Unveiling the Chemistry and Synthetic Potential of Catalytic Cycloaddition Reaction of Allenes: A Review

Allenes with two carbon–carbon double bonds belong to a unique class of unsaturated hydrocarbons. The central carbon atom of allene is sp hybridized and forms two σ-bonds and two π-bonds with two terminal sp2 hybridized carbon atoms. The chemistry of allenes has been well documented over the last decades. They are more reactive than alkenes due to higher strain and exhibit significant axial chirality, thus playing a vital role in asymmetric synthesis. Over a variety of organic transformations, allenes specifically undergo classical metal catalyzed cycloaddition reactions to obtain chemo-, regio- and stereoselective cycloadducts. This review briefly describes different types of annulations including [2+2], [2+2+1], [3+2], [2+2+2], [4+2], [5+2], [6+2] cycloadditions using titanium, cobalt, rhodium, nickel, palladium, platinum, gold and phosphine catalyzed reactions along with a mechanistic study of some highlighted protocols. The synthetic applications of these reactions towards the synthesis of natural products such as aristeromycin, ent-[3]-ladderanol, waihoensene(−)-vindoline and (+)-4-epi-vindoline have also been described.


Introduction
The carbon-carbon bond formation by various chemical processes is extremely important in organic chemistry, especially when cyclic systems with complex structures are generated from simple precursors [1][2][3][4][5]. Cycloaddition reactions play a pivotal role in this regard for the synthesis of a number of heterocyclic molecule systems with high yield. Moreover, they proceed with chemo-, regio-and stereoselectivity and thus attracting a great attention of organic chemists. A major part of a literature review in organic chemistry highlights the latest discoveries, shedding new insights on synthetic and mechanistic aspects of cycloaddition processes [6][7][8]. Cycloaddition reactions are generally single-step reactions which occurs on joining two π-systems at their ends forming a cyclic compound through formation of two sigma bonds, while each reactant loses one π-bond in the process [9]. However, recently, there have been various attempts made on the postulation of the step-wise mechanism of cycloaddition reactions, specifically Diels-Alder reactions [10]. They are proposed to proceed via zwitterionic or biradical intermediates [11]. Moreover, these reactions are not only important for simple organic molecule synthesis but are also vital for the modern synthesis of natural products as well as biologically active substances [12][13][14][15]. Metal catalysts in these reactions also enhance the selective formation of several stereocenters and their integration in target molecules [16].
All allenes whether synthetic intermediates or in natural products are based on a 1,2-propadiene structure. Their synthetic origin traces back to 1887. Allenes though devoid of chirality are useful for synthesizing chiral compounds. Their significant applications in organometallic chemistry is also well documented [17][18][19][20]. Allenes and their derivatives reacting with various unsaturated compounds via cycloaddition reactions are involved in the synthesis of indole, pyridine, furan and other cyclic compounds. In addition to this, their symmetry, isomeric properties and characteristic reactivity (with nucleophiles, electrophiles and radical species) have fascinated researchers in the recent past to explore wide open possibilities to discover various building blocks required for the construction of biologically active materials through a variety of cycloaddition reactions of allenes including [ [21][22][23][24][25][26]. All data related to transition metal catalyzed and phosphine catalyzed cycloaddition reactions of allenes, investigated since 2015, are represented in this review. Moreover, synthetic applications of these reactions towards the synthesis of natural products are also highlighted.
Moreover, these reactions are not only important for simple organic molecule synthesis but are also vital for the modern synthesis of natural products as well as biologically active substances [12][13][14][15]. Metal catalysts in these reactions also enhance the selective formation of several stereocenters and their integration in target molecules [16].
All allenes whether synthetic intermediates or in natural products are based on a 1,2propadiene structure. Their synthetic origin traces back to 1887. Allenes though devoid of chirality are useful for synthesizing chiral compounds. Their significant applications in organometallic chemistry is also well documented [17][18][19][20]. Allenes and their derivatives reacting with various unsaturated compounds via cycloaddition reactions are involved in the synthesis of indole, pyridine, furan and other cyclic compounds. In addition to this, their symmetry, isomeric properties and characteristic reactivity (with nucleophiles, electrophiles and radical species) have fascinated researchers in the recent past to explore wide open possibilities to discover various building blocks required for the construction of biologically active Resultsthrough a variety of cycloaddition reactions of allenes including [ [21][22][23][24][25][26]. All data related to transition metal catalyzed and phosphine catalyzed cycloaddition reactions of allenes, investigated since 2015, are represented in this review. Moreover, synthetic applications of these reactions towards the synthesis of natural products are also highlighted.

Palladium Catalyzed Reactions
In contrast to the construction of 2H-chromenes via the reaction of allenes with 2-alkenylphenols, Gulìas and co-workers carried out the synthesis of benzoxepines via the Pd(II)-catalyzed [5+2] annulation of allenes with ortho-alkenylphenols under oxidative conditions [50]. A variety of benzoxepines was obtained by the reaction of readily available 2-alkenylphenols and allenes using catalytic amount of Pd(II) and Cu(II); however, benzoxepine 67 bearing electron withdrawing substituent at para carbon was obtained in highest yield (97%) from ortho-alkenylphenol 65 and allene 66. Computational studies showed that the geometry of metal catalysts (square planar in case of palladium) determined the reaction outcome. A plausible mechanism of this protocol starts from the exchange of ligand between phenol substrate and palladium acetate that generates intermediate (B) after the intramolecular reaction of alkene with palladium. This intermediate, after coordination with allene followed by migratory insertion and reductive elimination reaction, gave the desired benzoxepine product (Scheme 22).

Palladium Catalyzed Reactions
In contrast to the construction of 2H-chromenes via the reaction of allenes with 2alkenylphenols, Gulìas and co-workers carried out the synthesis of benzoxepines via the Pd(ΙΙ)-catalyzed [5+2] annulation of allenes with ortho-alkenylphenols under oxidative conditions [50]. A variety of benzoxepines was obtained by the reaction of readily available 2-alkenylphenols and allenes using catalytic amount of Pd(ΙΙ) and Cu(ΙΙ); however, benzoxepine 67 bearing electron withdrawing substituent at para carbon was obtained in highest yield (97%) from ortho-alkenylphenol 65 and allene 66. Computational studies showed that the geometry of metal catalysts (square planar in case of palladium) determined the reaction outcome. A plausible mechanism of this protocol starts from the exchange of ligand between phenol substrate and palladium acetate that generates intermediate (B) after the intramolecular reaction of alkene with palladium. This intermediate, after coordination with allene followed by migratory insertion and reductive elimination reaction, gave the desired benzoxepine product (Scheme 22). Mascareñas and co-workers published another report on the Pd-catalyzed formal [5+2] cycloaddition of allenes [51]. They reported the formation of 2,3-dihydro-1Hbenzo[b]azepines via the [5+2] annulation of allenes with 2-alkenyltriflylanilides using a catalytic amount of Pd(ΙΙ) and Cu(ΙΙ). Among different substituted allenes, 2-vinylidenecyclohexane 13 was found to be highly reactive with 2-alkenylanilide 68 bearing electron Mascareñas and co-workers published another report on the Pd-catalyzed formal [5+2] cycloaddition of allenes [51]. They reported the formation of 2,3-dihydro-1H-benzo[b]azepines via the [5+2] annulation of allenes with 2-alkenyltriflylanilides using a catalytic amount of Pd(II) and Cu(II). Among different substituted allenes, 2-vinylidenecyclohexane 13 was found to be highly reactive with 2-alkenylanilide 68 bearing electron acceptor CF 3 group to give 2,3-dihydrobenzoazepine 69 with 92% yield using 5 mol% Pd(OAc) 2 and Cu(OAc) 2 ·H 2 O. Density functional theory (DFT) calculations showed that the synthesis of benzazepines took place through the C-H activation of 2-alkenyltriflylanilides that involved a metalation-deprotonation (CMD) mechanism (Scheme 23).
Vidal et al. described that benzyl and allyltriflimides successfully underwent oxidative [4+2] cycloaddition with allenes using Pd-catalyst to afford tetrahydroisoquinoline and dihydropyridine derivatives [52]. N-benzyltriflimides 72 and N-allyl amines 74 were used in Pd-catalyzed annulation with substituted allenes 70 to synthesize tetrahydroisoquinoline 73 (91% yield) and dihydropyridine 75 (90% yields) in the presence of N-protected amino acid as metal ligand 71. They also obtained enantioenriched isoquinolines using amino acid ligand via desymmetrizing C-H activation of prochiral diarylmethylamines with an enantiomeric ratio of up to 98:2 (Scheme 24). Vidal et al. described that benzyl and allyltriflimides successfully underwent oxidative [4+2] cycloaddition with allenes using Pd-catalyst to afford tetrahydroisoquinoline and dihydropyridine derivatives [52]. N-benzyltriflimides 72 and N-allyl amines 74 were used in Pd-catalyzed annulation with substituted allenes 70 to synthesize tetrahydroisoquinoline 73 (91% yield) and dihydropyridine 75 (90% yields) in the presence of N-protected amino acid as metal ligand 71. They also obtained enantioenriched isoquinolines using amino acid ligand via desymmetrizing C-H activation of prochiral diarylmethylamines with an enantiomeric ratio of up to 98:2 (Scheme 24). An advanced procedure for the synthesis of cyclopropenes was developed via palladiumcatalyzed allenylic [4+1] cycloaddition using a planar-chiral ligand by Shao and coworkers [53]. In addition, [4+3] cycloaddition/cross-coupling reaction was observed by replacement of ligand of the palladium catalyst that resulted into the formation of carbocycles bearing 4-spiropyrazolones. Their methodology was proved to be very useful as it provided a facile approach for the formation of [3] dendralenes and led to the discovery of novel compounds with antitumor activity. Cycloaddition of allene acetate 75 with pyrazolone 76 gave spirocyclic product 78 in 82% yield with 93% ee using 2.5 mol% [Pd(allyl)Cl] 2 catalyst and 5.5 mol% of planar-chiral phanePhos ligand 77.
[4+3] Cycloadduct 79 was obtained in 98% yield by loading 5 mol% Pd(cod)Cl 2 catalyst and 12 mol% triphenyl phosphine ligand (Scheme 25). An advanced procedure for the synthesis of cyclopropenes was developed via palladium-catalyzed allenylic [4+1] cycloaddition using a planar-chiral ligand by Shao and coworkers [53]. In addition, [4+3] cycloaddition/cross-coupling reaction was observed by replacement of ligand of the palladium catalyst that resulted into the formation of carbocycles bearing 4-spiropyrazolones. Their methodology was proved to be very useful as it provided a facile approach for the formation of [3]dendralenes and led to the discovery of novel compounds with antitumor activity. Cycloaddition of allene acetate 75 with pyrazolone 76 gave spirocyclic product 78 in 82% yield with 93% ee using 2.5 mol% [Pd(allyl)Cl]2 catalyst and 5.5 mol% of planar-chiral phanePhos ligand 77.
[4+3] Cycloadduct 79 was obtained in 98% yield by loading 5 mol% Pd(cod)Cl2 catalyst and 12 mol% triphenyl phosphine ligand (Scheme 25).   On the other side, in gold catalyzed reaction intermediate (E) after passing through an intramolecular nucleophilic reaction, tandem cyclization, hydride migration and elimination reaction afforded targeted product (Scheme 26). Construction of methylidene cyclobutane-indoles via Au-catalyzed dearomative [2+2] cycloaddition of N-protected indoles with alleneamides and aryloxyallenes was reported by Ocello et al. [55]. Several N-protected 2,3-disubstitutive indoles underwent cycloaddition reaction with allenamides and aryloxyallenes to afford different cycloadducts in the presence of (R)-DTBM-segphos(AuCl) 2  Construction of methylidene cyclobutane-indoles via Au-catalyzed dearomative [2+2] cycloaddition of N-protected indoles with alleneamides and aryloxyallenes was reported by Ocello et al. [55]. Several N-protected 2,3-disubstitutive indoles underwent cycloaddition reaction with allenamides and aryloxyallenes to afford different cycloadducts in the presence of (R)-DTBM-segphos ( Triazines act as efficient substitutes for aryl amines and take part in hydroaminomethylation by inserting an amino methyl group to synthesize target molecules. Sun and co-workers reported the Au-catalyzed stepwise [2+2+2] cycloaddition of functionalized allenes with several substituted 1,3,5 triazines to functionalize six-membered N-heterocyclic compounds in high yields (60-96%) [56]. N-Heterocyclic compounds 91 (96%) and 93 (89%) were prepared by the cycloaddition of triazine 89 with allenamide 90 and Triazines act as efficient substitutes for aryl amines and take part in hydroaminomethylation by inserting an amino methyl group to synthesize target molecules. Sun and coworkers reported the Au-catalyzed stepwise [2+2+2] cycloaddition of functionalized allenes with several substituted 1,3,5 triazines to functionalize six-membered N-heterocyclic compounds in high yields (60-96%) [56]. N-Heterocyclic compounds 91 (96%) and 93 (89%) were prepared by the cycloaddition of triazine 89 with allenamide 90 and allenoate 92, respectively using 5 mol% of Ph 3 PAuCl catalyst and NaBAr F (Ar F : tetrakis [3,5bis(triflouromethyl)phenyl]borate) (5 mol%) as an additive (Scheme 28). Polycyclic aromatic compounds were synthesized from the cyclization of propargyl carbonates or esters with furan-ynes via gold catalysis by Liu and co-workers [57]. The reaction was initiated with the synthesis of allene by 3,3 rearrangement of propargyl carbonates or esters which underwent a Diels-Alders reaction of furan (IMDAF) to synthesize anthracene derivatives after ring opening of cycloadduct. Using 1,4-furan-yne as substrate, 9-oxygenated anthracene derivatives were formed by aromatization of the cycloadduct while in the case of 1,5-furan-yne, oxa-bridge cleaved in the cycloadduct in association with aryl group 1,2-migration to afford anthracen1(2H)-ones. The highest yield (96%) of the functionalized anthracene 95 was obtained from 94 using 5 mol% gold catalyst at 50 °C (Scheme 29). A convenient approach for the synthesis of tetrahydropyrans via the [2+2+2] cycloaddition reaction was reported by research group of López [58]. A highlighted example is presented in Scheme 30, showing that the reaction of allenamide 85 with alkene 96 and aldehyde 97 was smoothly processed in the presence of gold catalyst 98 using DCM as Polycyclic aromatic compounds were synthesized from the cyclization of propargyl carbonates or esters with furan-ynes via gold catalysis by Liu and co-workers [57]. The reaction was initiated with the synthesis of allene by 3,3 rearrangement of propargyl carbonates or esters which underwent a Diels-Alders reaction of furan (IMDAF) to synthesize anthracene derivatives after ring opening of cycloadduct. Using 1,4-furan-yne as substrate, 9-oxygenated anthracene derivatives were formed by aromatization of the cycloadduct while in the case of 1,5-furan-yne, oxa-bridge cleaved in the cycloadduct in association with aryl group 1,2-migration to afford anthracen1(2H)-ones. The highest yield (96%) of the functionalized anthracene 95 was obtained from 94 using 5 mol% gold catalyst at 50 • C (Scheme 29). Polycyclic aromatic compounds were synthesized from the cyclization of propargyl carbonates or esters with furan-ynes via gold catalysis by Liu and co-workers [57]. The reaction was initiated with the synthesis of allene by 3,3 rearrangement of propargyl carbonates or esters which underwent a Diels-Alders reaction of furan (IMDAF) to synthesize anthracene derivatives after ring opening of cycloadduct. Using 1,4-furan-yne as substrate, 9-oxygenated anthracene derivatives were formed by aromatization of the cycloadduct while in the case of 1,5-furan-yne, oxa-bridge cleaved in the cycloadduct in association with aryl group 1,2-migration to afford anthracen1(2H)-ones. The highest yield (96%) of the functionalized anthracene 95 was obtained from 94 using 5 mol% gold catalyst at 50 °C (Scheme 29). A convenient approach for the synthesis of tetrahydropyrans via the [2+2+2] cycloaddition reaction was reported by research group of López [58]. A highlighted example is presented in Scheme 30, showing that the reaction of allenamide 85 with alkene 96 and aldehyde 97 was smoothly processed in the presence of gold catalyst 98 using DCM as A convenient approach for the synthesis of tetrahydropyrans via the [2+2+2] cycloaddition reaction was reported by research group of López [58]. A highlighted example is presented in Scheme 30, showing that the reaction of allenamide 85 with alkene 96 and aldehyde 97 was smoothly processed in the presence of gold catalyst 98 using DCM as unique solvent. As a result, the desired product 99 was obtained in 98% yield (Scheme 5). The reaction is highly stereoselective as well as atom economical and covered a wide substrate scope including a variety of aldehydes (aliphatic, aromatic), alkenes (styrene also) and enol ethers or enamides. A similar approach was carried out by this research group in 2017 using gold catalyst 100 to obtain excellent chemo-, regio-and stereoselective tetrahydropyrans and significant results were obtained in this regard (Figure 1) [59].
Molecules 2022, 27, x FOR PEER REVIEW 21 of 49 unique solvent. As a result, the desired product 99 was obtained in 98% yield (Scheme 5). The reaction is highly stereoselective as well as atom economical and covered a wide substrate scope including a variety of aldehydes (aliphatic, aromatic), alkenes (styrene also) and enol ethers or enamides. A similar approach was carried out by this research group in 2017 using gold catalyst 100 to obtain excellent chemo-, regio-and stereoselective tetrahydropyrans and significant results were obtained in this regard (Figure 1) [59].  unique solvent. As a result, the desired product 99 was obtained in 98% yield (Scheme 5). The reaction is highly stereoselective as well as atom economical and covered a wide substrate scope including a variety of aldehydes (aliphatic, aromatic), alkenes (styrene also) and enol ethers or enamides. A similar approach was carried out by this research group in 2017 using gold catalyst 100 to obtain excellent chemo-, regio-and stereoselective tetrahydropyrans and significant results were obtained in this regard (Figure 1) [59].

Phosphine Catalyzed Cycloaddition Reactions of Allenes
Pyrroloisoquinolines exist in many natural products that exhibit many activities, e.g.,

Scheme 35. Synthesis of efsevin 120-S and 120-R via [3+2] annulation.
Due to the presence of five-membered N-heterocycles, a broad range of biologically active compounds, many procedures for the construction of these chiral heterocycles using phosphine catalysts have been described. In this respect, Kramer and Fu presented the synthesis of 2,5-dihydropyrroles via [4+1] annulation of a variety of allenes with different amines catalyzed by spirophosphine catalyst [66]. Among different dihydropyrroles, 124 was synthesized in highest yield (95%) with 89% ee by [4+1] annulation of γ-substituted allenes 121 with p-nitrophenyl sulfonamide 122 in the presence of chiral spirophosphine catalyst 123 at 40 °C (Scheme 36).

Conner et al. reported a chiral Lewis acid (140) catalyzed [2+2] cycloaddition reaction
between allenoate and alkene to achieve excellent enantioselectivity of the corresponding products [70]. The methodology covered a wide substrate scope that was equally suitable for inactivated alkenes. However, trisubstituted alkenes and α-or γ-substituted allenes gave the desired products with low selectivity via this protocol. A highlighted example of this protocol is depicted in Scheme 40. When alkene 138 was treated with allene 139 in the

Conner et al. reported a chiral Lewis acid (140) catalyzed [2+2] cycloaddition reaction
between allenoate and alkene to achieve excellent enantioselectivity of the corresponding products [70]. The methodology covered a wide substrate scope that was equally suitable for inactivated alkenes. However, trisubstituted alkenes and α-or γ-substituted allenes gave the desired products with low selectivity via this protocol. A highlighted example of this protocol is depicted in Scheme 40. When alkene 138 was treated with allene 139 in the Scheme 39. Amine-catalyzed synthesis of 4H-pyran-fused-pyrrolin-2-one 137.

Conner et al. reported a chiral Lewis acid (140) catalyzed [2+2] cycloaddition reaction
between allenoate and alkene to achieve excellent enantioselectivity of the corresponding products [70]. The methodology covered a wide substrate scope that was equally suitable for inactivated alkenes. However, trisubstituted alkenes and α-or γ-substituted allenes gave the desired products with low selectivity via this protocol. A highlighted example of this protocol is depicted in Scheme 40. When alkene 138 was treated with allene 139 in the presence of 20 mol% catalyst 140, as a result, a targeted product 141 was obtained in 82% yield with 98:2 er and 7:1 E:Z. Another report on the synthesis of cyclobutane derivatives via the intramolecular [2+2] cycloaddition of alkenes and allenoates was published by Xu et al. [71]. Among different substrates, allene 142 gave cycloadducts 144-E, 144-Z in highest yield (70%) and good enantioselectivity (1:20 E:Z) by loading 20 mol% chiral oxazaborolidine catalyst 143 (Scheme 41).
Garg and co-workers studied azacyclic allenes and heteroatom bearing cyclic allenes, which could not gain enough attention by synthetic chemists [78]. They reported (1) the synthesis of azacyclic allene precursors in mild reaction conditions, (2) the trapping of the desired cyclic allenes in the Diels-Alder reaction to afford functionalized piperidine products and ( Garg and co-workers studied azacyclic allenes and heteroatom bearing cyclic allenes, which could not gain enough attention by synthetic chemists [78]. They reported (1) the synthesis of azacyclic allene precursors in mild reaction conditions, (2) the trapping of the desired cyclic allenes in the Diels-Alder reaction to afford functionalized piperidine products and (3)  Garg and co-workers studied azacyclic allenes and heteroatom bearing cyclic allenes, which could not gain enough attention by synthetic chemists [78]. They reported (1) the synthesis of azacyclic allene precursors in mild reaction conditions, (2) the trapping of the desired cyclic allenes in the Diels-Alder reaction to afford functionalized piperidine products and (3)  A one pot three component reaction of allenic ketones/allenoates, amines and enones was reported by Feng et al. to synthesize cyclohexa-1,3-dienes (in the absence of oxidant) and 2-aminobenzophenones/benzoate derivatives (in the presence of oxidant) at elevated temperature (120 • C) in dioxane [79]. The synthesis of the desired products proceeded with the synthesis of the enaminone intermediate by the nucleophilic addition of allenic ketone with amine preceded by Michael addition which underwent catalyst/base-free [3+3] annulation with enone. Electron donating substituents on the phenyl ring of allenic ketones resulted in better yields as compared to phenyl bearing electron withdrawing groups. For example, highly functionalized cyclohexa-1,3-diene 174 and 2-aminobenzophenone 175 were obtained from allenic ketone 171, amine 172 and enone 173 in highest yield (86% and 79%, respectively) (Scheme 47).
Shi and co-workers proved that allenes could act as analogous to alkynes in the building of bioactive spiro[indoline-3,2 -pyrrole] with excellent yields and good enantioselectivities [82]. They described the usage of allenes instead of alkynes to afford enantioselective spiro[indoline-3,2 -pyrrole] derivatives via catalytic asymmetric isatin-involved 1,3-dipolar cycloaddition (1,3-DC). They reported asymmetric 1,3-DC of allenes with azomethine ylides (derived from isatin) to afford enantioenriched spiroindolinepyrroles. An unexpected formation of spirooxindole with an intraannular carbon double bond was also observed. Shi and co-workers proved that allenes could act as analogous to alkynes in the building of bioactive spiro[indoline-3,2′-pyrrole] with excellent yields and good enantioselectivities [82]. They described the usage of allenes instead of alkynes to afford enantioselective spiro[indoline-3,2′-pyrrole] derivatives via catalytic asymmetric isatin-involved 1,3dipolar cycloaddition (1,3-DC). They reported asymmetric 1,3-DC of allenes with azomethine ylides (derived from isatin) to afford enantioenriched spiroindolinepyrroles. An unexpected formation of spirooxindole with an intraannular carbon double bond was also observed. Bis-phosphoric acid (Bis-PA) 185 (15 mol%) efficiently catalyzed 1,3-DC and assembled isatin 182, 2,3-allenoate 183 and amino-ester 184 afforded desired product 186 in 65% yield with 93% ee along with the formation of compound 187 (Scheme 49). Yu and co-workers developed a metal-free approach towards the construction of pyrrolidines via the cycloisomerization and intramolecular [4+3] cycloaddition of allene-alkynylbenzenes, respectively mediated by Brønsted acids (TfOH, HBF4 or Me3OBF4) [83]. The synthesis of pyrrolidine derivatives was proceeded via the formation of vinyl cation by the reaction of alkyne with allylic cation (generated from allene), grabbed by triflate (TfO) anion to afford the desired product. In excess acid, the cycloisomerization product Yu and co-workers developed a metal-free approach towards the construction of pyrrolidines via the cycloisomerization and intramolecular [4+3] cycloaddition of allenealkynylbenzenes, respectively mediated by Brønsted acids (TfOH, HBF 4 or Me 3 OBF 4 ) [83]. The synthesis of pyrrolidine derivatives was proceeded via the formation of vinyl cation by the reaction of alkyne with allylic cation (generated from allene), grabbed by triflate (TfO) anion to afford the desired product. In excess acid, the cycloisomerization product underwent Friedel-Crafts reaction to attain seven membered rings by TfOH-mediated intramolecular [4+3] cycloaddition reaction. Pyrrolidine derivative 189 was obtained in 85% yield from substrate 188 at room temperature using 1.1 equivalents of TfOH while [4+3] cycloadduct 190 was synthesized at 60 • C in the presence of excess TfOH (10 equivalents) in highest yield (94%) (Scheme 50). This protocol can also be used to synthesize F-incorporated products using HBF 4 or Me 3 OBF 4 as the fluoro source.
Liu and co-workers described the preparation of 1-sulfonyl-trifluoromethyl allenes and their utilization in [3+2] cycloaddition reaction with nitrones to afford a series of trifluoromethylated isoxazolidine derivatives without using any catalyst [84]. Starting An easy and simple approach towards the synthesis of strained polycyclic compounds without using any catalyst was reported by Cheng et al. that involved an Ugi/Himbert arene/allene Diels-Alder cycloaddition reaction [85]. The desired strained polycycles were synthesized via a multicomponent reaction of several substituted aldehydes/ketones, aniline, isocyanide and allenic acid in methanol. The highest yielded (67%) polycycle 198 was synthesized using benzaldehyde 18, aniline 195, isocyanide 196 and allenic acid 197 (Scheme 52). Their synthetic approach proceeded through the formation of a Ugi adduct that underwent a Diels-Alder reaction between the terminal allene and aromatic ring. This terminology has some advantages including (1) wide substrate scope, (2) no need for protection and (3) no transformation of acid into acyl chloride. Yu and co-workers developed a metal-free approach towards the construction of pyrrolidines via the cycloisomerization and intramolecular [4+3] cycloaddition of allene-alkynylbenzenes, respectively mediated by Brønsted acids (TfOH, HBF4 or Me3OBF4) [83]. The synthesis of pyrrolidine derivatives was proceeded via the formation of vinyl cation by the reaction of alkyne with allylic cation (generated from allene), grabbed by triflate (TfO) anion to afford the desired product. In excess acid, the cycloisomerization product underwent Friedel-Crafts reaction to attain seven membered rings by TfOH-mediated intramolecular [4+3] cycloaddition reaction. Pyrrolidine derivative 189 was obtained in 85% yield from substrate 188 at room temperature using 1.1 equivalents of TfOH while [4+3] cycloadduct 190 was synthesized at 60 °C in the presence of excess TfOH (10 equivalents) in highest yield (94%) (Scheme 50). This protocol can also be used to synthesize F-incorporated products using HBF4 or Me3OBF4 as the fluoro source. fluoromethylated isoxazolidine derivatives without using any catalyst [84]. Starting w 2-bromo-3,3,3-trifluoropropene 191, a variety of substituted allenes 192 were synthesiz in 67-88% yields using various aldehydes or ketones. The synthesized 1-sulfonyl-triflu romethyl allenes 192 underwent [3+2] cycloaddition with different substituted nitron 193 that resulted in the formation of trifluoromethylated isoxazolidines 194 in excelle yields (86-94%) (Scheme 51).

Scheme 51. Synthesis of trifluoromethylated isoxazolidine derivatives 194.
An easy and simple approach towards the synthesis of strained polycyclic co pounds without using any catalyst was reported by Cheng et al. that involved Ugi/Himbert arene/allene Diels-Alder cycloaddition reaction [85]. The desired strain polycycles were synthesized via a multicomponent reaction of several substituted ald hydes/ketones, aniline, isocyanide and allenic acid in methanol. The highest yielded (67 polycycle 198 was synthesized using benzaldehyde 18, aniline 195, isocyanide 196 a allenic acid 197 (Scheme 52). Their synthetic approach proceeded through the formati of a Ugi adduct that underwent a Diels-Alder reaction between the terminal allene a aromatic ring. This terminology has some advantages including (1) wide substrate sco (2) no need for protection and (3) no transformation of acid into acyl chloride. An easy and simple approach towards the synthesis of strained polycyclic compounds without using any catalyst was reported by Cheng et al. that involved an Ugi/Himbert arene/allene Diels-Alder cycloaddition reaction [85]. The desired strained polycycles were synthesized via a multicomponent reaction of several substituted aldehydes/ketones, aniline, isocyanide and allenic acid in methanol. The highest yielded (67%) polycycle 198 was synthesized using benzaldehyde 18, aniline 195, isocyanide 196 and allenic acid 197 (Scheme 52). Their synthetic approach proceeded through the formation of a Ugi adduct that underwent a Diels-Alder reaction between the terminal allene and aromatic ring. This terminology has some advantages including (1) wide substrate scope, (2) no need for protection and (3) no transformation of acid into acyl chloride. Arai and Ohkuma reported the [2+2] photochemical cycloaddition of substituted indole derivatives to afford stereoselective methylenecyclobutane-fused indolines in the presence of aromatic ketones as sensitizers irradiated by a high pressure Hg-lamp by Pyrex [86]. This protocol is very significant as it affords heterocyclic compounds via photochemical reaction without using any catalyst. Among different ketones, 3,4-dimethoxyacetophenone was more effective to synthesize all-cis-fused methylenecyclobutane-type compounds in good yields. For example, methylenecyclobutane-type product 201 was synthesized in 72% yield accompanied by 14% terminal alkyne 202 in the presence of 50 mol% 3,4dimethoxyacetophenone 200 under irradiation. However, only [2+2] cycloadduct 203 was formed from trisubstituted allene 199, suggesting an internal transposition of the terminal hydrogen of allene to C3 of indole resulted in alkyne moiety (Scheme 53).
An efficient diastereoselective formation of chiral tetrahydrofuran was reported by Wang et al. [87]. They found α-allenic amides as suitable dipolarophile in the [3+2] cycloaddition with vinyl epoxides using Pd-catalyst and N-heterocyclic carbene (NHC) as ligands which resulted in tetrahydrofuran derivatives having three functionalities; (1) tetrasubstituted enolether, (2) monosubstituted alkene and (3)  Arai and Ohkuma reported the [2+2] photochemical cycloaddition of substituted indole derivatives to afford stereoselective methylenecyclobutane-fused indolines in the presence of aromatic ketones as sensitizers irradiated by a high pressure Hg-lamp by Pyrex [86]. This protocol is very significant as it affords heterocyclic compounds via photochemical reaction without using any catalyst. Among different ketones, 3,4-dimethoxyacetophenone was more effective to synthesize all-cis-fused methylenecyclobutane-type compounds in good yields. For example, methylenecyclobutane-type product 201 was synthesized in 72% yield accompanied by 14% terminal alkyne 202 in the presence of 50 mol% 3,4-dimethoxyacetophenone 200 under irradiation. However, only [2+2] cycloadduct 203 was formed from trisubstituted allene 199, suggesting an internal transposition of the terminal hydrogen of allene to C3 of indole resulted in alkyne moiety (Scheme 53).

Synthesis of Natural Products
Allenes act as unique building blocks in synthetic organic chemistry for the construction of complex bioactive compounds and natural products in a straightforward manner. Many reports on the construction of natural products via the cycloaddition of allenes have been published using different transition metal complexes.

Synthesis of Natural Products
Allenes act as unique building blocks in synthetic organic chemistry for the construction of complex bioactive compounds and natural products in a straightforward manner. Many reports on the construction of natural products via the cycloaddition of allenes have been published using different transition metal complexes.

Synthesis of Guaiane Family
Evans and co-workers described the stereoselective synthesis of tri-and tetrasubstituted exocyclic alkenes via carbocyclization of several alkynylidenecyclopropanes (ACPs) with activated and inactivated allenes [88]. Their synthetic protocol for the formation of substituted exocyclic olefins was well suited for the synthesis of the guaiane family of sesquiterpenes via distal insertion of disubstituted allenes into ACPs. The desired carbon skeleton of guaiane 210 was constructed by carbocyclization of malonate tether ACP 208 with activated allene 209 using [Rh(cod)Cl] 2 (5 mol%) and triphenylphosphite (P(OPh) 3 ) (30 mol%) in p-xylene at 120 • C (Scheme 55).

Synthesis of Natural Products
Allenes act as unique building blocks in synthetic organic chemistry for the construction of complex bioactive compounds and natural products in a straightforward manner. Many reports on the construction of natural products via the cycloaddition of allenes have been published using different transition metal complexes.

Formal Synthesis of (−)-Galanthamine
(−)-Galanthamine 219 is an alkaloid having 3,4-cyclohexenol skeleton, belongs to the Amaryllidaceae family, and was accidentally discovered in the early 1950s and initially used to treat poliomyelitis. It has been recently approved for the treatment of Alzheimer's disease as it acts as a reversible competitive inhibitor of acetyl cholinesterase (Figure 3) [91]. Scheme 56. Total synthesis of (−)-vindoline 211, (+)-4-epi-vindoline 212 and 4-epi-vin 2.4.3. Formal Synthesis of (−)-Galanthamine (−)-Galanthamine 219 is an alkaloid having 3,4-cyclohexenol skeleton, Amaryllidaceae family, and was accidentally discovered in the early 1950 used to treat poliomyelitis. It has been recently approved for the treatment o disease as it acts as a reversible competitive inhibitor of acetyl cholinester [91]. Liu and Yu developed a useful methodology for the synthesis of 2-me cyclohexenones via Rh-catalyzed [5+1] cycloaddition of ACPs with carbon m Their synthetic protocol was utilized for the formal synthesis of (−)-galantha Liu and Yu developed a useful methodology for the synthesis of 2-methylidene-3,4cyclohexenones via Rh-catalyzed [5+1] cycloaddition of ACPs with carbon monoxide [92]. Their synthetic protocol was utilized for the formal synthesis of (−)-galanthamine 219 from cycloadduct 221 prepared from the [5+2] cycloaddition of ACP 220 with CO using [Rh(CO) 2 Cl] 2 (5 mol%). Alcohol 223 was formed in 79% yield with 97% ee using CBS reduction, which after several steps formed aldehyde 224. A reduction of aldehyde 224 with sodium borohydride gave Brown's intermediate 225 that eventually transformed to (−)-galanthamine 219 using a previously reported method [93] (Scheme 57).

Diastereoselective Synthesis of Diquinanes and Triquinanes
Polyquinanes (class of carbocyclic frameworks) are part of many natural products such as steroids and terpenoids that contain condensed five-membered rings. Waihoensene 226 (a tetracyclic diterpene) was first isolated in 1997 by Weavers and co-workers from New Zealand podocarp Podocarpus totara var waihoensis (Figure 4) [94].

Diastereoselective Synthesis of Diquinanes and Triquinanes
Polyquinanes (class of carbocyclic frameworks) are part of many natural products such as steroids and terpenoids that contain condensed five-membered rings. Waihoensene 226 (a tetracyclic diterpene) was first isolated in 1997 by Weavers and co-workers from New Zealand podocarp Podocarpus totara var waihoensis (Figure 4) [94]. Scheme 57. Construction of natural product (−)-galanthamine 219.

Synthesis of Hebelophyllene E
Hebelophyllene E 246 is one of eight members of cis-fused caryophyllene-type sesquiterpenes that were isolated from Hebeloma longicaudum (an actomycorrhizal fungus) in the late 1990s, and structurally consist of geminal dimethyl cyclobutane (Figure 7) [103].

Synthesis of Hebelophyllene E
Hebelophyllene E 246 is one of eight members of cis-fused cary quiterpenes that were isolated from Hebeloma longicaudum (an actomyc the late 1990s, and structurally consist of geminal dimethyl cyclobutan An enantioselective synthesis of chiral gem dimethylcyclobutane ported using a novel oxazaborolidine catalyst in [2+2] cycloaddition o kenes by Wiest et al. [104]. They developed the first synthesis of he (sesquiterpene) and assigned the relative configuration to the side ch epi-ent-hebelophyllene E. For this purpose, they synthesized fully fu 249 from enantiopure acetate 248, from a previously reported meth [105] starting from compound 247 using amino lipase PS, by (1) the magnesium bromide and (2) acetonide protection in 59% yield and > tivity (Scheme 62).  An enantioselective synthesis of chiral gem dimethylcyclobutane derivatives was reported using a novel oxazaborolidine catalyst in [2+2] cycloaddition of allenoates and alkenes by Wiest et al. [104]. They developed the first synthesis of hebelophyllene E 246 (sesquiterpene) and assigned the relative configuration to the side chain by synthesizing epi-ent-hebelophyllene E. For this purpose, they synthesized fully functionalized alkene 249 from enantiopure acetate 248, from a previously reported method by Wessjohann [105] starting from compound 247 using amino lipase PS, by (1) the addition of vinylmagnesium bromide and (2) acetonide protection in 59% yield and >99:1 diastereoselectivity (Scheme 62). An enantioselective synthesis of chiral gem dimethylcyclobutane derivatives was ported using a novel oxazaborolidine catalyst in [2+2] cycloaddition of allenoates and kenes by Wiest et al. [104]. They developed the first synthesis of hebelophyllene E (sesquiterpene) and assigned the relative configuration to the side chain by synthesiz epi-ent-hebelophyllene E. For this purpose, they synthesized fully functionalized alke 249 from enantiopure acetate 248, from a previously reported method by Wessjoha [105] starting from compound 247 using amino lipase PS, by (1) the addition of vin magnesium bromide and (2) acetonide protection in 59% yield and >99:1 diastereosel tivity (Scheme 62).