Recent Advances in the Catalytic Synthesis of the Cyclopentene Core

Five‐membered carbocycles are ubiquitously found in natural products, pharmaceuticals, and other classes of organic compounds. Within this category, cyclopentenes deserve special attention due to their prevalence as targets and as well as key intermediates for synthesizing more complex molecules. Herein, we offer an overview summarizing some significant recent advances in the catalytic assembly of this structural motif. A great variety of synthetic methodologies and strategies are covered, including transition metal‐catalyzed or organocatalyzed processes. Both inter‐ and intramolecular transformations are documented. On this ground, our expertise in the application of C−H functionalization reactions oriented towards the formation of this ring and its subsequent selective functionalization is embedded.

Synthetic organic chemists have shown a longstanding interest in the synthesis of the cyclopentane ring due to its prevalence in natural products, pharmaceuticals, and other important classes of organic molecules.Most of the classical methods are based on stoichiometric transformations.Due to the great variety of strategies used for that purpose, their systematization results in a somewhat difficult task.This review is restricted to catalytic methodologies for preparing cyclopentene derivatives, mainly due to their versatility for constructing more complex scaffolds.Several reviews on the synthesis of the cyclopentene core are available in the literature, however, most of them are restricted to the use of a specific transformation (i.e. isomerization of cyclobutanes). [1]Most of the contributions gathered herein fall within the last decade; however, seminal contributions from each section are included in order to provide the reader with an appropriate framework.In this review, the information concerning the different strategies covered is arranged according to the general scheme depicted in Figure 1.The five-membered ring may be assembled by means of [3 + 2] cyclizations, both by an intermolecular reaction between a 3 C and a 2 C synthons and by the rearrangement of a vinyl cyclopropane, in which the cyclopropane ring acts as 3 C component and the vinyl substituent as 2 C unit.In addition, a [4 + 1] cyclization between a diene scaffold and an appropriate 1 C synthon may also achieve the formation of cyclopentene derivatives.Furthermore, substrates bearing unsaturations at strategic positions may also undergo intra-molecular a [5 + 0] cyclization towards the cyclopentene core either by means of cycloisomerization or metathesis processes.Finally, within the latter category, we would like to highlight the synthetic potential of CÀ H functionalization processes that allow the transformation of ubiquitous and generally difficultto-differentiate CÀ H bonds into valuable CÀ C bonds in a selective manner.
Hence, in accordance with the general scheme depicted above, this review will be organized according to the following sections:

Transition-Metal Catalyzed [3 + 2] Cyclizations
Transition-metal catalysis lies amongst the most active fields of research within the realm of synthetic organic chemistry.Several recent Nobel Prizes being awarded to Knowles, Noyori, and Sharpless (2001), [2] Chauvin, Grubbs, and Schrock (2005), [3] and Heck, Negishi, and Suzuki (2010) bear witness to such a statement. [4]Transition metal-catalyzed [3 + 2] cyclizations are very abundant, herein we will only highlight some of the recent trends in the field, always limited to the construction of cyclopentene derivatives

Vinyldiazo Compounds
The decomposition of diazo compounds still represents one of the most common approaches to achieving metal-carbene intermediates. [5]In recent years, vinyldiazo compounds have been added to the synthetic toolbox as very useful reagents. [6]mong their applications, the synthesis of cyclopentene derivatives by means of formal [3 + 2] cycloadditions is perhaps the most relevant.The development of this transformation is summarized below.
In 1998, an interesting work developed by Davies and coworkers described the use of diazobutenoates 2 and vinyl ethers 1 as reagents and [(Rh 2 (S-DOSP) 4 ] as catalyst providing donor/acceptor-substituted vinylciclopropanes 3 in high diastereo-and enantioselectivity.Then, these vinylcyclopropanes 3 yielded the corresponding cyclopentenes 4 with excellent stereocontrol through a Et 2 AlCl-mediated rearrangement (Scheme 1). [7]Two years later, Davies and colleagues carried out the same overall transformation employing [(Rh 2 (S-DOSP) 4 ] as catalyst without the requirement of additional Lewis acid.These cyclopentenes were obtained in high yield and better enantioselectivity than before.Moreover, these compounds were further functionalized using different conditions to generate new pentasubstituted cyclopentanes with Rubén Miguélez (1997) studied chemistry at the University of Oviedo where he graduated in 2019.Then, he moved to Valencia starting his master's degree under the supervision of Gonzalo Blay.Later, he started the Doctoral Thesis under the supervision of Pablo Barrio focusing on C(sp 3 )À H functionalization of bromoalkynes with gold (I) catalysis.He is an enthusiast of science, and he really likes playing sports and listening to music, specially hip hop style.
Pablo Barrio completed his Ph.D. at the University of Oviedo in 2007 under the supervision of Prof. Barluenga.After a postdoctoral stay in the group of Prof. Carreira at ETH Zurich, he joined the group of Prof. Fustero in 2009 as a Juan de la Cierva Fellow working for several years in the field of organofluorine chemistry.In 2018 he moved to Oviedo as a Ramón y Cajal Fellow joining the Selective Organic Synthesis group (SOS).His current research interests are focused on gold catalysis.José M. González graduated in Chemistry and he received his Ph.D. (1988) from the University of Oviedo (Prof.Barluenga, Asensio and Campos).After two years' postdoctoral stay at the University of California, Berkeley, as a Fulbright-MEC fellow (Prof.Vollhardt), in December 1990 he started as assistant professor at the University of Oviedo and in 1993 was promoted to associate professor.In 2007 he became professor.In 2020 he was awarded with the "Felix Serratosa Medal" by the Organic Division of the Spanish Royal Society of Chemistry.He is interested in the discovery of catalytic organic transformations.
full control of the stereochemistry at five contiguous stereocenters. [8]n 2013, a two-step method for the cyclopentannulation of conjugated enones 5 using methyl 3-(tert-butyldimethylsiloxy)-2-diazo-3-butenoate 6 as a bifunctional reagent was developed by Guerrero and coworkers. [9]The first step consists of the nucleophilic attack from an enol silane to the electrophilic β-carbon of a conjugated enone.In the second step, a formal α,α'-diketone coupling catalyzed by Cu(I) takes place.Cyclopentenes 8 were obtained in excellent yields and good diastereoselectivities (Scheme 2).The implementation of a one-pot thermal decarboxylation allows for obtaining cyclopentanones. [10]nother interesting reaction to obtaining cyclopentenes was developed by López and coworkers in 2017. [11]They developed an efficient copper-mediated [3 + 2] cycloaddition of vinyl diazocompounds 9 and vinylazides 10 under mild conditions.Noteworthy, the thus obtained densely functionalized cyclopentene derivates 11 contain an azide group, amenable for further transformations (Scheme 3).They proposed a mechanism beginning with the reaction between the vinyldiazo compound and the copper (I) complex affording alkenylcarbene I.Then, this species reacts with vinylazide 10.In this case, the vinylazide behaves as an enamine attacking the vinylogous position of the alkenylcarbene to form intermediate II.Subsequent cyclization generates the [3 + 2] cycloadduct intermediate III.Finally, an allylic rearrangement of the azide group affords the observed product 11 (Scheme 3).
Then, López and colleagues described two related formal [3 + 2] cycloaddition reactions towards the cyclopentene moiety employing gold (I) catalysis. [12,13]First, in 2017, they developed a [3 + 2] cycloaddition between alkenyldiazo compounds 12 and styrene derivates 13 to obtain the corresponding cyclopentenes 14 in good yields (Scheme 4a). [12]Other compounds such as the vinylcyclopropane corresponding to direct cyclopropanation or a cycloheptene derivative arising from a formal [3 + 2 + 2] were also observed in low yields.Then, in 2020, they developed a related transformation replacing the styrene derivates 15 with alkenylboronates 16 affording the corresponding borylated cyclopentene derivatives 17. [13] This reaction proceeded in high regio-and stereoselectivity.The mechanism proposed in Scheme 4 proceeds as follows: the first step was the generation of a gold vinylcarbene IV with dinitrogen release; then, the alkenylboronate 16 attacks at the vinylogous position of the gold carbene generating a cationic intermediate V which would then undergo cyclization reaction generating the cyclopentene ring.
For most examples, the reaction showed stereospecificity.However, the use of an E-alkenylboronate with electrondonating groups, such as c-C 3 H 5 or 4-MeOC 6 H 4 afforded the cis-configurated [3 + 2] adduct.In order to rationalize this unexpected outcome, the authors invoke the increased stability of the benzylic carbocation that enables the fast rotation between the C 4 and C 5 providing the other isomer.Finally, they carried out different further transformations on the boron functional group.One of them was the oxidation with NaBO 3 affording the hydroxylated product.Also, a Matteson homologation reaction was carried out in good yield (Scheme 4b).
In 2018, Ferreira and coworkers developed a direct [3 + 2] cycloaddition between alkenes 19 and vinyl diazo compounds 18 employing chromium-or ruthenium-based metal catalysts and light to produce a variety of cyclopentenes 20 in good yields and diastereoselectivities. [14] As discussed earlier, vinyl diazo compounds usually act as electrophilic reagents.However, the photocatalytic generation of a more reactive electrophilic partner (radical cation) results in an umpolung of the reactivity of the vinyl diazo acting as a nucleophile.The reaction showed broad substituent tolerance in the vinyl diazo and alkene.However, gamma-substitution on the diazo reagent was not tolerated (Scheme 5).This reaction always yielded the trans product regardless of the initial configuration of the alkene used.Finally, the products were diversified employing different organic reactions.
In 2021, Sá and coworkers developed an interesting intramolecular reaction of α-diazo-γ,δ-unsaturated esters 21 employing a rhodium catalyst. [15]The most salient feature of this report would be the selective formation of two different products depending on the reagent and catalyst used.On the one hand, the use of Rh 2 (pfb) 4 in acetonitrile resulted in a βhydride migration to give 2Z-4E dienes (not shown).On the other hand, the use of aryl-diazo compounds 21 b along with Rh(OAc) 4 as catalyst in toluene, afforded 5,7-fused bicyclic tetraenes 22 b in high yields through a regioselective intramolecular Buchner reaction (Scheme 6).Finally, the alkylsubstituted analogs 21 a undergo an intramolecular CÀ H insertion to yield anti-configurated cyclopentenes 22 a, due to the stereoelectronic factors in the transition state during the insertion of the carbene into the CÀ H bond (Scheme 6).
Another reaction employing diazocompounds was developed by Chang and coworkers using α-aryldiazoester compounds 23 as precursors of carbenes and terminal alkynes 24 to form the corresponding indenes 25, using IPrCuCl as the catalyst (Scheme 7). [16]They observed that phenylacetylenes bearing electron-donating groups reacted more readily than the electron-deficient ones.The mechanism started with the nucleophilic attack of the alkyne to the copper carbenoid X, affording zwitterionic species XI.Then intermediate XI is attacked by the aromatic ring to generate intermediate XII that, through the release of copper, forms the isoindene XIII.Finally, after an isomerization product 25 is formed (Scheme 7).In 2023, Koenigs and Zhou developed a photoredox dimerization process of vinyldiazo compounds 26 affording cyclpentenyl α-diazocompounds 27, versatile synthetic intermediates (Scheme 8). [17][18]An in-depth mechanistic study combining experimental and computational data, allowed the authors to suggesting a detailed mechanism.The reaction starts with the excitation of the photocatalyst with visible light followed by single-electron transfer (SET) oxidation of the substrate.The thus obtained radical cation XIV would then undergo the nucleophilic attack of a second molecule of vinyldiazo compound.Ring closure with concomitant nitrogen extrusion affords intermediate XVI that accepts a single electron from the iridium (II) species affording the final product and regenerating the Ir (III) photocatalyst (Scheme 8).The authors showed the versatility of the obtained scaffolds by subjecting them to a series of transformations affording a number of synthetically useful derivatives.

Vinylcyclopropanes
The vinyl cyclopropane-cyclopentene (VCP-CP) rearrangement was discovered in 1959 and has attracted considerable attention ever since. [19]However, several restrictions related to substrate substitution and harsh reaction conditions somewhat hampered its synthetic applicability.The dawn of the new century witnessed some improvements brought about by transition metal-catalysis (and organocatalysis as well, vide infra).Some significant examples are discussed below.
In 2004, Louie and coworkers developed the isomerization of unactivated vinyl cyclopropanes 28 to cyclopentenes 29 using [Ni(cod) 2 ] as precatalyst and IPr as a NHC ligand being the optimum Ni:IPr ratio 2 : 1. [20] An important application of this reaction is the synthesis of bicyclic frameworks because of its abundance in natural products (Scheme 9).
In 2018, Uyeda and colleagues described the activation of strained three-membered rings using a dinuclear nickel complex to form the corresponding cyclopentene derivatives. [21]Their initial studies were carried out using stoichiometric quantities of [iPrNDI]Ni 2 (C 6 H 6 ) 30 and Ntosyl-2-vinylaziridine to form complex 31 as a crystalline solid.Coordinating with the aziridine resulted in the shortening of the NiÀ Ni distance as compared to complex 30, suggesting that the electron pair required for the two-electron oxidative addition is being provided by the reduced ligand pi-system rather than from the NiÀ Ni bond.This conclusion was also supported by DFT calculations.Then, the reaction with vinyl cyclopropanes was studied by variating the catalyst.The aforementioned dinuclear catalyst was found to be the best of all catalysts tried.A computational study showed that when the catalyst is a monoligated Ni species like in Louie's report the CÀ C oxidative addition is likely rate-determining.In this case, they could obtain neither intermediate.The rearrangement of 32 to generate the cyclopentene 33 b was carried out under catalytic conditions at 80 °C (Scheme 10).This reaction affords a different cyclopentene isomer as compared to the thermal conditions (233 °C) (Scheme 10).
In 2023, Miura and colleagues developed an interesting catalytic vinyl cyclopropane rearrangement towards 1,4-and 1,5-disubstituted cyclopentenes, regiocontrolled by the ligand geometry. [22]The reaction was carried out employing Ni(cod) 2 as a pre-catalyst in toluene at 100 °C (Scheme 11).Different ligands were tested, showing that the use of PBu 3 yielded 1,4disubstituted cyclopentenes 35 a in good regiocontrol and excellent yields.However, switching to IPr* as ligand resulted in the formation of 1,5-disubstituted cyclopentenes 35 b (Scheme 10).They carried out mechanistic experiments observing a stereoretentive process, with only a slight erosion of the enantiomeric excess in the product when an enantiomerically enriched vinyl cyclopropane was used.Moreover, DFT calculations were performed observing that when the vinyl cyclopropane 34 reacts under nickel catalyst and PMe 3 as a ligand the intermediate XIXa arising from cleavage of the C1-C3 bond was formed.This intermediate evolved through the lowest energy transition state TS-2 a to give the corresponding cyclopentene 35 a.However, when 34 reacts under nickel catalyst and IPr* as a ligand the intermediate XIXb arising from cleavage of the C1-C2 bond was formed.Even if intermediate XIXa is higher in energy than the corresponding intermediate XIXb it can evolve then through a lower energy transition state TS-2 b explaining the formation of the regioisomeric cyclopentene 35 b.Thus, the product selectivity is controlled by the rate-determining reductive elimination steps.A complete kinetic study of the reaction also supported this mechanistic rationale.

Fischer Carbene Complexes
Since the seminal report by Fischer and Maasbol in 1964, the chemistry of Fischer carbene complexes has fascinated both organometallic and synthetic organic chemistry due to their incomparable balance between rich reactivity and chemical stability. [23][24]Amongst the innumerable cyclization reactions in which these organometallic entities participate, [3 + 2] cyclizations hold a prominent position.
In 1999, Barluenga and coworkers described one of the first [3 + 2] reactions using Fischer carbene complexes. [25]In this work they employed (alkoxyalkenylcarbene)tungsten (0) complexes 36 and tertiary enamines 37 to synthesize cyclopentene derivates 38 with excellent yields, regio-and distereoselectivities (Scheme 12).Moreover, when enamines derived from chiral amines were used the corresponding products were obtained in high facial selectivity, delivering enantioenriched cyclopentenones upon hydrolysis of the enol ether and elimination of the amine.Noteworthy, a regioselectivity switch was observed when aldimines 40 were used instead of ketimines 37 (Scheme 12).In this case, the regioselectivity was moderate when a methoxy carbene and an enamine derived from a linear aldehyde were used.Fortunately, they found that the bulkiness of the alkoxy group and the substituent of the enamine played a definitive role in the cyclization, by dictating the regioselectivity of the reaction (Scheme 12).These products were derivatized through hydrolysis with diluted acid, followed by SmI 2 -mediated reductive CÀ N bond cleavage, providing the corresponding cyclopentanones.
In 2003, Barluenga and coworkers developed a [3 + 2] cyclization reaction of alkenyl Fischer carbene complexes 42 with lithium enolates 43 derived from methyl ketones forming five-membered ring derivatives 44, 45. [26] The most interesting feature of this report is the high influence of the solvent on the stereochemical outcome of the process (Scheme 13).When the reaction was carried out in highly coordinating solvents the approach of the allylic carbon atom of the α-allyltungsten moiety to the carbonyl center illustrated by the trajectory depicted for XX was favored.However, when the reaction was carried out in a less coordinating solvent the approach was opposite due to the coordination of the three oxygen atoms of the intermediate with the lithium atom as in XXI (Scheme 13).
In 2004, Barluenga and coworkers developed a new reaction to generate cyclopentenones 47 using novel cationic rhodium (I) alkoxycarbene complexes 46. [27]These complexes were synthesized by transmetalation from chromium alkenylcarbene complexes 48 (Scheme 14). [28]Moreover, the reaction could be carried out from the parent chromium carbene 46 with catalytic amounts of the rhodium complex (Scheme 14).The reaction was limited to the use of electron-poor alkynes 49 (alkynoates and alkynones) and the regio-and the stereochemistry of the process was highly dependent on the substitution at the other carbon of the triple bond (Scheme 14).Hence, while terminal alkynes afford the cyclopentenone derivative with the electron-withdrawing group at the distal position 50 (relative to the carbonyl), internal ones result in the opposite regiochemistry (Scheme 14).Moreover, when the second substituent is a phenyl or a cyclohexenyl ring the reaction proceeds in complete diastereoselectivity (Scheme 14, 51), while the reaction with a methyl substituent (methyl butynoate as substrate) results in the isomerization of the double bond to the most stable doubly conjugated position 52 (Scheme 14).
In 2007, in a further extension of the transmetallation strategy Barluenga and coworkers described a nickel (0)mediated [3 + 2] cyclization of alkenyl carbene complexes 53 and internal alkynes 54 to form substituted cyclopentenones 56. [29]The reaction worked in good yields and in excellent regioselectivity with electron-donating and with electron withdrawing groups (Scheme 15).This reaction showed a wide functional group tolerance allowing the preparation of boron-and tin-substituted cyclopentenones amenable for further functionalizations by means of classical palladium-catalyzed CÀ C cross-coupling processes (Scheme 15).
The last paper in this section was developed by Barluenga and coworkers in 2012.The reaction between a vinyllithium reagent 57 and an alkynyl Fischer carbene complex 58 affords, after hydrolysis polysubstituted cyclopentenones 60 (Scheme 16). [30]The reaction starts with conjugate addition of the organolithium reagent 57.Protonation of the allenylchromate intermediate XXV occurs at the β-position generating a dienyl carbene XXVI that evolves to a methoxy-substituted cyclopentadiene 59 (Scheme 16).Hydrolysis of the enolether unit affords the observed cyclopentenone 60 (Scheme 16).Interestingly, fully substituted derivatives may be obtained by transmetallation of the allenylchromate intermediate XXV with copper and trapping with different electrophiles (Scheme 16).

Miscellanea
An elegant synthesis of cyclopentene carbocycles was reported by Takai employing β-ketoesters 61 and allenes 62 as reagents, in 2008. [31]In this publication, the authors described the synthesis of polysubstituted cyclopentenes 63 in good stereoselectivity using rhenium as catalyst (Scheme 17).The corresponding cis relationship between the ester and the hydroxy group is explained by a mechanistic proposal supported by deuterium labeling experiments.The first step is the formation of rhenacyclopentane intermediate XXVII by an oxidative cyclometallation between the enol form of the ketoester 61' and the substituted double bond of the allene 62 (Scheme 17).Then, a β-hydride elimination affords the diene intermediate XXVIII that undergoes hydrometallation of the exo double bond forming a more stable π-allyl rhenium intermediate XXIX (Scheme 17).Finally, rearrangement to intermediate XXX, followed by reductive elimination would yield the corresponding cyclopentene derivatives (Scheme 17).
Another interesting reaction was developed by Wang and coworkers in 2020. [32]They report the synthesis of cyclopentenes 66 via ring opening addition and intermolecular nucleophilic vinylic substitution (S N V) reaction between donor-acceptor cyclopropanes 65 and α-oxo ketene dithioacetals 64 employing Sc(OTf) 3 as Lewis acid catalyst (Scheme 18).The reaction tolerated a wide range of functional groups.In other to explain the observed regioselectivity, the authors proposed the following mechanism.Activation of cyclopropane 65 with Sc(OTf) 3 would trigger the nucleophilic attack of the α-carbon from the ketene dithioacetals 64 to the electrophilic carbon of species XXXI affording zwitterionic species XXXII (Scheme 18).Then, ring closure would take place by nucleophilic attack of the enolate carbon to the electrophilic carbon of the dithioacetal producing species XXXIII (Scheme 18).This intermediate, that may be observed at low temperature, spontaneously eliminates EtSH upon warming to room temperature to yield the corresponding cyclopentene 66 (Scheme 18).
In 2021, Procter and coworkers developed a radical crosscoupling of aryl cyclopropyl ketones 67 and terminal alkynes 68 catalyzed by substoichiometric amounts of SmI 2 (Kagan's reagent). [33]The reaction tolerated a broad range of substitution in the (aryl)alkyne 68 and in the (aryl)cyclopropyl ketones 67 giving the corresponding cyclopentenes 69 in excellent yields (Scheme 19).However, functional groups sensitive to reduction such as bromo and nitrile were not amenable under the reaction conditions.The presence of the gem-dimethyl unit in the cyclopropyl was crucial to facilitate the reaction due to the formation of a tertiary radical in the carbon attached to those methyl groups.Finally, the proposed mechanism was in line with previous work. [34]The ketone was reduced through a reversible SET from the SmI 2 giving radical XXXIV which fragmented to give enolate/radical XXXV.This intermediate reacted with the alkyne to give radical XXXVI which undergoes 5-exo-dig cyclization to form the new ketyl radical XXXVII.Regeneration of SmI 2 through a back electron transfer yields the corresponding cyclopentene 69.
The radical ring-opening of cyclopropanes may also be achieved by means of photocatalysis.Cyclopropanes bearing electron-withdrawing groups, i. e. cyclopropyl ketones, are prone to single electron-reduction while electron rich cyclopropanes, i. e. cyclopropyl amines, undergo single electron oxidations.
In 2011, Yoo described a photocatalytic intramolecular [3 + 2] cycloaddition of cyclopropylketones. [35]In order to lower the reduction potential of the ketone, a Lewis acid additive, namely La(OTf) 3 , was used in combination with Ru(bpy) 3 Cl 2 as phorocatalyst and TMEDA as reductive quencher.In most cases, an olefin was the 2 C counterpart; however, in two examples the use of a tethered alkyne 70 a,b afforded fused bycyclic cyclopentene derivatives 71 a,b in good yields and diastereoselectivities (Scheme 20).
The authors studied in detail the scope of the transformation with respect to substitution at the nitrogen atom (only secondary anilines work succesfully), the cyclopropyl unit (substitution at C1 and C2 is tolerated) and the alkyne (terminal aryl and heteroaryl alkynes, propiolates, enynes and diynes, could be engaged in the transformation).When enynes where used chemoselectivity issues arose in some cases.The proposed mechanism is analogous related transformations.The excited photocatalyst is able to oxidize the cyclopropyl amine 72 to the corresponding radical cation XXXIX that undergoes ring opening towards distonic radical cation XL.Radical addition to the alkyne 73, followed by ring  In 2022, Reiser and Verma described a related copper catalyzed [3 + 2] cycloaddition between N-tosyl-cyclopropyl amines with alkenes and alkynes, respectively, under blue LED irradiation. [39]The reaction is limited to the use of terminal aryl alkynes 76 and only unsubstituted cyclopropyl rings 75 were tested (Scheme 22).The mechanistic proposal differs substantially from the previous photoredox examples.In this case, the reaction occurs with the intermediacy of organometallic copper species instead of free radicals (Scheme 22).

Organocatalytic [3 + 2]
During the last two decades, asymmetric organocatalysis has become a fully mature field. [40]This statement finds more than enough ground on the Nobel Prize in Chemistry to be awarded to professors List and MacMillan in 2021 for the development of asymmetric aminocatalysis. [41]In addition to chiral amines, several other kinds of organocatalysts have been developed in recent years.In the following sections, organocatalyzed [3 + 2] cyclization reactions that allow the construction of the cyclopentene core will be summarized.

NHC-Catalyzed
In 2006, Nair described the synthesis of cyclopentenes 80 by means of an N-heteocyclic carbene (NHC)-catalyzed reaction between enals 78 and chalcone derivatives 79 (Scheme 23). [42]his new reaction relies on the novel conceptual approach to homoenolate equivalents introduced by Bode and Glorius just two years before. [43]This approach consists of the formation of a Breslow-like intermediate XLVIII upon nucleophilic addition of the NHC to the enal 78, followed by tautomerization.The reaction shows a somewhat limited scope since mostly triaryl-substituted cyclopentenes were obtained, with just two exceptions (Scheme 23).
As indicated above, the proposed mechanism starts with the formation of a Breslow-like intermediate XLVIII (Scheme 24).This intermediate behaves as a homoenolate, triggering the nucleophilic addition of the β-carbon of the enal 78 to the β-carbon of the chalcone 79 (Scheme 24).The thus obtained enolate evolves by the nucleophilic addition of the α- Just one year later, Bode reported a surprising finding, when 4-oxoenoates 82 were used as coupling partners instead of chalcones 79 the corresponding cis cyclopentenes 83 were formed (Scheme 25). [44]In addition, the use of a chiral triazonium pre-catalyst afforded the products in very high enantioselectivities (Scheme 25).A series of experiments allowed the authors to explain this discrepancy by suggesting a complementary reaction pathway.According to Bode, the reaction starts with a cross-benzoin condensation followed by an NHC-catalyzed oxy-Cope rearrangement (Scheme 25).The boat-like transition state for the latter step sets the observed cis-selectivity.The following steps are similar to Nair's mechanism, intramolecular aldol followed by lactonization regenerates the catalyst.Finally, decarboxylation affords the final product (Scheme 25).The main difference between both mechanisms would be the way in which the C β À C β bond is formed, which determines the opposite relative stereochemistry.Bode ascribes the divergent stereochemical outcomes to the preferred reactive conformation of each electrophile.Hence, oxoenoates 82 seem to react predominantly as the s-cis conformer, leading to a boat-like transition state, affording cisproducts 83.On the other hand, the observed trans-selectivity for chalcones 79, could arise from a different reaction pathway as proposed by Nair, see above, or from an oxy-Cope reaction through the corresponding s-trans conformer, leading to a chair-like transition state, affording the trans-products 80. [45] The same conditions applied to chalcones afforded the transisomer as the major one but in moderate enantioselectivities.
In the same year, Scheidt envisioned an alternative approach to intermediates analogous to LII and LV, by means of an intramolecular aldol-type reaction of the Breslow-like intermediate affording the desired transition state TS-3 (Scheme 26). [46]The evolution through this transition state as above regenerates the catalysts and accounts for the formation of the cyclopentene product 85.Again, the use of a chiral triazolium NHC-precursor affords the desymmetrization of 1,3-diketones 84 in moderate to good yields and good to excellent enantioselectivities (Scheme 26).
In a further degree of sophistication, Scheidt described the dynamic kinetic resolution of β-ketoesters 86 under very similar reaction conditions (Scheme 27). [47]In this case, only substrates bearing electron-rich aryl rings on the ketone moiety evolved to the corresponding cyclopentenes 88 while other substrates afforded the corresponding β-lactones 87 (Scheme 27).
In 2010, Scheidt overcame the moderate enantioselectivities obtained for chalcones derivatives 90 by using a Lewis acid in combination with the chiral NHC catalyst. [48]nantioenriched cis-cyclopentane derivatives 91 were obtained from enals 89 and chalcones 90 in good yields and excellent enantioselectivities (Scheme 28).Coordination of both carbonyl oxygens to the titanium co-catalyst, pre-organizes the transition state TS-4 fixing the s-cis conformation for the chalcone moiety and hence reversing their inherent transselectivity. [49]

Amine-Catalyzed
As compared to other fields, amine-catalysis has not been very frequently used for assembling the cyclopentene core. [50]The first example, by Wang, relies on a tandem Michael/aldol sequence for the construction of the desired core. [51]Hence, the reaction between an enal 92 and a malonate derive aldehyde 93 using a Jorgensen-Hayashi catalyst C-1* afforded the corresponding cyclopentenals 94 in good yields and enantioselectivities (Scheme 29).
A few years later, Córdova reported a dynamic kinetic asymmetric transformation (DYKAT) by means of a combined amino-/ transition-metal catalyzed enantioselective cyclization. [52]In this case, the first CÀ C bond is formed by a Michael reaction again; however, the reversibility of this step results in a lack of enantioselectivity (Scheme 30).Nevertheless, when the enyne LIX formed upon Michael addition is engaged in a subsequent palladium-catalyzed cycloisomerization event, a DYKAT process takes place affording the desired cyclopentenes 97 in high optical purities (Scheme 30).Moreover, the use of a cyanoacetate derivative 96 b allows for Recently, Reyes and Vicario have reported an organocatalytic enantioselective vinylcyclopropane-cyclopentene (VCP-CP) rearrangement. [53]The key feature for the success of this transformation is the design of the substrate.The introduction of a Michael acceptor and an acetaldehyde moiety in contiguous carbons of substrate 98 affords a donor-acceptor cyclopropane intermediate upon condensation with the organocatalyst (Scheme 27).The push-pull character of key intermediate LXI results in the ring-opening of the cyclopropane towards zwitterionic intermediate LXII that has lost the stereochemical information of the substrate.This loss of chiral information allows for a DYKAT process since the subsequent intramolecular Michael addition proceeds exclusively under catalyst control.In this way, an array of cisdisubstituted cyclopentenes 99 was obtained in good yields and enantioslectivities, although only in moderate diastereoselectivities.To overcome the poor diastereoselectivity observed in most cases, the corresponding products were isomerized under basic conditions to the more stable α,β-unsaturated products 100 bearing a single stereocenter (Scheme 31).DFT calculations confirmed the stereoconvergent nature of the process.
This pioneering work has been followed by numerous improvements, variants, and applications. [57]58a] This intramolecular version allows to overcome the regio-and diastereoselectivity issues observed for the intermolecular variant.58b] Regarding the enantioselective variant, as soon as in 1997, only two years after Lu's seminal report, Zhang developed the asymmetric variant. [59]In this study, the authors described the use of a new class of chiral phosphines (Scheme 34).Indeed, this transformation, Lu's phosphine-catalyzed [3 + 2] cycloaddition, has been adopted as a benchmark transformation for testing the asymmetric competence of new phosphines ever since then. [62]The synthesis of the organocatalyst starts with known enantioenriched diol 113, obtained in three steps from the corresponding 1,4-disubstituted benzene 112.Mesylation of both hydroxy groups, followed by double nucleophilic displacement and by standard phosphine manipulations afforded the novel chiral bicyclic phosphine PR 3 * (Scheme 34).The authors showed that the new phosphines lead to better results than commonly used ones such as DUPHOS or BINAP in the organocatalyzed [3 + 2] cycloaddition, both in terms of regio-and enantioselectivity.
In a series of reports, Fu described the use of a phosphepine-derived chiral phosphine as an organocatalyst in this transformation. [60]60a] Moreover, a switch in the regiochemistry was observed without affecting the high enantioselectivity (Scheme 35A).60c] Another interesting addition was provided by Loh who reported the enantioselective [3 + 2]-cycloaddition reaction using 3-butynoates 123 as substrates, that were isomerized in situ to the corresponding allenes (Scheme 36). [61]In addition, the reaction showed complete regio-and diastereoselectivity (Scheme 36).In this case, a commercially available chiral-at-phosphorous diphosphine PR 3 -D* was the organocatalyst of choice (Scheme 36).
[63] [64] Although the original conditions used stoichiometric amounts of Co 2 (CO) 8 both as the transition metal mediator and the CO source, several catalytic variants have been developed since the pioneering work of Rautenstrauch in 1990. [65]The catalytic PKR has been extensively reviewed before and somehow lays beyond the scope of this review since it is intrinsically restricted to the synthesis of cyclopentenones 126, while this review is devoted to cyclopentenes. [64[66]However, some succinct general considerations on this pivotal transformation are described in this section.
An initial improvement was introduced by Buchwald with the use of commercially available titanocene dicarbonyl, allowing the reaction to proceed under lower pressures of CO and with an excellent functional group tolerance (Scheme 37B). [68]Moreover, the use of a chiral titanocene derivative afforded the first catalytic enantioselective PKR. [69]The next key improvement in this field was the use of CO surrogates, which allowed the suppression of the hazards derived from the use of a toxic gas (Scheme 37C). [70]Aldehydes, alcohols and formic acid could be used as surrogates.As it is generally the case for the PKR most of the examples described in these catalytic variants are intramolecular, and hence, they could be described as [4 + 1] cyclizations.

[4 + 1] Cyclizations
As compared with other cyclization modes, [4 + 1] cyclizations are relatively rare. [71]Early examples were limited to the carbonylative Mizoroki-Heck reaction of suitable vinyl halides. [72]In this section, a few recent examples leading to the cyclopentene core will be discussed.
Another example employing gold (I) catalysis was disclosed by González and coworkers in 2009. [74]In this report, a [4 + 1] reaction between propargyl tosylates 130 and N-tosylaldimines 131 affording cyclopent-2-enimines 132 was described.Noteworthy, a deep reorganization of both substrates was observed (formation of a cyclic structure, methyl migration, cleavage of the carbon-nitrogen bond).The reaction proceeds in short periods of time and under mild conditions.The coordinating effect of the counter anion affected the reaction yield, with the lower coordinating ones such as BF 4 affording the best results.The reaction tolerated different groups in the imine and the propargyl tosylate 130; however, the only substituent tolerated at the imine nitrogen was the N-tosyl.They proposed the mechanism depicted in Scheme 39, supported by experimental and computational evidence. [75]The mechanism would consist of two independent catalytic cycles.In the first of them, the activation of the propargyl tosylate 130 by gold would explain the formation of diene LXXII.Coordination of catalyst to the alkyne 130 followed by an intramolecular nucleophilic attack of the oxygen of the tosyl group affords intermediate LXIX (Scheme 39).Subsequently, a vicinal methyl migration followed by elimination and a protodeauration gave the 1,3-diene skeleton LXXII (Scheme 39).Then, diene LXXII would enter the second catalytic cycle (Scheme 39, catalytic cycle on the left) attacking the imine activated by the catalyst LXXIII.Intramolecular nucleophilic substitution gave azetidine LXXV that, through a formal metathesis process, ring-opens to a 1,4pentadiene LXXVII.The final product 132 is formed via an "imino-Nazarov-like" reaction mediated by the gold (I) catalyst (Scheme 39).Most importantly, intermediate diene LXXII could be isolated in the absence of imine and subsequently reacted with imine 131 under the reaction conditions providing the cyclopentene imine 132.
A few years later, an interesting stereoselective [4 + 1] reaction towards cyclopentene derivatives 135 was developed by Fu and coworkers employing chiral tertiary phosphines PR 3 -E/F*. [76]Under these conditions, the products were obtained in good yields and enantioselectivities (Scheme 40).When ketone, amide or ester groups were present in substrate 133 the best enantioselectivities were obtained employing catalyst PR 3 -E*.On the other hand, the presence of sulfone, phosphine oxide and phosphonate groups in 133 required a catalyst switch to PR 3 -F* in order to maintain the high enantioselectivities.To gain insight into the mechanism they determined the order of the reaction experimentally and they observed that the reaction was first-order in catalyst and zeroorder in the nucleophile and the electrophile.They also determined by 31 P NMR that the primary resting state of the phosphine was the phosphonium salt instead of the free phosphine.
In 2019, a powerful methodology to obtain cyclopentenes was developed by Uyeda and coworkers. [77]They reported that dinickel complexes catalyzed [4 + 1]-cycloaddition reactions between 1,3-dienes 136 and in situ generated vinylidene intermediates as a C1 partner (Scheme 41).The latter were easily accessed from 1,1-dicloroalkenes 137 in the presence of stochiometric zinc.The reaction allowed obtaining the corresponding cycloadducts both in intra-and intermolecular fashions.Moreover, high levels of asymmetric induction were obtained employing a C2-symmetric chiral ligand.This methodology overcame previous attempts to obtain cyclopentenes using carbenes.In that case, the [2 + 1]-cycloaddition is favored due to the excessive closed-shell repulsion between the carbene lone pair and the filled Ψ 1 orbital of the diene in the symmetry-allowed transition state geometry.In this case, new alkylidenecyclopentenes 138 with a huge capacity of derivatization to form high-added value compounds were obtained.Finally, they carried out experimental studies and DFT calculations to determine the mechanism of the reaction, observing the role of zinc was as a reductant.For this proposal the most reduced form of the catalyst was synthesized, isolated,

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and added to a solution of 1,1-chloroalkene and 2,3-dimethylbutadiene, obtaining the cycloadduct in moderate yield.
Alternative methods for the catalytic generation of metal carbene species that may participate in a subsequent [4 + 1] cycloaddition were reported by Echavarren and Kusama, respectively. [78,79] The reaction is restricted to aryl substituents in the cycloheptatriene precursor 139 of the carbene and in the double bond of the cyclobutene 140, while the vinylcyclopropane 141 also tolerates alkyl substituents at the double bond (Scheme 42).Gold plays several roles in the catalytic cycle: 1) generates the gold carbene from the cycloheptatriene; 2) catalyzes the vinylcyclopropane/ cyclobutene isomerization; and 3) catalyzes the formal [4 + 1] cycloaddition.Herein, only a simplified mechanism will be shown (Scheme 42).
On the other hand, Kusama used a visible light-induced acylsilane/silyloxy carbene rearrangement to catalytically generate copper Fischer carbene intermediates (Scheme 43). [79]he thus obtained intermediates reacted with silyloxy dienes affording substituted cyclopentenes in good yields and moderate diastereoselectivities (Scheme 43).The mechanism suggested by the author consists of the nucleophilic addition of the silyloxi diene to the insitu formed copper carbene intermediate, followed by ring-closure (Scheme 43).

[5 + 0] Strategies
Several kinds of difunctionalized substrates are able to undergo intramolecular cyclizations affording cyclopentenes.Perhaps the Nazarov reaction of dienyl ketones is the most emblematic process in this context.In addition, diallyl compounds are known to be amongst the best-suited substrates for ring-closing metathesis (RCM).More recently carbonyl-olefin metathesis has emerged as an appealing alternative for the synthesis of this interesting scaffold.Finally, CÀ H insertion strategies relying in either carbene (vinylidene) like, radical and vinyl cation like intermediates have recently been developed into powerful synthetic tools in this arena.

Nazarov Reactions
The Nazarov reaction has been studied in depth since the 1940s. [81]This reaction has been used by organic chemists as a powerful synthetic tool to produce five-membered rings.Besides, the stereospecific nature of the cyclization allows the control of the torquoselectivity of the reaction (the preference for conrotatory or disrotatory cyclization).However, this 4π  The first catalytic Nazarov reaction was described by Frontier in 2003. [82]The design of polarized divinyl ketones 146 with a vinyl nucleophile and a vinyl electrophile enabled the reaction to occur under mild Lewis acid activation.Upon activation, pentadienyl cation intermediate LXXXIV is produced which further cyclizes towards the corresponding cyclopentenone 147 (Scheme 44).Each cyclopentenone was isolated as a single regio-and stereoisomer.Moreover, when the divinyl ketone was unpolarized the regioselective was affected.In conclusion, the more polarizing the groups on the divinyl ketone the more efficient the cyclization (Scheme 44).
One of the most important limitations associated with the Nazarov reaction is the racemization of the product when the cyclization step proceeds slowly.Due to the importance of stereochemistry in this reaction, Trauner and coworkers developed the first enantioselective Nazarov reaction employing the chiral scandium triflate pybox complex C-4* as catalyst. [83]The reaction with disubstituted alkenes gives rise to a mixture of diastereoisomers in low enantioselectivities.
In the following years, many original reports and reviews about the Nazarov reaction were published. [84]For example, West and coworkers developed the vinylogous Nazarov reaction with a good wide of cross-conjugated trienes via the zwitterionic species LXXXVI (Scheme 46A). [85]Another interesting variant was developed by Burnell using allenyl vinyl ketones 151 and TFA or BF 3 •OEt 2 as catalysts affording regioisomeric cyclopentenes depending on the substituent (Scheme 46B). [86]A similar reaction was developed by West using vinylallenes 152 as reagents and TFA as electrophilic source to obtain the corresponding products (Scheme 46C). [87]nother addition to the original Nazarov reaction was the development of the corresponding imino-Nazarov variant.The first reaction of this kind was reported by Tius in 2001. [88]A pioneering catalytic variant was already discussed in Section 4 (see Scheme 39, and reference 79).Despite several stoichiometric reports may be found in the literature, catalytic variants are scarcer.The first literature report that claims an imino-Nazarov step in a catalytic reaction was discussed in section 4 (see Scheme 39 and reference 79).A few years later, Hsung reported the gold-catalysed imino-Nazarov reaction using Ntosyl-N-aryl allenamides 153 as substrates (Scheme 47). [89]The introduction of the tosyl substituent at the nitrogen atom was key for destabilizing the cylopentadienyl cation, one of the reasons that disfavor the imino-Nazarov reaction with respect to the original oxa-variant. [90]n 2014, Liu described that understoichiometric amounts of several Lewis acids were able to promote an intramolecular interrupted imino-Nazarov reaction between dienals 155 and secondary amines 156 (Scheme 48). [91]Moreover, divergent products were obtained by using two distinct Lewis acid catalysts; while the reaction with AgClO 4 afforded the expected interrupted imino-Nazarov product 157, the reaction with Gd(OTf) 3 gave rise to a different polycyclic skeleton 158 (Scheme 48).The authors could prove that using Gd(OTf) 3 the interrupted imino-Nazarov product 157 was initially formed and it evolved towards rearranged product 158 under the reaction conditions (Scheme 48).In a next report, the use N-heterocycles as interrupting nucleophiles afforded carbocyclic nucleoside analogs, being the first example of an intramolecular interrupted imino-Nazarov reaction. [92]egarding the enantioselective version, in 2015 Toste reported an enantioselective gold(I)-catalyzed dearomative Rautenstrauch rearrangement, containing an imino-Nazarov-like reaction as the key and enantiodetermining step (Scheme 49). [93]Following a rational design, the authors switched from their initial acetate substrate to the corresponding indolyl propargyl ketal derivative 159 (Scheme 49).This subtle change resulted in a fully planar intermediate, better suited for ligand-controlled enantioselectivity.Under the optimized conditions cyclopenta [b]indoles 160 were obtained in good yields and high enantioselectivities (Scheme 49).The mechanism would start with the gold-catalyzed Rautenstrauch rearrangement affording planar intermediate XCIV after acetaldehyde extrusion.Ligand-controlled enantioselective imino-Nazarov reaction would achieve the desired products after decomplexation of gold (Scheme 49).
Regarding the enantioselective organocatalyzed variant, Ye, Zhang, and Huang, preliminary studied the chiral Bronstedacid-catalyzed imino-Nazarov, although with little success (Scheme 50). [94]The study was reported in the context of a one-pot vinylation/4π electrocyclization process.
Finally, in 2020 Schomaker and Fernández studied a rhodium-catalyzed imino-Nazarov reaction inspired in the

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The authors described that treatment of enallene substrates bearing a sulfamate group as nitrene precursor 163 with PhIO as oxidant and catalytic amounts of Rh(TPA) 4 afforded the corresponding methylene aziridines XCVI that spontaneously opened up towards the corresponding 2-amidoallyl cation XCVII that further evolves towards the observed products 164 by means of a 4π-electrocyclization (imino-Nazarov reaction) (Scheme 51).
In addition to the imino-Nazarov variant, recently, Frontier and coworkers developed a one-pot nitrogen-interrupted halo-Prins/halo-Nazarov coupling cascade as a powerful methodology to synthesize sp 3 -rich N-heterocycles diastereoselectively. [97] The reaction between appropriately designed enynes 165 and carbonyl compounds 166 in the presence of triflic acid and tetrabutylammonium iodide afforded iodinated cyclopenta [b]indole derivatives 168 (Scheme 52).The protective group on the amine was essential to carry out the reaction due to the formation of the corresponding imine when the corresponding unprotected amine was used instead.A broad scope of aldehydes both with aryl and alkyl groups was tolerated.The reaction also employed several ketone derivatives, being an enol ether the most reactive.Finally, the influence of substitution at the aniline aromatic ring was also studied.The mechanism proposed started with a formation of oxycarbenium XCV through condensation of the hydroxy group present in aniline 165 with carbonyl compound 166 under acidic conditions.Intermediate XCVIII evolves towards the halo-Prins product 167 which could be isolated or can also participate in a cascade reaction by the addition of HFIP.The CÀ O is broken affording the pentadienyl cation XCIX which evolves via a 4π conrotatory electrocyclization to the halo-cyclopentenyl cation C. Finally, this cation is trapped by the neighboring nitrogen atom to yield the corresponding N-heterocycle 168 (Scheme 52).
In conclusion, an extensive bibliography related to the catalytic Nazarov reaction employing different catalysts such as copper-or palladium-based, Lewis, and Brönsted acids may be found in the literature. [98]Moreover, this methodology has been applied in the total synthesis of natural products due to its versatility and the increase in the structural complexity of the products. [99]

CÀ H Cyclization
As we mentioned before the formation of the five-membered ring requires a preorganized structure or a structure with specific functional groups to form the specific bonds.For this reason, many research groups have focused their attention on cyclization processes without the need for these requirements.Thus, an outstanding chemistry tool has been developed in the last decades, namely C(sp 3 )À H functionalization. [100] This transformation is very challenging due to the relative inertness of these bonds and the similar reactivity of most C(sp 3 )À H bonds within a molecule. [101]Most commonly, the selectivity issue has been tackled by using tailor-made directing groups that, by means of chelation, allow the activation of a specific CÀ H bond. [102] However, several reactive intermediates are known to react with a [1,5] preference.More specifically, recently carbenes (vinylidene), radicals, and cations (vinyl cations) have been successfully used in the generation of the cyclopentene ring.

Vinylidene-Mediated
Free vinylidenes are elusive highly reactive intermediates and their generation requires harsh conditions.For instance, the formation of the five-membered ring through insertion of a vinylidene into a C(sp 3 )À H bond could be carried out by the gas-phase thermolysis of α-acetylenic ketones at 550-740 °C.
However, this methodology with extreme conditions produced low yields and very poor functional group compatibility. [103] seminal contribution that allowed to overcome those extreme conditions was developed by Stang and coworkers. [104]hey synthesized a variety of 2-cyclopentenones 170 in good yields via 1,5-CÀ H bond insertion using β-ketoethynyliodonium triflates 169 with different aliphatic chains, carbo-, and heterocycles (Scheme 52).Substrate 169 reacts with sodium ptoluenesulfinate affording intermediate CI which evolves to form the vinylidene CII releasing iodobenzene (Scheme 53).Finally, an intramolecular 1,5-C(sp 3 )À H insertion yields the corresponding product 170 (Scheme 53).
Years later, in 2015, González and coworkers studied the gold-catalyzed intramolecular CÀ H insertion of iodoalkynes 171. [105]In this case, the activation of a benzylic CÀ H bond afforded a broad spectrum of indenes 172 in good yields.They observed a [1,2]-iodine shift, formulating the formation of vinylidene CIV as key intermediate.They also showed that the reaction was intramolecular by means of isotopic labeling experiments with deuterium.In addition, the CÀ H functionalization at a chiral center was also studied, noting that the chiral information was maintained.With all these results, the mechanism depicted in Scheme 54 was proposed.The first step would be the coordination of gold (I) catalyst to the alkyne 171 to form intermediate CIII which undergoes a [1,2]-iodine shift to form gold vinylidene CIV (Scheme 54).Finally, CÀ H insertion yielded the corresponding product 172 (Scheme 54).
In 2016, Zhang and coworkers developed an interesting powerful CÀ H functionalization methodology for the preparation of cyclopentenones using more accesible and safer reagents than the previous repot by Stang. [106]
In 2022, an interesting photocatalytic reaction was reported by Zhu. [107]Sulfonylcyclopentenes 177 were achieved by virtue of a photocatalytic cascade pathway comprising a Markovnikov-type sulfonylation, 1,5-hydrogen atom transfer, 5-endo-trig cyclization, and β-elimination (Scheme 56).The reaction tolerated a broad spectrum of functional groups.Moreover, the products were further derivatized using different reaction conditions, showing their great potential.The presence of a radical intermediate was supported by the inhibition of the reaction in the presence of a radical inhibitor (TEMPO).Labelling experiments were also carried out showing a KIE = 3.2 which indicated that the remote C-(sp 3 )À H cleavage may be the rate-determining step of the reaction.Finally, they observed racemization when the reaction proceeded at a chiral centre, validating the radical pathway.With these results they suggested that the first step was a single electron transfer (SET) from the tosyl anion to the photoexcited ruthenium catalyst producing tosyl radical that would then add to the β-position of the thioalkyne 176 to form CVIII (Scheme 56).Subsequent 1,5-HAT would afford alkyl radical CIX (Scheme 56).Finally, 5-endo-trig radical cyclization achieves radical CX which evolves via β-elimination to form the corresponding product 177 (Scheme 56).

Vinyl Cation-Mediated
Carbocations have played a central role in organic chemistry. [108]In recent years, a specific kind of carbocations, namely vinyl cations have received particular attention. [109]nce again, although [1,2]-H shifts are more common in the chemistry of carbocations, [1,5]-H shifts are also commonly found in the literature.
The first report related to the topic of this review came from the group of Gaunt. [110]A vinyl cation intermediate CXI formed upon treatment of an alkyne 179 with a diaryliodonium triflate 178 under copper catalysis, evolves by means of an unprecedented [1,5]-H shift / CÀ C bond-forming cyclopentanulation affording substituted cyclopentenes 180 in moderate to good yields (Scheme 57).This unexpected mechanistic pathway, in addition to its fundamental interest, results in an important synthetic feature, the retention of the stereochemistry when the CÀ H bond that participates in the insertion belongs to a stereocentre (Scheme 57).A stepwise [1,5]-H shift carbocation interception pathway, as initially proposed by the authors, would have resulted in racemization

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by virtue of the planar nature of the sp 3 carbocation intermediate.
More recently, Nelson has pioneered the use of readily accessible vinyl sulfonates 181 as precursors of vinyl cations. [111]Hence, the asymmetric intramolecular CÀ H bond insertion of thus generated intermediates afford bicyclic cyclopentenes 182 in moderate to high yields and enantioselectivities (Scheme 58). [112]The chiral environment required for enantiocontrol was supplied by the use of List's imidodiphophorimidate (IDPi) as strong acid for the ionization of the substrates. [113]The reaction starts with the formation of a silylium cation CXII by the reaction of an allylsilane with IDPi. [114]The oxophilicity of this cation would then ionization of the substrate affording the key vinyl cation intermediate CXIII with a chiral environment provided by the couteranion.Enantiodetermining CÀ H insertion followed by deprotonation of carbocation CXIV would afford the final product while restoring turnover (Scheme 58).
In 2023, Barrio described a gold-catalyzed cycloisomerization reaction of 1-bromoalkynes 183 affording substituted cyclopentenes 184 by virtue of a C(sp 3 )À H insertion reaction. [115][116]Several features of this transformation are remarkable: the starting materials are easily synthesized from readily available starting materials, the reaction conditions are extremely simple, the products contain an easy-to-functionalize C(sp 2 )À Br bond and, most importantly, the C(sp 3 )À H bond that undergoes the insertion is a truly non-activated one (Scheme 59).In addition, a variety of molecular architectures are available depending on the structure of the substrate: simple cyclopentenes, bridged-, fused-, and spiro bicycles (Scheme 59).
Despite the authors initially proposed a gold-vinylidene as the key intermediate, a mechanistic study combining experimental (isotope labeling, KIEs, cross-over experiments) and computational work ruled out this mechanistic pathway (Scheme 60).The calculated energy barrier for the insertion of the gold-vinylidene intermediate was almost negligible It is worth noting that such a mechanistic scenario was unprecedented in gold [117]

Miscellanea
In section 5.1 the Nazarov reaction of dienones was described in some detail.However, not only dienones but other bisunsaturated substrates undergo intramolecular cyclizations towards the cyclopentene core.Perhaps the most obvious transformation of this kind would be the RCM of diallyl substrates. [118]This reaction is so favoured that the RCM of diallyl substrates has commonly been used as a benchmark reaction in the development of new catalysts. [119,120]Herein, only two recent examples that we have found remarkable for the way in which the 1,6-diene unit was assembled will be highlighted.In the first of them, dienes bearing three contiguous stereocenters 190 are obtained in high stereoselectivity by means of a carboalumination-Claisen rearrangement-carbonyl addition cascade reaction (Scheme 61). [121]The reaction starts with the Zr-mediated syn carboalumination of a terminal alkyne 185, affording a vinylaluminum species 186 (Scheme 61).This species plays a double role in the cascade.First, it serves as Lewis acid catalyst for the Claisen rearrangement of an allyl vinyl ether 187 giving rise to a γ,δ-enal 188.
Then, the same species 186 acts as a nucleophile affording the desired 1,6-diene 189 featuring three consecutive stereocenters on the three carbons of the tether between the two olefins (Scheme 61).Finally, as a possible application, the authors describe the RCM of one of these complex dienes using standard conditions (Grubss' second-generation catalyst in DCM at rt) (Scheme 61).Using an organocatalytic approach, Palomo and co-workers also afforded the synthesis of stereodefined γ,δ-enals featuring several stereocenter in the carbon tether (Scheme 62). [122]More specifically, the authors described the organocatalytic enanioand diastereoselective α-alkylation of aldehydes using substituted 2-(bromomethyl)acrylates 192 as electrophiles (Scheme 62).In one of these examples, the use of 4-pentenal 191 as substrate affords 1,6-enynes 193 that were in turn engaged in a RCM reaction using standard reaction conditions (Scheme 62).The final cyclopentene products 194 were obtained without erosion of the optical purity (Scheme 62).
Recently, the synthetic potential of a different kind of ringclosing metathesis, namely carbonyl-olefin metathesis has been disclosed by Schindler and co-workers. [123][124]δand ɛ-enones 195 were found to afford cyclopentenes 196 and cyclohexenes (not shown) under FeCl 3 catalysis at room temperature (Scheme 63).The synthetic availability of the required substrates and the simple and economic reaction conditions make this strategy a valuable addition added to the toolbox of synthetic organic chemists for synthesizing cyclopentene In 2004, Toste and co-workers described gold-catalyzed intramolecular Conia-ene reaction using acetylenic dicarbonyl compounds 198 as substrates. [125]Depending on the length of the tether and the substitution at the triple bond, alkylidene cyclopentanes 200 or cyclopentenes 199 are obtained by means of 5-exo-or 5-endo-trig cyclization modes, respectively (Scheme 64).
In a related report, Barluenga described the transition metal-free iodocarbocyclization of analogous substrates 201, using elemental iodine (Scheme 65). [126]The methodology is amenable for the construction of simple iodocyclopentenes In 2005, Rovis reported an unprecedented ring-contraction strategy for the synthesis of formyl-substituted cycopentenes 206 (Scheme 66). [127]The reaction uses 2,5-dihydrooxepines 205 as starting materials, formed in turn by a retro-Claisen reaction of vinylformylcyclopropanes 204 (Scheme 66).Taken altogether, the reaction sequence would be analogous to a VCP-CP rearrangement described above (see section 1.2).Indeed, the reaction may be carried out from the corresponding vinylformylcyclopropanes 204 without the need to isolate the 2,5-dihydrooxepines 205.The authors cannot distinguish between the two possible pathways, a stepwise mechanism featuring a 2,5-dihydrooxepine intermediate or the direct VCP-CP rearrangement.The epimerization to the trans isomer and the stereoretentive nature of the reaction when using an enantioenriched substrate were also studied, alongside one post-functionalization step (double-bond dihydroxylation).
In a recent publication, the photoswitching behavior of donor-acceptor Stenhouse adducts 208 (DASAs) is studied in detail. [128]As for the scope of this review, we will only note that these adducts, consisting of electron-donating and electron-releasing moieties connected by a triene linker 207, behave as reverse photochromes, acting as non-linear optical (NLO) switches.Hence, under visible light irradiation, they undergo a series of trans-cis isomerizations followed by a 4πelectrocyclization affording cyclopentenone derivatives 208 (Scheme 67).The process may be reverted under thermal conditions.

Outlook
As has been emphasized in this Review, the synthesis of the cyclopentene core has attracted enormous attention from the synthetic community.The significance of the substructure along with the great variety of approaches amenable for its preparation resulted in a plethora of methodologies, of which some of the most significant, in our opinion, have been highlighted herein.The continuous implementation of modern strategies based on more efficient and sustainable methodologies ensures further developments in the near future.In addition, numerous methodologies for the transformation of simple cyclopentene derivatives into more elaborated frameworks have also been reported in the recent scientific literature. [129]However, herein we have only covered strategies for the assembly of the cyclopentene ring.It would be our wish that this Review may serve both as consulting reference and as a source of inspiration for synthetic organic chemists, especially for those interested in the construction of cyclopentene derivatives.

Scheme 18 .
Scheme 18. Formation cyclopentenes via Lewis acid-catalyzed ring opening addition / intermolecular S N V cascade.
closure and reduction of radical cation XLII, affords the final product 74 and regenerates the catalyst (Scheme 21).
. 2023, 23, e202300254 (18 of 30) © 2023 The Authors.The Chemical Record published by The Chemical Society of Japan and Wiley-VCH GmbH electrocyclic reaction was not carried out in a catalytic fashion until roughly 60 years after.Herein, only pioneering works of the catalytic version will be mentioned.

Scheme 57 .
Scheme 57.In situ generation of a vinyl cation intermediate and subsequent cyclopentannulation by means of CÀ H insertion.

Scheme 60 .
Scheme 60.Proposed mechanism featuring a gold-stabilised vinyl cation as key transition state.
202 a, along with bridged 202 b and fused bicycles 202 c (Scheme 65).The presence of the highly reactive C(sp 2 )À I bond in the final products allows their further functionalization by means of well-stablished palladium-catalyzed crosscoupling chemistry (Sonogashira 203 a, Suzuki 203 b and Heck 203 c products shown on Scheme 65).