 by 6-endo-dig cyclization of the 3-alkynyl-indole-2-carboxylic acids 20, using in this case gold(III) chloride as the catalyst (Scheme9)[ 38]. The reactions proceeded in high yields and short times in the absence of base, but harsher temperature conditions were needed (reﬂuxing acetonitrile). The excellent regioselectivity observed in these reactions was explained by the authors on the basis of the greater strain associated with the formation of two fused 5-membered rings in the potential 5-exo-dig cyclization products. Noteworthily, compounds 21 displayed cytotoxic

Scheme 8. Catalytic cycloisomerization of alkyne-containing amino acid derivatives. Scheme 8. Catalytic cycloisomerization of alkyne-containing amino acid derivatives.

Catalysts 2020, 10, x FOR PEER REVIEW 5 of 37

Related reactions employing as substrates 2-alkynyl-substituted benzoic acids 13 also afforded mixtures of the regioisomers 14 and 15; the exo-dig mode of cyclization predominated again [34,35].

Scheme 6. AuCl-catalyzed cycloisomerization of 2-alkynyl-substituted phenylacetic and benzoic acids.

Much more selective transformations were described by Estévez and co-workers, starting from the related 2-[(2-nitrophenyl)ethynyl]phenylacetic acids 16, since lactones 17, resulting from a regiospecific 6-exo-dig cyclization, were exclusively obtained (Scheme 7) [36]. According to the authors, the strong resonance effect of the nitro group was probably behind the exquisite selectivity observed with these particular substrates.

Scheme 7. AuCl-catalyzed cycloisomerization of 2-[(2-nitrophenyl)ethynyl]phenylacetic acids 16.

Employing the AuCl/K2CO3 combination too, Testero and co-workers reported the regioselective Catalysts 2020, 10, 1206 6 of 36 and stereoselective conversion of the amino acid-derived alkynoic acids 18 into the respective enol- lactones 19 (Scheme 8) [37]. Remarkably, secondary products derived from the addition of the N–H unitactivity to the against C≡C bond human were cervix in no adenocarcinoma case observed, despite (HeLa) them cell lines, easily comparable occurring when in some the CO cases2H togroup that wasshown replaced by the by standard the estercis one-platin CO drug.2Me. Catalysts 2020,, 10,, xx FORFOR PEERPEER REVIEWREVIEW 6 of 37

On the other hand, Perumal and co-workers described the synthesis of several pyrano[3,4- b]indol-1(9H)-ones 21 by 6-endo-dig cyclization of the 3-alkynyl-indole-2-carboxylic acids 20, using in this case gold(III) chloride as the catalyst (Scheme 9) [38]. The reactions proceeded in high yields and short times in the absence of base, but harsher temperature conditions were needed (refluxing acetonitrile). The excellent regioselectivity observed in these reactions was explained by the authors on the basis of the greater strain associated with the formation of two fused 5-membered rings in the potential 5-exo-dig cyclization products. Noteworthily, compounds 21 displayed cytotoxic activity against human cervix adenocarcinoma (HeLa) cell lines, comparable in some cases to that shown by the standard cis-platin drug. the standardScheme cis-platin 8. Catalytic drug. cycloisomerization of alkyne-containing amino acid derivatives.

SchemeScheme 9.9. AuCl3-catalyzed-catalyzed synthesis of pyrano[3,4- b]indol-1(9H)-ones.

TheThe same same protocol protocol was was addition additionallyally employed employed for the for preparation the preparation of the related of thepyrano[4,3- related pyrano[4,3-b]indol-1(5Hb]indol-1(5)-one derivativesH)-one derivatives 23, which also23, which featured also inhibitory featured inhibitoryactivity against activity HeLa against cells, HeLa from cells, the fromcorresponding the corresponding 2-alkynyl-ind 2-alkynyl-indole-3-carboxylicole-3-carboxylic acids 22 acids (Scheme22 (Scheme 10) [39]. 10 It)[ should39]. It shouldbe mentioned be mentioned at this atpoint this that point the that present the present cyclization cyclization process processseems to seems be restricted to be restricted to substrates to substrates containing containing an internal an 2 internalalkyne unit alkyne (R2 unit≠ H), (R since, H), a control sincea experiment control experiment with a terminal with a terminalone led, oneunder led, identical underidentical reaction reactionconditions, conditions, to the recovery to the recovery of the starting of the startingmaterial—mostly material—mostly unchanged unchanged after 3 h after of heating. 3 h of heating. AuCl3- AuClcatalyzed3-catalyzed 6-exo-dig 6-exo-dig cyclizationscyclizations of N-propargylpyrrole of N-propargylpyrrole and indole-2-carboxylic and indole-2-carboxylic acids acidshave havealso been also beendescribed described [40]. [40].

SchemeScheme 10.10. AuCl3-catalyzed-catalyzed synthesis of pyrano[4,3- b]indol-1(5H)-ones.

InIn additionaddition toto thethe chloride chloride salts salts AuCl AuCl and and AuCl AuCl3,3 several, several molecular molecular gold gold complexes complexes are are known known to promoteto promote cycloisomerization cycloisomerization reactions reactions of alkynoic of alky acids.noic acids. For example, For example, Hammond, Hammond, Xu and Xu co-workers and co- reportedworkers reported the use of the [AuCl(JohnPhos)] use of [AuCl(JohnPhos)] [41,42], and [41,42], an analogous and an gold(I)-chlorideanalogous gold(I)-chloride complex containing complex thecontaining more sterically the more demanding sterically demandingo-biphenyl o-biphenyl phosphine phosphine24 (see Figure 24 (see1)[ Figure43], as 1) catalysts [43], as catalysts for the exofor cyclizationthe exo cyclization of the model of the substrates model substrates pent-4-ynoic pent-4-ynoic acid and hex-5-ynoic acid and hex-5-ynoic acid. Both showedacid. Both remarkable showed remarkable activity leading to the corresponding alkylidene-lactones in a quantitative manner, and short times (from 5 min to 1 h), while employing metal loadings of only 0.01–0.3 mol%. However, it should be noted that the presence of a chloride abstractor (AgOTf or AgSbF6) was needed to activate the catalysts and generate the required vacant coordination site on the metal for alkyne binding. More elaborated examples include platinum-based nanospheres functionalized with a phosphine-gold(I)-

Catalysts 2020, 10, 1206 7 of 36 activity leading to the corresponding alkylidene-lactones in a quantitative manner, and short times (from 5 min to 1 h), while employing metal loadings of only 0.01–0.3 mol%. However, it should be noted that the presence of a chloride abstractor (AgOTf or AgSbF6) was needed to activate the catalysts andCatalysts generate 2020, 10 the, x FOR required PEER REVIEW vacant coordination site on the metal for alkyne binding. More elaborated7 of 37 examples include platinum-based nanospheres functionalized with a phosphine-gold(I)-chloride complexchloride [complex44] and AuCl [44] linkedand AuCl to a resorcinarenelinked to a re cavitandsorcinarene phosphine cavitand ligand phosphine [45]. These ligand supramolecular [45]. These systemssupramolecular proved systems to be active proved in the to be of cyclizationactive in the of of linear cyclizationγ-alkynoic of linear acids, γ-alkynoic showing acids, diﬀerences showing in reactivitydifferences compared in reactivity to the compared standard to gold(I) the standard chloride gold(I) salt (lower chloride selectivity salt (lower towards selectivity the exo towardscyclization the inexo the cyclization former case in the or reactionformer case rates or strongly reactiondependent rates strongly on thedependent sizes of on the the substituents sizes of the present substituents in the substratespresent in inthe the substrates latter). in the latter).

Figure 1.1. Structure of the o-biphenyl-biphenyl phosphinephosphine ligandsligands JohnPhosJohnPhos andand 2424..

The gold(I) complexes [AuCl(PPh )] and [AuCl{P(O-2,4-C H tBu ) }], in combination with The gold(I) complexes [AuCl(PPh33)] and [AuCl{P(O-2,4-C6 6H33tBu2)3}], in combination with AgSbF , were used by Porcel and co-workers to promote the cyclization of a series of alkynoic acids 25 AgSbF66, were used by Porcel and co-workers to promote the cyclization of a series of alkynoic acids derived25 derived from from salicylic salicylic acid, acid, reactions reactions that that proceeded proceeded effi cientlyefficiently in1,2-dichloroethane in 1,2-dichloroethane at r.t. at orr.t. 50or ◦50C with°C with catalyst catalyst loadings loadings of 5of mol% 5 mol% (Figure (Figure2)[ 2)46 [46].]. The The regioselective regioselective formation formation of of thethe correspondingcorresponding seven-memberedseven-membered ringring lactones lactones26 26was was observed observed for for those those substrates substrates containing containing a terminal a terminal alkyne alkyne unit, whileunit, while the cycloisomerization the cycloisomerization of their of non-terminal their non-term counterpartsinal counterparts was not was always not regioselective,always regioselective, leading toleading mixtures to mixtures of the respective of the respective exo- and exo- endocyclic and endocyclic enol-lactones enol-lactones26 (major 26 products)(major products) and 27 (minorand 27 products).(minor products). In addition, In addition, certain certain non-terminal non-terminal alkynoic alkynoic acids led acids to theled preferentialto the preferential formation formation of the 2ofH -chromenesthe 2H-chromenes28, products 28, products coming coming from the from hydroarylation the hydroarylati of theon alkyne of the group. alkyne In group. a later work,In a later the samework, group the same studied group the studied arylative the cyclization arylative cyclization of compounds of compounds25 with arenediazonium 25 with arenediazonium salts employing salts a stoichiometric amount of [AuCl(SMe )] and two equivalents of Li CO as the promoters [47]. employing a stoichiometric amount of [AuCl(SMe2 2)] and two equivalents2 of3 Li2CO3 as the promoters Regardless[47]. Regardless of the of terminal the terminal or internal or internal nature ofnatu there alkynes, of the alkynes, mixtures mixtures of the corresponding of the corresponding lactones 26lactonesand 27 26arylated and 27 on arylated the C= Con bond the wereC=C bond systematically were systematically generated,thereby generated, revealing thereby a di revealingfference in a regioselectivitydifference in regioselectivity compared to that compared found in theto that cycloisomerization found in the reactionscycloisomerization just mentioned. reactions just mentioned.Cyclizations of alkynoic acids with gold complexes containing N-heterocyclic carbene (NHC) ligands can also be found in the literature. In this context, the first example was reported by Spenger and Friksdahl with the cycloisomerization of the bispropargylic carboxylic acid 29 employing [AuCl(IMes)] (IMes = 1,3-dimesitylimidazole-2-ylidene) as the catalyst (Scheme 11)[48]. In the presence of K2CO3, [AuCl(IMes)] was able to convert selectively 29 into the 5-exo-dig cyclization product 30, while mixtures of 30, the tetrahydropyranone 31 (6-endo-dig cyclization) and the bicyclic species 32 (resulting from the cyclization of 31) were obtained when the K2CO3 co-catalyst was replaced by silver(I) salts (AgSbF6, AgOTf, AgNTf2 or AgBPh4). Similar observations were made when [AuCl(PEt3)] was employed as the gold source, although the yields were in general lower.

Figure 2. Structure of the alkynoic acids 25 and their cyclization products 26–28.

Cyclizations of alkynoic acids with gold complexes containing N-heterocyclic carbene (NHC) ligands can also be found in the literature. In this context, the first example was reported by Spenger and Friksdahl with the cycloisomerization of the bispropargylic carboxylic acid 29 employing

Catalysts 2020, 10, x FOR PEER REVIEW 7 of 37 chloride complex [44] and AuCl linked to a resorcinarene cavitand phosphine ligand [45]. These supramolecular systems proved to be active in the of cyclization of linear γ-alkynoic acids, showing differences in reactivity compared to the standard gold(I) chloride salt (lower selectivity towards the exo cyclization in the former case or reaction rates strongly dependent on the sizes of the substituents present in the substrates in the latter).

Figure 1. Structure of the o-biphenyl phosphine ligands JohnPhos and 24.

The gold(I) complexes [AuCl(PPh3)] and [AuCl{P(O-2,4-C6H3tBu2)3}], in combination with AgSbF6, were used by Porcel and co-workers to promote the cyclization of a series of alkynoic acids 25 derived from salicylic acid, reactions that proceeded efficiently in 1,2-dichloroethane at r.t. or 50 °C with catalyst loadings of 5 mol% (Figure 2) [46]. The regioselective formation of the corresponding seven-membered ring lactones 26 was observed for those substrates containing a terminal alkyne unit, while the cycloisomerization of their non-terminal counterparts was not always regioselective, leading to mixtures of the respective exo- and endocyclic enol-lactones 26 (major products) and 27 (minor products). In addition, certain non-terminal alkynoic acids led to the preferential formation of the 2H-chromenes 28, products coming from the hydroarylation of the alkyne group. In a later work, the same group studied the arylative cyclization of compounds 25 with arenediazonium salts employing a stoichiometric amount of [AuCl(SMe2)] and two equivalents of Li2CO3 as the promoters [47]. Regardless of the terminal or internal nature of the alkynes, mixtures of the corresponding lactones 26 and 27 arylated on the C=C bond were systematically generated, thereby revealing a differenceCatalysts 2020 ,in10 , 1206regioselectivity compared to that found in the cycloisomerization reactions8 ofjust 36 mentioned.

Catalysts 2020, 10, x FOR PEER REVIEW 8 of 37

[AuCl(IMes)] (IMes = 1,3-dimesitylimidazole-2-ylidene) as the catalyst (Scheme 11) [48]. In the presence of K2CO3, [AuCl(IMes)] was able to convert selectively 29 into the 5-exo-dig cyclization product 30, while mixtures of 30, the tetrahydropyranone 31 (6-endo-dig cyclization) and the bicyclic species 32 (resulting from the cyclization of 31) were obtained when the K2CO3 co-catalyst was replaced by silver(I) salts (AgSbF6, AgOTf, AgNTf2 or AgBPh4). Similar observations were made when [AuCl(PEtFigure3)] was 2. StructureStructure employed of of the the as alkynoic the gold acids source, 25 and alth their ough cyclization the yields products were in 26–28 general. lower.

SchemeScheme 11.11. Cyclization of the bispropargylic carboxylic acid 29 catalyzedcatalyzed byby thethe NHCNHC complexcomplex [AuCl(IMes)].[AuCl(IMes)].

The dinuclear hydroxo-brigded gold(I) complex [{Au(IPr)} (µ-OH)][BF ](33; IPr = The dinuclear hydroxo-brigded gold(I) complex [{Au(IPr)}2(µ-OH)][BF2 4] (33; IPr4 = N,N´-bis(2,6- N,Ndi-iso´-bis(2,6-di--propylphenyl)imidazole-2-ylidene)iso-propylphenyl)imidazole-2-ylidene) synthesized synthesized by Nolan´s bygroup Nolan was´s particularly group was particularly effective in effective in the cyclization of linear γ and δ-alkynoic acids of general composition the cyclization of linear γ and δ-alkynoic acids of general composition RC≡C(CH2)nCHRĆO2H (n = RC C(CH2)nCHRĆO2H (n = 1, 2; R = H, Me, Br or aryl group; R´ = H, CO2Me), allowing to 1, 2;≡ R = H, Me, Br or aryl group; R´ = H, CO2Me), allowing to perform the reactions at r.t. with performremarkably the low reactions catalyst at loadings r.t. with (25 remarkably ppm-0.1 mol%) low catalyst [49]. The loadings outstanding (25 ppm-0.1 activity mol%)of 33 is [related49]. The to outstanding activity of 33 is related to its ability to dissociate in solution into the two mononuclear its ability to dissociate in solution into the two mononuclear species [Au(IPr)][BF4] and species[Au(OH)(IPr)], [Au(IPr)][BF the former4] and acting [Au(OH)(IPr)], as a Lewis the acid former for the acting activation as a Lewis of the acid alkyne for thebond, activation and the of latter the alkyneas a Brønsted bond, and base the capable latter asof agenerating Brønsted base the more capable nucleophilic of generating carboxylate the more anions nucleophilic by deprotonation carboxylate anionsof the bycarboxylic deprotonation acid. ofAn the exqu carboxylicisite regioselectivity acid. An exquisite for regioselectivitythe exo cyclization for the wasexo incyclization all the cases was inobserved, all the cases except observed, with internal except withalkynes internal bearing alkynes a methyl bearing substituent, a methyl substituent, for which mixtures for which of mixtures the exo of the exo and endo addition products were obtained. Of note is the fact that [{Au(IPr)} (µ-OH)][BF ] and endo addition products were obtained. Of note is the fact that [{Au(IPr)}2(µ-OH)][BF2 4] (33) proved4 (to33 )be proved also effective to be also in e fftheective more in thechallenging more challenging cyclization cyclization of ε-acetylenic of ε-acetylenic acids, although acids, although higher highertemperatures temperatures and catalyst and catalyst loadings loadings were needed were needed (see Scheme (see Scheme 12). 12). On the other hand, an interesting approach to challenging oxepin-2-one derivatives 35 was developed by Aguilar and co-workers through the cycloisomerization of the corresponding alkynylcyclopropane carboxylic acids 34 promoted by the in situ generated cation [Au(IPr)]+ (Scheme 13)[50]. The process, which requires strictly anhydrous conditions, involves the regioselective 6-endo-dig nucleophilic addition of the carboxylic acid unit to the activated C C bond. According to the ≡ authors, the 6-endo-dig cyclization is favored over the 5-exo-dig one by the simultaneous coordination of the C C and OMe groups to the gold atom (intermediate C). The subsequent cyclopropane ring-opening ≡

Scheme 12. Cyclization of ε-alkynoic acids catalyzed by the dinuclear complex [{Au(IPr)}2(µ- OH)][BF4] (33).

Catalysts 2020, 10, x FOR PEER REVIEW 8 of 37

[AuCl(IMes)] (IMes = 1,3-dimesitylimidazole-2-ylidene) as the catalyst (Scheme 11) [48]. In the presence of K2CO3, [AuCl(IMes)] was able to convert selectively 29 into the 5-exo-dig cyclization product 30, while mixtures of 30, the tetrahydropyranone 31 (6-endo-dig cyclization) and the bicyclic species 32 (resulting from the cyclization of 31) were obtained when the K2CO3 co-catalyst was replaced by silver(I) salts (AgSbF6, AgOTf, AgNTf2 or AgBPh4). Similar observations were made when [AuCl(PEt3)] was employed as the gold source, although the yields were in general lower.

Scheme 11. Cyclization of the bispropargylic carboxylic acid 29 catalyzed by the NHC complex [AuCl(IMes)].

The dinuclear hydroxo-brigded gold(I) complex [{Au(IPr)}2(µ-OH)][BF4] (33; IPr = N,N´-bis(2,6- di-iso-propylphenyl)imidazole-2-ylidene) synthesized by Nolan´s group was particularly effective in the cyclization of linear γ and δ-alkynoic acids of general composition RC≡C(CH2)nCHR´CO2H (n = 1, 2; R = H, Me, Br or aryl group; R´ = H, CO2Me), allowing to perform the reactions at r.t. with remarkably low catalyst loadings (25 ppm-0.1 mol%) [49]. The outstanding activity of 33 is related to its ability to dissociate in solution into the two mononuclear species [Au(IPr)][BF4] and [Au(OH)(IPr)], the former acting as a Lewis acid for the activation of the alkyne bond, and the latter as a Brønsted base capable of generating the more nucleophilic carboxylate anions by deprotonation of the carboxylic acid. An exquisite regioselectivity for the exo cyclization was in all the cases Catalysts 2020, 10, 1206 9 of 36 observed, except with internal alkynes bearing a methyl substituent, for which mixtures of the exo and endo addition products were obtained. Of note is the fact that [{Au(IPr)}2(µ-OH)][BF4] (33) proved toin thebe bicyclealso effectiveD thus generatedin the more would challenging lead to the cyclization seven-membered of ε-acetylenic ring intermediate acids, althoughE, which evolveshigher temperaturesinto the ﬁnal oxepinoneand catalyst product loadings by were protodemetalation. needed (see Scheme 12).

Catalysts 2020, 10, x FOR PEER REVIEW 9 of 37

On the other hand, an interesting approach to challenging oxepin-2-one derivatives 35 was developed by Aguilar and co-workers through the cycloisomerization of the corresponding alkynylcyclopropane carboxylic acids 34 promoted by the in situ generated cation [Au(IPr)]+ (Scheme 13) [50]. The process, which requires strictly anhydrous conditions, involves the regioselective 6-endo- dig nucleophilic addition of the carboxylic acid unit to the activated C≡C bond. According to the authors, the 6-endo-dig cyclization is favored over the 5-exo-dig one by the simultaneous coordination of the C≡C and OMe groups to the gold atom (intermediate C). The subsequent cyclopropane ring- opening in the bicycle D thus generated would lead to the seven-membered ring intermediate E, Scheme 12.12. CyclizationCyclization ofofε -alkynoicε-alkynoic acids acids catalyzed catalyzed by theby dinuclearthe dinuclear complex complex [{Au(IPr)} [{Au(IPr)}2(µ-OH)]2(µ- which evolves into the final oxepinone product by protodemetalation. OH)][BF[BF4](334).] (33).

SchemeScheme 13. 13.Gold(I)-catalyzed Gold(I)-catalyzed synthesis synthesis of of oxepinones oxepinones by by cycloisomerization cycloisomerization of of the the alkynoic alkynoic acids acids34 . 34. It is important to note that the presence of the donor OMe substituent in the cyclopropane ring is decisiveIt isfor important the formation to note of that the the oxepinones presence to of take the place.donor Thus,OMe substituent when the non-substituted in the cyclopropane derivative ring 36is wasdecisive subjected for the tothe formation action of [AuCl(IPr)]of the oxepinones/AgOTs, underto take identical place. experimentalThus, when conditions,the non-substituted a mixture ofderivative compounds 36 37wasand subjected38, still bearing to the theaction cyclopropane of [AuCl(IP ring,r)]/AgOTs, was formed under in low identical yield (Scheme experimental 14)[50]. conditions, a mixture of compounds 37 and 38, still bearing the cyclopropane ring, was formed in low yield (Scheme 14) [50].

Scheme 14. Gold-catalyzed cyclization of the alkynylcyclopropane carboxylic acid 36.

In marked contrast with the behavior of compounds 34, the cycloisomerization of the related alkynylcyclobutane carboxylic acid 39 catalyzed in this case by the gold(I)-phosphine complex [Au(JohnPhos)(NCMe)][SbF6] was not accompanied by the cyclobutane ring-opening, and the cyclobutane-fused heterocycles 40 and 41 were obtained in a very high combined yield (Scheme 15) [51]. Moreover, the major product 40 resulted in this case from a 5-exo-dig cyclization, thereby

Catalysts 2020, 10, x FOR PEER REVIEW 9 of 37

On the other hand, an interesting approach to challenging oxepin-2-one derivatives 35 was developed by Aguilar and co-workers through the cycloisomerization of the corresponding alkynylcyclopropane carboxylic acids 34 promoted by the in situ generated cation [Au(IPr)]+ (Scheme 13) [50]. The process, which requires strictly anhydrous conditions, involves the regioselective 6-endo- dig nucleophilic addition of the carboxylic acid unit to the activated C≡C bond. According to the authors, the 6-endo-dig cyclization is favored over the 5-exo-dig one by the simultaneous coordination of the C≡C and OMe groups to the gold atom (intermediate C). The subsequent cyclopropane ring- opening in the bicycle D thus generated would lead to the seven-membered ring intermediate E, which evolves into the final oxepinone product by protodemetalation.

Scheme 13. Gold(I)-catalyzed synthesis of oxepinones by cycloisomerization of the alkynoic acids 34.

It is important to note that the presence of the donor OMe substituent in the cyclopropane ring is decisive for the formation of the oxepinones to take place. Thus, when the non-substituted derivative 36 was subjected to the action of [AuCl(IPr)]/AgOTs, under identical experimental

Catalystsconditions,2020, 10a ,mixture 1206 of compounds 37 and 38, still bearing the cyclopropane ring, was formed10 of 36in low yield (Scheme 14) [50].

Scheme 14.14. Gold-catalyzed cyclization of the alkynylcyclopropane carboxyliccarboxylic acidacid 3636.. In marked contrast with the behavior of compounds 34, the cycloisomerization of the related In marked contrast with the behavior of compounds 34, the cycloisomerization of the related alkynylcyclobutane carboxylic acid 39 catalyzed in this case by the gold(I)-phosphine complex alkynylcyclobutane carboxylic acid 39 catalyzed in this case by the gold(I)-phosphine complex [Au(JohnPhos)(NCMe)][SbF6] was not accompanied by the cyclobutane ring-opening, and the [Au(JohnPhos)(NCMe)][SbF6] was not accompanied by the cyclobutane ring-opening, and the cyclobutane-fused heterocycles 40 and 41 were obtained in a very high combined yield (Scheme 15)[51]. Catalystscyclobutane-fused 2020, 10, x FOR heterocycles PEER REVIEW 40 and 41 were obtained in a very high combined yield (Scheme10 of 15) 37 Moreover, the major product 40 resulted in this case from a 5-exo-dig cyclization, thereby pointing out [51]. Moreover, the major product 40 resulted in this case from a 5-exo-dig cyclization, thereby thatpointing the ring out sizethat playsthe ring an size important plays an role important in the regioselectivity role in the regioselectivity of the cycloisomerization of the cycloisomerization reactions of thisreactions particular of this class particular of cycloalkane-based class of cycloalkane-based alkynoic acids. alkynoic As shown acids. in Scheme As shown 15, whenin Scheme39 was 15, treated when with39 was the treated same gold with catalyst the same in thegold presence catalyst of inN the-iodosuccinimide presence of N-iodosuccinimide (NIS), the iodinated (NIS), molecules the iodinated42 and 43moleculescould be 42 generated and 43 could in excellent be generated yield, in with excellent the 5- exoyield,-dig withcyclization the 5-exo product-dig cyclization being again product the majorbeing componentagain the major of the component mixture (an of inverted the mixture regioselectivity (an invert toed that regioselectivity observed when to that the iodocyclization observed when of the39 wasiodocyclization performed, of employing 39 was performed, directly elemental employing iodine directly [51]). elemental iodine [51]).

Scheme 15. Gold-catalyzed cyclization reactions of the alkynylcyclobutane carboxylic acidacid 3939..

The groups of Michelet, Cadierno and Conejero reportedreported the preparation of two families of Au(I) and Au(III)Au(III) complexescomplexes containingcontaining zwitterioniczwitterionic NHCNHC ligandsligands functionalizedfunctionalized withwith 3-sulfonatopropyl3-sulfonatopropyl and protonated 2-pyridyl, 2-pycolyl or 2-pyridylethyl groups,groups, i.e., compounds 44 and 45,, capablecapable ofof catalyzing thethe cycloisomerization cycloisomerization of γof-alkynoic γ-alkynoic acids acids under under biphasic biphasic toluene toluene/water/water conditions conditions [52,53]. As[52,53]. illustrated As illustrated with the with examples the examples depicted depicted in Scheme in Scheme 16, the reactions16, the reactions proceeded proceeded in air at in r.t. air and at r.t. in theand absence in the absence of silver of additives, silver additives, with all thewith complexes all the complexes showing comparableshowing comparable eﬃciency andefficiency selectivity. and Regardingselectivity. thisRegarding last point, this 5-membered last point, 5-membered ring enol-lactones ring enol-lactones were exclusively were exclusively obtained when obtained substrates when featuring terminal C C bonds were employed, while mixtures of the corresponding 5 and 6-membered substrates featuring≡ terminal C≡C bonds were employed, while mixtures of the corresponding 5 and ring6-membered lactones werering lactones formed startingwere formed from internal starting alkynes from internal (an increase alkynes in the(an catalyst increase loading in the fromcatalyst 0.1 toloading 2.5 mol% from was 0.1 alsoto 2.5 required mol% was in these also required cases). It in is these noteworthy cases). It that is noteworthy in no case was that the in competitiveno case was hydrationthe competitive of the hydration alkyne units of observed,the alkyne even units in observed, cases of diynic even substrates.in cases of diynic Another substrates. interesting Another aspect ofinteresting these NHC-gold aspect of complexes these NHC-gold is that their complexes high solubility is that their in water highenabled solubility their in water recycling enabled by simple their separationrecycling by of thesimple organic separation phase containing of the organic the lactone phase products containing (up to the ten lactone consecutive products runs; cumulative(up to ten consecutive runs; cumulative turnover number (TON) = 400). In this regard, the recyclability of the gold(III) derivatives 45 proved to be much more effective due to their higher stability in the aqueous reaction medium (the Au(I) complexes 44 decompose into catalytically inactive Au(0) nanoparticles much faster than 45).

Catalysts 2020, 10, 1206 11 of 36 turnover number (TON) = 400). In this regard, the recyclability of the gold(III) derivatives 45 proved toCatalysts be much 2020, 10 more, x FOR eﬀ PEERective REVIEW due to their higher stability in the aqueous reaction medium (the11 Au(I) of 37 Catalystscomplexes 2020,44 10,decompose x FOR PEER REVIEW into catalytically inactive Au(0) nanoparticles much faster than 45). 11 of 37

Scheme 16. Cyclosiomerization of different γ-alkynoic acids in a biphasic medium catalyzed by the Schemewater-soluble 16. Cyclosiomerization NHC-gold complexes of different di 44-45ﬀerent. γ-alkynoic acids in a biphasic medium catalyzed by the water-soluble NHC-gold complexes 44–4544-45. Compounds 46 and 47a–f are additional examples of recyclable NHC-Au(I) complexes able to promoteCompounds the cycloisomerization 4646 andand 47a–f47a–f areare of additional additionalγ-alkynoic examplesexamples acids in of ofaqueous recyclable recyclable environments NHC-Au(I) NHC-Au(I) complexesunder complexes silver-free able able to promotetoconditions promote the (Figure the cycloisomerization cycloisomerization 3). As in the examples of ofγ-alkynoicγ-alkynoic just discussed, acids acids in in theaqueous aqueous silica-supported environments environments one, under under46, proved silver-free to be conditionsactive at room (Figure temperature 33).). AsAs inin thethe in examplesexamples a toluene/water justjust discussed,discussed, biphasic thethe mixture silica-supportedsilica-supported (up to six one,one, consecutive 46, proved toruns; be activecumulative atat room room TON temperature temperature = 178), showing in ain toluene a toluene/wateran/ waterexcellent biphasic regioselectivity biphasic mixture mixture (up totowards six (up consecutive tothe six 5- exoconsecutive runs;-dig cumulativecyclization runs; TONcumulativeproducts= 178), in theTON showing case = 178),of an substrates excellent showing regioselectivity bearing an exce a llentterminal towardsregioselectivity C≡C the bond 5-exo [54]. -towardsdig However,cyclization the 5-similarly productsexo-dig cyclizationto in the the case productsof substrates44–45, mixturesin the bearing case of aofthe terminal substrates corresponding C Cbearing bond 5- [and54a terminal]. 6-membered However, C≡C similarly bond ring lactones[54]. to the However, case were of obtained44–45 similarly, mixtures starting to the of from case the ≡ ofcorrespondinginternal 44–45 ,γ mixtures-alkynoic 5- and of acids. the 6-membered corresponding ring lactones5- and 6-membered were obtained ring starting lactones from were internal obtainedγ-alkynoic starting acids.from internal γ-alkynoic acids.

Figure 3. Structure of the NHC-gold(I) complexes 46 and 47a–f. Figure 3. Structure of the NHC-gold(I) complexes 46 and 47a–f. Concerning the ammonium salt-tagged Au(I)-NHC complexes 47a–f, they catalyzed efficiently the 5-Concerningexo-dig cyclization the ammonium of different salt -taggedγ-alkynoic Au(I)-NHC acids containing complexes both 47a–f terminal, they catalyzedand internal efficiently alkyne theunits 5- atexo room-dig cyclization temperature of (up different to 5 consecutive γ-alkynoic ru acidsns; cumulative containing TON both = terminal 198) [55]. and The internal reactions alkyne were unitsperformed at room employing temperature pure (up water to 5 consecutiveor an aqueous ru ns;triethylammonium cumulative TON buffer= 198) [55].solution The asreactions the solvent, were performedwith yields employingin general higherpure water in the or latter an aqueous medium triethylammonium since in pure water buffer partial solution decomposition as the solvent, of the withgold complexesyields in general takes place. higher For in somethe latter particularly medium hydrophobic since in pure substrates, water partial the additiondecomposition of an organic of the gold complexes takes place. For some particularly hydrophobic substrates, the addition of an organic

Catalysts 2020, 10, 1206 12 of 36

Concerning the ammonium salt-tagged Au(I)-NHC complexes 47a–f, they catalyzed efficiently the 5-exo-dig cyclization of different γ-alkynoic acids containing both terminal and internal alkyne units at room temperature (up to 5 consecutive runs; cumulative TON = 198) [55]. The reactions were performed employing pure water or an aqueous triethylammonium buffer solution as the solvent, with yields in general higher in the latter medium since in pure water partial decomposition of the Catalysts 2020, 10, x FOR PEER REVIEW 12 of 37 gold complexes takes place. For some particularly hydrophobic substrates, the addition of an organic co-solvent (THF) was needed. This This was was the case case,, for example, for the chiral alkynoic acid 48, whose cycloisomerization intointo the the enol enol lactone lactone49 catalyzed49 catalyzed by 47b byallowed 47b allowed the authors the authors to develop to adevelop synthetic a syntheticroute to 2-routeepi-clausemarine to 2-epi-clausemarine A (Scheme 17A ),(Scheme an epimer 17), of thean naturallyepimer of occurring the naturally furanocoumarin occurring furanocoumarinclausemarine A isolated clausemarine from Clausena A isolated lansium from. Clausena The selective lansium 5-exo. The-dig selectivecyclization 5-exo of- pent-4-ynoicdig cyclization acid of pent-4-ynoicin water was acid additionally in water describedwas additionally by Krause described and co-workers by Krause employing and co-workers a series employing of water-soluble a series ofβ-cyclodextrin-tagged water-soluble β-cyclodextrin-tagged NHC-gold(I) complexes NHC-gold(I) [56]. complexes [56].

Scheme 17. Au-catalyzed cycloisome cycloisomerizationrization of the chiral γ-alkynoic acid 48.

The iminophosphorane-based gold(I)-chloride complex complex 5050 proved to be an active and selective catalyst for for the the 5- 5-exoexo-dig-dig cyclizationcyclization of ofγ-alkynoicγ-alkynoic acids acids in water in water (Figure (Figure 4) [57].4)[ However,57]. However, it was itmuch was moremuch effective more eff whenective using when the using eutectic the eutectic mixture mixture 1ChCl/2Urea1ChCl (ChCl/2Urea =(ChCl choline= chloride)choline chloride) as the solvent. as the Thus,solvent. by Thus,employing by employing a metal loading a metal of loading 1 mol%, of se 1veral mol%, 5-membered several 5-membered ring enol ringlactones enol could lactones be synthesizedcould be synthesized in high yields in high and yields short and times short (from times 15 (frommin to 15 3 minh) at to room 3 h) attemperature, room temperature, under aerobic under conditionsaerobic conditions and in the and absence in the of absence co-catalysts, of co-catalysts, starting from starting terminal from γ-alkynoic terminal acids.γ-alkynoic In addition, acids. the In recyclabilityaddition, the of recyclability 50 in this alternative of 50 in this and alternative biorenewable and biorenewablereaction medium reaction could medium also be demonstrated could also be (updemonstrated to four consecutive (up to four runs; consecutive cumulative runs; TON cumulative = 374). TONThe =cyclization374). The of cyclization the model of thesubstrates model HCsubstrates≡CCH2CR HC2COCCH2H 2(RCR =2 COH, 2Me)H (R into= H, the Me) corresponding into the corresponding 5-membered 5-membered ring lactones ring in lactones aqueous in ≡ solutionaqueous (buffered solution (bu at pHffered 6.0) at was pH additionally 6.0) was additionally studied by studied employing by employing the phosphine-gold(I) the phosphine-gold(I) complex [AuCl(tcep)]complex [AuCl(tcep)] (tcep = (tceptris(2-carboxyethyl)phosphine)= tris(2-carboxyethyl)phosphine) confined confined in a inprotein a protein nanoreactor nanoreactor [58]. [58]. Interestingly, somesome of of the the intermediates intermediates involved involved in the in catalytic the catalytic cycle could cycle be detectedcould be by detected monitoring by monitoringthe changes the in thechanges ionic in current the ionic flow current through flow the through protein the pores protein when pores the reactions when the were reactions performed were performedunder stoichiometric under stoichiometric conditions. conditions. Very recently, the 5-exo-dig cyclization of several γ-alkynoic acids containing terminal C C ≡ units in a biphasic water/toluene system was successfully achieved by employing water-soluble gold nanoparticles (NPs) stabilized by the PEG-tagged imidazolium salts 51 and 52 (PEG = polyethylene glycol; see Figure4)[ 59]. In terms of both activity and recyclability (up to six consecutive runs; cumulative TON = 560), the PEG-tagged tris-imidazolium bromide 52 provided the best results due to the higher solubility of the Au NPs in the aqueous phase. At this point it should also be mentioned that catalytic systems consisting of Au NPs supported on zeolites [60–62], ultra-small mesoporous silica nanoparticles [63] and thiol-functionalized siliceous mesocellular foams [64] stabilized in interfacially cross-linked reverse micelles (ICRMs) [65] active in organic solvents, have also been described. Most of them showed a superior reactivity to Au2O3, which is the simplest gold-based heterogeneous catalyst for the 5-exo-dig cyclization of γ-alkynoic acids reported to date in the literature (typically operating at r.t. with a loading of 2.5 mol%) [66]. In this regard, the Au@ICRM systems (see Figure5)

Figure 4. Structures of the gold(I) complex 50 and the PEG-tagged imidazolium salts 51-52.

Catalysts 2020, 10, x FOR PEER REVIEW 12 of 37 co-solvent (THF) was needed. This was the case, for example, for the chiral alkynoic acid 48, whose cycloisomerization into the enol lactone 49 catalyzed by 47b allowed the authors to develop a synthetic route to 2-epi-clausemarine A (Scheme 17), an epimer of the naturally occurring furanocoumarin clausemarine A isolated from Clausena lansium. The selective 5-exo-dig cyclization of pent-4-ynoic acid in water was additionally described by Krause and co-workers employing a series of water-soluble β-cyclodextrin-tagged NHC-gold(I) complexes [56].

Scheme 17. Au-catalyzed cycloisomerization of the chiral γ-alkynoic acid 48.

The iminophosphorane-based gold(I)-chloride complex 50 proved to be an active and selective catalyst for the 5-exo-dig cyclization of γ-alkynoic acids in water (Figure 4) [57]. However, it was much more effective when using the eutectic mixture 1ChCl/2Urea (ChCl = choline chloride) as the solvent. Thus, by employing a metal loading of 1 mol%, several 5-membered ring enol lactones could be synthesized in high yields and short times (from 15 min to 3 h) at room temperature, under aerobic

Catalystsconditions2020 ,and10, 1206 in the absence of co-catalysts, starting from terminal γ-alkynoic acids. In addition,13 of the 36 recyclability of 50 in this alternative and biorenewable reaction medium could also be demonstrated (up to four consecutive runs; cumulative TON = 374). The cyclization of the model substrates deserveHC≡CCH to2CR be2 highlighted,CO2H (R = H, since Me) they into enabled the corresponding a drastic reduction 5-membered of the catalyst ring lactones loading in (up aqueous to 100 timessolution lower) (buffered [65]. A at possible pH 6.0) explanation was additionally for this studied enhanced by employing activity is that the the phosphine-gold(I) ICRM pulls the substratecomplex from[AuCl(tcep)] the environment (tcep = towardstris(2-carboxyethyl)phosphine) the catalytic metal, and once confined converted, in a the protein lactone productnanoreactor is rapidly [58]. ejectedInterestingly, since it some prefers of the the less inte polarrmediates environment involved rather in thanthe thecatalytic charged cycle ICRM could core. be An detected additional by heterogeneousmonitoring the catalyst changes for in the the cyclization ionic current of γ -alkynoicflow through acids the in organicprotein media,pores when generated the reactions by supporting were Catalysts 2020, 10, x FOR PEER REVIEW 13 of 37 [Au(PPhperformed3)][BF under4] on stoichiometric the mesoporous conditions. silica SBA-15, can also be found in the literature [67]. Very recently, the 5-exo-dig cyclization of several γ-alkynoic acids containing terminal C≡C units in a biphasic water/toluene system was successfully achieved by employing water-soluble gold nanoparticles (NPs) stabilized by the PEG-tagged imidazolium salts 51 and 52 (PEG = polyethylene glycol; see Figure 4) [59]. In terms of both activity and recyclability (up to six consecutive runs; cumulative TON = 560), the PEG-tagged tris-imidazolium bromide 52 provided the best results due to the higher solubility of the Au NPs in the aqueous phase. At this point it should also be mentioned that catalytic systems consisting of Au NPs supported on zeolites [60–62], ultra-small mesoporous silica nanoparticles [63] and thiol-functionalized siliceous mesocellular foams [64] stabilized in interfacially cross-linked reverse micelles (ICRMs) [65] active in organic solvents, have also been described. Most of them showed a superior reactivity to Au2O3, which is the simplest gold-based heterogeneous catalyst for the 5-exo-dig cyclization of γ-alkynoic acids reported to date in the literature (typically operating at r.t. with a loading of 2.5 mol%) [66]. In this regard, the Au@ICRM systems (see Figure 5) deserve to be highlighted, since they enabled a drastic reduction of the catalyst loading (up to 100 times lower) [65]. A possible explanation for this enhanced activity is that the ICRM pulls the substrate from the environment towards the catalytic metal, and once converted, the lactone product is rapidly ejected since it prefers the less polar environment rather than the charged ICRM core. An additional heterogeneous catalyst for the cyclization of γ-alkynoic acids in organic media, generated by supporting [Au(PPh3)][BF4] on the mesoporous silica SBA-15, can also be found in the literatureFigureFigure 4.4.[67]. Structures of thethe gold(I)gold(I) complexcomplex 5050 andand thethe PEG-taggedPEG-tagged imidazoliumimidazolium saltssalts 51–5251-52.

Figure 5. Schematic representation of the Au@ICMR catalysts.

Gold NPs supported supported on on beta beta zeolite zeolite proved proved to to be be active active in in the the cycloisomerization cycloisomerization of ofterminal terminal γ- γalkynoic-alkynoic acids acids when when employing employing a arange range of of ionic ionic liquids liquids (ILs) (ILs) as as the the reaction reaction media media [62]. [62]. However, However, in most cases, the lactone products couldcould not be separated from the ILs at the end of the process.process. Only [C6mim][Cl]mim][Cl] (C 66mimmim == 1-hexyl-3-methylimidazolium)1-hexyl-3-methylimidazolium) was was found found to to separate separate effectively eﬀectively from Et2O, and the cycloisomerized products could be selectively extracted with this solvent and isolated in pure form. In the same work, thethe abilityability ofof gold(III)gold(III) chloride-basedchloride-based ionicionic liquidsliquids ofof typetype [C[Cnnmim][AuClmim][AuCl44] (n = 2, 4, 6, 18) to promotepromote thethe processprocess waswas alsoalso demonstrated.demonstrated. In In particular, using 2.5 mol% of [C6mim][AuCl4] and [C6mim][Cl] as the solvent, the selective 5-exo-dig cyclization of several hindered and unhindered γ-alkynoic acids was successfully achieved in the absence of base (Scheme 18). The lactone products could be isolated in high yields after extraction with Et2O and the IL-catalyst recycled three times without loss of activity (cumulative TON = 120). Although no detailed data were provided by the authors, they indicated that [C2mim][AuCl4], [C4mim][AuCl4] and [C18mim][AuCl4] show reactivity and recyclability similar to that of [C6mim][AuCl4].

Catalysts 2020, 10, 1206 14 of 36

[C6mim][AuCl4] and [C6mim][Cl] as the solvent, the selective 5-exo-dig cyclization of several hindered and unhindered γ-alkynoic acids was successfully achieved in the absence of base (Scheme 18). The lactone products could be isolated in high yields after extraction with Et2O and the IL-catalyst recycled three times without loss of activity (cumulative TON = 120). Although no detailed data were provided by the authors, they indicated that [C2mim][AuCl4], [C4mim][AuCl4] and [C18mim][AuCl4] show reactivityCatalysts 2020 and, 10, recyclabilityx FOR PEER REVIEW similar to that of [C6mim][AuCl4]. 14 of 37

Catalysts 2020, 10, x FOR PEER REVIEW 14 of 37

Scheme 18. Cycloisomerization of γ-alkynoic acids catalyzed by a gold(III) chloride-based IL. Scheme 18. Cycloisomerization of γ-alkynoic acids catalyzed by a gold(III) chloride-based IL. 2.2. Cascade Processes Involving the Cycloisomerization of Alkynoic Acids 2.2. Cascade Processes Involving the Cycloisomerization of Alkynoic Acids 2.2. Cascade Processes Involving the Cycloisomerization of Alkynoic Acids Taking advantage of the intrinsic reactivity of lactones, a number of cascade processes involving Taking advantage of the intrinsic reactivity of lactones, a number of cascade processes involving the initialTaking gold-catalyzed advantage of cyclization the intrinsic of reactivity an alkynoic of lactones, acid havea number been of developed.cascade processes The involving ﬁrst one was the initialthe initial gold-catalyzed gold-catalyzed cyclization cyclization of of an an alkynoicalkynoic acidacid have have been been developed. developed. The The first firstone wasone was described by Dixon and co-workers in 2007 with the coupling of diﬀerent linear γ- and δ-alkynoic describeddescribed by Dixon by Dixon and and co-workers co-workers in in 2007 2007 withwith the couplingcoupling of of different different linear linear γ- and γ- andδ-alkynoic δ-alkynoic acids with 2-(2-pyrrolyl)ethylamine or tryptamine to generate fused polycyclic pyrroles and indoles acids with 2-(2-pyrrolyl)ethylamine or tryptamine to generate fused polycyclic pyrroles and indoles acids with 2-(2-pyrrolyl)ethylamine or tryptamine to generate fused polycyclic pyrroles+ and indoles (Scheme 19)[68]. The reactions were catalyzed by the in situ generated cation [Au(PPh3)] and+ required (Scheme(Scheme 19) 19)[68]. [68]. The The reactions reactions were were catalyzed catalyzed by thethe inin situ situ generated generated cation cation [Au(PPh [Au(PPh3)] and3)]+ and prolonged heating in toluene or xylene to obtain the products in high yields. requiredrequired prolonged prolonged heating heating in intoluene toluene or or xylene xylene to obtain the the products products in inhigh high yields. yields.

SchemeScheme 19. 19.Gold-catalyzed Gold-catalyzed synthesis synthesis of fused polycyclic polycyclic pyrroles pyrroles and and indoles. indoles.

As exemplified with the coupling of pent-4-ynoic acid and tryptamine, the initial step of the process is the generation of the corresponding enol-lactone, which rapidly evolves into the linear keto-amidesScheme F by aminolysis 19. Gold-catalyzed of the C–O synthesis bond (Scheme of fused 20). polycyclic In a subsequent pyrroles step,and indoles.the key one, an N- acyliminium ion G is formed through an intramolecular reaction probably facilitated by the gold As exemplified with the coupling of pent-4-ynoic acid and tryptamine, the initial step of the process is the generation of the corresponding enol-lactone, which rapidly evolves into the linear keto-amides F by aminolysis of the C–O bond (Scheme 20). In a subsequent step, the key one, an N- acyliminium ion G is formed through an intramolecular reaction probably facilitated by the gold

Catalysts 2020, 10, 1206 15 of 36

CatalystsAs 2020 exempliﬁed, 10, x FOR PEER with REVIEW the coupling of pent-4-ynoic acid and tryptamine, the initial step15 of of the 37 process is the generation of the corresponding enol-lactone, which rapidly evolves into the linear catalyst. The final attack of the nucleophilic C-2 carbon of the indolic unit on the iminium carbon keto-amidesCatalysts 2020, 10F, xby FOR aminolysis PEER REVIEW of the C–O bond (Scheme 20). In a subsequent step, the key one,15 of an 37 leadsN-acyliminium to the polycyclic ion G isproduct. formed through an intramolecular reaction probably facilitated by the gold catalyst. TheThe ﬁnalfinal attack attack of of the the nucleophilic nucleophilic C-2 C-2 carbon carbon of theof the indolic indolic unit unit on the on iminium the iminium carbon carbon leads toleads the to polycyclic the polycyclic product. product.

Scheme 20. Proposed mechanism for the gold-catalyzed coupling of pent-4-ynoic acid with tryptamine. Scheme 20.20.Proposed Proposed mechanism mechanism for thefor gold-catalyzedthe gold-catalyzed coupling coupling of pent-4-ynoic of pent-4-ynoic acid with tryptamine.acid with Following this pioneering work, related Au-catalyzed coupling reactions of alkynoic acids with tryptamine. indole-Following and pyrrole-containing this pioneering work,amines related were Au-catalyzedsubsequently couplingdescribed reactions in the literature, of alkynoic allowing acids with the rapidindole-Following construction and pyrrole-containing this of pioneering a wide variety amines work, of wererelatednitrogen-c subsequently Au-catalyzedontaining described polycyclic coupling in reactions thecompounds literature, of alkynoic [69–72]. allowing Moreover,acids the rapid with theconstructionindole- synthetic and pyrrole-containing of utility a wide of variety these ofcascade amines nitrogen-containing wereprocesses subsequently was polycyclic fully described demonstrated compounds in the literature,with [69– 72the]. Moreover, useallowing of other thethe functionalizedsyntheticrapid construction utility amines of theseof a wide[71,72]. cascade variety For processes example, of nitrogen-c was starting fullyontaining demonstrated from polycyclic2-aminobenzyl with compounds theuse alcohols of other [69–72]. and functionalized different Moreover, γ- andaminesthe syntheticδ-alkynoic [71,72 ].utility Foracids, example, of anthese efficient starting cascade and from processes general 2-aminobenzyl wassynthesis fully alcohols ofdemonstrated pyrrolo- and di (nﬀ erent with= 1) γ the-and and use pyrido[2,1-δ -alkynoicof other bacids,functionalized]benzo[ and e][1,3]oxazin-1-onesﬃcient amines and general [71,72]. synthesis(n For = example,2) ofwas pyrrolo- describedstarting (n = from 1)by and 2-aminobenzylLiu pyrido[2,1- and co-workersb]benzo[ alcoholsd ][1,3]oxazin-1-oneswhile and differentemploying γ- (n[Au(JohnPhos)(NCMe)][SbFand= 2)δ-alkynoic was described acids, by an Liu efficient6] and as co-workersthe andcatalyst general while (Scheme synthesis employing 21) [73].of [Au(JohnPhos)(NCMe)][SbF pyrrolo-The formation (n = 1) of andcompounds pyrido[2,1-6] as the53 involvescatalystb]benzo[(Scheme dthe][1,3]oxazin-1-ones intramolecular 21)[73]. The nucleophilic (n formation = 2) was a ofttack compoundsdescribed of the OH by53 group involvesLiu toand the the co-workerscorresponding intramolecular while N-acyliminium nucleophilic employing ion.attack[Au(JohnPhos)(NCMe)][SbF of the OH group to the6] correspondingas the catalystN -acyliminium(Scheme 21) [73]. ion. The formation of compounds 53 involves the intramolecular nucleophilic attack of the OH group to the corresponding N-acyliminium ion.

Scheme 21. Au(I)-catalyzed coupling of alkynoic acids with 2-aminobenzyl alcohols.

Pyrrolo/pyrido[2,1-Pyrrolo/pyrido[2,1-a][1,3]benzoxazinone][1,3]benzoxazinone 5454 [74],[74], pyrrolo/pyrido[2,1- pyrrolo/pyrido[2,1-aa]quinazolinone]quinazolinone 5555 [74],[74], Scheme 21. Au(I)-catalyzed coupling of alkynoic acids with 2-aminobenzyl alcohols. benzo[4,5]imidazo[1,2-cc]pyrrolo/pyrido[1,2-]pyrrolo/pyrido[1,2-aa]quinazolinone]quinazolinone 5656 [75[75],], benzo[benzo[e]indolo[1,2-e]indolo[1,2-a] a]pyrrolo/pyrido[2,1-Pyrrolo/pyrido[2,1-c][1,4]-diazepine-3,9-dionea][1,3]benzoxazinone 54 [74],57 [76]pyrrolo/pyrido[2,1- and pyrrolo[1,2-a]quinazolinonea:2´,1´-c]-/pyrido[2,1- 55 [74], cbenzo[4,5]imidazo[1,2-]pyrrolo[1,2-a]quinoxalinonec]pyrrolo/pyrido[1,2- 58 [77] derivativesa]quinazolinone were also accessed 56 by the[75], same groupbenzo[ bye]indolo[1,2- employing 2-aminobenzoica]pyrrolo/pyrido[2,1- acids,c][1,4]-diazepine-3,9-dione 2-aminobenzamides, 57 [76]2-(1 H-benzo[and pyrrolo[1,2-d]imidazol-2-yl)anilines,a:2´,1´-c]-/pyrido[2,1- (2- c]pyrrolo[1,2-a]quinoxalinone 58 [77] derivatives were also accessed by the same group by employing 2-aminobenzoic acids, 2-aminobenzamides, 2-(1H-benzo[d]imidazol-2-yl)anilines, (2-

Catalysts 2020, 10, 1206 16 of 36 pyrrolo/pyrido[2,1-c][1,4]-diazepine-3,9-dione 57 [76] and pyrrolo[1,2-a:2´,1´-c]-/pyrido[2,1-c] pyrrolo[1,2-Catalysts 2020, a10]quinoxalinone, x FOR PEER REVIEW58 [77] derivatives were also accessed by the same group16 of by 37 employing 2-aminobenzoic acids, 2-aminobenzamides, 2-(1H-benzo[d]imidazol-2-yl)anilines, (2-aminophenyl)(1aminophenyl)(1H-indol-1-yl)methanonesH-indol-1-yl)methanones and and 2-(1 2-(1HH-pyrrol-1-yl)anilines,-pyrrol-1-yl)anilines, respectively, respectively, as as thethe coupling partnerspartners (Figure(Figure6 6).). Complex Complex [Au(JohnPhos) [Au(JohnPhos)(NCMe)][SbF (NCMe)][SbF66] ](2–10 (2–10 mol%) mol%) was was in all casescases used toto promotepromote the the reactions, reactions, which which required required temperatures temperatures in the in range the range 80–120 80–120◦C. However, °C. However, it should it beshould mentioned be mentioned at this point at this that, point to obtainthat, to compounds obtain compounds56–58 in high56–58 yields, in high the yields, addition the ofaddition a Brønsted of a orBrønsted Lewis acidor Lewis co-catalyst acid wasco-catalyst needed was to facilitate needed theto intramolecularfacilitate the intramolecular attack of the correspondingattack of the nucleophilecorresponding to thenucleophileN-acyliminium to the intermediate.N-acyliminium On intermediate. the other hand, On it the is also other worth hand, noting it is that,also worth in the casenoting of that, the pyrrolo[1,2- in the case aof:2 ´the,1´- cpyrrolo[1,2-]-/pyrido[2,1-a:2´,1´-c]pyrrolo[1,2-c]-/pyrido[2,1-a]quinoxalinonesc]pyrrolo[1,2-58a]quinoxalinones, the reactions could 58, the be convenientlyreactions could carried be conveniently out in water. carried out in water.

Figure 6. Structures of the fused polycyclic compounds 54–58..

Related couplingcoupling processes processes employing benzene-1,2-diaminesemploying benzene-1,2-diamines and 2-(aminomethyl)benzenamines and 2- as(aminomethyl)benzenamines the nucleophiles were reported as the by Patilnucleophiles and co-workers were reported using the by [AuCl(PPh Patil and3 )]co-workers/AgOTf combination using the as[AuCl(PPh the catalyst3)]/AgOTf [78]. Thecombination reactions allowedas the catalyst the regioselective [78]. The reactions preparation allowed of broad the series regioselective of fused preparation of broad series of fused dihydrobenzimidazoles 59 and tetrahydroquinazolines 60 starting from both terminal and internal γ- and δ-alkynoic acids (Scheme 22). Interestingly, in the case of α-substituted γ-alkynoic acids (i.e., n = 0 and X = CHR3 or CR4R5), the corresponding products were obtained in high diastereoselectivities as a consequence of the steric interaction between the substituents in this position with the CH2R1 unit. By applying the same reaction conditions, the

Catalysts 2020, 10, 1206 17 of 36 dihydrobenzimidazoles 59 and tetrahydroquinazolines 60 starting from both terminal and internal γ- and δ-alkynoic acids (Scheme 22). Interestingly, in the case of α-substituted γ-alkynoic acids (i.e., n = 0 3 4 5 andCatalysts X = 2020CHR, 10, xor FOR CR PEERR ), REVIEW the corresponding products were obtained in high diastereoselectivities17 of as 37 a 1 consequence of the steric interaction between the substituents in this position with the CH2R unit. Byefficient applying access the to same different reaction pyrrolo- conditions, and theindolo-fused efficient access quinazolinones, to different pyrrolo-some of and them indolo-fused featuring quinazolinones,anticancer activities, some was of them possible featuring by reacting anticancer γ- and activities, δ-alkynoic was possibleacids with by 2-aminobenzohydrazides reacting γ- and δ-alkynoic acids[79]. In with addition, 2-aminobenzohydrazides Patil´s group also demonstrated [79]. In addition, the utility Patil of´ theses group Au-catalyzed also demonstrated coupling theprocesses utility offorthese the preparation Au-catalyzed of couplinga huge variety processes of multifunctional for the preparation polyheterocyclic of a huge variety scaffolds, of multifunctional starting from polyheterocyclicselected alkynoic sca acidsffolds, and starting functionalized from selected amines alkynoic through acids the and so-called functionalized “relay catalytic amines through branching the so-calledcascade” “relay(RCBC) catalytic technique branching [80]. Cascade cascade” reactions (RCBC) involving technique the [80 ].cycloaromatization Cascade reactions of involving 2,4-dien-6- the cycloaromatizationyne carboxylic acids of 2,4-dien-6-yne[81] and the assembly carboxylic of acids fused [81 indeno-pyranones] and the assembly from of fused enediynic indeno-pyranones carboxylic fromacids enediynic[82] have also carboxylic been described. acids [82] have also been described.

Scheme 22. Gold(I)-catalyzedGold(I)-catalyzed synthesis of fused fused dihydr dihydrobenzimidazolesobenzimidazoles and tetrahydroquinazolines.

Additional studiesstudies by by Dixon Dixon and and co-workers co-workers in the in ﬁeldthe field revealed revealed that the that coupling the coupling of enol-lactones of enol- withlactones tryptamine with tryptamine derivatives, derivatives, via the viaN-acyliminium the N-acyliminium cyclization cyclization cascades cascades just just mentioned, mentioned, can can be promotedbe promoted in anin enantioselectivean enantioselective manner manner by chiralby chir Brønstedal Brønsted acids, acids, processes processes that arethat compatible are compatible with thewith in the situ in generationsitu generation of the of enol-lactonethe enol-lactone through through a gold-catalyzed a gold-catalyzed cycloisomerization cycloisomerization reaction, reaction, as illustratedas illustrated in Schemein Scheme 23 [2383 ].[83]. Within the ﬁeld of asymmetric synthesis, the work described by García-Álvarez, González-Sabín and co-workers is also noteworthy; they developed a highly enantioselective synthesis of the chiral γ-hydroxy amides 62 starting from pent-4-ynoic acid and secondary aromatic amines through the sequential action of KAuCl4 and a ketoreductase (KRED) enzyme (Scheme 24)[84]. Thus, the initial gold-catalyzed cyclization of the alkynoic acid leads to the corresponding enol-lactone which immediately undergoes aminolysis to generate the linear γ-keto amides 61. The subsequent addition of the KRED, along with the cofactor NADP+ (nicotinamide adenine dinucleotide phosphate) and the hydrogen source iPrOH, to the medium, enables the bioreduction of the keto group of 61. The chiral γ-hydroxy amides 62 were obtained in all cases in almost quantitative yields, and by selecting the appropriate KRED, both enantiomers were accessible with ee values 99%. Similarly, the synthesis of ≥ enantiopure (R)- and (S)-γ-hydroxyvaleric acid could also be achieved in a quantitative manner by

Catalysts 2020, 10, x FOR PEER REVIEW 18 of 37

Catalysts 2020, 10, 1206 18 of 36

replacing the amine with water, since, at 50 ◦C, the initially formed enol-lactone is transformed into levulinicCatalysts 2020 acid, 10, by x FOR hydrolysis. PEER REVIEW 18 of 37

Scheme 23. Enantioselective cyclization cascade of alkynoic acids and trytamine derivatives.

Within the field of asymmetric synthesis, the work described by García-Álvarez, González-Sabín and co-workers is also noteworthy; they developed a highly enantioselective synthesis of the chiral γ-hydroxy amides 62 starting from pent-4-ynoic acid and secondary aromatic amines through the sequential action of KAuCl4 and a ketoreductase (KRED) enzyme (Scheme 24) [84]. Thus, the initial gold-catalyzed cyclization of the alkynoic acid leads to the corresponding enol-lactone which immediately undergoes aminolysis to generate the linear γ-keto amides 61. The subsequent addition of the KRED, along with the cofactor NADP+ (nicotinamide adenine dinucleotide phosphate) and the hydrogen source iPrOH, to the medium, enables the bioreduction of the keto group of 61. The chiral γ-hydroxy amides 62 were obtained in all cases in almost quantitative yields, and by selecting the appropriate KRED, both enantiomers were accessible with ee values ≥ 99%. Similarly, the synthesis of enantiopure (R)- and (S)-γ-hydroxyvaleric acid could also be achieved in a quantitative manner by replacing the amine with water, since, at 50 °C, the initially formed enol-lactone is transformed into levulinic acid by hydrolysis. Scheme 23. Enantioselective cyclization cascade of alkynoic acids and trytamine derivatives.

Within the field of asymmetric synthesis, the work described by García-Álvarez, González-Sabín and co-workers is also noteworthy; they developed a highly enantioselective synthesis of the chiral γ-hydroxy amides 62 starting from pent-4-ynoic acid and secondary aromatic amines through the sequential action of KAuCl4 and a ketoreductase (KRED) enzyme (Scheme 24) [84]. Thus, the initial gold-catalyzed cyclization of the alkynoic acid leads to the corresponding enol-lactone which immediately undergoes aminolysis to generate the linear γ-keto amides 61. The subsequent addition of the KRED, along with the cofactor NADP+ (nicotinamide adenine dinucleotide phosphate) and the hydrogen source iPrOH, to the medium, enables the bioreduction of the keto group of 61. The chiral γ-hydroxy amides 62 were obtained in all cases in almost quantitative yields, and by selecting the appropriate KRED, both enantiomers were accessible with ee values ≥ 99%. Similarly, the synthesis of enantiopure (R)- and (S)-γ-hydroxyvaleric acid could also be achieved in a quantitative manner by replacing the amine with water, since, at 50 °C, the initially formed enol-lactone is transformed into levulinic acid by hydrolysis. Scheme 24. Synthesis of enantiopure γ-hydroxy amidesamides fromfrom pent-4-ynoicpent-4-ynoic acidacid andand anilines.anilines.

OnOn thethe otherother hand,hand, aa syntheticallysynthetically usefuluseful approachapproach toto butenolidebutenolide derivatives 63 andand 6464 waswas developeddeveloped byby JiJi andand co-workers through a three-componentthree-component couplingcoupling ofof terminalterminal alkynes, secondary aminesamines andand glyoxylicglyoxylic acidacid (Scheme(Scheme 2525))[ [85].85]. The process, which proceeds under mild conditions in the presence of catalytic amounts of AuBr3, involves the selective 5-endo-dig cyclization of the in situ formed α-N-substituted β-alkynoic acids 65 (see Scheme 26). These intermediate species are generated through the initial condensation between the amines and glyoxylic acid, and subsequent addition of alkyne to the resulting iminium cation via the corresponding gold-acetylide. Depending on the nature of the alkyne, compounds 63 and 64 were selectively obtained by electrophilic trapping of the metallated intermediate H with a proton (aliphatic alkynes) or the iminium cation (aromatic alkynes) along with a 1,2-hydride shift.

Scheme 24. Synthesis of enantiopure γ-hydroxy amides from pent-4-ynoic acid and anilines.

On the other hand, a synthetically useful approach to butenolide derivatives 63 and 64 was developed by Ji and co-workers through a three-component coupling of terminal alkynes, secondary amines and glyoxylic acid (Scheme 25) [85].

Catalysts 2020, 10, x FOR PEER REVIEW 19 of 37

Catalysts 2020, 10, 1206 19 of 36 Catalysts 2020, 10, x FOR PEER REVIEW 19 of 37

Scheme 25. Access to butenolide derivatives though a three-component tandem process.

The process, which proceeds under mild conditions in the presence of catalytic amounts of AuBr3, involves the selective 5-endo-dig cyclization of the in situ formed α-N-substituted β-alkynoic acids 65 (see Scheme 26). These intermediate species are generated through the initial condensation between the amines and glyoxylic acid, and subsequent addition of alkyne to the resulting iminium cation via the corresponding gold-acetylide. Depending on the nature of the alkyne, compounds 63 and 64 were selectively obtained by electrophilic trapping of the metallated intermediate H with a proton (aliphaticScheme alkynes) 25. Access or to the butenolide iminium derivativesderi cationvatives (aromatic though a alkynes) three-componentthree-component along with tandem a 1,2-hydride process. shift.

The process, which proceeds under mild conditions in the presence of catalytic amounts of AuBr3, involves the selective 5-endo-dig cyclization of the in situ formed α-N-substituted β-alkynoic acids 65 (see Scheme 26). These intermediate species are generated through the initial condensation between the amines and glyoxylic acid, and subsequent addition of alkyne to the resulting iminium cation via the corresponding gold-acetylide. Depending on the nature of the alkyne, compounds 63 and 64 were selectively obtained by electrophilic trapping of the metallated intermediate H with a proton (aliphatic alkynes) or the iminium cation (aromatic alkynes) along with a 1,2-hydride shift.

Scheme 26. Proposed mechanism for the formation of butenolides 63 and 64. 2.3. IntermolecularScheme Addition 26. Proposed of Carboxylic mechanism Acids to for Alkynes the formation of butenolides 63 and 64.

2.3. IntermolecularCompared to Addition the cycloisomerization of Carboxylic Acids reactions to Alkynes of alkynoic acids, intermolecular additions of carboxylic acids to alkynes have been much less studied with gold-based catalysts. In this context, the ﬁrstCompared example, to reported the cycloisomerization by Schmidbaur reactions and co-workers of alkynoic in 2004, acids, involved intermolecular the addition additions of glacial of carboxylic acids to alkynes have been much less studied with gold-based catalysts. In this context, acetic acid to hex-3-yne catalyzed by the carboxylate-gold(I) complex [Au{OC(O)C2F5}(PPh3)] (0.134 mol%)the first in example, the presence reported of BF byEt SchmidbaurO as a co-catalyst and co-w (5.25orkers mol%) in [86 2004,]. However, involved after the heating addition the of mixture glacial 3· 2 inacetic THF acid at 60 to hex-3-yneC for 1 h, thecatalyzed desired by enol the estercarboxylate-gold(I) hex-3-en-3-yl acetate complex was [Au{OC(O)C generated2 inF5 only}(PPh 6%3)] (0.134 yield ◦ togethermol%) in with the hexan-3-onepresence of (12%BF3·Et yield),2O as resultinga co-catalyst from (5.25 the hydration mol%) [86]. of theHowever, alkyne. Aafter few heating years later, the mixture in THFScheme at 60 °C 26. for Proposed 1 h, the mechanismdesired enol for ester the formation hex-3-en-3-yl of butenolides acetate was 63 and generated 64. in only 6%+ Chary and Kim reported an eﬃcient and general protocol employing the gold(I) cation [Au(PPh3)] (generatedyield together in situ with from hexan-3-one [AuCl(PPh (12%)] and yield), AgPF result) asing a catalyst from the (Scheme hydration 27)[ of87 the]. alkyne. A few years 2.3. Intermolecular Addition of Carboxylic3 Acids to 6Alkynes later,The Chary addition and processKim reported was operative an efficient for both and terminal general andprotocol internal employing alkynes working the gold(I) in toluene cation [Au(PPh3)]+ (generated in situ from [AuCl(PPh3)] and AgPF6) as a catalyst (Scheme 27) [87]. at 60–110Compared◦C with to metalthe cycloisomerization loadings of 5 mol%. reactions Starting of alkynoic from terminal acids, alkynes,intermolecular the corresponding additions of Markovnikovcarboxylic acids addition to alkynes products have been were much selectively less studied obtained, with and gold-based in the case catalysts. of the In internal this context, ones thethe first reactions example, proceeded reported with by Schmidbaur a complete and (Z )co-w stereoselectivityorkers in 2004, (antiinvolved-addition). the addition Moreover, of glacial an exquisiteacetic acid regioselectivity to hex-3-yne catalyzed was observed by the whencarboxylate-gold(I) the non-symmetrically complex [Au{OC(O)C substituted2 internalF5}(PPh3)] alkynes (0.134 1-propynylbenzenemol%) in the presence and of ethyl BF3 3-phenylpropiolate·Et2O as a co-catalyst were (5.25 employed mol%) [86]. as substrates. However, In after the sameheating study, the Charymixture and in THF Kim at found 60 °C for that 1 h, enol the estersdesired of enol type ester RCH hex-3-en-3-yl2C(O2CR´) =acetateCH2 easily was generated isomerize in intoonly the6% thermodynamicallyyield together with morehexan-3-one stable species (12% yield), RCH= resultC(O2CRing´ )CHfrom3, the compounds hydration that of the can alkyne. be directly A few accessed years + bylater, performing Chary and the Kim corresponding reported an [Au(PPh efficient3)] -catalyzedand general addition protocol reactions employing using the AgOTf gold(I) instead cation of + AgPF[Au(PPh6. 3)] (generated in situ from [AuCl(PPh3)] and AgPF6) as a catalyst (Scheme 27) [87]. Complex [AuCl(PPh3)], in combination with AgOTf, was subsequently employed by Schreiber and co-workers for the preparation of several substituted α-pyrone derivatives by coupling propiolic acids with terminal alkynes (Scheme 28)[88]. The process involves the initial formation of vinyl

Catalysts 2020, 10, x FOR PEER REVIEW 20 of 37

Catalysts 2020, 10, 1206 20 of 36 propiolate intermediates I, resulting from the Au(I)-catalyzed Markovnikov addition of the propiolic acids to the terminal alkynes, which readily evolve into the cyclic oxocarbenium species J through a + 6-endo cyclization (also promoted by the [Au(PPh3)] cation). The α-pyrone products 66 are ﬁnally generatedCatalysts 2020 from, 10, x JFORthrough PEER REVIEW a deprotonation /protodemetalation sequence. 20 of 37

Scheme 27. Intermolecular addition of carboxylic acids to alkynes catalyzed by [Au(PPh3)]+.

The addition process was operative for both terminal and internal alkynes working in toluene at 60–110 °C with metal loadings of 5 mol%. Starting from terminal alkynes, the corresponding Markovnikov addition products were selectively obtained, and in the case of the internal ones the reactions proceeded with a complete (Z) stereoselectivity (anti-addition). Moreover, an exquisite regioselectivity was observed when the non-symmetrically substituted internal alkynes 1- propynylbenzene and ethyl 3-phenylpropiolate were employed as substrates. In the same study, Chary and Kim found that enol esters of type RCH2C(O2CR´)=CH2 easily isomerize into the thermodynamically more stable species RCH=C(O2CR´)CH3, compounds that can be directly accessed by performing the corresponding [Au(PPh3)]+-catalyzed addition reactions using AgOTf instead of AgPF6. Complex [AuCl(PPh3)], in combination with AgOTf, was subsequently employed by Schreiber and co-workers for the preparation of several substituted α-pyrone derivatives by coupling propiolic acids with terminal alkynes (Scheme 28) [88]. The process involves the initial formation of vinyl propiolate intermediates I, resulting from the Au(I)-catalyzed Markovnikov addition of the propiolic acids to the terminal alkynes, which readily evolve into the cyclic oxocarbenium species J through a 3 + 6-endo cyclization (also promoted by the [Au(PPh )] cation). The α-pyrone products 66 are++ finally SchemeScheme 27.27. IntermolecularIntermolecular additionaddition ofof carboxyliccarboxylic acidsacids toto alkynesalkynes catalyzedcatalyzed byby [Au(PPh[Au(PPh33)])] .. generated from J through a deprotonation/protodemetalation sequence. The addition process was operative for both terminal and internal alkynes working in toluene at 60–110 °C with metal loadings of 5 mol%. Starting from terminal alkynes, the corresponding Markovnikov addition products were selectively obtained, and in the case of the internal ones the reactions proceeded with a complete (Z) stereoselectivity (anti-addition). Moreover, an exquisite regioselectivity was observed when the non-symmetrically substituted internal alkynes 1- propynylbenzene and ethyl 3-phenylpropiolate were employed as substrates. In the same study, Chary and Kim found that enol esters of type RCH2C(O2CR´)=CH2 easily isomerize into the thermodynamically more stable species RCH=C(O2CR´)CH3, compounds that can be directly accessed by performing the corresponding [Au(PPh3)]+-catalyzed addition reactions using AgOTf instead of AgPF6. Complex [AuCl(PPh3)], in combination with AgOTf, was subsequently employed by Schreiber and co-workers for the preparation of several substituted α-pyrone derivatives by coupling propiolic acids with terminal alkynes (Scheme 28) [88]. The process involves the initial formation of vinyl propiolate intermediates I, resulting from the Au(I)-catalyzed Markovnikov addition of the propiolic acids to the terminal alkynes, which readily evolve into the cyclic oxocarbenium species J through a Scheme 28. Au(I)-catalyzed synthesis of α-pyrones from propiolic acids and terminal alkynes. 6-endo cyclizationScheme 28. (alsoAu(I)-catalyzed promoted synthesis by the [Au(PPhof α-pyrones3)]+ fromcation). propiolic The α acids-pyrone and terminalproducts alkynes. 66 are finally generated from J through a deprotonation/protodemetalation sequence. As shown in Scheme 29 with a couple of representative examples, when the propiolic acids were + subjected to the action of [Au(PPh3)] in the absence of the terminal alkyne partner, they dimerized into the 4-hydroxy α-pyrones 67 [88]. The formation of 67 involves the intermolecular addition of the CO H unit of one of the propiolic acid molecules to the C C bond of the second one and the generation 2 ≡ of the corresponding oxocarbenium intermediate, which then evolves into the ﬁnal products by acyl group migration.

Scheme 28. Au(I)-catalyzed synthesis of α-pyrones from propiolic acids and terminal alkynes.

Catalysts 2020,, 10,, xx FORFOR PEERPEER REVIEWREVIEW 21 of 37

As shown in Scheme 29 with a couple of representative examples, when the propiolic acids were + subjected to the action of [Au(PPh3)]+ inin thethe absenceabsence ofof thethe terminalterminal alkynealkyne partner,partner, theythey dimerizeddimerized into the 4-hydroxy α-pyrones 67 [88].[88]. TheThe formationformation ofof 67 involvesinvolves thethe intermolecularintermolecular additionaddition ofof thethe CO2H unit of one of the propiolic acid molecules to the C≡C bond of the second one and the generation of the corresponding oxocarbenium intermediate, which then evolves into the final Catalystsgeneration2020, 10of, 1206the corresponding oxocarbenium intermediate, which then evolves into the21 final of 36 products by acyl group migration.

Scheme 29. Au(I)-catalyzed dimerization of propiolic acids into 4-hydroxy αα-pyrones.-pyrones.

EmployingEmploying the catalytic catalytic [AuCl(PPh [AuCl(PPh33)]/AgPF)]/AgPF6 6system,system,system, aa ageneralgeneral general procedureprocedure procedure forfor for thethe the preparationpreparation preparation ofof of(Z)- (Zβ-iodoenol)-β-iodoenol esters esters 68 68bybyby thethe the additionaddition addition ofof of carboxyliccarboxylic carboxylic acidsacids acids toto to iodoalkynesiodoalkynes iodoalkynes waswas developed developed by CadiernoCadierno andand co-workersco-workers (Scheme(Scheme 3030))[ [89,90].89,90]. The reactions proceeded withwith highhigh yields,yields, underunder mildmild conditionsconditions (toluene(toluene/r.t.),/r.t.), and and in in a a complete complete regio- regio- and and stereoselective stereoselective manner manner (selective (selectiveanti anti-addition-addition of theof the carboxylate carboxylate group group to the to more the more electrophilic electrophilicelectrophilic C-2 carbon C-2C-2 carboncarbon of the π ofof-activated thethe π-activated iodoalkyne). iodoalkyne). In addition, In theaddition, process the featured process afeatured wide scope a wide and scope tolerated and tole therated presence the presence of diﬀerent of different functional functional groups ingroups both thein both alkyne the andalkyne acid and partners. acid partners. It should It should also be alsoalso remarked bebe remarkedremarked at this pointatat thisthis that pointpoint the thatthat (Z)- thetheβ-iodoenol ((Z)-β-iodoenol esters 68estersare very68 areare useful veryvery compoundsusefuluseful compoundscompounds from a syntheticfromfrom aa syntheticsynthetic point of pointpoint view, ofof as view, theyview, can asas they participatethey cancan participateparticipate in Pd-catalyzed inin Pd-Pd- Suzuki–Miyauracatalyzed Suzuki–Miyaura [89,91] and [89,91] Sonogashira and Sonogashira [90] cross-couplings, [90] cross-couplings, and in Ni-catalyzed and in homocoupling Ni-catalyzed processeshomocoupling [92,93 processes], thereby [92,93], allowing thereby access allowing to a wide access range to ofa wide stereochemically range of stereochemically deﬁned β-aryl-vinyl defined estersβ-aryl-vinyl69, enynyl esters esters 69,, enynylenynyl70 and estersesters buta-1,3-diene-1,4-diyl 70 andand buta-1,3-diene-1,4-diylbuta-1,3-diene-1,4-diyl diesters 71, respectively. diestersdiesters 71,, respectively.respectively.

SchemeScheme 30.30.Au(I)-catalyzed Au(I)-catalyzed synthesis synthesis of (Zof)- β(-iodoenolZ)-β-iodoenol esters esters and their and derived their derived C–C coupling C–C products.coupling products. Based on the [AuCl(PPh3)]/AgPF6-catalyzed addition of β-aryl acrylic acids to iodoalkynes, a syntheticBased route on the to (E[AuCl(PPh)-3-(arylidene)-5-substituted-2(33)]/AgPF6-catalyzed additionH)-furanones of β-aryl73 acrylicwas subsequently acids to iodoalkynes, reported by a subjectingsynthetic route the resulting to (E)-3-(arylidene)-5-substituted-2(3 (Z)-β-iodoenol esters 72 to aH palladium-catalyzed)-furanones 73 waswas subsequentlysubsequently Mizoroki–Heck reportedreported reaction byby (Schemesubjecting 31 the)[94 resulting]. Although (Z)- theβ-iodoenol process esters was routinely 72 toto aa palladium-catalyzedpalladium-catalyzed performed in two separate Mizoroki–HeckMizoroki–Heck steps, the reactionreaction authors demonstrated(Scheme 31) [94]. with Although a couple the of process examples was the routinel possibilityy performed of carrying in two out separate both transformations steps, the authors in a one-potdemonstrated manner, with i.e., a couple without of theexamples need to the isolate possib theility intermediate of carrying out species both transformations72, just by replacing in a one- the solventpot manner, and adding i.e., without the palladium the need catalystto isolateisolate and thethe the intermediateintermediate KOAc base speciesspecies after the 72,, initial justjust byby Au-catalyzed replacingreplacing thethe reaction. solventsolvent and addingVery recently, the palladium the catalytic catalyst addition and the of KOAc indole-2-carboxylic base after the acidinitial to Au-catalyzed hex-1-yne was reaction. explored with diﬀerent ruthenium and gold catalysts [95]. As shown in Scheme 32, by employing catalytic amounts of

[AuCl(PPh3)]/AgPF6 in toluene at 100 ◦C, the reaction led to the enol ester 74, which resulted from the addition of both the acid and NH groups of the indole derivative to hex-1-yne molecules. In the case of ruthenium, the expected monoaddition product of the acid to the alkyne was preferentially formed. Catalysts 2020, 10, x FOR PEER REVIEW 22 of 37

Catalysts 2020, 10, x FOR PEER REVIEW 22 of 37

Catalysts 2020, 10, 1206 22 of 36 Catalysts 2020, 10, x FOR PEER REVIEW 22 of 37

Scheme 31. Synthesis of 2(3H)-furanones from iodoalkynes and β-aryl acrylic acids. Scheme 31. Synthesis of 2(3H)-furanones from iodoalkynes and β-aryl acrylic acids. Very recently, the catalytic addition of indole-2-carboxylic acid to hex-1-yne was explored with differentVery ruthenium recently, the and catalytic gold catalysts addition [95]. of Asindole-2-carboxylic shown in Scheme acid 32, byto hex-1-yneemploying was catalytic explored amounts with ofdifferent [AuCl(PPh ruthenium3)]/AgPF and6 in gold toluene catalysts at 100 [95]. °C, Asthe shown reaction in ledScheme to the 32, enol by esteremploying 74, which catalytic resulted amounts from the addition of both the acid and NH groups of the indole derivative to hex-1-yne molecules. In the of [AuCl(PPh3)]/AgPF6 in toluene at 100 °C, the reaction led to the enol ester 74, which resulted from casethe addition of ruthenium, of both the the expected acid and monoaddition NH groups of prodthe indoleuct of derivativethe acid to tothe hex-1-yne alkyne was molecules. preferentially In the formed. case of ruthenium, the expected monoaddition product of the acid to the alkyne was preferentially formed. Scheme 31. Synthesis of 2(3 H)-furanones from iodoalkynes and β-aryl acrylic acids.acids.

Very recently, the catalytic addition of indole-2-carboxylic acid to hex-1-yne was explored with different ruthenium and gold catalysts [95]. As shown in Scheme 32, by employing catalytic amounts of [AuCl(PPh3)]/AgPF6 in toluene at 100 °C, the reaction led to the enol ester 74, which resulted from the addition of both the acid and NH groups of the indole derivative to hex-1-yne molecules. In the case of ruthenium, the expected monoaddition product of the acid to the alkyne was preferentially Scheme 32. Au(I)-catalyzed double addition of indole-2-carboxylic acid to 1-hexyne. formed. SchemeScheme 32.32. Au(I)-catalyzed double addition of indole-2-carboxylicindole-2-carboxylic acidacid toto 1-hexyne.1-hexyne. On the other hand, it is also noteworthy that complex [AuCl(PPh3)], associated now with AgOAc,On thewas other successfully hand, it isemployed also noteworthy to promote that complexthe intermolecular [AuCl(PPh3 addition)], associated of carboxylic now with acids AgOAc, to On the other hand, it is also noteworthy that complex [AuCl(PPh3)], associated now with wasnon-activatedAgOAc, successfully was successfullyinternal employed alkynes employed to promote in water, to the allowingpromote intermolecular thethe synthesis intermolecular addition of a of wide carboxylic addition variety of acids of carboxylic trisubstituted to non-activated acids enol to internalestersnon-activated (37 alkynes examples) internal in water, in alkynesmoderate allowing in towater, high the allowing synthesisyields and the of with synthesis a wide complete variety of a ( Zwide) of stereoselectivity trisubstituted variety of trisubstituted enol(anti- estersaddition) enol (37 examples)[96].esters The (37 examples)lower in moderate reactivity in moderate to high of yieldsthe to alkyl-high and yields withand completearyl-substitutedand with complete (Z) stereoselectivity alkynes (Z) stereoselectivity employed (anti-addition) in (anti-this addition) [study96]. The in lowercomparison reactivity to that of theof the alkyl- terminal and aryl-substituted or iodo-substituted alkynes ones employed required inthe this reactions study into comparisonbe carried out to [96]. The lower reactivity of the alkyl- and aryl-substituted alkynes employed in this study in thatin this of thecase terminal at 60 °C or instead iodo-substituted of room temperatur ones requirede. Related the reactions addition to bereactions carried in out water in this were case more at 60 comparison Schemeto that of32. theAu(I)-catalyzed terminal or double iodo-substit additionuted of inonesdole-2-carboxylic required the acid reactions to 1-hexyne. to be carried out ◦recentlyinC this instead case described of at room 60 °C temperature. byinstead employing of room Related as temperatur catalysts addition reactionse.the Related gold(I) in addition water chloride were reactions complexes more recentlyin water 75 described, werecontaining more by employinghydrophilic as ferrocenylphosphino catalysts the gold(I) chloride sulfonate complexes ligands 75(see, containing Figure 7), hydrophilic which allowed ferrocenylphosphino the authors to recentlyOn thedescribed other hand,by employing it is also noasteworthy catalysts thatthe complexgold(I) chloride[AuCl(PPh complexes3)], associated 75, containingnow with sulfonatereduce the ligands metal (seeloadings Figure from7), which 5 to allowed2 mol% the[97]. authors As observed to reduce with the metal[AuCl(PPh loadings3)], mixtures from 5 to of 2 AgOAc,hydrophilic was ferrocenylphosphinosuccessfully employed sulfonate to promote ligands the (seeintermolecular Figure 7), additionwhich allowed of carboxylic the authors acids to mol%regioisomers [97]. As were observed in most with cases [AuCl(PPh obtained 3when)], mixtures non-symmetrically of regioisomers substitute were ind alkynes most cases were obtained used as non-activatedreduce the metal internal loadings alkynes from in water, 5 to 2allowing mol% [97].the synthesis As observed of a wide with variety [AuCl(PPh of trisubstituted3)], mixtures enol of whensubstrates. non-symmetrically substituted alkynes were used as substrates. estersregioisomers (37 examples) were in in most moderate cases obtainedto high yields when and no n-symmetricallywith complete (Z substitute) stereoselectivityd alkynes (anti- wereaddition) used as [96].substrates. The lower reactivity of the alkyl- and aryl-substituted alkynes employed in this study in comparison to that of the terminal or iodo-substituted ones required the reactions to be carried out in this case at 60 °C instead of room temperature. Related addition reactions in water were more recently described by employing as catalysts the gold(I) chloride complexes 75, containing hydrophilic ferrocenylphosphino sulfonate ligands (see Figure 7), which allowed the authors to reduce the metal loadings from 5 to 2 mol% [97]. As observed with [AuCl(PPh3)], mixtures of regioisomers were in most cases obtained when non-symmetrically substituted alkynes were used as substrates. Figure 7. Structure of the water-soluble gold(I) complexes 7575.. Figure 7. Structure of the water-soluble gold(I) complexes 75. Additional examples of gold-based catalysts ableable to promotepromote thethe intermolecularintermolecular addition of carboxylic acids to alkynes are the dinuclear hydroxo-brigded NHC complex [{Au(IPr)} (µ-OH)][BF ] carboxylicAdditional acids toexamples alkynes areof gold-basedthe dinuclear catalysts hydroxo-brigded able to promote NHC complex the intermolecular [{Au(IPr)}22( µaddition-OH)][BF of44] (33 in Scheme 12)[98] and the mononuclear derivative 76 containing an amide-functionalized carboxylic acids to alkynes are the dinuclear hydroxo-brigded NHC complex [{Au(IPr)}2(µ-OH)][BF4] biphenylphosphine ligand (see Figure8)[ 99]. Thus, 33 proved to be highly eﬃcient in the hydrocarboxylation of internal alkynes under solvent-free and silver-free conditions, leading to the enol-ester products in high yields and with complete (Z) stereoselectivity by performing the reactions at 80 ◦C with a catalyst loading of 0.5 mol%. In addition, very good regioselectivity was observed with non-symmetricallyFigure 7. Structure substituted of the water-soluble alkynes (three gold(I) representative complexes 75 examples. are shown in Scheme 33). Concerning the mononuclear complex 76, it was employed to promote, in combination Additional examples of gold-based catalysts able to promote the intermolecular addition of carboxylic acids to alkynes are the dinuclear hydroxo-brigded NHC complex [{Au(IPr)}2(µ-OH)][BF4]

Catalysts 2020, 10, x FOR PEER REVIEW 23 of 37 Catalysts 2020, 10, x FOR PEER REVIEW 23 of 37 (33 in Scheme 12) [98] and the mononuclear derivative 76 containing an amide-functionalized (33 in Scheme 12) [98] and the mononuclear derivative 76 containing an amide-functionalized biphenylphosphine ligand (see Figure 8) [99]. Thus, 33 proved to be highly efficient in the biphenylphosphine ligand (see Figure 8) [99]. Thus, 33 proved to be highly efficient in the hydrocarboxylation of internal alkynes under solvent-free and silver-free conditions, leading to the hydrocarboxylation of internal alkynes under solvent-free and silver-free conditions, leading to the enol-ester products in high yields and with complete (Z) stereoselectivity by performing the reactions enol-ester products in high yields and with complete (Z) stereoselectivity by performing the reactions at 80 °C with a catalyst loading of 0.5 mol%. In addition, very good regioselectivity was observed at 80 °C with a catalyst loading of 0.5 mol%. In addition, very good regioselectivity was observed Catalystswith non-symmetrically2020, 10, 1206 substituted alkynes (three representative examples are shown in Scheme23 of33). 36 with non-symmetrically substituted alkynes (three representative examples are shown in Scheme 33). Concerning the mononuclear complex 76, it was employed to promote, in combination with AgNTf2, Concerning the mononuclear complex 76, it was employed to promote, in combination with AgNTf2, the addition of a broad range of aromatic and aliphatic carboxylic acids to both terminal and internal withthe addition AgNTf2 ,of the a broad addition range of a of broad aromatic range and of aromaticaliphatic andcarboxylic aliphatic acids carboxylic to both acidsterminal to both and terminal internal alkynes. Excellent results in terms of activity were achieved while working at 80 °C in fluorobenzene, andalkynes. internal Excellent alkynes. results Excellent in terms results of activity in terms were of achieved activity were while achieved working whileat 80 °C working in fluorobenzene, at 80 ◦C in conditions that allowed them to generate the corresponding anti-addition products in excellent yields fluorobenzene,conditions that conditionsallowed them that to allowed generate them the corresponding to generate the anti corresponding-addition productsanti-addition in excellent products yields in with remarkably low metal loadings (in the range of 25-150 ppm in most of the cases). The excellentwith remarkably yields with low remarkably metal loadings low metal (in loadingsthe range (in of the 25-150 range ofppm 25-150 in ppmmost inof most the ofcases). the cases). The outstanding effectiveness of this catalyst, with which TON values of up to 34,400 were reached, was Theoutstanding outstanding effectiveness effectiveness of this of catalyst, this catalyst, with with whic whichh TON TON values values of up of to up 34,400 to 34,400 were were reached, reached, was reasoned in terms of the cooperative effect exerted by the basic amide group present in the ligand. wasreasoned reasoned in terms in terms of the of thecooperative cooperative effect effect exerte exertedd by by the the basic basic amide amide group group present present in in the the ligand. ligand. This group would interact with the carboxylic acid, enhancing in this way its nucleophilicity. ThisThis groupgroup wouldwould interactinteract withwith thethe carboxyliccarboxylic acid,acid, enhancingenhancing inin thisthis wayway itsits nucleophilicity.nucleophilicity.

Figure 8. Structure of the gold(I)-biphenylphosphine complex 76. Figure 8. Structure of the gold(I)-biphenylphosphine complex 7676..

Scheme 33. Regio-Regio- and stereoselective addition of benzoicbenzoic acid to non-symmetricallynon-symmetrically substituted Scheme 33. Regio- and stereoselective addition of benzoic acid to non-symmetrically substituted internal alkynes catalyzed by the dinuclear complexcomplex [{Au(IPr)}[{Au(IPr)}22(µ-OH)][BF4]]( (3333).). internal alkynes catalyzed by the dinuclear complex [{Au(IPr)}2(µ-OH)][BF4] (33). 3. Addition of Carboxylic Acids to Allenes 3. Addition of Carboxylic Acids to Allenes 3. Addition of Carboxylic Acids to Allenes 3.1. Cycloisomerization of Allenoic Acids 3.1. Cycloisomerization of Allenoic Acids 3.1. Cycloisomerization of Allenoic Acids The ﬁrst example of this type of cyclization processes catalyzed by gold was described by Toste and The first example of this type of cyclization processes catalyzed by gold was described by Toste co-workersThe first in example 2007 [100 of]. Asthis shown type of in cyclization Scheme 34, pr theyocesses studied catalyzed the enantioselective by gold was described cycloisomerization by Toste and co-workers in 2007 [100]. As shown in Scheme 34, they studied the enantioselective ofand the co-workers trisubstituted in 2007γ-allenoic [100]. acid As 77shownwith dinuclearin Scheme Au(I) 34, complexesthey studied of generalthe enantioselective composition cycloisomerization of the trisubstituted γ-allenoic acid 77 with dinuclear Au(I) complexes of general [(AuCl)cycloisomerization2(µ-L)], containing of the trisubstituted optically pure γ-allenoic (R)/(S)-BINAP acid 77 or with bis(diphenylphosphino)methane dinuclear Au(I) complexes of (dppm)general composition [(AuCl)2(µ-L)], containing optically pure (R)/(S)-BINAP or ascomposition bridging L ligands,[(AuCl) in combination2(µ-L)], containing with a silver(I) optically salt featuring pure an achiral ( orR)/( anS)-BINAP optically activeor bis(diphenylphosphino)methane (dppm) as bridging L ligands, in combination with a silver(I) salt counteranionbis(diphenylphosphino)methane (p-nitribenzoate or the (dppm binaphthol-based) as bridging L phosphate ligands, in (R )-TRIP,combination respectively). with a silver(I) In all cases, salt featuring an achiral or an optically active counteranion (p-nitribenzoate or the binaphthol-based thefeaturing regioselective an achiral formation or an optically of the ﬁve-membered active counteranion ring lactone (p-nitribenzoate78 was observed, or the withbinaphthol-based yields in the phosphate (R)-TRIP, respectively). In all cases, the regioselective formation of the five-membered ring rangephosphate 80–91% (R)-TRIP, after 24 respectively). h of stirring inIn benzeneall cases, at the room regios temperature.elective formation Concerning of the the five-membered enantioselectivity ring lactone 78 was observed, with yields in the range 80–91% after 24 h of stirring in benzene at room oflactone the process, 78 was a observed, maximum with enantiomeric yields in excessthe range of 82% 80–91% was reachedafter 24 whenh of stirring the (S)-BINAP in benzene diphosphine at room temperature. Concerning the enantioselectivity of the process, a maximum enantiomeric excess of andtemperature. the chiral Concerning counteranion the (R )-TRIPenantioselectivity made part ofof thethe catalytic process, system. a maximum enantiomeric excess of 82% was reached when the (S)-BINAP diphosphine and the chiral counteranion (R)-TRIP made part 82% was reached when the (S)-BINAP diphosphine and the chiral counteranion (R)-TRIP made part of the catalytic system. of the catalytic system.

Catalysts 2020, 10, 1206 24 of 36 CatalystsCatalysts 20202020,, 1010,, xx FORFOR PEERPEER REVIEWREVIEW 2424 ofof 3737

SchemeScheme 34.34. Gold-catalyzedGold-catalyzed enantioselective enantioselective cyclization cyclization of of the the γγ-allenoic-allenoic acid acid 7777..

TheThe same same group group also also successfully successfully accomplished accomplished the the enantioselective enantioselective bromocyclization bromocyclization ofof 7777 andand oneone of of its its congeners, congeners, through through the the use use of of a a rela relatedrelatedted dinuclar dinuclar Au(I) Au(I) comple complexcomplexx associated associated with with Ag-( Ag-(SS)-TRIP)-TRIP andand aa NN-bromolactam,-bromolactam, the the latter latter acting acting as as an an electrophilicelectrophilic bromine bromine source source able able to to promotepromote thethe halodeaurationhalodeauration ofof thethe correspondingcorresponding vinylgoldvinylgold intermediateintermediate KKK (see(see(see SchemeSchemeScheme 3535)35))[ [101].[101].101].

SchemeScheme 35. 35. Gold-catalyzedGold-catalyzed enantioselective enantioselective bromoyclization bromoyclization of of γγ-allenoic-allenoic acids.acids.

78 77 TheThe high high yield yield synthesis synthesis of of lactone lactone 7878 inin racemic racemic form form by by cyclization cyclization of of 7777 waswas later later reported reported by by HashmiHashmi andandand co-workers, co-workers,co-workers, who whowho employed employedemployed the achiral thethe acac mono-hiralhiral andmono-mono- dinuclear andand dinucleardinuclear gold(I)-phosphine gold(I)-phosphinegold(I)-phosphine complexes complexes79–81complexesdepicted 79–8179–81 in depicteddepicted Figure9[ inin102 FigureFigure,103]. 99 All [102,103].[102,103]. of them All wereAll ofof able themthem to werewere promote ableable the toto promotepromote process at thethe room processprocess temperature atat roomroom temperaturetemperature inin CC66DD66 withwith metalmetal loadingsloadings ofof 0.05–0.50.05–0.5 mol%mol% inin thethe casecase ofof 79–8079–80 andand 2.52.5 mol%mol% inin thethe casecase ofof 8181,, thethe latterlatter requiringrequiring thethe presencepresence ofof aa silver(I)silver(I) saltsalt asas co-catalystco-catalyst [103].[103].

Catalysts 2020, 10, 1206 25 of 36

in C6D6 with metal loadings of 0.05–0.5 mol% in the case of 79–80 and 2.5 mol% in the case of 81, the latterCatalysts requiring 2020, 10, x theFOR presence PEER REVIEW of a silver(I) salt as co-catalyst [103]. 25 of 37

FigureFigure 9.9. Structure ofof thethe gold(I)-phosphinegold(I)-phosphine complexescomplexes 79–8179-81.

The group group of of Lipshutz Lipshutz desc describedribed the the asymmetric asymmetric cycloi cycloisomerizationsomerization of different of different γ-allenoicγ-allenoic acids acidsin an aqueous in an aqueous micellar micellar medium medium while employing while employing the ionic thedinuclear ionic dinuclearAu(I) complex Au(I) 82 complex, containing82, containing(R)-MeO-BIPHEP (R)-MeO-BIPHEP as bridging asligand bridging and the ligand (R)-TRIP and the counteranion, (R)-TRIP counteranion, and the surfactant and the TPGS-750-M surfactant TPGS-750-M(Scheme 36) [104]. (Scheme The reactions36)[104]. gave The high reactions yields under gave highmild conditions yields under (r.t.), mild leading conditions to the vinyl- (r.t.), leadinglactones towith the good vinyl-lactones to excellent with ee´s good (72-96%). to excellent The recyclabilityee´s (72-96%). of the The aqueous recyclability solution of containing the aqueous 82 solutionwas possible containing after extraction82 was possible of the lactone after extraction products with of the an lactone ether/hexane products mixture—the with an ether yields/hexane and mixture—theee´s remained yieldsconstant and throughoutee´s remained six successive constant throughoutreactions. It sixshould successive be mentioned reactions. at this It shouldpoint that be mentionedToste and co-workers at this point also that developed Toste and a recyclable co-workers catalytic also system developed for the a recyclableenantioselective catalytic conversion system forof γ the- and enantioselective δ-allenoic acids conversioninto chiral 5- of andγ- and6-memberedδ-allenoic ring acids vinyl-lactones into chiral 5-(ee´s and in the 6-membered 81–93% range) ring vinyl-lactones (ee´s in the 81–93% range) by supporting the dinuclear gold(I) complex [Au (µ-L)][BF ] by supporting the dinuclear gold(I) complex [Au2(µ-L)][BF4]2 (L = (R)-(+)-2,2'-bis[di(3,5-2 4 2 (Lxylyl)phosphino]-6,6'-dimethoxy-1,1'-biphenyl)= (R)-(+)-2,2’-bis[di(3,5-xylyl)phosphino]-6,6’-dimethoxy-1,1’-biphenyl) on the mesoporous silica SBA-15 on the mesoporous[67]. In this silicacase, SBA-15the heterogeneous [67]. In this catalyst case, thewas heterogeneous easily recovered catalyst from the was solution easily recoveredby centrifugation from the and solution could bybe centrifugationreused for 11 consecutive and could cycles be reused with no for decrease 11 consecutive in the activity cycles and with enantioselectivity no decrease in (cumulative the activity andTON enantioselectivity = 507). In addition, (cumulative for all the TON substrates= 507). st Inudied, addition, the enantioselectivity for all the substrates reached studied, with the enantioselectivity reached with the supported catalyst was superior to that obtained with complex supported catalyst was superior to that obtained with complex [Au2(µ-L)][BF4]2 under homogeneous [Auconditions.2(µ-L)][BF The4]2 sameunder authors homogeneous also explored conditions. the cata Thelytic same behavior authors of also silica-s exploredupported the catalytic Au NPs behavior coated ofwith silica-supported chiral NHC ligands Au NPs in coated the lactonization with chiral NHC of two ligands model in the γ-allenoic lactonization acids of [105]. two modelAlthoughγ-allenoic good acidsresults [105 in terms]. Although of activity good and results recyclability in terms (up of activity to five consecutive and recyclability runs; cumulative (up to five consecutive TON = 227) runs;were cumulativeobtained, the TON enantiomeric= 227) were excesses obtained, did the not enantiomeric exceed 16%. excesses did not exceed 16%. In a subsequent study, Lipshutz and co-workers reported the racemic version of the cyclization reactions depicted in Scheme 36; they employed ppm levels of [AuCl(HandaPhos)]/AgSbF6 (1000 and 2000 ppm, respectively) in an aqueous micellar medium generated with the surfactant Nok (see Figure 10)[106]. On the other hand, Ohfume and co-workers studied the cycloisomerization of different β-allenoic acids containing a silyl group attached to the allenic terminus—for example, the chiral allenylglycine derivatives 83, employing different Pd, Pt, Hg, Ag and Au-based catalysts. Among them, best results were obtained with the cationic oxo-bridged trinuclear gold(I) complex [{(Ph3P)Au}3(µ-O)][BF4], which allowed the regioselective access to the corresponding 2-amino-4-silylmethylene-substituted γ-butyrolactones 84 resulting from the addition of the carboxylate to the central sp-carbon of the allene (Scheme 37)[107]. Regarding the stereoselectivity of the process, it was found to be strongly dependent on the substitution pattern at the C-2 position of the substrates. Thus, while in the case of R = H the product was obtained in an almost diastereomerically pure manner, those substrates featuring a quaternary carbon center (R = Me, Bn) led to the respective γ-butyrolactones 84 as mixtures of diastereoisomers.

Catalysts 2020, 10, 1206 26 of 36 Catalysts 2020, 10, x FOR PEER REVIEW 26 of 37

SchemeScheme 36. 36. Gold(I)-catalyzedGold(I)-catalyzed enantioselective enantioselective lactonization lactonization of γ-allenoic of γ-allenoic acids in aqueous acids in micellar aqueous Catalysts 2020, 10, x FOR PEER REVIEW 27 of 37 micellarmedium. medium.

In a subsequent study, Lipshutz and co-workers reported the racemic version of the cyclization reactions depicted in Scheme 36; they employed ppm levels of [AuCl(HandaPhos)]/AgSbF6 (1000 and 2000 ppm, respectively) in an aqueous micellar medium generated with the surfactant Nok (see Figure 10) [106].

Figure 10. Structures of the phosphine ligand HandaPhos and the surfactant Nok.Nok.

On the other hand, Ohfume and co-workers studied the cycloisomerization of different β- allenoic acids containing a silyl group attached to the allenic terminus—for example, the chiral allenylglycine derivatives 83, employing different Pd, Pt, Hg, Ag and Au-based catalysts. Among them, best results were obtained with the cationic oxo-bridged trinuclear gold(I) complex [{(Ph3P)Au}3(µ-O)][BF4], which allowed the regioselective access to the corresponding 2-amino-4- silylmethylene-substituted γ-butyrolactones 84 resulting from the addition of the carboxylate to the central sp-carbon of the allene (Scheme 37) [107]. Regarding the stereoselectivity of the process, it was found to be strongly dependent on the substitution pattern at the C-2 position of the substrates. Thus, while in the case of R = H the product was obtained in an almost diastereomerically pure manner, those substrates featuring a quaternary carbon center (R = Me, Bn) led to the respective γ- butyrolactones 84 as mixtures of diastereoisomers.

Scheme 37. Au(I)-catalyzed cycloisomerization of the silyl-substituted allenoic acids 83.

Taking advantage of this initial work, the total synthesis of the natural product (-)-funebrine, in which the two γ-butyrolactone units of the molecule were generated by cycloisomerization of the related allenylsilane 85 into 86, could be developed (Scheme 38) [108]. Although the use of the dimethylphenylsilyl group instead of the tert-butyldimethylsilyl (TBS) one reduced the diasteroselectivity of the cyclization process (diastereomeric ratio d.r. = 10:1 vs. > 20:1), said group was chosen by the authors, since its subsequent removal proceeds under milder conditions, thereby avoiding epimerization at the C-3 carbon. Of note is the fact that, by adding 20 mol% of iPr2NEt to the reaction medium, the catalyst loading could be reduced from 3 to 1 mol%.

Catalysts 2020, 10, x FOR PEER REVIEW 27 of 37

Figure 10. Structures of the phosphine ligand HandaPhos and the surfactant Nok.

On the other hand, Ohfume and co-workers studied the cycloisomerization of different β- allenoic acids containing a silyl group attached to the allenic terminus—for example, the chiral allenylglycine derivatives 83, employing different Pd, Pt, Hg, Ag and Au-based catalysts. Among them, best results were obtained with the cationic oxo-bridged trinuclear gold(I) complex [{(Ph3P)Au}3(µ-O)][BF4], which allowed the regioselective access to the corresponding 2-amino-4- silylmethylene-substituted γ-butyrolactones 84 resulting from the addition of the carboxylate to the central sp-carbon of the allene (Scheme 37) [107]. Regarding the stereoselectivity of the process, it was found to be strongly dependent on the substitution pattern at the C-2 position of the substrates. Thus, while in the case of R = H the product was obtained in an almost diastereomerically pure manner, Catalyststhose substrates2020, 10, 1206 featuring a quaternary carbon center (R = Me, Bn) led to the respective27 of 36γ- butyrolactones 84 as mixtures of diastereoisomers.

SchemeScheme 37.37. Au(I)-catalyzed cycloisomerization ofof thethe silyl-substitutedsilyl-substituted allenoicallenoic acidsacids 8383..

TakingTaking advantageadvantage of this initial initial work, work, the the total total synthesis synthesis of of the the natural natural product product (-)-funebrine, (-)-funebrine, in inwhich which the thetwo two γ-butyrolactoneγ-butyrolactone units units of the of molecule the molecule were weregenerated generated by cycloi bysomerization cycloisomerization of the ofrelated the related allenylsilane allenylsilane 85 into85 86into, could86, couldbe developed be developed (Scheme (Scheme 38) [108]. 38)[ Although108]. Although the use the of usethe ofdimethylphenylsilyl the dimethylphenylsilyl group groupinstead instead of the of theterttert-butyldimethylsilyl-butyldimethylsilyl (TBS) (TBS) one one reduced reduced thethe diasteroselectivitydiasteroselectivity of the the cyclization cyclization process process (diastereomeric (diastereomeric ratio ratio d.r. d.r. = 10:1= 10:1 vs. > vs. 20:1),> said20:1), group said groupwas chosen was chosen by the byauthors, the authors, since its since subsequent its subsequent removal removal proceeds proceeds under milder under conditions, milder conditions, thereby therebyCatalystsavoiding 2020 avoiding epimerization, 10, x FOR epimerization PEER at REVIEW the C-3 at carbon. the C-3 Of carbon. note is Of the note fact isthat, the by fact adding that, by 20 addingmol% of 20 iPr mol%2NEt28 of of37to i CatalyststhePr2 NEtreaction 2020 to the, 10 medium,, reactionx FOR PEER the medium, REVIEW catalyst the loading catalyst could loading be reduced could be from reduced 3 to 1 from mol%. 3 to 1 mol%. 28 of 37

Scheme 38. γ-Butyrolactonization of the allenylsilane 85 employed in the total synthesis of (-)- Schemefunebrine. 38.38. γ γ-Butyrolactonization-Butyrolactonization of theof the allenylsilane allenylsilane85 employed 85 employed in the totalin the synthesis total synthesis of (-)-funebrine. of (-)- funebrine. It is also also worth worth noting noting that that the the regioselectivity regioselectivity of of the the cyclization cyclization reactions reactions to toprovide provide γ- γbutyrolactones-butyrolactonesIt is also worthcollected collected noting in inSchemes that Schemes the 37 regioselectivity 37and and 38 seem38 seemss toof be tothe governed be cyclization governed by thereactions by presence the presence to provideof the of silyl theγ- silylgroup.butyrolactones group. In fact, In fact, whencollected when it was itin was replacedSchemes replaced by37 byaand tBu a tBu38 one, seem one, such suchs to as be as in in governedcompound compound by 87 87the, ,hydroamination hydroamination presence of the at at silyl the terminalgroup. In carbon fact, when of the it allenic was replaced unit prefer preferentially byentially a tBu one, occurred such as to give in compound the pyrrolidine 87, hydroamination 88 (Scheme(Scheme 39)39)[ at[107].107 the]. terminal carbon of the allenic unit preferentially occurred to give the pyrrolidine 88 (Scheme 39) [107].

SchemeScheme 39.39. CyclizationCyclization ofof thethe allenoicallenoic acidacid 8787 catalyzedcatalyzed byby [{(Ph[{(Ph33P)Au}33(µ-O)][BF4].].

Scheme 39. Cyclization of the allenoic acid 87 catalyzed by [{(Ph3P)Au}3(µ-O)][BF4]. After screening of didifferentﬀerent gold(I)gold(I) complexescomplexes with phosphinephosphine and NHC type ligands, Ma and co-workersAfter screening identiﬁedidentified of [AuCl(LB-Phos)] different[AuCl(LB-Phos)] gold(I) (89 complexes ) as(89 a) suitableas a with suitable catalyst phosphine forcatalyst the and highly for NHC regio-the type highly and ligands, stereoselective regio- Ma and cyclizationstereoselectiveco-workers ofidentified optically cyclization pure[AuCl(LB-Phos)] of 1,3-disubstituted optically pure (89 1,3-disubstituted) γ-allenoicas a suitable acids γ90catalyst-allenoic(Scheme foracids 40 )[the 10990 highly(Scheme]. Thus, regio- using40) [109]. thisand Thus,stereoselective using this cyclization complex in of combination optically pure with 1,3-disubstituted AgOTf, the access γ-allenoic to a broad acids range 90 (Scheme of chiral 40)γ-vinylic [109]. γThus,-butyrolactones using this complex 91 could in be combination achieved with with an AgOTf,excellent the axial-to-central access to a broad chirality range transfer of chiral (ee γ´s-vinylic in the rangeγ-butyrolactones 85–99%). 91 could be achieved with an excellent axial-to-central chirality transfer (ee´s in the range 85–99%).

Scheme 40. Gold-catalyzed stereoselective cycloisomerization of allenoic acids 90. Scheme 40. Gold-catalyzed stereoselective cycloisomerization of allenoic acids 90.

Catalysts 2020, 10, x FOR PEER REVIEW 28 of 37

Scheme 38. γ-Butyrolactonization of the allenylsilane 85 employed in the total synthesis of (-)- funebrine.

It is also worth noting that the regioselectivity of the cyclization reactions to provide γ- butyrolactones collected in Schemes 37 and 38 seems to be governed by the presence of the silyl group. In fact, when it was replaced by a tBu one, such as in compound 87, hydroamination at the terminal carbon of the allenic unit preferentially occurred to give the pyrrolidine 88 (Scheme 39) [107].

Scheme 39. Cyclization of the allenoic acid 87 catalyzed by [{(Ph3P)Au}3(µ-O)][BF4].

After screening of different gold(I) complexes with phosphine and NHC type ligands, Ma and co-workersCatalysts 2020, 10identified, 1206 [AuCl(LB-Phos)] (89) as a suitable catalyst for the highly regio-28 and of 36 stereoselective cyclization of optically pure 1,3-disubstituted γ-allenoic acids 90 (Scheme 40) [109]. Thus, using this complex in combination with AgOTf, the access to a broad range of chiral γ-vinylic γcomplex-butyrolactones in combination 91 could with be achieved AgOTf, the with access an excellent to a broad axial-to-central range of chiral chiralityγ-vinylic transferγ-butyrolactones (ee´s in the range91 could 85–99%). be achieved with an excellent axial-to-central chirality transfer (ee´s in the range 85–99%).

Catalysts 2020, 10Scheme, x FOR PEER40. Gold-catalyzedGold-catalyzed REVIEW stereoselective stereoselective cycloisomerization of allenoic acids 90. 29 of 37

Moreover,Moreover, they they developed developed a Pd /C-baseda Pd/C-based C–O bond C–O cleavage-free bond cleavage-free procedure forprocedure the hydrogenation for the of lactones 91, through which some biologically active molecules of natural origin such as hydrogenation of lactones 91, through which some biologically active molecules of natural origin (suchR)/(S )-4-tetradecalactone,as (R)/(S)-4-tetradecalactone, (R)-γ-palmitolactone (R)-γ-palmitolactone or (R)-4-decalactone or (R)-4-decalactone could could be synthesized be synthesized (see Figure(see Figure 11)[109 11)]. [109].

FigureFigure 11.11. Structure ofof somesome naturallynaturally occurringoccurring γγ-alkyl-substituted-alkyl-substituted γγ-butyrolactones.-butyrolactones.

InIn thethe samesame work,work, the the naturally naturally occurring occurringγ -vinyl-substitutedγ-vinyl-substitutedγ -butyrolactonesγ-butyrolactones xestospongiene xestospongiene F, G,F, G, H andH and E wereE were also also conveniently conveniently prepared prepared by by cycloisomerization cycloisomerization of theof the appropriate appropriate stereoisomer stereoisomer of theof the chiral chiralγ-allenoic γ-allenoic acid acid92 (Scheme92 (Scheme 41)[ 41)109 [109].]. In additional studies, Ma’s group accomplished the total synthesis of the natural products (R)-traumatic lactone, (S)-traumatic lactone and (S)-rhizobialide through strategies in which the chiral five-membered ring lactone units of these compounds were generated by means of the [AuCl(LB-Phos)]/AgOTf-catalyzed cyclization of the corresponding enantiomer of the allenoic acid 93 (Scheme 42)[110,111]. On the other hand, the behavior of different mononuclear gold(I)-chloride complexes containing phosphine, phosphite and NHC-type ligands, such as [AuCl(PPh3)], [AuCl(JohnPhos)], [AuCl{P(OPh)3}], [AuCl(IMes)] or [AuCl(H2IMes)], in the cyclization of 2,2-diaryl substituted γ-allenoic acids 94, was explored by Slaughter and co-workers (Scheme 43)[112]. The formation of mixtures of three isomeric products was in most the cases observed—i.e., the expected γ-vinyl-substituted γ-butyrolactones 95, compounds 96 resulting from the double bond isomerization in 95, and the tricyclic derivatives 97 which arise from a tandem hydroacyloxylation/hydroarylation process involving 95 as intermediates. However, an in-depth study of the process made it possible to selectively generate lactones 95 and 96 by exploiting Brønsted acid/base and ligand effects. Thus, as shown in Scheme 43, using the phosphite complex [AuCl{P(OPh)3}] in combination with AgOTf, compounds 95 were preferentially formed in the presence of a base, whereas a Brønsted acid oriented the reaction towards

Scheme 41. Gold-catalyzed synthesis of some natural xestospongienes.

In additional studies, Ma's group accomplished the total synthesis of the natural products (R)- traumatic lactone, (S)-traumatic lactone and (S)-rhizobialide through strategies in which the chiral five-membered ring lactone units of these compounds were generated by means of the [AuCl(LB- Phos)]/AgOTf-catalyzed cyclization of the corresponding enantiomer of the allenoic acid 93 (Scheme 42) [110,111].

Catalysts 2020, 10, x FOR PEER REVIEW 29 of 37

Moreover, they developed a Pd/C-based C–O bond cleavage-free procedure for the hydrogenation of lactones 91, through which some biologically active molecules of natural origin such as (R)/(S)-4-tetradecalactone, (R)-γ-palmitolactone or (R)-4-decalactone could be synthesized (see Figure 11) [109].

Catalysts 2020, 10, 1206 29 of 36 Figure 11. Structure of some naturally occurring γ-alkyl-substituted γ-butyrolactones. the isomerizedIn products the same work,96. Withthe naturally a limited occurring substrate γ-vinyl-substituted scope, the γ authors-butyrolactones also developed xestospongiene protocols to obtain theF, bridged G, H and tricyclicE were also lactones conveniently97 in prepared a selective by cycloisomerization manner. of the appropriate stereoisomer of the chiral γ-allenoic acid 92 (Scheme 41) [109].

Catalysts 2020, 10, xScheme FOR PEERScheme 41. REVIEWGold-catalyzed 41. Gold-catalyzed synthesis synthesis of of so someme natural natural xestospongienes. xestospongienes. 30 of 37

SchemeScheme 42. 42.Enantioselective Enantioselective cyclizations cyclizations involved involved in the intotal the synthesis total of synthesis some naturally of some occurring naturally occurringlactones. lactones.

On the other hand, the behavior of different mononuclear gold(I)-chloride complexes containing phosphine, phosphite and NHC-type ligands, such as [AuCl(PPh3)], [AuCl(JohnPhos)], [AuCl{P(OPh)3}], [AuCl(IMes)] or [AuCl(H2IMes)], in the cyclization of 2,2-diaryl substituted γ- allenoic acids 94, was explored by Slaughter and co-workers (Scheme 43) [112]. The formation of mixtures of three isomeric products was in most the cases observed—i.e., the expected γ-vinyl- substituted γ-butyrolactones 95, compounds 96 resulting from the double bond isomerization in 95, and the tricyclic derivatives 97 which arise from a tandem hydroacyloxylation/hydroarylation process involving 95 as intermediates. However, an in-depth study of the process made it possible to selectively generate lactones 95 and 96 by exploiting Brønsted acid/base and ligand effects. Thus, as shown in Scheme 43, using the phosphite complex [AuCl{P(OPh)3}] in combination with AgOTf, compounds 95 were preferentially formed in the presence of a base, whereas a Brønsted acid oriented the reaction towards the isomerized products 96. With a limited substrate scope, the authors also developed protocols to obtain the bridged tricyclic lactones 97 in a selective manner.

Scheme 43. Gold(I)-catalyzed cyclization of the γ-allenoic acid 94.

Catalysts 2020, 10, x FOR PEER REVIEW 30 of 37

Scheme 42. Enantioselective cyclizations involved in the total synthesis of some naturally occurring lactones.

Catalyststhe reaction2020, 10 towards, 1206 the isomerized products 96. With a limited substrate scope, the authors30 also of 36 developed protocols to obtain the bridged tricyclic lactones 97 in a selective manner.

Catalysts 2020, 10, x FOR PEER REVIEW 31 of 37 Catalysts 2020, 10, x FOR PEERScheme REVIEW 43. Gold(I)-catalyzed cyclization of the γ-allenoic acid 94.. 31 of 37

Finally,Finally, itit shouldshould bebe notednoted thatthat ReekReek andand co-workersco-workers successfullysuccessfully employedemployed aa supramolecularsupramolecular platinum-basedplatinum-based nanosphere nanosphere functionalized functionalizedtionalized with withwith a phosphine-gold(I)-chloride aa phosphine-gold(I)-chloridephosphine-gold(I)-chloride complex complex incomplex the cyclization inin thethe ofcyclization the closely ofrelated the closely 2,2-diphenylhexa-4,5-dienoic related 2,2-diphenylhexa-4,5-dienoic acid into the correspondingacid into the ﬁve-memberedcorresponding five- ring vinyl-lactonemembered ring [44 vinyl-lactone]. [44].

3.2.3.2. Intermolecular Addition of Carboxylic AcidsAcids toto AllenesAllenes UnlikeUnlike otherother metals,metals, suchsuch asas palladiumpalladium oror rhodium,rhodium,ium, forfor whichwhich variousvarious catalyticcatalytic systemssystems capablecapable ofof promotingpromoting thethe intermolecularintermolecular additionaddition ofof carboxyliccarboxylic acidsacids toto allenesallenes havehave beenbeen describeddescribed [[113],113], thethe useuse ofof goldgold inin thisthis typetype ofof transformationtransformation hashas hardlyhardly beenbeen documented.documented. InIn fact,fact, onlyonly twotwo examplesexamples cancan currently be be found found in in the the literature. literature. The The firs ﬁrsttt oneone one waswas was describeddescribed described ZhangZhang Zhang andand andWidenhoeferWidenhoefer Widenhoefer inin 20082008 in 2008and involved and involved the addition the addition of propionic of propionic acid acid to tothe the 1,3-disubstituted 1,3-disubstituted allene allene 9898 catalyzedcatalyzedcatalyzed byby thethethe carbene-gold(I)carbene-gold(I) complexcomplex [AuCl(IPr)] [AuCl(IPr)] in in combination combination with with AgOTf AgOTf (Scheme (Scheme 44 )[44)114 [114].]. The The reaction reaction led led to thetoto thethe regio- regio-regio- and andand stereoselective stereoselectivestereoselective formation formationformation of the ofof thethe allylic allylicallylic ester esterester99, 99 which,, whichwhich was waswas isolated isolatedisolated in 80% inin 80%80% yield. yield.yield.

SchemeScheme 44.44. Gold(I)-catalyzed addition of propionic acidacid toto thethe 1,3-disubstituted1,3-disubstituted alleneallene 9898...

InIn aa moremore recent recent study, study, the the group group of Ichikawaof Ichikawa reported reported the synthesisthe synthesis of the of fluorinated the fluorinated allyl esters allyl 101estersby 101 addition byby additionaddition of acetic, ofof acetic,acetic, trifluoroacetic trifluoroacetictrifluoroacetic or benzoic oror benzoibenzoi acidc toacid the to trisubstituted the trisubstituted 1,1-difluoroallene 1,1-difluoroallene100 + (Scheme 45)[115]. The reactions were promoted by the in situ generated [Au(PPh )]3 +cation and 100 (Scheme(Scheme 45)45) [115].[115]. TheThe reactionsreactions werewere prpromoted by the in situ generated [Au(PPh3 3)]+ cationcation andand proceeded again with complete regio- and stereoselectivity. AuCl3 proved to also be active in the proceeded again with complete regio- and stereoselectivity. AuCl33 provedproved toto alsoalso bebe activeactive inin thethe process,process, butbut ledled toto estersesters 101101 asasas mixtures mixturesmixtures of ofof the thethe corresponding correspondingcorresponding( (E(E)) and and ( (Z)Z)isomers. isomers.isomers.

SchemeScheme 45. 45.Gold(I)-catalyzed Gold(I)-catalyzed intermolecular intermolecular addition addition of of carboxylic carboxylic acids acids to to the the 1,1-diﬂuoroallene 1,1-difluoroallene73 . 73..

4. Summary In this contribution, the application of gold-based catalysts in the hydrofunctionalization of alkynes and allenes with carboxylic acids has been comprehensivelycomprehensively reviewed.reviewed. TheThe cyclisomerizationcyclisomerization reactions of alkynoic acids have been the processes most widely studied, and several homogeneous and heterogeneous systems have demonstrated their utility for the regio- and stereoselective construction of different types of enol lactones underunder mildmild conditions,conditions, eveneven inin unconventionalunconventional reaction media, such as water, ionic liquids or deep eutecticeutectic solvents.solvents. InIn addition,addition, aa largelarge numbernumber ofof elaborated nitrogen-containing polycyclic compounds have been successfully accessed using readily available alkynoic acids and functionalized amines as starting materials through cascade-type processes. Gold-based catalysts have also demonstrated their utility in the intermolecular addition of carboxylic acids to both terminal and internal alkynes, showing again high regio- and stereoselectivities. Concerning allenes, the most remarkable results concern the preparation of chiral vinyl-lactones with good enentioselectivities by using chiral catalysts or through axial-to-central chirality transfer strategies; the latter found applications in the total synthesis of several natural products. It is hoped that in the near future more attention will be paid to the intermolecular addition of carboxylic acids to allenes, a process for which only two isolated examples are currently known.

Catalysts 2020, 10, 1206 31 of 36

4. Summary In this contribution, the application of gold-based catalysts in the hydrofunctionalization of alkynes and allenes with carboxylic acids has been comprehensively reviewed. The cyclisomerization reactions of alkynoic acids have been the processes most widely studied, and several homogeneous and heterogeneous systems have demonstrated their utility for the regio- and stereoselective construction of diﬀerent types of enol lactones under mild conditions, even in unconventional reaction media, such as water, ionic liquids or deep eutectic solvents. In addition, a large number of elaborated nitrogen-containing polycyclic compounds have been successfully accessed using readily available alkynoic acids and functionalized amines as starting materials through cascade-type processes. Gold-based catalysts have also demonstrated their utility in the intermolecular addition of carboxylic acids to both terminal and internal alkynes, showing again high regio- and stereoselectivities. Concerning allenes, the most remarkable results concern the preparation of chiral vinyl-lactones with good enentioselectivities by using chiral catalysts or through axial-to-central chirality transfer strategies; the latter found applications in the total synthesis of several natural products. It is hoped that in the near future more attention will be paid to the intermolecular addition of carboxylic acids to allenes, a process for which only two isolated examples are currently known.

Funding: Financial support from the Spanish Ministry of Economy, Industry and Competitiveness (MINECO project CTQ2016-75986-P) is gratefully acknowledged. Conﬂicts of Interest: The author declares no conﬂict of interest.

References

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