Organophosphine-Catalyzed [4C+X] Annulations

In recent years, there have been extraordinary developments of organophosphine-catalyzed reactions. This includes progress in the area of [4C+X] annulations, which are of particular interest due to their potential for the rapid construction of 5–8-membered cyclic products. In this short overview, we summarize the remarkable progress, emphasizing reaction mechanisms and key intermediates involved in the processes. The discussion is classified according to the type of electrophilic reactants that acted as C4 synthons in the annulation process, in the order of α-alkyl allenoates, γ-alkyl allenoates, α-methyl allene ketones, β′-OAc allenoate, δ-OAc allenoate, activated dienes and cyclobutenones.


Introduction
The continuous innovation of synthetic methodologies is one of the sources for sustainable progress in modern organic chemistry. Since the Diels-Alder reaction was reported in 1928, cycloaddition reactions have evolved into one of the most fascinating fields in organic chemistry because of their powerful applications in convergent synthesis of cyclic compounds from simple starting materials. Apart from the electrocyclic reactions, nucleophilic phosphine catalysis, which go through different dipolar cycloaddition modes, also played a significant role in the development of cycloaddition chemistry . Those novel annulations provide efficient and powerful approaches to a wide array of carbo-and heterocyclic motifs which are frequently found in natural products as well as biologically active molecules, usually in a regio-and stereoselective manner . In addition, due to their merits such as readily availability of starting materials, mild and metal-free reaction conditions, simple post-reaction workup, high atom economy, low environmental pollution, etc., the tertiary phosphine-promoted cycloaddition reactions have received extensive interest from synthetic chemists, and become an important means in sustainable organic synthesis.
In 1995, Lu et al. first reported the PPh 3 -catalyzed [3+2] cycloaddition reactions of 2,3-butadienoates or 2-butynoates with electron-deficient olefins for the preparation of cyclopentenes [23]. Intrigued by this pioneering work, the potential of allenes acting as a type of C 3 synthons were further exploited. Since then, a wide variety of [3+2] annulations together with their asymmetric catalytic versions have been developed. Further studies disclosed that allenes could also play the roles of C 2 [24][25][26][27][28][29][30][31][32][33] and C 1 [34][35][36] units in various cycloadditions under some circumstances. In addition to allenes, electron-deficient alkynes, and MBHADs (Morita-Baylis-Hillman alcohol derivatives) were often used as C 3 synthons in the tertiary phosphine catalyzed [3+2] cycloaddition reactions with electron-poor olefins or imines as well. With the help of newly developed chiral phosphine catalysts, many synthetic In 2005, the group of Fu achieved the asymmetric version of Kwon's [4+2] annulation of α-alkyl allenoates with imines for the first time by using an axial chiral tertiary phosphine catalyst TP-1 with a binaphthyl skeleton (Scheme 5) [43]. For most substrates, this reaction has excellent diastereoselectivity, moderate to excellent yields and ee values. However, the electron-rich p-methoxybenzaldehyde-derived imine appears to be relatively unreactive and can only achieve 42% yield of target product 25a, although the ee value is as high as 98%. Besides, imines with electron-poor substituents on the ortho-position of the aromatic groups resulted in unsatisfactory stereoselectivities (e.g., 25b).
The asymmetric [4+2] cycloaddition of α-alkyl allenoates with N-tosyl aldimines were achieved by Zhao et. al. as well in 2011 (Scheme 6) [44]. A simple bifunctional N-acyl amino phosphine catalyst TP-2 derived from isoleucine was identified to be the best catalyst for the [4+2] cycloaddition, providing a series of chiral tetrahydropyridines in good to high enantioselectivities whose absolute configuration was just opposite to those reported by the Fu's group. It is worth noting that the electron-rich 4-anisyl imine 9a which was once a reluctant coupling partner in Fu's catalytic system worked as well and gave the corresponding product ent-25a in an excellent yield and 90% ee. 2-chlorobenzene aldimine 9b, which performed unsatisfactorily previously, also gave an improved result: from 75% to 88% yield and from 60% to 96% ee.

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The asymmetric [4+2] cycloaddition of α-alkyl allenoates with N-tosyl aldimines were achieved by Zhao et. al. as well in 2011 (Scheme 6) [44]. A simple bifunctional N-acyl amino phosphine catalyst TP-2 derived from isoleucine was identified to be the best catalyst for the [4+2] cycloaddition, providing a series of chiral tetrahydropyridines in good to high enantioselectivities whose absolute configuration was just opposite to those reported by the Fu's group. It is worth noting that the electron-rich 4-anisyl imine 9a which was once a reluctant coupling partner in Fu's catalytic system worked as well and gave the corresponding product ent-25a in an excellent yield and 90% ee. 2-chlorobenzene aldimine 9b, which performed unsatisfactorily previously, also gave an improved result: from 75% to 88% yield and from 60% to 96% ee. Scheme 6. Catalytic asymmetric [4+2] annulation of α-alkyl allenoates with imines (PMP: p-methoxyphenyl) [44].
In 2014, Guo's group achieved a [4+2] cycloaddition reaction of sulfamate-derived cyclic imines with α-alkyl allenoates (Scheme 9) [47]. For the racemic version, n-PrPPh2 was proved as the best catalyst that effected the reaction to provide a variety of sulfamate-fused tetrahydropyridines 30 in high yield with excellent diastereoselectivities. Similar to previous mechanisms proposed by Kwon, Fu, Zhao , the zwitterionic intermediate exhibited normal regioselectivity: nucleophilic attack took place at the γ-position. When a chiral bifunctional tertiary phosphine catalyst TP-4 derived from natural amino acids was employed as the catalyst, the asymmetric [4+2] cycloaddition proceeded smoothly to afford a series of chiral sulfamate-fused tetrahydropyridines 30 in good yields with moderate to excellent enantioselectivities. Scheme 6. Catalytic asymmetric [4+2] annulation of α-alkyl allenoates with imines (PMP: p-methoxyphenyl) [44].
In 2014, Guo's group achieved a [4+2] cycloaddition reaction of sulfamate-derived cyclic imines with α-alkyl allenoates (Scheme 9) [47]. For the racemic version, n-PrPPh 2 was proved as the best catalyst that effected the reaction to provide a variety of sulfamate-fused tetrahydropyridines 30 in high yield with excellent diastereoselectivities. Similar to previous mechanisms proposed by Kwon, Fu, Zhao, the zwitterionic intermediate exhibited normal regioselectivity: nucleophilic attack took place at the γ-position. When a chiral bifunctional tertiary phosphine catalyst TP-4 derived from natural amino acids was employed as the catalyst, the asymmetric [4+2] cycloaddition proceeded smoothly to afford a series of chiral sulfamate-fused tetrahydropyridines 30 in good yields with moderate to excellent enantioselectivities.  [43,44,46].
In 2012, a different [4+2] cycloaddition of 2-methyl-2,3-butadienoate 4 with cyclic saccharin-derived ketimines 31 was reported by the group of Ye (Scheme 10) [48]. Nucleophilic attack of the zwitterionic intermediate exhibited β′-position selectivity rather than the γ-selectivity that was favored in other [4+2] cycloaddition of α-methyl allenoate with imines. Thus, in the whole reaction process, α-alkyl allenoate was equal to type-B 1,4-dipole which posed a reversed polarity compared to previously introduced [4+2] annulations. The electronic property of the phosphine catalyst was conjectured to be the determining factor for the regioselectivity: electron-poor phosphine catalysts are inclined to promote β′-addition while electron-rich nucleophilic catalysts usually lead to γ-addition.

[4+2] Annulations of α-Alkyl Allenoates with Electron-Deficient Olefins
Under the catalysis of organophosphines, α-alkyl allenoates, as effective novel C 4 synthons, reacted not only with activated imines to produce tetrahydropyridines, but could also couple with electron-deficient alkenes to prepare all-carbon cyclohexenes. In 2007, Kwon et al. realized the organophosphine-catalyzed [4+2] cycloaddition of 2-alkyl allenoates with arylidenemalononitrile 34 (Scheme 12) [50]. Interestingly, a reversal of regioselectivity was found when different organophosphine catalysts were employed: the stronger nucleophilic hexamethylphosphine triamide (HMPT) effected the annulation reaction with normal γ-position selectivity while the less nucleophilic triarylphosphines with electron-deficient aryl groups converted the α-alkyl allenoates to an inverted 1,4-dipole equivalent D (β -position selectivity). The explanation for this intriguing reversal of regioselectivity was that the phosphonium dienolate-to-phosphorus ylide equilibrium (C to D) favored the ylide D when a more electron-withdrawing triarylphosphine was utilized. Later, more extensive electrophilic olefins were used in the [4+2] annulation reaction by Kwon and coworkers (Scheme 13) [51]. Similarly, HMPT was identified as the best nucleophilic phosphine catalyst. Reaction of arylidene cyanoacetates 37 with 2-methyl allenoate 4 afforded the normal γ-position cycloadducts 38. However, when the less-reactive arylidene malonates 39 were employed as the olefin substrates, both cycloadducts 40 and 41 resulted from two different reaction pathways were produced. It was rationalized that there was enough time for the isomerization of phosphonium dienolate C into vinylogous ylide D when relatively unreactive olefin substrates were used. It should be noted that triarylphosphine or some other electron-rich tertiary phosphines were ineffective at mediating the cycloaddition reactions.
In 2012, the group of Lu and Zhao independently realized the first asymmetric [4+2] annulation reaction of α-alkyl allenoates with activated olefins by employing the amino acid-derived LB-BA (short for Lewis base-Brønsted acid) bifunctional chiral tertiary phosphine catalyst.
In the research work of Lu (Scheme 14) [52], two different types of LB-BA bifunctional chiral phosphine catalysts were identified to be suitable for two different types of activated alkene substrates: for the [4+2] cycloaddition of arylidene malononitrile 34, threonine-derived bifunctional chiral tertiary phosphine catalyst TP-6 with a sterically bulky tris(trimethylsilyl)silyl (TTMSS) group on the oxygen atom was found to be the best catalyst, enabling the formation of cyclohexenes 42 in high to excellent yields with excellent enantioselectivities and moderate to good diastereoselectivities, while, for the [4+2] cycloaddition of isatylidenemalononitrile 43, the Scheme 12.
Later, more extensive electrophilic olefins were used in the [4+2] annulation reaction by Kwon and coworkers (Scheme 13) [51]. Similarly, HMPT was identified as the best nucleophilic phosphine catalyst. Reaction of arylidene cyanoacetates 37 with 2-methyl allenoate 4 afforded the normal γ-position cycloadducts 38. However, when the less-reactive arylidene malonates 39 were employed as the olefin substrates, both cycloadducts 40 and 41 resulted from two different reaction pathways were produced. It was rationalized that there was enough time for the isomerization of phosphonium dienolate C into vinylogous ylide D when relatively unreactive olefin substrates were used. It should be noted that triarylphosphine or some other electron-rich tertiary phosphines were ineffective at mediating the cycloaddition reactions. Later, more extensive electrophilic olefins were used in the [4+2] annulation reaction by Kwon and coworkers (Scheme 13) [51]. Similarly, HMPT was identified as the best nucleophilic phosphine catalyst. Reaction of arylidene cyanoacetates 37 with 2-methyl allenoate 4 afforded the normal γ-position cycloadducts 38. However, when the less-reactive arylidene malonates 39 were employed as the olefin substrates, both cycloadducts 40 and 41 resulted from two different reaction pathways were produced. It was rationalized that there was enough time for the isomerization of phosphonium dienolate C into vinylogous ylide D when relatively unreactive olefin substrates were used. It should be noted that triarylphosphine or some other electron-rich tertiary phosphines were ineffective at mediating the cycloaddition reactions.
In 2012, the group of Lu and Zhao independently realized the first asymmetric [4+2] annulation reaction of α-alkyl allenoates with activated olefins by employing the amino acid-derived LB-BA (short for Lewis base-Brønsted acid) bifunctional chiral tertiary phosphine catalyst.
In the research work of Lu (Scheme 14) [52], two different types of LB-BA bifunctional chiral phosphine catalysts were identified to be suitable for two different types of activated alkene substrates: for the [4+2] cycloaddition of arylidene malononitrile 34, threonine-derived bifunctional chiral tertiary phosphine catalyst TP-6 with a sterically bulky tris(trimethylsilyl)silyl (TTMSS) group on the oxygen atom was found to be the best catalyst, enabling the formation of cyclohexenes 42 in high to excellent yields with excellent enantioselectivities and moderate to good diastereoselectivities, while, for the [4+2] cycloaddition of isatylidenemalononitrile 43, the Scheme 13.
In 2012, the group of Lu and Zhao independently realized the first asymmetric [4+2] annulation reaction of α-alkyl allenoates with activated olefins by employing the amino acid-derived LB-BA (short for Lewis base-Brønsted acid) bifunctional chiral tertiary phosphine catalyst.
In the research work of Lu (Scheme 14) [52], two different types of LB-BA bifunctional chiral phosphine catalysts were identified to be suitable for two different types of activated alkene substrates: for the [4+2] cycloaddition of arylidene malononitrile 34, threonine-derived bifunctional chiral tertiary phosphine catalyst TP-6 with a sterically bulky tris(trimethylsilyl)silyl (TTMSS) group on the oxygen atom was found to be the best catalyst, enabling the formation of cyclohexenes 42 in high to excellent yields with excellent enantioselectivities and moderate to good diastereoselectivities, while, for the [4+2] cycloaddition of isatylidenemalononitrile 43, the performance of the chiral tertiary phosphine catalyst TP-6 was not ideal as only 17% ee value could be induced, however, the chiral tertiary phosphine catalyst TP-7 based on the skeleton of dipeptide O-TBDPS-D -Thr-L -N-Boc-tert-Leu was adequate to mediate the annulation and provide the desired 3-spirocyclohexene-2-oxidoles 44 and 45 in high yield with excellent enantioselectivities and diastereoselectivities. Due to the ester group at the β position of the allenoates, which increases the steric hindrance of the β position, γ-addition cycloadducts were formed exclusively for the two types of [4+2] cycloadditions. After replacement of the ester group at the β position with electron-poor aromatic rings, the [4+2] annulation could also proceed smoothly to afford cyclization products in moderate yields with good dr and excellent ee. However, β -substitution of electron neutral phenyl ring was not tolerated in the reaction. performance of the chiral tertiary phosphine catalyst TP-6 was not ideal as only 17% ee value could be induced, however, the chiral tertiary phosphine catalyst TP-7 based on the skeleton of dipeptide O-TBDPS-D-Thr-L-N-Boc-tert-Leu was adequate to mediate the annulation and provide the desired 3-spirocyclohexene-2-oxidoles 44 and 45 in high yield with excellent enantioselectivities and diastereoselectivities. Due to the ester group at the β′ position of the allenoates, which increases the steric hindrance of the β′ position, γ-addition cycloadducts were formed exclusively for the two types of [4+2] cycloadditions. After replacement of the ester group at the β′ position with electron-poor aromatic rings, the [4+2] annulation could also proceed smoothly to afford cyclization products in moderate yields with good dr and excellent ee. However, β′-substitution of electron neutral phenyl ring was not tolerated in the reaction.
At the same time, by employing L-isoleucine-derived LB-BA bifunctional chiral tertiary phosphine compound TP-8 as the catalyst, Zhao and coworkers successfully achieved the asymmetric [4+2] cycloadditions of 2-alkyl substituted allenoates with 2-cyano acrylate derived activated olefins (Scheme 15) [53]. In addition to the frequently-used aryl aldehydes-derived alkenes, aliphatic aldehyde-derived olefin (46, R = aliphatic) was also applied to such a stereoselective transformation for the first time, and the corresponding isopropyl cyclohexene 47b could be obtained in 92% yield with 97% ee.
In recent years, some electron-deficient olefins that are embodied in novel skeleton scaffolds have been developed as dipolarophiles as well in the phosphine-catalyzed [4+2] cycloadditions with α-alkyl allenoates. To establish an efficient and concise synthetic access to the naturally occurring tricyclic benzopyrone framework, in 2011, Kumar and coworkers applied the electron-deficient 3-formy chromone as the alkene in [4+2] annulations with zwitterion C (γ-addition selectivity) generated by the addition of phosphine catalyst to α-alkyl allenoates (Scheme 16) [54]. A cascade sequence of [4+2] annulation followed by a deformylation that provided the desired tricyclic cyclohexene-fused chromone rings 50 with up to three stereogenic centers as a single Scheme 14. Asymmetric [4+2] cycloaddition of α-alkylallenoates with activated olefins [52].
At the same time, by employing L-isoleucine-derived LB-BA bifunctional chiral tertiary phosphine compound TP-8 as the catalyst, Zhao and coworkers successfully achieved the asymmetric [4+2] cycloadditions of 2-alkyl substituted allenoates with 2-cyano acrylate derived activated olefins (Scheme 15) [53]. In addition to the frequently-used aryl aldehydes-derived alkenes, aliphatic aldehyde-derived olefin (46, R = aliphatic) was also applied to such a stereoselective transformation for the first time, and the corresponding isopropyl cyclohexene 47b could be obtained in 92% yield with 97% ee.
In recent years, some electron-deficient olefins that are embodied in novel skeleton scaffolds have been developed as dipolarophiles as well in the phosphine-catalyzed [4+2] cycloadditions with α-alkyl allenoates. To establish an efficient and concise synthetic access to the naturally occurring tricyclic benzopyrone framework, in 2011, Kumar and coworkers applied the electron-deficient 3-formy chromone as the alkene in [4+2] annulations with zwitterion C (γ-addition selectivity) generated by the addition of phosphine catalyst to α-alkyl allenoates (Scheme 16) [54]. A cascade sequence of [4+2] annulation followed by a deformylation that provided the desired tricyclic cyclohexene-fused chromone rings 50 with up to three stereogenic centers as a single diastereoisomer was observed.
The exocyclic allenic lactone 51 proved to be a competent 1,4-dipolar C 4 synthon as well in the same [4+2] annulations, smoothly delivering the tetracyclic benzopyrones 52 in high diastereoselectivities.  [55]. Instead of the 3-formychromone, 3-cyano-chromones were employed as the activated alkenes. L-Threonine-derived bifunctional N-acylaminophosphine (TP-9) proved to be the best catalyst, mediating the [4+2] annulations with α-alkyl allenoates 17 to generate tricyclic tetrahydroxanthones 54 containing three continuous chiral centers in high yields with excellent enantioselectivitiies and moderate to high diastereoselectivities.   [55]. Instead of the 3-formychromone, 3-cyano-chromones were employed as the activated alkenes. L-Threonine-derived bifunctional N-acylaminophosphine (TP-9) proved to be the best catalyst, mediating the [4+2] annulations with α-alkyl allenoates 17 to generate tricyclic tetrahydroxanthones 54 containing three continuous chiral centers in high yields with excellent enantioselectivitiies and moderate to high diastereoselectivities.  [55]. Instead of the 3-formychromone, 3-cyano-chromones were employed as the activated alkenes. L-Threonine-derived bifunctional N-acylaminophosphine (TP-9) proved to be the best catalyst, mediating the [4+2] annulations with α-alkyl allenoates 17 to generate tricyclic tetrahydroxanthones 54 containing three continuous chiral centers in high yields with excellent enantioselectivitiies and moderate to high diastereoselectivities.  [55]. Instead of the 3-formychromone, 3-cyano-chromones were employed as the activated alkenes. L-Threonine-derived bifunctional N-acylaminophosphine (TP-9) proved to be the best catalyst, mediating the [4+2] annulations with α-alkyl allenoates 17 to generate tricyclic tetrahydroxanthones 54 containing three continuous chiral centers in high yields with excellent enantioselectivitiies and moderate to high diastereoselectivities. In 2015, Guo and coworkers employed the unsaturated pyrazolone 55 as a novel type of activated alkene to examine the similar phosphine-catalyzed [4+2] cycloaddition with α-substituted allenoates (Scheme 18) [56]. The moderately nucleophilic MePPh 2 was capable of triggering the desired racemic annulation with diethyl 2-vinylidenesuccinate to afford the corresponding spiropyrazolone products in 49-99% yields as a single diastereomer. Reaction of β -aryl-substituted allenoates with the unsaturated pyrazolone resulted in poor diastereoselectivities although the annulation proceeded smoothly to provide the corresponding cycloadducts in good to excellent yields (75-99%). Utilization of a chiral thiourea-based bifunctional phosphine TP-4 (Scheme 9) as the chiral organocatalyst allowed the formation of a variety of chiral polysubstituted spiropyrazolones in moderate to excellent yields with excellent enantioselectivities and moderate to good diastereoselectivities (Scheme 18). allenoates (Scheme 18) [56]. The moderately nucleophilic MePPh2 was capable of triggering the desired racemic annulation with diethyl 2-vinylidenesuccinate to afford the corresponding spiropyrazolone products in 49-99% yields as a single diastereomer. Reaction of β′-aryl-substituted allenoates with the unsaturated pyrazolone resulted in poor diastereoselectivities although the annulation proceeded smoothly to provide the corresponding cycloadducts in good to excellent yields (75-99%). Utilization of a chiral thiourea-based bifunctional phosphine TP-4 (Scheme 9) as the chiral organocatalyst allowed the formation of a variety of chiral polysubstituted spiropyrazolones in moderate to excellent yields with excellent enantioselectivities and moderate to good diastereoselectivities (Scheme 18).
In 2016, Guo, Zhou, and co-workers found that the barbiturate-derived alkenes 58 were another type of ideal dipolar olefin in the phosphine-catalyzed asymmetric [4+2] annulation with α-alkyl allenoates (Scheme 19) [57]. The spirocyclic chiral phosphine catalyst TP-10 was capable of inducing high to excellent enantioselectivities. It is noteworthy that, compared to previously reported chiral phosphine-catalyzed [4+2] annulations where only β′-alkoxy carbonyl substituted allenoate were tolerated in most cases, the allenoate scope were quite wide in this work. Not only β′-ethoxy carbonyl substitution, but non-substituted α-methyl allenoate, and α-methyl allenoates with electron-rich, -neutral, and -deficient aromatic moieties (include naphthyl substitution) on the β′-positions were also tolerated in the annulation reactions. With the adoption of this methodology, a wide variety of pharmaceutically important spirobarbiturate-cyclohexenes 59 were obtained in good to excellent yields with excellent diastereo-and enantioselectivities.  [58], and found that the expected spiroannulation could proceed smoothly to deliver two separable regioisomers 61 and 62 derived from γ-and β′-addition, respectively, when conducting the reaction at 80 °C with the use of PPh3 as the catalyst. In 2016, Guo, Zhou, and co-workers found that the barbiturate-derived alkenes 58 were another type of ideal dipolar olefin in the phosphine-catalyzed asymmetric [4+2] annulation with α-alkyl allenoates (Scheme 19) [57]. The spirocyclic chiral phosphine catalyst TP-10 was capable of inducing high to excellent enantioselectivities. It is noteworthy that, compared to previously reported chiral phosphine-catalyzed [4+2] annulations where only β -alkoxy carbonyl substituted allenoate were tolerated in most cases, the allenoate scope were quite wide in this work. Not only β -ethoxy carbonyl substitution, but non-substituted α-methyl allenoate, and α-methyl allenoates with electron-rich, -neutral, and -deficient aromatic moieties (include naphthyl substitution) on the β -positions were also tolerated in the annulation reactions. With the adoption of this methodology, a wide variety of pharmaceutically important spirobarbiturate-cyclohexenes 59 were obtained in good to excellent yields with excellent diastereo-and enantioselectivities. allenoates (Scheme 18) [56]. The moderately nucleophilic MePPh2 was capable of triggering the desired racemic annulation with diethyl 2-vinylidenesuccinate to afford the corresponding spiropyrazolone products in 49-99% yields as a single diastereomer. Reaction of β′-aryl-substituted allenoates with the unsaturated pyrazolone resulted in poor diastereoselectivities although the annulation proceeded smoothly to provide the corresponding cycloadducts in good to excellent yields (75-99%). Utilization of a chiral thiourea-based bifunctional phosphine TP-4 (Scheme 9) as the chiral organocatalyst allowed the formation of a variety of chiral polysubstituted spiropyrazolones in moderate to excellent yields with excellent enantioselectivities and moderate to good diastereoselectivities (Scheme 18).
In 2016, Guo, Zhou, and co-workers found that the barbiturate-derived alkenes 58 were another type of ideal dipolar olefin in the phosphine-catalyzed asymmetric [4+2] annulation with α-alkyl allenoates (Scheme 19) [57]. The spirocyclic chiral phosphine catalyst TP-10 was capable of inducing high to excellent enantioselectivities. It is noteworthy that, compared to previously reported chiral phosphine-catalyzed [4+2] annulations where only β′-alkoxy carbonyl substituted allenoate were tolerated in most cases, the allenoate scope were quite wide in this work. Not only β′-ethoxy carbonyl substitution, but non-substituted α-methyl allenoate, and α-methyl allenoates with electron-rich, -neutral, and -deficient aromatic moieties (include naphthyl substitution) on the β′-positions were also tolerated in the annulation reactions. With the adoption of this methodology, a wide variety of pharmaceutically important spirobarbiturate-cyclohexenes 59 were obtained in good to excellent yields with excellent diastereo-and enantioselectivities.  [58], and found that the expected spiroannulation could proceed smoothly to deliver two separable regioisomers 61 and 62 derived from γ-and β′-addition, respectively, when conducting the reaction at 80 °C with the use of PPh3 as the catalyst.  [58], and found that the expected spiroannulation could proceed smoothly to deliver two separable regioisomers 61 and 62 derived from γand β -addition, respectively, when conducting the reaction at 80 • C with the use of PPh 3 as the catalyst. Regioselectivities were unsatisfactory in most cases except for halogen-substituted N-Ac isatin-derived alkenes (R = Ac, 61:62 = 5:95). In addition, indan-1,3-dione-derived alkenes 63 were tested as well, similarly, the

[4+3] Annulations of α-Alkyl Allenoates with Azomethine Imines
Due to the intrinsic ring strain and competing cyclization pathways, phosphine-catalyzed cycloaddition of α-alkyl allenoates with other dipolarophiles usually lead to the formation of normal-sized 5-or 6-membered rings. Despite its great efficiency in construction of 5-or 6-membered rings, phosphine-catalyzed preparation of medium-sized rings was elusive until in 2012. Guo

[4+3] Annulations of α-Alkyl Allenoates with Azomethine Imines
Due to the intrinsic ring strain and competing cyclization pathways, phosphine-catalyzed cycloaddition of α-alkyl allenoates with other dipolarophiles usually lead to the formation of normal-sized 5-or 6-membered rings. Despite its great efficiency in construction of 5-or 6-membered rings, phosphine-catalyzed preparation of medium-sized rings was elusive until in 2012. Guo

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Guo and coworkers later found that the PBu3-catalyzed annulation of α-substituted allenoates with C,N-cyclic aromatic azomethine imines 77, including N-acetyliminoisoquinolinium betaine (77a), N-acetyliminoquinolinium betaine (77b), and N-acetyliminophenanthridinium betaine (77c), exclusively produced the [4+3] cycloadducts 78, providing dinitrogen-fused heterocyclic compounds in moderate to excellent yields (Scheme 24) [61]. Both alkyl and ethoxy carbonyl, and methylene aryl groups with different electronic substitution patterns were compatible at the α-position of the allenoates in the [4+3] annulations. Compared with the initial report, this catalytic [4+3] cycloaddition process was a practical synthetic method for biologically important heterocycles, suggesting immense synthetic utility. In their following research, the enantioselective version of the phosphine-catalyzed [4+3] cycloaddition of α-substituted allenoates with C,N-cyclic azomethine imines was realized for the first time (Scheme 25) [62]. The commercially available Kwon phosphine TP-11 was identified as the optimal catalyst, mediating the asymmetric [4+3] cycloaddition to produce the seven-membered ring-fused quinazoline-based tricyclic heterocycles 80 in high to excellent yields with high to excellent enantioselectivities and mostly excellent diastereoselectivities. The substrate scope of both the allenoate and the azomethine imine was rather wide. Not only various allenoates bearing different electronic properties of substituents on the benzene ring of the β′-aryl allenoates but also β′-carboxylate-or alkyl-substituted allenoates were compatible in the reaction. The obtained chiral tricyclic adducts 80 could be easily transformed into monocyclic diazepines 81 which frequently show significant biological activities in pharmaceutical chemistry by an oxidation-ring opening procedure. In their following research, the enantioselective version of the phosphine-catalyzed [4+3] cycloaddition of α-substituted allenoates with C,N-cyclic azomethine imines was realized for the first time (Scheme 25) [62]. The commercially available Kwon phosphine TP-11 was identified as the optimal catalyst, mediating the asymmetric [4+3] cycloaddition to produce the seven-membered ring-fused quinazoline-based tricyclic heterocycles 80 in high to excellent yields with high to excellent enantioselectivities and mostly excellent diastereoselectivities. The substrate scope of both the allenoate and the azomethine imine was rather wide. Not only various allenoates bearing different electronic properties of substituents on the benzene ring of the β -aryl allenoates but also β -carboxylate-or alkyl-substituted allenoates were compatible in the reaction. The obtained chiral tricyclic adducts 80 could be easily transformed into monocyclic diazepines 81 which frequently show significant biological activities in pharmaceutical chemistry by an oxidation-ring opening procedure. Guo and coworkers later found that the PBu3-catalyzed annulation of α-substituted allenoates with C,N-cyclic aromatic azomethine imines 77, including N-acetyliminoisoquinolinium betaine (77a), N-acetyliminoquinolinium betaine (77b), and N-acetyliminophenanthridinium betaine (77c), exclusively produced the [4+3] cycloadducts 78, providing dinitrogen-fused heterocyclic compounds in moderate to excellent yields (Scheme 24) [61]. Both alkyl and ethoxy carbonyl, and methylene aryl groups with different electronic substitution patterns were compatible at the α-position of the allenoates in the [4+3] annulations. Compared with the initial report, this catalytic [4+3] cycloaddition process was a practical synthetic method for biologically important heterocycles, suggesting immense synthetic utility. In their following research, the enantioselective version of the phosphine-catalyzed [4+3] cycloaddition of α-substituted allenoates with C,N-cyclic azomethine imines was realized for the first time (Scheme 25) [62]. The commercially available Kwon phosphine TP-11 was identified as the optimal catalyst, mediating the asymmetric [4+3] cycloaddition to produce the seven-membered ring-fused quinazoline-based tricyclic heterocycles 80 in high to excellent yields with high to excellent enantioselectivities and mostly excellent diastereoselectivities. The substrate scope of both the allenoate and the azomethine imine was rather wide. Not only various allenoates bearing different electronic properties of substituents on the benzene ring of the β′-aryl allenoates but also β′-carboxylate-or alkyl-substituted allenoates were compatible in the reaction. The obtained chiral tricyclic adducts 80 could be easily transformed into monocyclic diazepines 81 which frequently show significant biological activities in pharmaceutical chemistry by an oxidation-ring opening procedure.

[4+4] Annulations of α-Methylallene Ketones with α,β-Unsaturated Imines
In 2017, Lu, Ullah and co-workers disclosed the first example of a phosphine-catalyzed cycloaddition for the synthesis of eight-membered rings, achieving an enantioselective phosphine-catalyzed [4+4] annulation reaction of α-methyl allene ketones with α,β-unsaturated imines (Scheme 29) [70]. The dipeptide L-Thr-L-Thr-derived bifunctional phosphine catalyst TP-13 was found to mediate the asymmetric [4+4] cycloadditions to produce eight-membered azocine in excellent yields with excellent enantioselectivities (>98% ee in most cases). A wide range of auroneor aza-aurone-derived α,β-unsaturated imines bearing different aromatic moieties were compatible in the reactions, affording the corresponding benzofuran-or indole-fused azocines respectively. A strong electron-withdrawing protecting group on the nitrogen atom of the imine was required, as sulfonamide was adequate to involve into the expected [4+4] cycloadditions while imines with an alkyl or aryl group on the N atoms were inert under the same reaction conditions. Employment of terminal α-methyl allene ketones was another crucial point for the success of the reactions because either the similar α-substituted allenoates or γ-substituted allene ketones failed to react with the α,β-unsaturated imines. The mechanism proposed for the

[4+4] Annulations of α-Methylallene Ketones with α,β-Unsaturated Imines
In 2017, Lu, Ullah and co-workers disclosed the first example of a phosphine-catalyzed cycloaddition for the synthesis of eight-membered rings, achieving an enantioselective phosphine-catalyzed [4+4] annulation reaction of α-methyl allene ketones with α,β-unsaturated imines (Scheme 29) [70]. The dipeptide L-Thr-L-Thr-derived bifunctional phosphine catalyst TP-13 was found to mediate the asymmetric [4+4] cycloadditions to produce eight-membered azocine in excellent yields with excellent enantioselectivities (>98% ee in most cases). A wide range of aurone-or aza-aurone-derived α,β-unsaturated imines bearing different aromatic moieties were compatible in the reactions, affording the corresponding benzofuran-or indole-fused azocines respectively. A strong electron-withdrawing protecting group on the nitrogen atom of the imine was required, as sulfonamide was adequate to involve into the expected [4+4] cycloadditions while imines with an alkyl or aryl group on the N atoms were inert under the same reaction conditions. Employment of terminal α-methyl allene ketones was another crucial point for the success of the reactions because either the similar α-substituted allenoates or γ-substituted allene ketones failed to react with the α,β-unsaturated imines.

[4+X] Annulations of β′-Acetoxy Allenoates
Generally, the zwitterionic intermediates derived from nucleophilic addition of the phosphine catalyst to the allenoates are nucleophilic to react with various electrophiles, but a remarkable reversal of polarity was witnessed after elimination of a negative charged group of the zwitterion. In 2010, Tong's group innovatively introduced an acetoxy group (-OAc) at the β′-position of 2,3-butadienoate as a leaving group, enabling it to serve as a versatile 1,4-biselectrophilic precursor and participate in [4C+X] annulations with 1,n-bisnucleophiles under the catalysis of triphosphine catalyst (Scheme 30) [71].

[4+X] Annulations of β -Acetoxy Allenoates
Generally, the zwitterionic intermediates derived from nucleophilic addition of the phosphine catalyst to the allenoates are nucleophilic to react with various electrophiles, but a remarkable reversal of polarity was witnessed after elimination of a negative charged group of the zwitterion. In 2010, Tong's group innovatively introduced an acetoxy group (-OAc) at the β -position of 2,3-butadienoate as a leaving group, enabling it to serve as a versatile 1,4-biselectrophilic precursor and participate in [4C+X] annulations with 1,n-bisnucleophiles under the catalysis of triphosphine catalyst (Scheme 30) [71].

[4+X] Annulations of β′-Acetoxy Allenoates
Generally, the zwitterionic intermediates derived from nucleophilic addition of the phosphine catalyst to the allenoates are nucleophilic to react with various electrophiles, but a remarkable reversal of polarity was witnessed after elimination of a negative charged group of the zwitterion. In 2010, Tong's group innovatively introduced an acetoxy group (-OAc) at the β′-position of 2,3-butadienoate as a leaving group, enabling it to serve as a versatile 1,4-biselectrophilic precursor and participate in [4C+X] annulations with 1,n-bisnucleophiles under the catalysis of triphosphine catalyst (Scheme 30) [71].
Almost at the same time, the asymmetric [4+1] annulations of β -acetoxy allenoates were reported by Fu and co-workers (Scheme 33) [73]. The biphenyl-derived axially chiral phosphine was used as the catalyst and a wide array of α-cyano compounds, such as α-cyano ketones, amides, esters, sulfones, phosphine oxides and phosphonates, were employed as the nucleophiles. A wide variety of functionalized cyclopentenes 103 bearing non-spirocyclic, fully substituted stereocenters (either all-carbon or heteroatom-substituted (sulfur and phosphorus)) were assembled in high yields with good to high enantiomeric excesses. Cyclopentenes bearing two consecutive stereocenters could also be generated under the catalytic system in good stereoselectivities when β -or γ-substituted β -acetoxy allenoates were employed (Scheme 34). Furthermore, a mechanistic study revealed that the turnover-limiting step occurs after the addition of the chiral phosphine to the allenoate, and likely after the addition of the second coupling partner as well. Almost at the same time, the asymmetric [4+1] annulations of β′-acetoxy allenoates were reported by Fu and co-workers (Scheme 33) [73]. The biphenyl-derived axially chiral phosphine was used as the catalyst and a wide array of α-cyano compounds, such as α-cyano ketones, amides, esters, sulfones, phosphine oxides and phosphonates, were employed as the nucleophiles. A wide variety of functionalized cyclopentenes 103 bearing non-spirocyclic, fully substituted stereocenters (either all-carbon or heteroatom-substituted (sulfur and phosphorus)) were assembled in high yields with good to high enantiomeric excesses. Cyclopentenes bearing two consecutive stereocenters could also be generated under the catalytic system in good stereoselectivities when β′or γ-substituted β′-acetoxy allenoates were employed (Scheme 34). Furthermore, a mechanistic study revealed that the turnover-limiting step occurs after the addition of the chiral phosphine to the allenoate, and likely after the addition of the second coupling partner as well. One example of [4+1] cycloaddition of 2-(acetoxymethyl)buta-2,3-dienoate 102 with nitrogen nucleophile (TsNH2) was reported in Tong's work, but the reaction afforded an achiral 2,5-dihydropyrrole 103i in low yield (Scheme 30) [71]. In 2015, the group of Fu disclosed an asymmetric [4+1] cycloaddition of γ-substituted 2-(acetoxymethyl)buta-2,3-dienoate 102 with Almost at the same time, the asymmetric [4+1] annulations of β′-acetoxy allenoates were reported by Fu and co-workers (Scheme 33) [73]. The biphenyl-derived axially chiral phosphine was used as the catalyst and a wide array of α-cyano compounds, such as α-cyano ketones, amides, esters, sulfones, phosphine oxides and phosphonates, were employed as the nucleophiles. A wide variety of functionalized cyclopentenes 103 bearing non-spirocyclic, fully substituted stereocenters (either all-carbon or heteroatom-substituted (sulfur and phosphorus)) were assembled in high yields with good to high enantiomeric excesses. Cyclopentenes bearing two consecutive stereocenters could also be generated under the catalytic system in good stereoselectivities when β′or γ-substituted β′-acetoxy allenoates were employed (Scheme 34). Furthermore, a mechanistic study revealed that the turnover-limiting step occurs after the addition of the chiral phosphine to the allenoate, and likely after the addition of the second coupling partner as well. One example of [4+1] cycloaddition of 2-(acetoxymethyl)buta-2,3-dienoate 102 with nitrogen nucleophile (TsNH2) was reported in Tong's work, but the reaction afforded an achiral 2,5-dihydropyrrole 103i in low yield (Scheme 30) [71]. In 2015, the group of Fu disclosed an asymmetric [4+1] cycloaddition of γ-substituted 2-(acetoxymethyl)buta-2,3-dienoate 102 with Scheme 34. Enantioselective [4+1] annulations to synthesize functionalized cyclopentenes with two consecutive stereocenters [73].
In 2016, α-aminonitriles 124 were employed as C,N-bisnucleophiles to react with 2-(acetoxymethyl)buta-2,3-dienoates by Liao, Zhang and coworkers (Scheme 36) [75]. Under the catalysis of PPh3, the [4+2] cycloaddition of a wide range of α-aminonitriles 124 proceeded smoothly to furnish the corresponding poly-substituted tetrahydropyridines 125 which include a quaternary carbon stereocenter in moderate to good yields. Although a variety of α-aminonitriles were compatible in the annulation, reaction of N-Ts protected α-aminonitrile did not form the same [4+2] cycloadduct. Concerning the mechanism, the authors proposed a firstly γ-addition of the nucleophilic carbanion to the 1,4-biselectrophile before proton transfer and cyclization.
In 2016, α-aminonitriles 124 were employed as C,N-bisnucleophiles to react with 2-(acetoxymethyl)buta-2,3-dienoates by Liao, Zhang and coworkers (Scheme 36) [75]. Under the catalysis of PPh3, the [4+2] cycloaddition of a wide range of α-aminonitriles 124 proceeded smoothly to furnish the corresponding poly-substituted tetrahydropyridines 125 which include a quaternary carbon stereocenter in moderate to good yields. Although a variety of α-aminonitriles were compatible in the annulation, reaction of N-Ts protected α-aminonitrile did not form the same [4+2] cycloadduct. Concerning the mechanism, the authors proposed a firstly γ-addition of the nucleophilic carbanion to the 1,4-biselectrophile before proton transfer and cyclization.

[4+2] Annulations of δ-Acetoxy Allenoates
In 2017, the group of Tong disclosed a novel type of phosphine-catalyzed, substrate-dependent [4+2] annulations of δ-acetoxy allenoates with ketones (Scheme 37) [76]. Under the optimized reaction conditions (running the reaction in MeTHF at 80 • C with the use of PPhMe 2 as the catalyst and i Pr 2 NEt as the base), the [4+2] cycloadditions of δ-acetoxy allenoates 129 with 2-substituted cyclic 1,3-diones 130 mainly formed the functional group rich and structurally complex 1,3-cyclohexadiene compounds 131. However, δ-acetoxy allenoates bearing an aryl group at the δ-position seemed unsuitable for the above [4+2] annulations, as reaction with the diketone 130 led to formation of a complex mixture under the same reaction conditions. With their continued efforts, soon after, they found that cyclic β-carbonyl amides 137 were suitable annulation partners to react with the allenoates 129. Interestingly, with the use of PPh 3 as the catalyst and K 2 CO 3 as the base when running the reaction in DCM at room temperature, reaction of the cyclic β-carbonyl amides 137 with δ-aryl-substituted δ-acetoxy allenoates involved in a cascade "[4+2] annulation/cyclic imide formation" process, furnishing a novel array of structurally more complicated tricyclic products 138 in good yields (50-94%) (Scheme 38).

2018, 23,x
21 of 31 cyclic 1,3-diones 130 mainly formed the functional group rich and structurally complex 1,3-cyclohexadiene compounds 131. However, δ-acetoxy allenoates bearing an aryl group at the δ-position seemed unsuitable for the above [4+2] annulations, as reaction with the diketone 130 led to formation of a complex mixture under the same reaction conditions. With their continued efforts, soon after, they found that cyclic β-carbonyl amides 137were suitable annulation partners to react with the allenoates 129. Interestingly, with the use of PPh3 as the catalyst and K2CO3 as the base when running the reaction in DCM at room temperature, reaction of the cyclic β-carbonyl amides 137 with δ-aryl-substituted δ-acetoxy allenoates involved in a cascade "[4+2] annulation/cyclic imide formation" process, furnishing a novel array of structurally more complicated tricyclic products 138 in good yields (50-94%) (Scheme 38).
With regard to mechanisms, initiation of the reaction was very similar to that of the β′-acetoxy allenoates, that is, firstly cationic intermediate 132, which has been proven to be a good With regard to mechanisms, initiation of the reaction was very similar to that of the β′-acetoxy allenoates, that is, firstly cationic intermediate 132, which has been proven to be a good Scheme 38. Phosphine-catalyzed [4+2] annulations of δ-acetoxy allenoates and cyclic β-carbonyl amides [76].
With regard to mechanisms, initiation of the reaction was very similar to that of the β -acetoxy allenoates, that is, firstly cationic intermediate 132, which has been proven to be a good 1,4-biselectrophile toward annulations with bisnucleophiles, was formed through an "addition−elimination" sequence. However, when 2-substituted cyclic 1,3-diones were utilized as the annulation partner, nucleophilic addition of the corresponding carbanionic diketone intermediate Preliminary catalytic asymmetric investigation of the two types of [4+2] annulations of δ-acetoxy allenoates was also conducted, and the results indicated that approximately 45% ee were obtained for the two reactions at this stage (Scheme 39).

[4+X] Annulations of Electron-Deficient 1,3-Dienes
In 2012, a novel phosphine-catalyzed asymmetric [4+1] annulation of MBH carbonates 145 with dicyano-2-methylenebut-3-enoates 144 was developed by Shi and coworkers (Scheme 40) [77]. Catalyst screening and reaction conditions optimization revealed that the multifunctional chiral phosphine catalyst TP-18 bearing an axially chiral binaphthyl scaffold was the most effective catalyst when the reaction was conducted in toluene at room temperature with 4 Å MS as the additive. A wide array of highly functionalized cyclopentenes 146 bearing an all-carbon quaternary stereogenic center was efficiently synthesized in moderate to good yields with excellent enantioselectivities. Based on previous correlative research works, a plausible reaction mechanism was proposed as: initially, an addition-elimination-deprotonation sequential processes resulted in the formation the 1,1-dipolar (

[4+X] Annulations of Electron-Deficient 1,3-Dienes
In 2012, a novel phosphine-catalyzed asymmetric [4+1] annulation of MBH carbonates 145 with dicyano-2-methylenebut-3-enoates 144 was developed by Shi and coworkers (Scheme 40) [77]. Catalyst screening and reaction conditions optimization revealed that the multifunctional chiral phosphine catalyst TP-18 bearing an axially chiral binaphthyl scaffold was the most effective catalyst when the reaction was conducted in toluene at room temperature with 4 Å MS as the additive. A wide array of highly functionalized cyclopentenes 146 bearing an all-carbon quaternary stereogenic center was efficiently synthesized in moderate to good yields with excellent enantioselectivities. Based on previous correlative research works, a plausible reaction mechanism was proposed as: initially, an addition-elimination-deprotonation sequential processes resulted in the formation the 1,1-dipolar (or 1,3-dipolar in other transfermations) phosphonium ylide 147; conjugate addition of phosphorus ylide 147 to the activated 1,3-dienes 144 at the C 1 -terminal position furnished intermediate 148; then, a consecutive proton transfer took place to cause alkene isomerization; and, finally, an intramolecular Michael addition followed by elimination of the phosphine catalyst gave rise to the [4+1] cycloadduct 146. Although Diels-Alder reaction are prevalent methods to assemble six-membered cyclohexenes, the sensitivity to steric hindrance and the strict requisite for proper electron-property usually limited the application. Delightedly, triphosphine initiated dipolar cycloadditions can supplement its deficiency. In 2018, Zhang's group firstly developed a phosphine-catalyzed [4+2] annulation of electron-deficient diene with the alkyl vinyl ketone that hardly occur in Diels-Alder reactions (Scheme 41) [78]. The [4+2] cycloaddition of a series of β,δ-diaryl-substituted electron-deficient dienes 151 with alkyl vinyl ketones 150 were carried out in THF at room temperature with the use of Ph2PMe (10 mol%) as the catalyst, which proceeded smoothly to produce functionalized cyclohexenes 152 in moderate to good yields with excellent diastereoselectivities. However, β-alkyl-substituted electron-deficient dienes and other electron-deficient olefins except alkyl vinyl ketone, such as acrolein and phenyl ketone, were incompatible in the [4+2] cycloadditions. Preliminary catalytic asymmetric investigation revealed that the use of Peng-Phos (TP-19) developed by their group afforded the chiral product 152a in 70% yield with 75% ee.
Although Diels-Alder reaction are prevalent methods to assemble six-membered cyclohexenes, the sensitivity to steric hindrance and the strict requisite for proper electron-property usually limited the application. Delightedly, triphosphine initiated dipolar cycloadditions can supplement its deficiency. In 2018, Zhang's group firstly developed a phosphine-catalyzed [4+2] annulation of electron-deficient diene with the alkyl vinyl ketone that hardly occur in Diels-Alder reactions (Scheme 41) [78]. The [4+2] cycloaddition of a series of β,δ-diaryl-substituted electron-deficient dienes 151 with alkyl vinyl ketones 150 were carried out in THF at room temperature with the use of Ph 2 PMe (10 mol%) as the catalyst, which proceeded smoothly to produce functionalized cyclohexenes 152 in moderate to good yields with excellent diastereoselectivities. However, β-alkyl-substituted electron-deficient dienes and other electron-deficient olefins except alkyl vinyl ketone, such as acrolein and phenyl ketone, were incompatible in the [4+2] cycloadditions. Preliminary catalytic asymmetric investigation revealed that the use of Peng-Phos (TP-19) developed by their group afforded the chiral product 152a in 70% yield with 75% ee. Although Diels-Alder reaction are prevalent methods to assemble six-membered cyclohexenes, the sensitivity to steric hindrance and the strict requisite for proper electron-property usually limited the application. Delightedly, triphosphine initiated dipolar cycloadditions can supplement its deficiency. In 2018, Zhang's group firstly developed a phosphine-catalyzed [4+2] annulation of electron-deficient diene with the alkyl vinyl ketone that hardly occur in Diels-Alder reactions (Scheme 41) [78]. The [4+2] cycloaddition of a series of β,δ-diaryl-substituted electron-deficient dienes 151 with alkyl vinyl ketones 150 were carried out in THF at room temperature with the use of Ph2PMe (10 mol%) as the catalyst, which proceeded smoothly to produce functionalized cyclohexenes 152 in moderate to good yields with excellent diastereoselectivities. However, β-alkyl-substituted electron-deficient dienes and other electron-deficient olefins except alkyl vinyl ketone, such as acrolein and phenyl ketone, were incompatible in the [4+2] cycloadditions. Preliminary catalytic asymmetric investigation revealed that the use of Peng-Phos (TP-19) developed by their group afforded the chiral product 152a in 70% yield with 75% ee.
Under the catalysis of phenylanine-derived LB-BA bifunctional chiral phosphine catalyst TP-20, the enantioselective 1,4-dipolar spiroannulations of cyclobutenones 153 with isatylidenemalononitriles 60 produced the enantioenriched 3-spiro-cyclohexenone-2-oxindoles 154 in good to excellent yields with up to 87% ee. Generally speaking, the organo-phosphine catalyzed reaction processes were usually initiated by the conjugate addition of the strong nucleophilic but weak basic phosphine atom to the C-C multiple bonds, such as alkenes, allenes and alkynes, but Zhang and coworkers proposed another unique and unclassical activation mode, that is, the nucleophilic phosphine catalyst initially chemoselectively attacked the carbonyl group of cyclobutenones to entice the reaction.

[4+2] Spiroannulations of Cyclobutenones
In 2015, the group of Zhang firstly exploited cyclobutenones as a novel type of 1,4-dipolar precursor in phosphine catalysis (Scheme 42) [79]. Under the catalysis of phenylanine-derived LB-BA bifunctional chiral phosphine catalyst TP-20, the enantioselective 1,4-dipolar spiroannulations of cyclobutenones 153 with isatylidenemalononitriles 60 produced the enantioenriched 3-spiro-cyclohexenone-2-oxindoles 154 in good to excellent yields with up to 87% ee. Generally speaking, the organo-phosphine catalyzed reaction processes were usually initiated by the conjugate addition of the strong nucleophilic but weak basic phosphine atom to the C-C multiple bonds, such as alkenes, allenes and alkynes, but Zhang and coworkers proposed another unique and unclassical activation mode, that is, the nucleophilic phosphine catalyst initially chemoselectively attacked the carbonyl group of cyclobutenones to entice the reaction. The subsequently formed oxygen anion of intermediate 155 promoted C-C single bond activation and cleavage of the small ring to furnish a novel type of vinyl-enolate-based 1,4-dipoles 156 and 157. Nucleophilic addition of the 1,4-dipoles to the isatylidenemalononitrile 60 formed intermediate 158.
Finally, cyclization accompanied with the regeneration of phosphine catalyst produced the spirocyclic products 154. Scheme

Other Miscellaneous [4C+X] Annulations
Usually, allenoates serve as C 2 or C 3 synthons in the phosphine-catalyzed cycloadditions, but in 2005, Kwon and coworkers demonstrated that the reaction of allenoates with aldehydes could also proceed via [4+2] cycloaddition process when bulky trialkyl phosphine catalysts were employed (Scheme 43) [80]. The subtlety of this unique chemoselectivity is that, when an allenoate was added by a phosphine catalyst, the use of sterically hindered trialkylphosphines, such as tricyclopentyl phosphine, facilitated the shift of equilibrium from the Ztoward E-isomeric zwitterionic intermediate to minimize the steric interaction between the phosphonium moiety and the ethoxy carbonyl group. Upon addition to the other aldehyde at the γ-carbon, the consequently formed alkoxide was in close proximity to the ester group, which would promote intramolecular nucleophilic attack of the alkoxide to the ester to furnish the lactone intermediate 166. The ejected ethoxide (EtO − ) then acts as a base to abstract proton from the lactone intermediate, which subsequently induce a successive proton-transfer processes. Elimination of the triphosphine catalyst released the final 2-pyrone products 160. In 2010, Shi, Wei and coworkers reported a highly enantioselective phosphine-catalyzed formal [4+2] tandem cyclizations between isatylidenemalononitriles 60 and 1,4-dien-3-one 169 to synthesize multi-stereogenic spirocyclicoxindoles 170 (Scheme 44) [81]. The LB-BA bifunctional chiral tertiary phosphine catalyst TP-21 derived from an axially chiral binaphthyl skeleton was able to achieve the asymmetric synthesis of the multi-stereogenic spirocyclicoxindoles 170 in high yields along with excellent enantioselectivities and diastereoselectivities. The whole reaction process progressed through a tandem "Rauhut-Currier/Michael/Rauhut-Currier" reaction sequence, where two molecules of 1,4-dien-3-one 169 were involved into the reaction and were embedded in the final product 170. Usually, allenoates serve as C2 or C3 synthons in the phosphine-catalyzed cycloadditions, but in 2005, Kwon and coworkers demonstrated that the reaction of allenoates with aldehydes could also proceed via [4+2] cycloaddition process when bulky trialkyl phosphine catalysts were employed (Scheme 43) [80]. The subtlety of this unique chemoselectivity is that, when an allenoate was added by a phosphine catalyst, the use of sterically hindered trialkylphosphines, such as tricyclopentyl phosphine, facilitated the shift of equilibrium from the Z-toward E-isomeric zwitterionic intermediate to minimize the steric interaction between the phosphonium moiety and the ethoxy carbonyl group. Upon addition to the other aldehyde at the γ-carbon, the consequently formed alkoxide was in close proximity to the ester group, which would promote intramolecular nucleophilic attack of the alkoxide to the ester to furnish the lactone intermediate 166. The ejected ethoxide (EtO − ) then acts as a base to abstract proton from the lactone intermediate, which subsequently induce a successive proton-transfer processes. Elimination of the triphosphine catalyst released the final 2-pyrone products 160. Scheme 44. Asymmetric synthesis of functionalized spirocyclohexanoneoxindoles [81].
In 2010, Shi, Wei and coworkers reported a highly enantioselective phosphine-catalyzed formal [4+2] tandem cyclizations between isatylidenemalononitriles 60 and 1,4-dien-3-one 169 to synthesize multi-stereogenic spirocyclicoxindoles 170 (Scheme 44) [81]. The LB-BA bifunctional chiral tertiary phosphine catalyst TP-21 derived from an axially chiral binaphthyl skeleton was able to achieve the asymmetric synthesis of the multi-stereogenic spirocyclicoxindoles 170 in high yields along with excellent enantioselectivities and diastereoselectivities. The whole reaction process progressed through a tandem "Rauhut-Currier/Michael/Rauhut-Currier" reaction sequence, where two molecules of 1,4-dien-3-one 169 were involved into the reaction and were embedded in the final product 170. Detailed reaction mechanism was proposed as below in scheme 45: firstly, nucleophilic addition of the chiral phosphine catalyst TP- 21  Most recently, the group of Jiang developed an efficient, chiral phosphine-triggered synthetic route to access functionalized cyclohexenes via a cascade [4+2] cycloaddition/semipinacol-type rearrangement (Scheme 46) [82]. In the presence of (+)-Duanphos (TP-22), a series of 2-(acyl)but-2-enenitriles 176 were treated with MBH (Morita-Baylis-Hillman) carbonates 175 in DCE, affording the desired cyclohexene derivatives 177 in high levels of enantio-and diastereoselectivities (up to 98% ee and >20:1 dr). This reaction was initiated by the nucleophilic addition of the chiral phosphine catalyst to the MBH carbonates and a subsequent ejection of CO2 and t BuO − to give the phosphonium intermediate 178, which would be attacked by the incoming nucleophiles 179 that were deprotonated from the (E)-2-benzoyl-3-phenylbut-2-enenitriles 176. Subsequent cyclization via intramolecular nucleophilic addition to the ketones formed the six-membered zwitterionic intermediate 181. Finally, semipinacol-type sigmatropic 1,3-hydrogen shift occurred leading to ring-opening, which was followed by intramolecular SN2 substitution to regenerate the phosphine catalyst to complete the catalytic cycle and deliver the cyclohexene product 177.
In the presence of (+)-Duanphos (TP-22), a series of 2-(acyl)but-2-enenitriles 176 were treated with MBH (Morita-Baylis-Hillman) carbonates 175 in DCE, affording the desired cyclohexene derivatives 177 in high levels of enantio-and diastereoselectivities (up to 98% ee and >20:1 dr). This reaction was initiated by the nucleophilic addition of the chiral phosphine catalyst to the MBH carbonates and a subsequent ejection of CO 2 and t BuO − to give the phosphonium intermediate 178, which would be attacked by the incoming nucleophiles 179 that were deprotonated from the (E)-2-benzoyl-3-phenylbut-2-enenitriles 176. Subsequent cyclization via intramolecular nucleophilic addition to the ketones formed the six-membered zwitterionic intermediate 181. Finally, semipinacol-type sigmatropic 1,3-hydrogen shift occurred leading to ring-opening, which was followed by intramolecular S N 2 substitution to regenerate the phosphine catalyst to complete the catalytic cycle and deliver the cyclohexene product 177.

Conclusions
In summary, with the continuous efforts to explore novel C4 annulation partners in the area of phosphine catalysis, many types of substrates have been successfully introduced into the [4C+X] cycloadditions. Except electron-deficient dienes and cyclobutenones, almost all others types of substrates are based on the skeleton of allenes, namely α-substituted allenoates, δ-substituted allenoates, α-methyl allene ketones, β′-acetoxy allenoates and δ-acetoxy allenoates. Despite these great studies together with the corresponding asymmetric [4C+X] annulations have been performed, there is still much to be discovered. Except for α-substituted allenoates, there are very few types of [4C+X] annulations based on the already known C4 synthons. Searching for even more extensive suitable coupling partners to cyclize with them is always highly desirable. On the other hand, finding novel C4 synthetic blocks and relevant novel annulation patterns as well as the development of the corresponding asymmetric catalytic forms are undoubtedly the permanent goals in this field due to its great efficiency to construct enantioenriched functionalized cyclic compounds. Meanwhile, some of the methodologies posed very obvious drawbacks, such as limited substrates compatibility and poor stereoselectivity, thus deep theoretical studies as well as appropriate catalyst design are also desired to address these issues. Nevertheless, with the increasing research interests thrown into the field of phosphine catalysis, we are confident that much more meaningful phosphine-catalyzed [4C+X] annulations will spring up in the next decade. We especially expect wonderful applications of these methodologies into the synthesis of natural products or the preparations of biologically important molecules in the future.

Conclusions
In summary, with the continuous efforts to explore novel C 4 annulation partners in the area of phosphine catalysis, many types of substrates have been successfully introduced into the [4C+X] cycloadditions. Except electron-deficient dienes and cyclobutenones, almost all others types of substrates are based on the skeleton of allenes, namely α-substituted allenoates, δ-substituted allenoates, α-methyl allene ketones, β -acetoxy allenoates and δ-acetoxy allenoates. Despite these great studies together with the corresponding asymmetric [4C+X] annulations have been performed, there is still much to be discovered. Except for α-substituted allenoates, there are very few types of [4C+X] annulations based on the already known C 4 synthons. Searching for even more extensive suitable coupling partners to cyclize with them is always highly desirable. On the other hand, finding novel C 4 synthetic blocks and relevant novel annulation patterns as well as the development of the corresponding asymmetric catalytic forms are undoubtedly the permanent goals in this field due to its great efficiency to construct enantioenriched functionalized cyclic compounds. Meanwhile, some of the methodologies posed very obvious drawbacks, such as limited substrates compatibility and poor stereoselectivity, thus deep theoretical studies as well as appropriate catalyst design are also desired to address these issues. Nevertheless, with the increasing research interests thrown into the field of phosphine catalysis, we are confident that much more meaningful phosphine-catalyzed [4C+X] annulations will spring up in the next decade. We especially expect wonderful applications of these methodologies into the synthesis of natural products or the preparations of biologically important molecules in the future.
Funding: Financial support was received from the "1000-Youth Talents Plan", Hunan Province Science Foundation for Youths (2018JJ3195).