Recent Advances in the Synthesis of Spiroheterocycles via N-Heterocyclic Carbene Organocatalysis

Spiroheterocycles are regarded as a privileged framework because of their wide distribution in various natural products and synthetic molecules and promising bioactivities. This review focuses on the recent advances in the synthesis of spiroheterocycles by using the strategy of N-heterocyclic carbene (NHC) organocatalysis, and is organized based on the stereoselectivity and the reactive intermediates. According to the stereochemistry, this review was divided into two main parts, covering racemic and enantioselective versions. In each part, we firstly describe the synthetic transformations using nucleophilic Breslow intermediates, and then discuss the reactions that employ electrophilic acylazolium or radical cation intermediates. With those distinct catalytic activation modes of NHC organocatlysis, we expect this synthetic protocol will possibly produce new molecules with structural novelty and complexity, which may warrant further research in the field of drug discovery.

In biological systems, many complicated biochemical transformations are catalyzed by enzymes; for example, the nucleophilic acylation reaction is catalyzed by transketolase enzymes [25], in the presence of a coenzyme named thiamine (1, Figure 2) [26]. This biocatalytic transformation is interesting to many chemists because it can help elucidate the nature and design of biomimic catalysis [27]. Early carbene chemistry was developed around the 1900s [27][28][29][30][31][32]. Since Bertrand [33,34], Arduengo [35] and their colleagues reported stable nucleophilic carbenes, chemists have set off a gold rush in this field, and NHCs have been successfully applied to organocatalysis, thereby enabling various unconventional chemical transformations via diverse reactive intermediates [36][37][38][39]. According to their different core structures, NHCs can be divided into four types, namely, thiazolium, triazolium, imidazolium, and imidazolin-2-ylidenes [37]. Rovis et al., further summarized diverse NHC catalysts with different substituents (for details, see Figure 3) [40]. Early carbene chemistry was developed around the 1900s [27][28][29][30][31][32]. Since Bertrand [33,34], Arduengo [35] and their colleagues reported stable nucleophilic carbenes, chemists have set off a gold rush in this field, and NHCs have been successfully applied to organocatalysis, thereby enabling various unconventional chemical transformations via diverse reactive intermediates [36][37][38][39]. According to their different core structures, NHCs can be divided into four types, namely, thiazolium, triazolium, imidazolium, and imidazolin-2-ylidenes [37]. Rovis et al., further summarized diverse NHC catalysts with different substituents (for details, see Figure 3) [40]. In the presence of these NHC catalysts, various reactive species can be generated from aldehydes and other carbonyls. For example, Breslow intermediate 2, enolate 3, homoenolate 4, acylazolium 5, and α,β-unsaturated acylazolium 6 are the most investigated. Among these species, Breslow intermediate, enolate, and homoenolate are typically used as nucleophiles, and acylazolium and α,β-unsaturated acylazolium are used as electrophilic species. Mutual transformation among these intermediates enables the unique NHC-catalyzed reactions (Scheme 1) [41]. This review includes recent examples of different catalysts and reactions used to synthesize spiroheterocycles via NHC organocatalysis. Examples have been selected to emphasize notable spirocyclization strategies and compare the reactivity and selectivity of different types of NHC organocatalysts. This synthetic protocol produces new spirocyclic molecules with structural novelty and complexity, which may warrant further research in the field of drug discovery. In the presence of these NHC catalysts, various reactive species can be generated from aldehydes and other carbonyls. For example, Breslow intermediate 2, enolate 3, homoenolate 4, acylazolium 5, and α,β-unsaturated acylazolium 6 are the most investigated. Among these species, Breslow intermediate, enolate, and homoenolate are typically used as nucleophiles, and acylazolium and α,β-unsaturated acylazolium are used as electrophilic species. Mutual transformation among these intermediates enables the unique NHC-catalyzed reactions (Scheme 1) [41].  In the presence of these NHC catalysts, various reactive species can be generated from aldehydes and other carbonyls. For example, Breslow intermediate 2, enolate 3, homoenolate 4, acylazolium 5, and α,β-unsaturated acylazolium 6 are the most investigated. Among these species, Breslow intermediate, enolate, and homoenolate are typically used as nucleophiles, and acylazolium and α,β-unsaturated acylazolium are used as electrophilic species. Mutual transformation among these intermediates enables the unique NHC-catalyzed reactions (Scheme 1) [41]. This review includes recent examples of different catalysts and reactions used to synthesize spiroheterocycles via NHC organocatalysis. Examples have been selected to emphasize notable spirocyclization strategies and compare the reactivity and selectivity of different types of NHC organocatalysts. This synthetic protocol produces new spirocyclic molecules with structural novelty and complexity, which may warrant further research in the field of drug discovery. This review includes recent examples of different catalysts and reactions used to synthesize spiroheterocycles via NHC organocatalysis. Examples have been selected to emphasize notable spirocyclization strategies and compare the reactivity and selectivity of different types of NHC organocatalysts. This synthetic protocol produces new spirocyclic molecules with structural novelty and complexity, which may warrant further research in the field of drug discovery.

Catalysis Involving Nucleophilic Breslow Intermediates
In 2006, Nair et al., reported the addition of enals to 1,2-dicarbonyl compounds via a homoenolate pathway, thereby opening a route to γ-spirolactones [42] (Scheme 2). In this reaction, α,β-unsaturated aldehydes 7 are used as nucleophiles in the presence of NHC catalyst, and 1,2-cyclohexanedione (8) and isatins 10 are used as competent electrophiles. The yield of spirocyclohexanone products 9 ranges from 60% to 74%, whereas spirooxindole γ-lactones 11 are obtained in 85-98% yields. However, the diastereoselectivity of this method (1:1 dr) was unsatisfactory. After addition of the NHC catalyst 12 to the aldehydes 7 and subsequent proton transfer in the intermediate 13, this reaction begins with the nucleophilic addition of Breslow intermediates 14 to 15, thereby giving enol azolium 16. Tautomerization of 16 produces acylazolium 17, which subsequently cyclizes to deliver the γ-lactone product 18 and release the catalyst.

Catalysis Involving Nucleophilic Breslow Intermediates
In 2006, Nair et al., reported the addition of enals to 1,2-dicarbonyl compounds via a homoenolate pathway, thereby opening a route to γ-spirolactones [42] (Scheme 2). In this reaction, α,β-unsaturated aldehydes 7 are used as nucleophiles in the presence of NHC catalyst, and 1,2-cyclohexanedione (8) and isatins 10 are used as competent electrophiles. The yield of spirocyclohexanone products 9 ranges from 60% to 74%, whereas spirooxindole γ-lactones 11 are obtained in 85-98% yields. However, the diastereoselectivity of this method (1:1 dr) was unsatisfactory. After addition of the NHC catalyst 12 to the aldehydes 7 and subsequent proton transfer in the intermediate 13, this reaction begins with the nucleophilic addition of Breslow intermediates 14 to 15, thereby giving enol azolium 16. Tautomerization of 16 produces acylazolium 17, which subsequently cyclizes to deliver the γ-lactone product 18 and release the catalyst. In 2011, Gravel and co-workers exploited a Stetter-aldol-aldol reaction starting with phthaldialdehydes 25 and the acceptors 26 to generate spiro bis-indanes 27 in a diastereoselective manner (Scheme 5). Electron-donating groups (EDGs) considerably affect the reactivity of the reaction, resulting in a modest yield (25%); however, electron-withdrawing groups (EWGs) enhance the electrophilicity of the Michael acceptor, thereby reducing the reaction time and increasing the product yield (75%) [44]. In 2011, Gravel and co-workers exploited a Stetter-aldol-aldol reaction starting with phthaldialdehydes 25 and the acceptors 26 to generate spiro bis-indanes 27 in a diastereoselective manner (Scheme 5). Electron-donating groups (EDGs) considerably affect the reactivity of the reaction, resulting in a modest yield (25%); however, electron-withdrawing groups (EWGs) enhance the electrophilicity of the Michael acceptor, thereby reducing the reaction time and increasing the product yield (75%) [44]. In 2011, Gravel and co-workers exploited a Stetter-aldol-aldol reaction starting with phthaldialdehydes 25 and the acceptors 26 to generate spiro bis-indanes 27 in a diastereoselective manner (Scheme 5). Electron-donating groups (EDGs) considerably affect the reactivity of the reaction, resulting in a modest yield (25%); however, electron-withdrawing groups (EWGs) enhance the electrophilicity of the Michael acceptor, thereby reducing the reaction time and increasing the product yield (75%) [44]. In 2011, Gravel and co-workers exploited a Stetter-aldol-aldol reaction starting with phthaldialdehydes 25 and the acceptors 26 to generate spiro bis-indanes 27 in a diastereoselective manner (Scheme 5). Electron-donating groups (EDGs) considerably affect the reactivity of the reaction, resulting in a modest yield (25%); however, electron-withdrawing groups (EWGs) enhance the electrophilicity of the Michael acceptor, thereby reducing the reaction time and increasing the product yield (75%) [44]. Chi and colleagues developed a diastereoselective method for a facile access to spirocyclic oxindoles 29 and 31 containing two quaternary carbons. Enal-derived homoenolate intermediates with three consecutive reactive positions are used in the reaction, and a special oxindole-derived α,β-unsaturated imines with β,β-disubstituents 28 and 30 are the reaction partner. Initial studies have shown that catalysts based on an imidazolium skeleton are ineffective in this reaction, whereas the triazolium-based catalyst D2 has proven to be promising. With this catalyst, the desired spiroindole products can be obtained in good to excellent isolated yields (69-96%) with moderate to good diastereoselectivity (2:1 to 12:1 dr) (Scheme 6) [45].
In 2013, Yao and co-workers employed an efficient NHC-catalyzed [4+2] annulation of α,β-dibromoaldehyde 32 or α-bromo-α,β-unsaturated aldehydes 34 bearing γ-H with isatin derivatives to prepare spirocyclic oxindole-dihydropyranones 33 (Scheme 7). In this reaction, the condensation of the NHC catalyst B1 and 34 produces Breslow intermediate 35, which is subsequently oxidized to 36 through intramolecular debromination. Then, acylazoliumion 36 is deprotonated at the γ-position to give the vinyl enolate 37 under basic conditions. Afterward, intermediate 37 reacts with isatins 10 probably through an oxo-Diels-Alder reaction mechanism or a non-concerted nucleophilic addition followed by intramolecular cyclization for the target product Chi and colleagues developed a diastereoselective method for a facile access to spirocyclic oxindoles 29 and 31 containing two quaternary carbons. Enal-derived homoenolate intermediates with three consecutive reactive positions are used in the reaction, and a special oxindole-derived α,β-unsaturated imines with β,β-disubstituents 28 and 30 are the reaction partner. Initial studies have shown that catalysts based on an imidazolium skeleton are ineffective in this reaction, whereas the triazolium-based catalyst D 2 has proven to be promising. With this catalyst, the desired spiroindole products can be obtained in good to excellent isolated yields (69-96%) with moderate to good diastereoselectivity (2:1 to 12:1 dr) (Scheme 6) [45]. Chi and colleagues developed a diastereoselective method for a facile access to spirocyclic oxindoles 29 and 31 containing two quaternary carbons. Enal-derived homoenolate intermediates with three consecutive reactive positions are used in the reaction, and a special oxindole-derived α,β-unsaturated imines with β,β-disubstituents 28 and 30 are the reaction partner. Initial studies have shown that catalysts based on an imidazolium skeleton are ineffective in this reaction, whereas the triazolium-based catalyst D2 has proven to be promising. With this catalyst, the desired spiroindole products can be obtained in good to excellent isolated yields (69-96%) with moderate to good diastereoselectivity (2:1 to 12:1 dr) (Scheme 6) [45].
In 2013, Yao and co-workers employed an efficient NHC-catalyzed [4+2] annulation of α,β-dibromoaldehyde 32 or α-bromo-α,β-unsaturated aldehydes 34 bearing γ-H with isatin derivatives to prepare spirocyclic oxindole-dihydropyranones 33 (Scheme 7). In this reaction, the condensation of the NHC catalyst B1 and 34 produces Breslow intermediate 35, which is subsequently oxidized to 36 through intramolecular debromination. Then, acylazoliumion 36 is deprotonated at the γ-position to give the vinyl enolate 37 under basic conditions. Afterward, intermediate 37 reacts with isatins 10 probably through an oxo-Diels-Alder reaction mechanism or a non-concerted nucleophilic addition followed by intramolecular cyclization for the target product In 2013, Yao and co-workers employed an efficient NHC-catalyzed [4+2] annulation of α,β-dibromoaldehyde 32 or α-bromo-α,β-unsaturated aldehydes 34 bearing γ-H with isatin derivatives to prepare spirocyclic oxindole-dihydropyranones 33 (Scheme 7). In this reaction, the condensation of the NHC catalyst B 1 and 34 produces Breslow intermediate 35, which is subsequently oxidized to 36 through intramolecular debromination. Then, acylazoliumion 36 is deprotonated at the γ-position to give the vinyl enolate 37 under basic conditions. Afterward, intermediate 37 reacts with isatins 10 probably through an oxo-Diels-Alder reaction mechanism or a non-concerted nucleophilic addition followed by intramolecular cyclization for the target product 33 and and the catalyst is released from intermediate 38 (Scheme 8). The yield of spirocyclic oxindole-dihydropyranones in this reaction ranges from 75% to 93% [46]. Later, Glorius and colleagues employed a conjugate umpolung strategy to synthesize spirooxindole scaffolds with contiguous quaternary stereocenters. The mechanism of this reaction involves an NHC catalyst and an enal 39 that initially form a tetrahedral intermediate and subsequently transform to the Breslow intermediate. In the presence of an acid co-catalyst, the species can react with isatin 10 via one of two possible pre-transition-state assemblies. The preference for the favored pathway leads to the observed major diastereoisomer. After an adduct diastereoselectively forms, an intramolecular alkoxide attack at the carbonyl group produces the desired spirooxindoles 40 and regenerates the NHC catalyst. The yields in this transformation range from 68% to 98%, and the diastereoselectivity is generally good (8:1 to >20:1 dr) (Scheme 9) [47]. Later, Glorius and colleagues employed a conjugate umpolung strategy to synthesize spirooxindole scaffolds with contiguous quaternary stereocenters. The mechanism of this reaction involves an NHC catalyst and an enal 39 that initially form a tetrahedral intermediate and subsequently transform to the Breslow intermediate. In the presence of an acid co-catalyst, the species can react with isatin 10 via one of two possible pre-transition-state assemblies. The preference for the favored pathway leads to the observed major diastereoisomer. After an adduct diastereoselectively forms, an intramolecular alkoxide attack at the carbonyl group produces the desired spirooxindoles 40 and regenerates the NHC catalyst. The yields in this transformation range from 68% to 98%, and the diastereoselectivity is generally good (8:1 to >20:1 dr) (Scheme 9) [47]. Later, Glorius and colleagues employed a conjugate umpolung strategy to synthesize spirooxindole scaffolds with contiguous quaternary stereocenters. The mechanism of this reaction involves an NHC catalyst and an enal 39 that initially form a tetrahedral intermediate and subsequently transform to the Breslow intermediate. In the presence of an acid co-catalyst, the species can react with isatin 10 via one of two possible pre-transition-state assemblies. The preference for the favored pathway leads to the observed major diastereoisomer. After an adduct diastereoselectively forms, an intramolecular alkoxide attack at the carbonyl group produces the desired spirooxindoles 40 and regenerates the NHC catalyst. The yields in this transformation range from 68% to 98%, and the diastereoselectivity is generally good (8:1 to >20:1 dr) (Scheme 9) [47].

Catalysis Involving Acylazolium Intermediates
In recent years, efforts have been devoted to investigating NHC-based acylazolium and azolium enolate intermediates. The most commonly used method to access NHC-derived α,β-unsaturated acylazolium intermediates is based on an internal redox activation of α-oxidizable aldehydes. Du, Lu and co-workers reported an effective strategy to synthesize spirooxindole 4H-pyran-2-one 43 derivatives through the NHC-catalyzed three-component domino reaction of oxindoles 42 and ynals 41. This reaction provides moderate to good yields (40-93%) with excellent diastereoselectivity (up to >95:5 dr) (Scheme 10) [48]. In 2017, the same group published an NHC-catalyzed formal [3+3] annulation of isatin-derived α,β-unsaturated acids 44 with 1,3-dicarbonyl compounds 45 to synthesize 3,4'-spirooxindole lactones 46. Of note, acid substrates are generally more bench stable than aldehydes; in this case, these substrates can be activated in situ (Scheme 11). Under optimized conditions, a wide range of substrates produce the corresponding products in moderate yields ranging from 18% to 90% [49].

Catalysis Involving Acylazolium Intermediates
In recent years, efforts have been devoted to investigating NHC-based acylazolium and azolium enolate intermediates. The most commonly used method to access NHC-derived α,β-unsaturated acylazolium intermediates is based on an internal redox activation of α-oxidizable aldehydes. Du, Lu and co-workers reported an effective strategy to synthesize spirooxindole 4H-pyran-2-one 43 derivatives through the NHC-catalyzed three-component domino reaction of oxindoles 42 and ynals 41. This reaction provides moderate to good yields (40-93%) with excellent diastereoselectivity (up to >95:5 dr) (Scheme 10) [48].

Catalysis Involving Acylazolium Intermediates
In recent years, efforts have been devoted to investigating NHC-based acylazolium and azolium enolate intermediates. The most commonly used method to access NHC-derived α,β-unsaturated acylazolium intermediates is based on an internal redox activation of α-oxidizable aldehydes. Du, Lu and co-workers reported an effective strategy to synthesize spirooxindole 4H-pyran-2-one 43 derivatives through the NHC-catalyzed three-component domino reaction of oxindoles 42 and ynals 41. This reaction provides moderate to good yields (40-93%) with excellent diastereoselectivity (up to >95:5 dr) (Scheme 10) [48]. In 2017, the same group published an NHC-catalyzed formal [3+3] annulation of isatin-derived α,β-unsaturated acids 44 with 1,3-dicarbonyl compounds 45 to synthesize 3,4'-spirooxindole lactones 46. Of note, acid substrates are generally more bench stable than aldehydes; in this case, these substrates can be activated in situ (Scheme 11). Under optimized conditions, a wide range of substrates produce the corresponding products in moderate yields ranging from 18% to 90% [49].

46.
Of note, acid substrates are generally more bench stable than aldehydes; in this case, these substrates can be activated in situ (Scheme 11). Under optimized conditions, a wide range of substrates produce the corresponding products in moderate yields ranging from 18% to 90% [49].

Catalysis Involving Chiral Acylazolium Intermediates
In recent years, many research groups have made impressive contributions to the applications of α,β-unsaturated acyl azoliums generated from different precursors, such as ynals, enals, α,β-unsaturated acyl fluorides, and esters. After Yao's work [61], Du
Biju, Yetra and co-workers presented an enantioselective NHC-catalyzed annulation of enals 7 with 3-hydroxy oxindoles 79, resulting in the formation of spiro γ-butyrolactones 80. The products are formed in moderate to good yields (63-88%) and with good enantioselectivity (up to 99:1 er) and diastereoselectivity (up to 7:1 dr). The reaction likely proceeds via the generation of the chiral α,β-unsaturated acyl azolium intermediate, followed by its interception with oxindoles in a formal [3+2] cyclization to afford the spiro compounds (Scheme 25) [63]. Recently, Qi and colleagues reported an efficient strategy to access 5,6-dihydropyridinones, 3,4-dihydropyridinones and spirooxindoles via the NHC-catalyzed [3+3] annulation of 2-aminoacrylates with cinnamaldehydes and oxindole-derived enals. Moreover, two different dihydropyridinones were produced by using this novel strategy with two different bases, namely, DABCO and LiOAc. They also synthesized a series of spirooxindole products in moderate to good Recently, Qi and colleagues reported an efficient strategy to access 5,6-dihydropyridinones, 3,4-dihydropyridinones and spirooxindoles via the NHC-catalyzed [3+3] annulation of 2-aminoacrylates with cinnamaldehydes and oxindole-derived enals. Moreover, two different dihydropyridinones were produced by using this novel strategy with two different bases, namely, DABCO and LiOAc. They also synthesized a series of spirooxindole products in moderate to good yields (61-98%). An asymmetric catalytic version of this methodology has been conducted to investigate this novel strategy, and the desired product yields range from 67% to 83% with up to 99% ee [50].

Selected Examples
In 2017, Ye and co-workers developed an NHC-promoted synthesis of chiral spirocyclopentene-2-oxindoles 82 via a Michael-aldol-lactonization decarboxylation cascade of bromoenals 76 and oxindoles 81. The spirocyclopentene-2-oxindoles bearing two contiguous stereocenters are obtained in good yields (35-74%) with good to excellent diastereoselectivity (up to >20:1 dr) and high enantioselectivities (up to 92% ee) (Scheme 26) [64]. yields (61-98%). An asymmetric catalytic version of this methodology has been conducted to investigate this novel strategy, and the desired product yields range from 67% to 83% with up to 99% ee [50]. In 2017, Ye and co-workers developed an NHC-promoted synthesis of chiral spirocyclopentene-2-oxindoles 82 via a Michael-aldol-lactonization decarboxylation cascade of bromoenals 76 and oxindoles 81. The spirocyclopentene-2-oxindoles bearing two contiguous stereocenters are obtained in good yields (35-74%) with good to excellent diastereoselectivity (up to >20:1 dr) and high enantioselectivities (up to 92% ee) (Scheme 26) [64]. An asymmetric intramolecular dearomatization of indoles using oxidative NHC catalysis was reported by Studer and co-workers. In this reaction, the NH-free indolyls 83 as starting materials, can be easily transformed to valuable spirocyclic indolenines 84 with an all-carbon quaternary stereocenter through catalytic asymmetric dearomatization of an indole core (Scheme 27). The products form in good yields of up to 98% and >99% ee are obtained [65]. An asymmetric intramolecular dearomatization of indoles using oxidative NHC catalysis was reported by Studer and co-workers. In this reaction, the NH-free indolyls 83 as starting materials, can be easily transformed to valuable spirocyclic indolenines 84 with an all-carbon quaternary stereocenter through catalytic asymmetric dearomatization of an indole core (Scheme 27). The products form in good yields of up to 98% and >99% ee are obtained [65]. An asymmetric intramolecular dearomatization of indoles using oxidative NHC catalysis was reported by Studer and co-workers. In this reaction, the NH-free indolyls 83 as starting materials, can be easily transformed to valuable spirocyclic indolenines 84 with an all-carbon quaternary stereocenter through catalytic asymmetric dearomatization of an indole core (Scheme 27). The products form in good yields of up to 98% and >99% ee are obtained [65].

Selected Examples
Proposed mechanism  Meanwhile, the cross-coupling of the homoenolate radical 87 and enolate radical 88 generated from dioxindole 79 affords adduct 89, which is tautomerized to acylazolium 90. Finally, with the assistant of base, the lactonization of 90 generates the spiro-product 80 and releases the NHC catalyst [66]. In the past decades, spiroheterocycles have attracted great interests among the scientific community due to their special physiological and pharmacological properties, such as antitubercular, antiparasitic, antifungal and antitumor activities [8,67,68]. Thus, chemists have made a lot of efforts on the synthesis of the corresponding skeletons to find promising compounds that might be useful in the area of drug research and development.

Conclusions
This review highlights the recent application of NHC organocatalysis in the synthesis of spiroheterocyles, and the aforementioned excellent works show that complex molecular skeletons can be constructed efficiently and rapidly by using simple starting materials under mild conditions. Although certain NHC catalysts and strategies are possible "privileged" routes for the efficient construction of spirocyclic derivatives, several problems, such as high catalyst loading and sensitivity to water and air, remain unsolved and thus need further investigations to develop new strategies. Nevertheless, we believe that the existing synthetic protocols and the developing transformations will provide powerful and efficient NHC organocatalytic reactions for the continuous construction of useful spiroheterocycles.