Next Article in Journal
Design, Synthesis and Anticancer Evaluation of Fangchinoline Derivatives
Next Article in Special Issue
Organocatalytic Access to Enantioenriched Spirooxindole-Based 4-Methyleneazetidines
Previous Article in Journal
Preparation and Bioactivity Assessment of Chitosan-1-Acetic Acid-5-Flurouracil Conjugates as Cancer Prodrugs
Previous Article in Special Issue
9,10-Dihydrophenanthrene with Two Spiro(dibenzocycloheptatriene) Units: A Highly Strained Caged Hydrocarbon Exhibiting Reversible Electrochromic Behavior
 
 
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

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

1
Antibiotics Research and Re-Evaluation Key Laboratory of Sichuan Province, Sichuan Industrial Institute of Antibiotics, Chengdu University, Chengdu 610052, China
2
Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu 610041, China
3
College of Ethnic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
4
University of Chinese Academy of Sciences, Beijing 100049, China
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Molecules 2017, 22(11), 1882; https://doi.org/10.3390/molecules22111882
Submission received: 26 September 2017 / Accepted: 30 October 2017 / Published: 8 November 2017
(This article belongs to the Special Issue Advances in Spiro Compounds)

Abstract

:
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.

1. Introduction

Spiroheterocycles are a class of privileged scaffolds widely occurring in many natural products and pharmaceutical compounds [1,2,3]. Recently, spiroheterocycles have received special attention in medicinal chemistry because of their promising bioactivities, such as antitubercular, antiparasitic, and antitumor properties [2,4,5]. For example, citrinadins A and B isolated from Penicillium citrinum N059 strain show modest cytotoxicity against murine leukemia L1210 cells [6]. The alkaloid citrinalin A, a bioactive secondary metabolite of Penicillium species, exhibits antimycobacterial, cytotoxic and antifungal activities [7]. The marine alkaloid discorhabdin A inhibits protein-protein interactions, interrupting the interaction between hypoxia-inducible factor 1a (HIF-1a) and its transcriptional coactivator p300 [8]. Trigolutes A–C isolated from Trigonostemon lutescens twigs, are used in Thai folk medicine to cure food poisoning, asthma, and poisonous snake bites [9]. Spirotryprostatin B, which is a diketopiperazine alkaloid isolated from Aspergillus fumigatus, displays cell cycle inhibitory activity [10] (Figure 1). Due to their important physiological functions, the corresponding skeletons have therefore attracted great interest from synthetic chemists.
During the last two decades, with extensive and in-depth research on cycloadditions [11,12,13,14], spirocyclization reactions, such as alkylation [15,16], ring-expansion method [17], rearrangement- based approaches [18], the palladium-catalyzed [3+2] cycloaddition [19], [2+1] cycloadditions [20] and other methods, have been established to construct and modify these frameworks. Although significant advances have been achieved, constructing complex molecules with congested tetrasubstituted carbon stereocenters in one step under mild conditions still remains challenging [21,22,23,24].
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].
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.

2. NHC-Catalyzed Synthesis of Spiroheterocycles

2.1. Synthesis of Racemic Spiroheterocycles via NHC-Catalyzed Reactions

2.1.1. 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.
Later, Gravel and co-workers developed one-pot intermolecular Stetter reactions coupled with intramolecular Michael or aldol reactions. In these reactions, after conjugate addition of the Breslow intermediate 19 to the Michael acceptor, enolate 20 is trapped by an aldehyde or an Michael acceptor and gives intermediate 21 or 22 (Scheme 3). Later on, they expanded this reaction to spiroindane skeletons. The corresponding spiroindanes 24 are synthesized from o-formylchalcone derivatives 23 in modest to good yields (31–86%) and with excellent diastereoselectivities (up to >20:1 dr) (Scheme 4) [43].
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 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].

2.1.2. 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].
Qi and co-workers established an NHC-catalyzed synthesis of dihydropyridinones and spirooxindoles. With the external oxidant 48, the reaction proceeds via a [3+3] annulation of cinnamaldehydes 7 or isatin-derived enals 51 in the presence of 2-aminoacrylates 47 (Scheme 12). Two different dihydropyridinones 49 and 50 are generated through this novel strategy by using different bases, and a series of spirooxindole derivatives 52 is also synthesized in moderate to good yields (61–98%) (Scheme 13) [50].

2.2. Synthesis of Chiral Spiroheterocycles via NHC-Catalyzed Reactions

2.2.1. Catalysis Involving Chiral Nucleophilic Breslow Intermediates

Ye and colleagues demonstrated an enantioselective NHC-catalyzed cycloaddition reaction that generates spirocyclic oxindole-β-lactones 54 from ketenes 53 and isatins 10 through a formal [2+2] annulation (Scheme 14). This reaction efficiently forms products in good yields (36–99%) with good diastereoselectivities (3:1 to >20:1 dr) and high enantioselectivities (83–99% ee) [51].
Ye and co-workers further demonstrated that bifunctional NHC with a free hydroxyl group is an efficient catalyst for the enantioselective Staudinger reaction of ketenes 53 with isatin-derived ketimines 55 (Scheme 15), thereby producing the corresponding spirocyclic oxindolo-β-lactams 56 in high yields (70–92%) with excellent diastereoselectivities (up to >20:1 dr) and enantioselectivities (87–99% ee) [52].
Xu and Ren developed an NHC-catalyzed oxidative [2+2] annulation reaction to generate spiro-β-lactams 56 bearing two vicinal stereogenic centers from simple aliphatic aldehydes 57 and isatin-derived ketimines 55. This reaction efficiently delivers products in 33–82% yield, 93–98% ee, and 5:1 to 20:1 dr. The remarkable features of this formal [2+2] annulation reaction include direct carbon functionalization of aliphatic aldehydes, easily accessible starting materials, mild reaction conditions, and readily removable protecting groups (Scheme 16) [53].
In 2014, Ma group illustrated an asymmetric formal [3+2] annulation of aryl 3-bromoenals 58 and isatins 10 to produce spirooxindole–butenolides 59 in excellent yield with high enantioselectivity through hydrogen-bonding activation-assisted chiral NHC catalysis (Scheme 17). This reaction provides excellent yield (85–99%) and high enantioselectivity (93:7–96:4 er) [54].
In the same year, Glorius and co-workers developed a highly enantioselective NHC-catalyzed formal [3+2] annulation of α,β-unsaturated aldehydes 7 with azaaurones or aurone 60. This reaction begins with an initial conjugate addition of homoenolate to a Michael acceptor. The resultant enol−azolium tautomerizes to acylazolium. After the pendant undergoes cyclization, the enolate liberates free carbenes and affords the desired spiro-products 61. This transformation provides moderate to good yields ranging from 42% to 83%, a generally good diastereoselectivity (3:1 to >20:1 dr) and an excellent enantioselectivity (88–95% ee) (Scheme 18) [36].
In 2016, Glorius and colleagues successfully used modified benzofurans and benzothiophenes 62 as substrates in an enantioselective NHC-catalyzed intramolecular hydroacylation/dearomatization transformation (Scheme 19). This reaction provides access to a class of scarcely explored spirocycles 63 and 64 with up to 99% ee in modest to good yields (51–97%). The products bear interesting three-dimensional pseudo-axial chirality and shows a typical ketone reactivity [55].
Scheidt’s group constructed chiral spirooxindole lactones 67 using a Lewis acid in conjunction with an NHC without additives [56,57]. After Scheidt’s work, Xu et al., described a 1-hydroxy- benzotriazole (HOBt, 66)-assisted, NHC-catalyzed direct β-functionalization reaction of saturated carboxylic esters 65 that undergo a formal [3+2] annulation with isatins 10 in a highly efficient, diastereoselective, and enantioselective manner to afford chiral spirooxindole lactones 67. Notably, the use of a catalytic amount of HOBt in this reaction remarkably improves diastereoselectivity (>20:1 dr) and enantioselectivity (58–98% ee) (Scheme 20) [58].
Later on, Xu and co-workers developed an efficient reaction to produce heterocyclic ortho-quinodimethanes 69 from 2-methyl-heteroarene-3-carboxylic esters 68 through NHC catalysis. The heterocyclic ortho-quinodimethanes generated in situ behave as 1,4-dipolarophiles to undergo a formal [4+2] annulation reaction with isatin-derived ketimines. The reaction affords chiral heteroarene-fused δ-lactams bearing a quaternary stereogenic center in moderate to good yields ranging from 57% to 81% and with high to excellent enantioselectivities (87 to >99% ee) (Scheme 21) [59].
Very recently, Enders and co-workers reported an NHC-catalyzed asymmetric synthesis of spirobenzazepinones 71, spiro-1,2-diazepinones 73 via [3+4]-cycloaddition reactions of enals derived from isatins 51 and aza-o-quinone methides or nitrosoalkenes in situ from N-(o-chloro-methyl)aryl amide 70 or a-halohydrazones 72. The spirocyclic products containing a seven-membered ring are synthesized in good yields with excellent enantioselectivities (Scheme 22) [60].
Wang and co-workers developed a cascade asymmetric Michael-intramolecular aldol-lactonization of enals 7 with oxindolyl-β,γ-unsaturated α-ketoesters 74. In this reaction, the desired β-propiolactone-fused spiro[cyclopentane-oxindoles] 75 contain four contiguous stereocenters, including a spiro all-carbon center and a quaternary carbon center. A variety of chiral NHC catalysts and bases have been investigated, and the results have shown that NHC D9 and DIPEA can provide the highest enantioselectivity (up to 99% ee) and diastereoselectivity (>99:1 dr) (Scheme 23) [22].

2.2.2. 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 and colleagues reported a formal [3+2] annulation of α-bromoenals 76-derived α,β-unsaturated acyl azoliums with 3-amino-oxindoles 77 via NHC organocatalysis. The functionalized spirooxindole γ-butyrolactams 78 are synthesized with high diastereoselectivities (up to >95:5 dr) and enantioselectivities (86–95% ee) (Scheme 24) [62].
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 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].

2.2.3. Catalysis Involving Radical Cation Intermediates

In addition to the aforementioned synthesis of spiroheterocycles via Breslow and acylazolium intermediates, the oxidative cross-coupling of homoenolate and enolate remains unexplored. Ye, Sun and co-workers developed an NHC-catalyzed oxidative cross-coupling of dioxindoles 79 and enals 7. The corresponding spirooxindole-γ-lactones 80 are generated in good yields (67–98%) with high to excellent diastereoselectivities (6:1 to >20:1 dr) and enantioselectivities (80–99% ee). This NHC-catalyzed oxidative [3+2] annulation reaction of dioxindoles and enals is proposed to occur via a radical-radical cross-coupling pathway (Scheme 28).

3. Conclusions

Firstly, Breslow intermediate 85 is formed by the addition of D8 and enals 7. Subsequently, in the presence of nitrobenzene 86, Breslow intermediate is oxidized to the radical cation intermediate 87. 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.
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.

Acknowledgments

Financial support from National Natural Science Foundation of China (No. 21502009, No. 81703809), the Science & Technology Department of Sichuan Province (No. 2017JQ0032), International Cooperation grant from the Science and Technology Department (No. 2016HH0012), Scientific Research Fund of Sichuan Provincial Education Department (No. 16ZB0430), “Thousand Talents Program” of Sichuan Province, “Chengdu Talents Program”, the Development of Medicinal and Edible Plant Resources Key Laboratory of Universities in Sichuan Province (No. 10Y201707), and the Start-up Fund of Chengdu University (No. 2081915026, No. 2081917019) is gratefully acknowledged.

Author Contributions

Jun-Long Li conceived and designed the paper; Yue Liu and Xiang Zhang wrote the paper; Rong Zeng, Ying Zhang, Qing-Song Dai and Hai-Jun Leng drew the pictures and reviewed the manuscript. Jun-Long Li and Xiao-Jun Gou supervised the paper. All authors polished and revised the manuscript.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Galliford, C.V.; Scheidt, K.A. Pyrrolidinyl-spirooxindole natural products as inspirations for the development of potential therapeutic agents. Angew. Chem. Int. Ed. Engl. 2007, 46, 8748–8758. [Google Scholar] [CrossRef] [PubMed]
  2. Saha, S.; Acharya, C.; Pal, U.; Chowdhury, S.R.; Sarkar, K.; Maiti, N.C.; Jaisankar, P.; Majumder, H.K. A novel spirooxindole derivative inhibits the growth of Leishmania donovani parasites both In Vitro and In Vivo by targeting type IB topoisomerase. Antimicrob. Agents Chemother. 2016, 60, 6281–6293. [Google Scholar] [CrossRef] [PubMed]
  3. Li, S.M. Prenylated indole derivatives from fungi: Structure diversity, biological activities, biosynthesis and chemoenzymatic synthesis. Nat. Prod. Rep. 2010, 27, 57–78. [Google Scholar] [CrossRef] [PubMed]
  4. Rajesh, S.M.; Perumal, S.; Yogeeswari, P.; Sriram, D. Antimycobacterial activity of spirooxindolo-pyrrolidine, pyrrolizine and pyrrolothiazole hybrids obtained by a three-component regio- and stereoselective 1,3-dipolar cycloaddition. Med. Chem. Commun. 2011, 2, 626–630. [Google Scholar] [CrossRef]
  5. Ding, K.; Lu, Y.; Nikolovska Coleska, Z.; Qiu, S.; Ding, Y.S.; Gao, W.; Stuckey, J.; Krajewski, K.; Roller, P.P.; Tomita, Y. Structure-based design of potent non-peptide MDM2 inhibitors. J. Am. Chem. Soc. 2005, 127, 10130–10131. [Google Scholar] [CrossRef] [PubMed]
  6. Mugishima, T.; Tsuda, M.; Kasai, Y.; Ishiyama, H.; Fukushi, E.; Kawabata, J.; Watanabe, M.; Akao, K.; Kobayashi, J. Absolute stereochemistry of citrinadins A and B from marine-derived fungus. J. Org. Chem. 2005, 70, 9430–9435. [Google Scholar] [CrossRef] [PubMed]
  7. Pimenta, E.F.; Vitamarques, A.M.; Tininis, A.; Seleghim, M.H.; Sette, L.D.; Veloso, K.; Ferreira, A.G.; Williams, D.E.; Patrick, B.O.; Dalisay, D.S. Use of experimental design for the optimization of the production of new secondary metabolites by two Penicillium species. J. Nat. Prod. 2010, 73, 1821–1832. [Google Scholar] [CrossRef] [PubMed]
  8. Goey, A.K.; Chau, C.H.; Sissung, T.M.; Cook, K.M.; Venzon, D.J.; Castro, A.; Ransom, T.R.; Henrich, C.J.; McKee, T.C.; McMahon, J.B. Screening and biological effects of marine pyrroloiminoquinone alkaloids: Potential inhibitors of the HIF-1α/p300 interaction. J. Nat. Prod. 2016, 79, 1267–1275. [Google Scholar] [CrossRef] [PubMed]
  9. Ma, S.S.; Mei, W.L.; Guo, Z.K.; Liu, S.B.; Zhao, Y.X.; Yang, D.L.; Zeng, Y.B.; Jiang, B.; Dai, H.F. Two new types of bisindole alkaloid from Trigonostemon lutescens. Org. Lett. 2013, 15, 1492–1495. [Google Scholar] [CrossRef] [PubMed]
  10. Cui, C.B.; Kakeya, H.; Osada, H. Novel mammalian cell cycle inhibitors, spirotryprostatins A and B, produced by Aspergillus fumigatus, which inhibit mammalian cell cycle at G2/M phase. Tetrahedron 1996, 52, 12651–12666. [Google Scholar] [CrossRef]
  11. Li, J.L.; Yang, K.C.; Li, Y.; Li, Q.; Zhu, H.P.; Han, B.; Peng, C.; Zhi, Y.G.; Gou, X.J. Asymmetric synthesis of bicyclic dihydropyrans via organocatalytic inverse-electron-demand oxo-Diels-Alder reactions of enolizable aliphatic aldehydes. Chem. Commun. 2016, 52, 10617–10620. [Google Scholar] [CrossRef] [PubMed]
  12. Li, J.L.; Li, Q.; Yang, K.C.; Li, Y.; Zhou, L.; Han, B.; Peng, C.; Gou, X.J. A practical green chemistry approach to synthesize fused bicyclic 4H-pyranes via an amine catalysed 1,4-addition and cyclization cascade. RSC Adv. 2016, 6, 38875–38879. [Google Scholar] [CrossRef]
  13. Li, J.L.; Liu, T.Y.; Chen, Y.C. Aminocatalytic asymmetric Diels–Alder reactions via HOMO activation. Acc. Chem. Res. 2012, 45, 1491–1500. [Google Scholar] [CrossRef] [PubMed]
  14. Trost, B.M.; Stambuli, J.P.; Silverman, S.M.; Schwörer, U. Palladium-catalyzed asymmetric [3+2] trimethylenemethane cycloaddition reactions. J. Am. Chem. Soc. 2006, 128, 13328–13329. [Google Scholar] [CrossRef] [PubMed]
  15. Posner, G.H.; Hamill, T.G. An asymmetric total synthesis of fragrant spiro[4.5]decane sesquiterpene (-)-β-vetivone via an enantiomerically pure vinylic sulfoxide. J. Org. Chem. 1988, 53, 6031–6035. [Google Scholar] [CrossRef]
  16. Yang, K.C.; Li, J.L.; Shen, X.D.; Li, Q.; Leng, H.J.; Huang, Q.; Zheng, P.K.; Gou, X.J.; Zhi, Y.G. Facile synthesis of novel spiroheterocycles via diastereoselective aziridination of cyclic enones. RSC Adv. 2017, 7, 21175–21179. [Google Scholar] [CrossRef]
  17. Dake, G.R.; Fenster, M.D.B.; Mélissa Fleury, A.; Patrick, B.O. Investigations of α-siloxy-epoxide ring expansions forming 1-azaspirocyclic ketones. J. Org. Chem. 2004, 69, 5676–5683. [Google Scholar] [CrossRef] [PubMed]
  18. Srikrishna, A.; Kumar, P.P. Claisen rearrangement based methodology for the spiroannulation of a cyclopentane ring. Formal total synthesis of (±)-acorone and isoacorones. Tetrahedron 2000, 56, 8189–8195. [Google Scholar] [CrossRef]
  19. Trost, B.M.; Cramer, N.; Silverman, S.M. Enantioselective construction of spirocyclic oxindolic cyclopentanes by palladium-catalyzed trimethylenemethane-[3+2]-cycloaddition. J. Am. Chem. Soc. 2007, 129, 12396–12397. [Google Scholar] [CrossRef] [PubMed]
  20. Li, Y.; Li, Q.Z.; Huang, L.; Liang, H.; Yang, K.C.; Leng, H.J.; Liu, Y.; Shen, X.D.; Gou, X.J.; Li, J.L. Diastereoselective synthesis of spirocyclopropanes under mild conditions via formal [2+1] cycloadditions using 2,3-dioxo-4-benzylidene-pyrrolidines. Molecules 2017, 22, 328. [Google Scholar] [CrossRef] [PubMed]
  21. Yao, H.; Zhou, Y.; Chen, X.; Zhang, P.; Xu, J.; Liu, H. N-heterocyclic carbene catalytic [4+2] cyclization of 3-alkylenyloxindoles with enals: A gamma-carbon activation for enantioselective assembly of spirocarbocyclic oxindoles. J. Org. Chem. 2016, 81, 8888–8899. [Google Scholar] [CrossRef] [PubMed]
  22. Zhang, J.Q.; Li, N.K.; Yin, S.J.; Sun, B.B.; Fan, W.T.; Wang, X.W. Chiral N-heterocyclic carbene-catalyzed asymmetric Michael–intramolecular aldol-lactonization cascade for enantioselective construction of β-propiolactone-fused spiro[cyclopentane-oxindoles]. Adv. Synth. Catal. 2017, 359, 1541–1551. [Google Scholar] [CrossRef]
  23. Rong, X.; Yao, H.; Xia, W.; Du, Y.; Zhou, Y.; Liu, H. Enantioselective assembly of spirolactones through NHC-catalyzed remote γ-carbon addition of enals with isatins. ACS Comb. Sci. 2016, 18, 220–224. [Google Scholar] [CrossRef] [PubMed]
  24. Franz, A.K.; Hanhan, N.V.; Ball-Jones, N.R. Asymmetric catalysis for the synthesis of spirocyclic compounds. ACS Catal. 2013, 3, 540–553. [Google Scholar] [CrossRef]
  25. Turner, N.J. Applications of transketolases in organic synthesis. Curr. Opin. Biotechnol. 2000, 11, 527–531. [Google Scholar] [CrossRef]
  26. Stryer, L. Biochemistry, 4th ed.; Freedman and Company: New York, NY, USA, 1995; pp. 739–740. ISBN 978-0716720096. [Google Scholar]
  27. Enders, D.; Niemeier, O.; Henseler, A. Organocatalysis by N-heterocyclic carbenes. Chem. Rev. 2007, 107, 5606–5655. [Google Scholar] [CrossRef] [PubMed]
  28. Mizuhara, S.; Handler, P. Mechanism of thiamine-catalyzed reactions 1. J. Am. Chem. Soc. 1954, 76, 571–573. [Google Scholar] [CrossRef]
  29. Maki, B.E.; Chan, A.; Phillips, E.M.; Scheidt, K.A. N-heterocyclic carbene-catalyzed oxidations. Tetrahedron 2009, 65, 3102–3109. [Google Scholar] [CrossRef] [PubMed]
  30. Phillips, E.M.; Chan, A.; Scheidt, K.A. Discovering new reactions with N-heterocyclic carbene catalysis. Aldrichim. Acta 2009, 42, 55–66. [Google Scholar]
  31. Buchner, E.; Curtius, T. Ueber die einwirkung von diazoessigäther auf aromatische kohlenwasserstoffe. Eur. J. Inorg. Chem. 1885, 18, 2377–2379. [Google Scholar] [CrossRef]
  32. Staudinger, H.; Kupfer, O. Über reaktionen des methylens. III. Diazomethan. Eur. J. Inorg. Chem. 1912, 45, 501–509. [Google Scholar] [CrossRef]
  33. Igau, A.; Grutzmacher, H.; Baceiredo, A.; Bertrand, G. Analogous .alpha.,.alpha.′-bis-carbenoid, triply bonded species: Synthesis of a stable. lambda.3-phosphino carbene-.lambda. 5-phosphaacetylene. J. Am. Chem. Soc. 1988, 110, 6463–6466. [Google Scholar] [CrossRef]
  34. Igau, A.; Baceiredo, A.; Trinquier, G.; Bertrand, G. [Bis(diisopropylamino)phosphino] trimethylsilylcarbene: A stable nucleophilic carbene. Angew. Chem. Int. Ed. Engl. 1989, 28, 621–622. [Google Scholar] [CrossRef]
  35. Arduengo, A.J., III; Harlow, R.L.; Kline, M. A stable crystalline carbene. J. Am. Chem. Soc. 1991, 113, 361–363. [Google Scholar] [CrossRef]
  36. Guo, C.; Schedler, M.; Daniliuc, C.G.; Glorius, F. N-Heterocyclic carbene catalyzed formal [3+2] annulation reaction of enals: An efficient enantioselective access to spiro-heterocycles. Angew. Chem. Int. Ed. Engl. 2014, 53, 10232–10236. [Google Scholar] [CrossRef] [PubMed]
  37. Enders, D.; Balensiefer, T. Nucleophilic carbenes in asymmetric organocatalysis. Acc. Chem. Res. 2004, 37, 534–541. [Google Scholar] [CrossRef] [PubMed]
  38. Sun, L.H.; Shen, L.T.; Ye, S. Highly diastereo-and enantioselective NHC-catalyzed [3+2] annulation of enals and isatins. Chem. Commun. 2011, 47, 10136–10138. [Google Scholar] [CrossRef] [PubMed]
  39. Li, J.L.; Fu, L.; Wu, J.; Yang, K.C.; Li, Q.Z.; Gou, X.J.; Peng, C.; Han, B.; Shen, X.D. Highly enantioselective synthesis of fused bicyclic dihydropyranones via low-loading N-heterocyclic carbene organocatalysis. Chem. Commun. 2017, 53, 6875–6878. [Google Scholar] [CrossRef] [PubMed]
  40. Flanigan, D.M.; Romanovmichailidis, F.; White, N.A.; Rovis, T. Organocatalytic reactions enabled by N-heterocyclic carbenes. Chem. Rev. 2015, 115, 9307–9387. [Google Scholar] [CrossRef] [PubMed]
  41. Breslow, R. On the mechanism of thiamine action. IV. 1 Evidence from studies on model systems. J. Am. Chem. Soc. 1958, 80, 3719–3726. [Google Scholar] [CrossRef]
  42. Nair, V.; Vellalath, S.; Poonoth, M.; Mohan, R.; Suresh, E. N-heterocyclic carbene catalyzed reaction of enals and 1,2-dicarbonyl compounds: Stereoselective synthesis of spiro γ-butyrolactones. Org. Lett. 2006, 8, 507–509. [Google Scholar] [CrossRef] [PubMed]
  43. Sánchez-Larios, E.; Holmes, J.M.; Daschner, C.L.; Gravel, M. NHC-catalyzed spiro bis-indane formation via domino Stetter-aldol-Michael and Stetter-aldol-aldol reactions. Org. Lett. 2011, 42, 5772–5775. [Google Scholar] [CrossRef]
  44. Sánchez-Larios, E.; Holmes, J.M.; Daschner, C.L.; Gravel, M. Synthesis of spiro bis-indanes via domino Stetter-aldol-Michael and Stetter-aldol-aldol reactions: Scope and limitations. Synthesis 2011, 2011, 1896–1904. [Google Scholar] [CrossRef]
  45. Jiang, K.; Tiwari, B.; Chi, Y.R. Access to spirocyclic oxindoles via N-heterocyclic carbene-catalyzed reactions of enals and oxindole-derived α,β-unsaturated imines. Org. Lett. 2012, 14, 2382–2385. [Google Scholar] [CrossRef] [PubMed]
  46. Yao, C.S.; Xiao, Z.X.; Liu, R.; Li, T.J.; Jiao, W.H.; Yu, C.X. N-heterocyclic-carbene-catalyzed reaction of α-bromo-α,β-Unsaturated aldehyde or α,β-dibromoaldehyde with isatins: An efficient synthesis of spirocyclic oxindole–dihydropyranones. Chemistry 2013, 19, 456–459. [Google Scholar] [CrossRef] [PubMed]
  47. Li, J.L.; Sahoo, B.; Daniliuc, C.G.; Glorius, F. Conjugate umpolung of β,β-disubstituted enals by dual catalysis with an N-heterocyclic carbene and a Bronsted acid: Facile construction of contiguous quaternary stereocenters. Angew. Chem. Int. Ed. Engl. 2014, 53, 10515–10519. [Google Scholar] [CrossRef] [PubMed]
  48. Du, D.; Hu, Z.; Jin, J.; Lu, Y.; Tang, W.; Wang, B.; Lu, T. N-heterocyclic carbene-catalyzed three-component domino reaction of alkynyl aldehydes with oxindoles. Org. Lett. 2012, 14, 1274–1277. [Google Scholar] [CrossRef] [PubMed]
  49. Zhang, W.G.; Xu, J.Y.; Cao, J.; Fang, C.; Zhu, J.D.; Lu, T.; Du, D. N-heterocyclic carbene-mediated formal [3+3] annulation of isatin-derived α,β-unsaturated acids: Access to functionalized 3,4′-spirooxindole d-lactones. Tetrahedron 2017, 73, 3249–3254. [Google Scholar] [CrossRef]
  50. Zhao, L.L.; Li, X.S.; Cao, L.L.; Zhang, R.; Shi, X.Q.; Qi, J. Access to dihydropyridinones and spirooxindoles: Application of N-heterocyclic carbene-catalyzed [3+3] annulation of enals and oxindole-derived enals with 2-aminoacrylates. Chem. Commun. 2017, 53, 5985–5988. [Google Scholar] [CrossRef] [PubMed]
  51. Wang, X.N.; Zhang, Y.Y.; Ye, S. Enantioselective synthesis of spirocyclic oxindole-β-lactones via N-heterocyclic carbene-catalyzed cycloaddition of ketenes and isatins. Adv. Synth. Catal. 2010, 352, 1892–1895. [Google Scholar] [CrossRef]
  52. Zhang, H.M.; Gao, Z.H.; Ye, S. Bifunctional N-heterocyclic carbene-catalyzed highly enantioselective synthesis of spirocyclic oxindolo-β-lactams. Org. Lett. 2014, 16, 3079–3081. [Google Scholar] [CrossRef] [PubMed]
  53. Xu, J.; Yuan, S.; Peng, J.; Miao, M.; Chen, Z.; Ren, H. Enantioselective [2+2] annulation of simple aldehydes with isatin-derived ketimines via oxidative N-heterocyclic carbene catalysis. Chem. Commun. 2017, 53, 3430–3433. [Google Scholar] [CrossRef] [PubMed]
  54. Zheng, C.G.; Yao, W.J.; Zhang, Y.C.; Ma, C. Chiral spirooxindole-butenolide synthesis through asymmetric N-heterocyclic carbene-catalyzed formal (3+2) annulation of 3-bromoenals and isatins. Org. Lett. 2014, 16, 5028–5031. [Google Scholar] [CrossRef] [PubMed]
  55. Janssen-Müller, D.; Fleige, M.; Schluens, D.; Wollenburg, M.; Daniliuc, C.G.; Neugebauer, J.; Glorius, F. NHC-catalyzed enantioselective dearomatizing hydroacylation of benzofurans and benzothiophenes for the synthesis of spirocycles. ACS Catal. 2016, 6, 5735–5739. [Google Scholar] [CrossRef]
  56. Dugal-Tessier, J.; O’Bryan, E.A.; Schroeder, T.B.; Cohen, D.T.; Scheidt, K.A. An N-heterocyclic carbene/Lewis acid strategy for the stereoselective synthesis of spirooxindole lactones. Angew. Chem. Int. Ed. Engl. 2012, 51, 4963–4967. [Google Scholar] [CrossRef] [PubMed]
  57. Reddi, Y.; Sunoj, R.B. Origin of stereoselectivity in cooperative asymmetric catalysis involving N-heterocylic carbenes and Lewis acids toward the synthesis of spirooxindole lactone. ACS Catal. 2017, 7, 530–537. [Google Scholar] [CrossRef]
  58. Xu, J.F.; Yuan, S.R.; Miao, M.Z.; Chen, Z.K. 1-Hydroxybenzotriazole-assisted, N-heterocyclic carbene catalyzed β-functionalization of saturated carboxylic esters: Access to spirooxindole lactones. J. Org. Chem. 2016, 81, 11454–11460. [Google Scholar] [CrossRef] [PubMed]
  59. Xu, J.F.; Yuan, S.R.; Miao, M.Z. N-Heterocyclic carbene catalyzed [4+2] annulation reactions with In Situ generated heterocyclic ortho-quinodimethanes. Org. Lett. 2016, 18, 3822–3825. [Google Scholar] [CrossRef] [PubMed]
  60. Wang, L.; Li, S.; Blümel, M.; Philipps, A.R.; Wang, A.; Puttreddy, R.; Rissanen, K.; Enders, D. Asymmetric synthesis of spirobenzazepinones with atroposelectivity and spiro-1,2-diazepinones by NHC-catalyzed [3+4] annulation reactions. Angew. Chem. Int. Ed. Engl. 2016, 55, 11110–11114. [Google Scholar] [CrossRef] [PubMed]
  61. Xiao, Z.; Yu, C.; Li, T.; Wang, X.S.; Yao, C. N-heterocyclic carbene/Lewis acid strategy for the stereoselective synthesis of spirocyclic oxindole–dihydropyranones. Org. Lett. 2014, 16, 3632–3635. [Google Scholar] [CrossRef] [PubMed]
  62. Jiang, D.L.; Dong, S.D.; Tang, W.F.; Lu, T.; Du, D. N-heterocyclic carbene-catalyzed formal [3+2] annulation of α-bromoenals with 3-aminooxindoles: A stereoselective synthesis of spirooxindole γ-butyrolactams. J. Org. Chem. 2015, 80, 11593–11597. [Google Scholar] [CrossRef] [PubMed]
  63. Mukherjee, S.; Joseph, S.; Bhunia, A.; Gonnade, R.G.; Yetra, S.R.; Biju, A.T. Enantioselective synthesis of spiro γ-butyrolactones by N-heterocyclic carbene (NHC)-catalyzed formal [3+2] annulation of enals with 3-hydroxy oxindoles. Org. Biomol. Chem. 2017, 15, 2013–2019. [Google Scholar] [CrossRef] [PubMed]
  64. Zhang, Z.F.; Chen, K.Q.; Zhang, C.L.; Ye, S. N-heterocyclic carbene-catalyzed synthesis of spirocyclopentene-oxindoles from bromoenals. Chem. Commun. 2017, 53, 4327–4330. [Google Scholar] [CrossRef] [PubMed]
  65. Bera, S.; Daniliuc, C.G.; Studer, A. Oxidative N-heterocyclic carbene catalyzed dearomatization of indoles to spirocyclic indolenines with a quaternary carbon stereocenter. Angew. Chem. Int. Ed. Engl. 2017, 56, 7402–7406. [Google Scholar] [CrossRef] [PubMed]
  66. Chen, X.Y.; Chen, K.Q.; Sun, D.Q.; Ye, S. N-heterocyclic carbene-catalyzed oxidative [3+2] annulation of dioxindoles and enals: Cross coupling of homoenolate and enolate. Chem. Sci. 2017, 8, 1936–1941. [Google Scholar] [CrossRef] [PubMed]
  67. Shi, L.; Li, L.; Wang, J.; Huang, B.; Zeng, K.; Jin, H.; Zhang, Q.; Jia, Y. Total synthesis of natural spiro-trisindole enantiomers similisines A, B and their stereoisomers. Tetrahedron Lett. 2017, 58, 1934–1938. [Google Scholar] [CrossRef]
  68. War May Zin, W.; Prompanya, C.; Buttachon, S.; Kijjoa, A. Bioactive secondary metabolites from a Thai collection of soil and marine-derived fungi of the genera Neosartorya and Aspergillus. Curr. Drug Deliv. 2016, 13, 378–388. [Google Scholar] [CrossRef]
Figure 1. Select natural products containing spiroheterocycles.
Figure 1. Select natural products containing spiroheterocycles.
Molecules 22 01882 g001
Figure 2. Coenzyme thiamine (vitamin B1).
Figure 2. Coenzyme thiamine (vitamin B1).
Molecules 22 01882 g002
Figure 3. General types of N-heterocyclic carbenes.
Figure 3. General types of N-heterocyclic carbenes.
Molecules 22 01882 g003
Scheme 1. Transformation of related intermediates under certain conditions.
Scheme 1. Transformation of related intermediates under certain conditions.
Molecules 22 01882 sch001
Scheme 2. Synthesis of spirolactone-γ-lactone derivatives via B1-catalyzed reactions.
Scheme 2. Synthesis of spirolactone-γ-lactone derivatives via B1-catalyzed reactions.
Molecules 22 01882 sch002
Scheme 3. General Stetter–aldol or Stetter–Michael sequential reactions.
Scheme 3. General Stetter–aldol or Stetter–Michael sequential reactions.
Molecules 22 01882 sch003
Scheme 4. Synthesis of spiroindanes 24 via Stetter–aldol–Michael reaction.
Scheme 4. Synthesis of spiroindanes 24 via Stetter–aldol–Michael reaction.
Molecules 22 01882 sch004
Scheme 5. Synthesis of spiroindanes 27 via Stetter–aldol–aldol reaction.
Scheme 5. Synthesis of spiroindanes 27 via Stetter–aldol–aldol reaction.
Molecules 22 01882 sch005aMolecules 22 01882 sch005b
Scheme 6. Synthesis of spirocyclic oxindoles 29 and 31 via D2-catalyzed cyclization.
Scheme 6. Synthesis of spirocyclic oxindoles 29 and 31 via D2-catalyzed cyclization.
Molecules 22 01882 sch006
Scheme 7. Synthesis of spirocyclic oxindole–dihydropyranones 33.
Scheme 7. Synthesis of spirocyclic oxindole–dihydropyranones 33.
Molecules 22 01882 sch007
Scheme 8. Proposed mechanism of the formation of spirocycles 33.
Scheme 8. Proposed mechanism of the formation of spirocycles 33.
Molecules 22 01882 sch008
Scheme 9. Synthesis of 40 via diastereoselective [3+2] annulations.
Scheme 9. Synthesis of 40 via diastereoselective [3+2] annulations.
Molecules 22 01882 sch009
Scheme 10. Synthesis of spirooxindole 4H-pyran-2-ones 43 from ynals.
Scheme 10. Synthesis of spirooxindole 4H-pyran-2-ones 43 from ynals.
Molecules 22 01882 sch010
Scheme 11. D2-catalyzed synthesis of spirooxindole lactones 46.
Scheme 11. D2-catalyzed synthesis of spirooxindole lactones 46.
Molecules 22 01882 sch011
Scheme 12. D1-catalyzed synthesis of dihydropyridinones 49 and 50.
Scheme 12. D1-catalyzed synthesis of dihydropyridinones 49 and 50.
Molecules 22 01882 sch012
Scheme 13. D1-catalyzed synthesis of spirooxindoles 52.
Scheme 13. D1-catalyzed synthesis of spirooxindoles 52.
Molecules 22 01882 sch013
Scheme 14. Enantioselective [2+2] cycloaddition of isatins 10 and ketenes 53.
Scheme 14. Enantioselective [2+2] cycloaddition of isatins 10 and ketenes 53.
Molecules 22 01882 sch014
Scheme 15. Enantioselective Staudinger reaction of ketenes 53 and isatin-derived ketimines 55.
Scheme 15. Enantioselective Staudinger reaction of ketenes 53 and isatin-derived ketimines 55.
Molecules 22 01882 sch015
Scheme 16. Synthesis of spirooxindole β-lactams 56 via NHC-catalyzed oxidative [2+2] annulation.
Scheme 16. Synthesis of spirooxindole β-lactams 56 via NHC-catalyzed oxidative [2+2] annulation.
Molecules 22 01882 sch016
Scheme 17. Asymmetric synthesis of the spirooxindole 58 via [3+2] annulation.
Scheme 17. Asymmetric synthesis of the spirooxindole 58 via [3+2] annulation.
Molecules 22 01882 sch017
Scheme 18. NHC-catalyzed [3+2] annulation of α,β-unsaturated aldehydes 7 and aurones 60.
Scheme 18. NHC-catalyzed [3+2] annulation of α,β-unsaturated aldehydes 7 and aurones 60.
Molecules 22 01882 sch018
Scheme 19. NHC-catalyzed enantioselective hydroacylation of benzoheterocycle 62.
Scheme 19. NHC-catalyzed enantioselective hydroacylation of benzoheterocycle 62.
Molecules 22 01882 sch019
Scheme 20. Asymmetric synthesis of spirooxindole lactones 67.
Scheme 20. Asymmetric synthesis of spirooxindole lactones 67.
Molecules 22 01882 sch020
Scheme 21. D9-Catalyzed [4+2] annulation reactions for the synthesis of 69.
Scheme 21. D9-Catalyzed [4+2] annulation reactions for the synthesis of 69.
Molecules 22 01882 sch021
Scheme 22. Asymmetric synthesis of spirobenzazepinones 71 and spiro-1,2-diazepinones 73.
Scheme 22. Asymmetric synthesis of spirobenzazepinones 71 and spiro-1,2-diazepinones 73.
Molecules 22 01882 sch022
Scheme 23. Asymmetric synthesis of β-propiolactone-fused spiro[cyclopentane-oxindoles] 75.
Scheme 23. Asymmetric synthesis of β-propiolactone-fused spiro[cyclopentane-oxindoles] 75.
Molecules 22 01882 sch023
Scheme 24. Asymmetric synthesis of spirooxindole γ-butyrolactams 78.
Scheme 24. Asymmetric synthesis of spirooxindole γ-butyrolactams 78.
Molecules 22 01882 sch024
Scheme 25. Synthesis of chiral spiro γ-butyrolactones 80 via [3+2] cyclization.
Scheme 25. Synthesis of chiral spiro γ-butyrolactones 80 via [3+2] cyclization.
Molecules 22 01882 sch025
Scheme 26. Asymmetric synthesis of spirocyclopentene-2-oxindoles 82.
Scheme 26. Asymmetric synthesis of spirocyclopentene-2-oxindoles 82.
Molecules 22 01882 sch026
Scheme 27. Oxidative NHC-catalyzed dearomatization to prepare spirocyclic indolenines 84.
Scheme 27. Oxidative NHC-catalyzed dearomatization to prepare spirocyclic indolenines 84.
Molecules 22 01882 sch027
Scheme 28. Enantioselective oxidative [3+2] annulation of enals.
Scheme 28. Enantioselective oxidative [3+2] annulation of enals.
Molecules 22 01882 sch028

Share and Cite

MDPI and ACS Style

Liu, Y.; Zhang, X.; Zeng, R.; Zhang, Y.; Dai, Q.-S.; Leng, H.-J.; Gou, X.-J.; Li, J.-L. Recent Advances in the Synthesis of Spiroheterocycles via N-Heterocyclic Carbene Organocatalysis. Molecules 2017, 22, 1882. https://doi.org/10.3390/molecules22111882

AMA Style

Liu Y, Zhang X, Zeng R, Zhang Y, Dai Q-S, Leng H-J, Gou X-J, Li J-L. Recent Advances in the Synthesis of Spiroheterocycles via N-Heterocyclic Carbene Organocatalysis. Molecules. 2017; 22(11):1882. https://doi.org/10.3390/molecules22111882

Chicago/Turabian Style

Liu, Yue, Xiang Zhang, Rong Zeng, Ying Zhang, Qing-Song Dai, Hai-Jun Leng, Xiao-Jun Gou, and Jun-Long Li. 2017. "Recent Advances in the Synthesis of Spiroheterocycles via N-Heterocyclic Carbene Organocatalysis" Molecules 22, no. 11: 1882. https://doi.org/10.3390/molecules22111882

APA Style

Liu, Y., Zhang, X., Zeng, R., Zhang, Y., Dai, Q. -S., Leng, H. -J., Gou, X. -J., & Li, J. -L. (2017). Recent Advances in the Synthesis of Spiroheterocycles via N-Heterocyclic Carbene Organocatalysis. Molecules, 22(11), 1882. https://doi.org/10.3390/molecules22111882

Article Metrics

Back to TopTop