Catalytic Enantioselective Construction of Spiro Quaternary Carbon

Review Cite This: ACS Catal. 2019, 9, 1820−1882

pubs.acs.org/acscatalysis

Catalytic Enantioselective Construction of Spiro Quaternary Carbon Stereocenters Peng-Wei Xu,† Jin-Sheng Yu,*,† Chen Chen,† Zhong-Yan Cao,† Feng Zhou,† and Jian Zhou*,†,‡,§

ACS Catal. Downloaded from pubs.acs.org by EASTERN KENTUCKY UNIV on 01/31/19. For personal use only.

†

Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, East China Normal University, Shanghai 200062, P. R. China ‡ Shanghai Key Laboratory of Green Chemistry and Chemical Process, East China Normal University, Shanghai 200062, P. R. China § State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, P. R. China ABSTRACT: The catalytic enantioselective assembly of spirocyclic molecules featuring a spiro quaternary carbon stereocenter is currently of great interest because such privileged 3D structures are widely present in natural products that exhibit a broad spectrum of biological and pharmacological activities. This review summarizes the advances based on six major synthetic strategies and showcases the reaction mechanisms in detail. The advantages and limitations of each synthetic strategy are presented, and the remaining synthetic opportunities are outlined.

KEYWORDS: spiro quaternary carbon stereocenters, catalytic enantioselective, reaction mechanism, organocatalysis, metal catalysis

1. INTRODUCTION Spirocyclic compounds are molecules containing two rings connected through a single shared atom (the spiroatom). Since first postulated by von Baeyer in 1900,1 such privileged structures have been found to occur in many natural and nonnatural products.2 At present, spirocycles play an important role in drug discovery and development because the incorporation of a spiro ring fusion can impose conformational constraints to reduce the conformational entropy penalty upon binding to a protein target in a favorable geometry.3 Therefore, the catalytic enantioselective synthesis of chiral spirocycles has attracted ever-increasing attention in the past decade. This is further fueled by the vast demand in chemistry, biology, and medicinal research for synthetic libraries derived from privileged scaffolds, considering that modern probe and drug discovery programs have met with diminishing returns from high-throughput screening of commercial libraries that lack the stereochemically rich polycyclic and/or spirocyclic structures of many bioactive natural products.4 In this context, spiro scaffolds bearing a chiral spiro quaternary carbon are particularly attractive.5 Such spirocycle subunits are widely present in natural products that exhibit a wide spectrum of biological and pharmacological activities. Some typical examples are shown in Figure 1. Acutumine, an alkaloid monomer extracted from the medicinal herb Sinomenium acutum, can selectively inhibit human T-cell growth with potential memory-enhancing properties.6a,b Elatol, one of the most widely studied chamigrenes, displays antibiofouling, antibacterial, and antifungal activity as well as © XXXX American Chemical Society

cytotoxicity against the HeLa and Hep-2 human carcinoma cell lines.6c Colletoic acid is a potent naturally occurring inhibitor of human 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1). 6d Spirotryprostatin A can inhibit the G2/M progression of cell division in mammalian tsFT210 cells.6e Horsfiline, an oxindole alkaloid found in the plant Horsfieldia superba, is a potential therapeutic agent.6f Fredericamycin A, which is isolated from Streptomyces griseus, exhibits potent antitumor activity against several tumor models.6g Rhynchophylline is a noncompetitive NMDA antagonist found in Mitragyna speciosa.6h,i Gelsemine is a toxic alkaloid isolated from the genus Gelsemium.6j,k Intrigued by the privileged structure and usefulness of spirocarbocycles featuring a spiro quaternary carbon, significant attention has been paid to their catalytic enantioselective synthesis; however, this represents a formidable task.7,8 It is well-known that catalytic enantioselective formation of quaternary carbon stereocenters is a daunting challenge in organic chemistry because of the huge steric hindrance and low steric dissimilarity of the two carbon substituents on the prochiral center.9−11 Apart from these difficulties, the generation of a spiro quaternary carbon stereocenter often requires overcoming ring strain to install useful functionalities, and the diastereoselectivity needs to be controlled because the construction of spiro systems is often accompanied by the Received: September 13, 2018 Revised: January 7, 2019

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DOI: 10.1021/acscatal.8b03694 ACS Catal. 2019, 9, 1820−1882

Review

ACS Catalysis

Figure 1. Selected natural products featuring spiro quaternary carbon stereocenters.

Figure 2. Synthetic strategies used to access spiro quaternary carbon stereocenters.

for catalytic enantioselective synthesis of optically active spirocycles, none of them focus on spiro quaternary carbon stereocenters, a unique subunit of quarternary carbons. In light of the above, we considered it necessary to present a timely comprehensive review to summarize synthetic strategies that are available for the catalytic enantioselective synthesis of spiro quaternary carbon stereocenters, introduce the latest achievements, outline the synthetic opportunities still open, and provide readers with some inspiration to develop newer and more efficient methods. To aid understanding and facilitate the future development of new reactions, this review is organized by the types of substrates employed in the reaction design and development, further subdivided by reaction type.

formation of multiple stereocenters. Therefore, this research has become a platform upon which new synthetic strategies and new catalysts can be developed. During the past decade, a number of elegant protocols that allow facile access to different spirocyclic systems featuring a spiro quaternary carbon stereocenter have been developed. According to the substrate type, these reactions can be classified into six major categories, as shown in Figure 2. Notably, some of these methods have found application in the total synthesis of natural products12 as well as in drug discovery and development.3 Despite these remarkable achievements, to our knowledge no comprehensive review that summarizes the advances in this field has been published. Because the catalytic enantioselective construction of quaternary carbon stereocenters represents a long-standing goal challenging organic chemists, a number of highlights and reviews on this topic have been published during the past decade,9−11 but all of them pay little attention to chiral quaternary spiro carbons. On the other hand, while there are several reviews on the construction of spirocycles from different viewpoints,13 including two independent general reviews by Rios7 and Franz8 to outline the synthetic strategies

2. VIA CYCLIC COMPOUNDS BEARING AN EXTERNAL OLEFIN Among the six strategies shown in Figure 2, catalytic asymmetric reactions involving cyclic substrates bearing an external olefin functionality represent a privileged approach toward the synthesis of various spirocyclic compounds bearing a spiro quaternary carbon stereocenter, not only because a 1821


Review

ACS Catalysis Scheme 1. D−A Reaction of α-Methylene Lactam and Diene

Scheme 2. Chiral Magnesium Phosphate-Catalyzed D−A Reaction of Methyleneindolines

have been accomplished for the creation of spiro quaternary carbon stereocenters, as illustrated in the following. 2.1. Enantioselective Cycloadditions. Catalytic enantioselective cycloaddition of various cyclic substrates bearing an external olefin functionality have gained considerable attention in the past few decades, and the approach has been identified as a powerful strategy for the assembly of spiro quaternary carbon stereocenters.14 Both chiral metal catalysis and organocatalysis exhibited great potential to access various

large number of cyclic substrates bearing an external olefin were easily prepared but also because the reactivity and selectivity can be nicely tuned by varying their functional groups or the reaction conditions. Furthermore, consecutive stereocenters with high stereoselective control can usually be generated at the same time by employing these types of cyclic substrates. In this context, a variety of catalytic enantioselective cycloadditions and Michael addition-initiated cascade reactions 1822


Review

ACS Catalysis Scheme 3. Chiral N,N′-Dioxide/Metal Complex-Catalyzed D−A Reactions of Methyleneindolines

Scheme 4. Asymmetric D−A/[3,3]-Sigmatropic Rearrangement Cascade Reactions

reported the first successful example of a Cu(II)-catalyzed asymmetric intermolecular Diels−Alder (D−A) reaction for the construction of optically enriched spirocyclic molecules featuring a spiro quaternary carbon stereocenter (Scheme 1).15 They found that the use of 40 mol % (−)-siam 3/Cu(SbF6)2 complex effectively catalyzed the D−A reaction of α-methylene six-membered lactam 1a and diene 2a, affording the desired cycloadduct 5a in 98% yield with >99% ee. Moreover, sevenmembered lactam 1b was also a suitable substrate in this highly exo-selective asymmetric D−A reaction, and the corresponding aza-spiro[5.5]undec-8-ene 5b was obtained in 82% yield with 99:1 exo/endo selectivity and 96% ee when the combination of (S,S)-tBu-BOX 4 with Cu(AsF6)2 was employed. Notably, the

spirocycles with a spiro quaternary carbon stereocenter through catalytic enantioselective [4 + 2] cycloadditions, [3 + 2] cycloadditions, and other cycloadditions. In organocatalytic cycloadditions, a variety of organocatalysts have been employed to activate electrophiles and/or nucleophiles through either non-covalent or covalent bond activation modes, thereby raising the LUMO energy and/or lowering the HOMO energy to facilitate the reaction and orienting the transition state to induce stereocontrol. This section does not provide an exhaustive list of reactions but rather highlights selected typical examples with different activation modes. 2.1.1. [4 + 2] Cycloadditions. In 2002, during their study on the total synthesis of marine toxins, Murai and co-workers 1823


Review

ACS Catalysis Scheme 5. Enantioselective D−A Reaction Enabled by H-Bonding Catalysis

synthetic utility of the method was further highlighted by the preparation of 6, a key intermediate for the synthesis of gymnodimine, which is a potent shellfish toxin.16 In 2013, the Antilla group utilized chiral magnesium phosphate as a catalyst to realize the asymmetric D−A reaction of methyleneindolines 7 and Danishefsky-type diene 8 (Scheme 2).17 This provided a facile protocol to access a class of very useful chiral spiro[cyclohexane-1,3′-oxindoline] derivatives 10, which constitute the core structures of numerous natural products and bioactive compounds. The use of 5−10 mol % chiral magnesium phosphate 9 enabled the asymmetric D−A reaction to give spirooxindole derivatives 10 in up to 99% yield with up to 20:1 dr and 99% ee. The N-Boc protecting group of 7 proved to be critical for achieving high reactivity and enantioselectivity because the use of a, N-Bn analogue required much longer reaction time and gave a lower ee value. Notably, the addition of 4 Å molecular sieves (MS) was also indispensable for high enantioselectivity and reactivity, possibly because the 4 Å MS plays a crucial role in increasing the Lewis acidity of the Mg(II) center and changing the coordinated conformation of Mg(II) intermediate through removal of water coordinated to the chiral Mg(II) center. On the basis of control experiments, a plausible transition state was illustrated in which the chiral Mg(II) phosphate first coordinated with the imide and Boc group to generate a tetrahedral intermediate, which then reacted with the diene from the open bottom face, as illustrated in Scheme 2. Remarkably, the stereoselectivities could be nicely controlled even though the desired products have three consecutive stereocenters, highlighting the advantage of asymmetric cycloaddition with cyclic substrates bearing an external olefin functionality in the construction of spiro quaternary carbon stereocenters. Later, Feng and co-workers showed that their developed chiral N,N′-dioxide-derived metal complexes were efficient catalysts for the asymmetric [4 + 2] cycloaddition of methyleneindolines 11 with various dienes. On one hand, a highly efficient asymmetric D−A reaction of methyleneindolines 11 and Brassard-type diene 12 was developed with the N,N′-dioxide 13/Zn(II) complex, which allowed access to chiral spiro[cyclohex[3]ene-1,3′-indoline]-1′-carboxylate-2,2′dione derivatives 14 containing three stereocenters in

moderate yields with 98% to >99% ee in a stereospecific manner (Scheme 3, eq 1).18 On the other hand, the stereoselective D−A reaction between methyleneindolinones 7 and 3-vinylindoles 15 was achieved by using the chiral N,N′dioxide 16/Ni(II) complex as the catalyst. A wide variety of the corresponding exo-carbazolespirooxindole derivatives 17 were produced exclusively in up to 99% yield with >20:1 dr and up to 97% ee under the optimal conditions (Scheme 3, eq 2).19 More recently, Feng and Liu further established a highly efficient and stereoselective D−A/[3,3]-sigmatropic rearrangement cascade reaction of methyleneindolinones 18 with 1thiocyanatobutadienes 19 using 10 mol % L-PiPr2 20/ Ni(BF4)2·6H2O complex (Scheme 4).20 A series of spiro cyclohexenyl isothiocyanates 21 featuring three stereogenic centers were obtained in high yields with excellent diastereoand enantioselectivities. By combining operando IR studies with control experiments, the authors proposed a reaction pathway with a plausible transition state, as described in Scheme 4. Methyleneindolinones 18 are first activated by the chiral L-PiPr2/Ni(II) complex generated in situ through coordination with two carbonyl groups, forming the corresponding intermediate 22. Then 1-thiocyanatobutadiene (19a) approaches methyleneindolinone 18a from the Re face and undergoes a stereoselective D−A reaction via concerted transition state TS-I to produce the trans spirocyclic oxindole product trans-23, which should be the rate-determining step. Finally, trans-23 rearranges into trans-21a through a suprafacial shift. Although the cis D−A product cis-23 is also formed via unfavored transition state TS-II, it does not rearrange in situ into the corresponding cis product cis-21a under the standard reaction conditions, as illustrated by control experiments, probably because the equatorial position of the isothiocyanate group in cis-23 is less favorable for the subsequent [3,3]sigmatropic rearrangement, in contrast to the axial orientation in trans-23. In parallel with the development of chiral Lewis acidcatalyzed approaches, the power of asymmetric organocatalysis was also showcased in the stereoselective [4 + 2] cycloaddition of cyclic substrates bearing an external olefin functionality. For example, in 2011, Barbas and colleagues presented a highly efficient asymmetric D−A reaction of methyleneindolinones 7 1824


Review

ACS Catalysis Scheme 6. Enantioselective D−A Reaction Enabled by Chiral Phosphoric Acid

Scheme 7. Enantioselective D−A Reaction Enabled by Trienamine Catalysis

with 3-vinylindoles 15 by employing chiral H-bonding catalysis, allowing the forging of enantioenriched carbazolespirooxindole derivatives containing three or four stereocenters, including spiro quaternary centers (Scheme 5).21 The use of 15 mol % chiral bisthiourea catalyst 24 was identified to be the best choice of catalyst and loading, affording exo-carbazolespirooxindoles 25 in less than 10 min in 75−99% yield with >20:1 dr and 88−99% ee. It is notable that the pure product 25 could be easily isolated by simple centrifugation because it has much poorer solubility than the reagents and catalyst in hexane. The recovered filtrate containing catalyst 24 and excess 3-vinylindole 15 could be recycled and reused at least five times in this cycloaddition while maintaining both the reactivity and selectivity at similar levels. On the basis of the initial NMR studies and the stereochemistry of product 25, a possible transition state was proposed in which thiourea

catalyst 24 activates the methyleneindolinones 7 through a Hbonding interaction to form a chiral intermediate, which then works with diene 15 to produce the desired cycloadducts. Aside from chiral thiourea catalysts, chiral phosphoric acids were also shown to be efficient H-bonding catalysts for the assembly of spiro quaternary carbon stereocenters in the asymmetric cycloaddition of cyclic substrates bearing an external olefin. As Shi and co-workers reported in 2015, the use of 10 mol % chiral phosphoric acid 27 enabled a highly stereoselective D−A reaction of methyleneindolinones 11 and 2-vinylindoles 26, which provided the spiro[tetrahydrocarbazole-3,3-oxindoles] 28 in high yields with good to excellent diastereo- and enantioselectivities (Scheme 6).22 The authors proposed that phosphoric acid 27 simultaneously activated 2-vinylindole and methyleneindolinone through dual H-bonding interactions, and the generated 1825


Review

ACS Catalysis Scheme 8. Asymmetric D−A Reaction of 18 with β-Indolyl Enals 34 by Trienamine Catalysis

Scheme 9. Enantioselective D−A Reaction by “Cross” Trienamine Catalysis

density functional theory (DFT) calculations. Furthermore, the obtained products 31 could be readily converted into structurally diversified spirocyclic compounds, as exemplified by the preparation of indoline 32 and hexahydrofuro[2,3b]indole 33. Shortly thereafter, the Melchiorre group presented a trienamine-catalyzed asymmetric D−A reaction of methyleneindolinones 18 with β-indolyl unsaturated aldehydes 34, providing straightforward access to a series of polycyclic tetrahydrocarbazole-containing spirooxindole derivatives 36 (Scheme 8).26 It was found that in the presence of 20 mol % Hayashi−Jørgensen catalyst 35 and PhCO2H, the D−A reaction proceeded smoothly to furnish the desired spirocycles 36 in 53−98% yield with 8:1 to >20:1 dr and 94−99% ee. A proposed reaction mechanism is illustrated in Scheme 8. Enal 34 first reacts with chiral amine 35 to form iminium intermediate I under the interaction of PhCO2H, and then the corresponding trienamine intermediate, heterocyclic oquinodimethane II, is generated with the aid of the resultant PhCO2− anion. Trienamine intermediate II subsequently undergoes D−A cycloaddition with 18 via the plausible transition state III, giving the target molecule with excellent stereocontrol. Moreover, this strategy could be further

intermediate subsequently underwent the D−A reaction in the chiral environment to deliver the target molecules 28 with excellent stereoselectivity. In the same year, Lu and Weng utilized cinchona-derived squaramide as the H-bonding catalyst to realize the same D−A reaction.23 Two years later, the Yang group developed a highly efficient and stereoselective D−A reaction of methyleneindolinones with 2-vinylindoles catalyzed by L-pyroglutamic acid sulfonamide, a newly designed H-bonding catalyst.24 In addition to activation of the substrates by the use of noncovalent bonding interactions, the covalent bond activation model has also been applied to construct spiro quaternary carbon stereocenters in cycloadditions involving cyclic substrates bearing an external olefin. By devising a novel trienamine catalysis strategy, in 2011 Chen and Jørgensen realized a stereoselective D−A reaction of methyleneindolinones 18 with polyenals 29 (Scheme 7).25 The combination of 20 mol % chiral secondary amine catalyst 30 and ofluorobenzoic acid (OFBA) effectively mediated the D−A reaction and afforded a diverse set of optically enriched spirooxindole derivatives 31 in high yields with excellent enantioselectivities. As shown in Scheme 7, a reaction pathway and plausible transition state through a trienamine intermediate were proposed on the basis of NMR studies and 1826


Review

ACS Catalysis Scheme 10. [4 + 2]-Cycloaddition of α,β-Unsaturated Acyl Chlorides by Nucleophilic Catalysis

Scheme 11. [4 + 2] Cycloaddition Using Enolizable Anhydrides with Methyleneindolinones

tional studies demonstrated that both “linear” trienamine I and “cross” trienamine II were present in the reaction system and that linear trienmanine I had a higher concentration than cross-trienamine II. However, cross-trienamine II was the real active species that underwent the cycloaddition with 7 to give the desired spirocycle 38, given that the reaction was under thermodynamic control. On the basis of these pioneering studies on trienamine catalysis, a lot of excellent research has been further advanced by the groups of Chen and Jørgensen for the forging of spiro quaternary carbon stereocenters via asymmetric cycloadditions involving trienamine intermedi-

extended to the D−A reaction of methyleneindolinones 18 with β-pyrrolyl- and β-furyl-substituted enals. Later, Jørgensen and co-workers adopted a new crosstrienamine catalysis strategy to develop the asymmetric D−A reaction of methyleneindolinones 7 with α,β,γ-unsaturated aldehydes 37 (Scheme 9).27 Various functionalized bridged pentacyclic spirocycles 38 were accessed in good yields with excellent diastereo- and enantioselectivities under the catalysis of 20 mol % amine catalyst 35 together with OFBA. Additionally, β-aryl-substituted olefinic azlactones were also viable substrates in this D−A reaction. NMR and computa1827


Review

ACS Catalysis Scheme 12. Asymmetric [3 + 2] Cycloaddition by Chiral Tertiary Phosphine Catalysis

Scheme 13. Asymmetric [3 + 2] Cycloaddition of Allene 52 and Electron-Deficient Olefins 51

ates.28 Remarkably, the tetraenamine catalysis strategy was also established and utilized by Jørgensen and co-workers in the asymmetric [4 + 2] cycloaddition of methyleneindolinones with 2-(cyclohepta-1,3,5-trien-1-yl)acetaldehyde, enabling the synthesis of a new class of highly functionalized spirocyclic cyclohexanes with four stereocenters in high yields with excellent stereoselectivities.29 In addition to the use of enamine catalysis for covalent bond activation, asymmetric nucleophilic catalysis with chiral tertiary amines has also been shown to have potential for the construction of spiro quaternary carbon stereocenters. In 2013, Ye and co-workers reported an efficient synthesis of enantioenriched spirocyclic oxindoles through the asymmetric [4 + 2] cycloaddition reaction of α,β-unsaturated acyl chlorides 40 and methyleneoxindoles 39 catalyzed by a chiral tertiary amine catalyst (Scheme 10).30 The use of 10 mol % Otrimethylsilyl (TMS) quinidine 41 enabled various spirocyclic oxindoles 42 to be obtained in 72−91% yield with 10:1 to >20:1 dr and 65−93% ee. As described in Scheme 10, chiral tertiary amine 41 acts as a nucleophilic catalyst to work with α,β-unsaturated acyl chlorides 40 in the presence of Et3N. The produced active diene species I subsequently reacts with methyleneoxindoles 39 through a D−A reaction process to give spirocyclic oxindoles 42 and regenerate chiral catalyst 41. Employing a chiral tertiary amine as a Brønsted base catalyst, Manoni and Connon31 later developed a stereoselective Tamura cycloaddition of alkylidene oxindoles 7 with enolizable

anhydrides 43, which provided a facile synthesis of densely functionalized spirocyclic oxindole derivatives (Scheme 11). With 5 mol % quinine-derived squaramide bifunctional catalyst 44, a variety of spirocyclic oxindoles 45 were obtained in moderate to high yields with excellent dr and ee values. As demonstrated in the transition state shown in Scheme 11, the chiral tertiary amine moiety of catalyst 44 deprotonates anhydrides 43 to form the corresponding active diene species. Meanwhile, alkylidene oxindoles 7 are activated by the squaramide motif through H-bonding interactions. Subsequently, a [4 + 2] cycloaddition proceeds to afford the desired products. Notably, a significant temperature effect on the diastereocontrol was observed in this Tamura cycloaddition, as exemplified by the fact that diastereomer 45a was generated in 92% yield with 95% ee from the reaction of 7a and 43a at 30 °C, while the syn diastereomer 45b could be accessed in 74% yield with 98% ee from the same reaction at −30 °C, which highlighted the synthetic potential of this methodology because the different diastereomers could be obtained simply by varying the reaction temperature. 2.1.2. [3 + 2] Cycloadditions. Along with the development of enantioselective [4 + 2] cycloadditions involving cyclic compounds bearing an external olefin, a series of catalytic asymmetric [3 + 2] cycloadditions of cyclic compounds bearing external olefin functionality with various 1,3-dipoles have also been successfully established in the past decade for 1828


Review

ACS Catalysis Scheme 14. Asymmetric [3 + 2] Cycloaddition of MBH Carbonates 56 and Methyleneindolinones 55

Scheme 15. Asymmetric [3 + 2] Cycloaddition of MBH Carbonates 60 and Alkenes 59

ing spirocycle 48 in 85% yield with 80% ee.33 By employing chiral tertiary phosphine catalysis, Marinetti and co-workers further explored the asymmetric [3 + 2] cycloaddition of methyleneindolinones and allenoates, which enabled the straightforward construction of spirocyclic oxindoles.34 Miller and co-workers reported an asymmetric [3 + 2] cycloaddition of enones 51 with allenoates 52 catalyzed by chiral tertiary phosphine H-bonding bifunctional catalyst 53 for the synthesis of spiro cyclopentene derivatives bearing spiro quaternary carbon stereocenters.35 As shown in Scheme 13, in the presence of 10 mol % catalyst 53, a number of spirocyclic products 54 were obtained in up to 95% yield with 84% ee. To rationalize the origin of the stereochemistry, a transition state

the installation of enantioenriched spirocycles featuring a spiro quaternary carbon center. In 2006, during their study of asymmetric [3 + 2] cycloaddition of enones with allenoate 47 catalyzed by chiral tertiary phosphine 49, Wilson and Fu32 found that various optically pure spirocyclic cyclopentene derivatives could be synthesized when indanone-, cyclopentanone-, and cyclohexanone-derived cyclic enones were used as substrates. The use of 10 mol % tertiary phosphine 49 efficiently promoted the cycloaddition to yield spirocyclic cyclopentene 48 in 97% yield with 89% ee (Scheme 12). Two years later, Marinetti and coworkers reported the same cycloaddition with 5 mol % planar chiral 2-phospha[3]ferrocenophane 50 as the catalyst, furnish1829


Review

ACS Catalysis Scheme 16. Asymmetric [3 + 2] Cycloaddition of Brominated MBH Adducts and Ketones

was proposed in which allenoates 52 first react with phosphine catalyst 53 to produce the zwitterionic intermediate. Subsequently, enones 51 approach the resulting intermediate from the π face opposite to the face of the phenyl substituents of phosphine catalyst 53, thereby delivering the corresponding adducts α-54 with good selectivity. In addition to allenoates, Morita−Baylis−Hillman (MBH) carbonates, as 1,3-dipole synthons, proved to be viable substrates for the creation of spiro quaternary stereogenic centers by means of tertiary-phosphine-catalyzed enantioselective [3 + 2] cycloaddition. In 2012, the Barbas group accomplished a highly efficient phosphine-catalyzed asymmetric [3 + 2] cycloaddition reaction of methyleneindolinones 55 with MBH carbonates 56 (Scheme 14).36 By the use of 10 mol % (R,R)-Ph-BPE 57 as the phosphine catalyst, a series of spiro cyclopenteneoxindole derivatives 58 were obtained in 47−91% yield with 2:1 to >20:1 dr and 46−99% ee. On the basis of mechanistic studies, a plausible reaction pathway and transition state are presented in Scheme 14. One phosphine substituent of phosphine 57 reacts with the MBH carbonate to generate the activated 1,3-dipolar intermediate I, while a second phosphine moiety might interact with the carbonyl group of 55, as illustrated in transition state II. Intermediate IV is then obtained after regioselective nucleophilic attack of 1,3-dipolar intermediate I on methyleneindolinone 55 and a subsequent ring-closing process through intramolecular conjugate addition. Ultimately the desired spirooxindole 58 is produced from the resulting intermediate IV accompanied by regeneration of catalyst 57. Later, the authors found that 3-substituted methylene benzofuranone derivatives also worked well with MBH carbonates 56 under the catalysis of phosphine 57.37

In the same year, Lu et al. employed their developed threonine-derived phosphine catalyst 61 to establish a stereoselective [3 + 2] cycloaddition of MBH carbonates 60 and isatin-derived tetrasubstituted alkenes 59 (Scheme 15).38 The authors found that the use of 10 mol % 61 rendered the synthesis of biologically important 3-spirocyclopentene-2oxindoles 62 in high yields with good to excellent selectivities. Control experiments demonstrated that the H-bond of the thiourea scaffold in catalyst 61 is essential for high regio- and enantioselectivity. On this basis, the authors speculated that tertiary phosphine reacts with MBH carbonate 60 to form an active ylide species and the thiourea motif concurrently activates the isatin-derived alkene 59 through coordination with the carbonyl group. Next, γ-addition of the ylide species with the activated alkene is carried out, followed by subsequent intramolecular cyclization to afford the product 62. In 2013, our group developed an asymmetric [3 + 2] cycloaddition of brominated MBH adducts 63 with various ketones 64 using a chiral tertiary amine as a nucleophilic catalyst (Scheme 16).39 The combination of 10 mol % BnOprotected β-isocupreidine 65 and K2CO3 turned out to be optimal for this stereoselective [3 + 2] cycloaddition, which afforded a wide range of spirocyclic oxindoles 66 featuring adjacent tetrasubstituted stereocenters with excellent stereoselectivities. As illustrated in Scheme 16, the transformation starts with nucleophilic attack of tertiary amine 65 to brominated MBH adduct 63 to generate the corresponding active 1,3-dipole in the presence of K2CO3. The active 1,3dipole intermediate subsequently undergoes a γ-regioselective [3 + 2] cycloaddition with ketone 64 to furnish spirooxindole 66. 1830


Review

ACS Catalysis Scheme 17. MBH/Bromination/Asymmetric [3 + 2] Annulation Sequence

Scheme 18. Asymmetric Three-Component 1,3-Dipolar Cycloaddition

Scheme 19. Asymmetric [3 + 2] Cycloaddition by Chiral Bis(phosphoric acid) Catalysis

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Review

ACS Catalysis Scheme 20. Asymmetric [3 + 2] Cycloaddition of Nitrones and Methyleneindolinones

Scheme 21. Asymmetric [3 + 2] Cycloaddition of Azlactones and Methyleneindolinones

In line with our previously developed highly enantioselective β-isocupreidine-catalyzed MBH reaction of isatins and acrolein,40 we further realized a novel chiral tertiary aminecatalyzed MBH/bromination/asymmetric [3 + 2] annulation sequence that enabled the highly efficient construction of a variety of spirocyclic oxindole derivatives in a one-pot fashion (Scheme 17).39 The one-pot tandem reaction was initiated by the tertiary amine 65-catalyzed MBH reaction, followed by bromination using HBr to afford brominated MBH adducts II, which then underwent a highly stereoselective [3 + 2] annulation with activated ketones 64 to deliver the corresponding products. In 2009, Gong and co-workers adopted chiral phosphoric acid catalysis to develop an asymmetric three-component 1,3dipolar cycloaddition of aldehydes 68, amino esters 69, and methyleneindolinones 70 (Scheme 18).41 A broad range of 3,3′-pyrrolidinyl spirooxindoles 72 with unusual regioselectivity were obtained in 59−97% yield with >20:1 dr and 81−98% ee under the catalysis of 10 mol % chiral phosphoric acid 71. On the basis of DFT calculations, the authors proposed that the azomethine ylides 73 generated in situ from aldehydes 68 and amino esters 69 were activated by chiral phosphoric acid 71 through H-bonding interactions, while the phosphoric acid coordinated with methyleneindolinones 70 through H-

bonding. The cycloaddition of the above-formed chiral intermediates subsequently occurred to yield the target 3,3′pyrrolidinyl spirooxindoles 72, as shown in Scheme 18. Notably, the double H-bonding activation of both the azomethine ylide and methyleneindolinone by the chiral phosphoric acid not only accounted for the high enantioand regioselectivity but also revealed that the unusual regioselectivity resulted from the favorable π−π stacking interaction between the conjugated esters and the oxindole skeleton. In 2013, Hong and Wang reported an asymmetric [3 + 2] cycloaddition of N,N′-cyclic azomethine imines 74 and methyleneindolinones 7 using a newly developed chiral bis(phosphoric acid) 75 bearing triple axial chirality, which provided various polycyclic spiro[pyrazolidin-3,3′-oxindoles] 76 with excellent enantioselectivity (Scheme 19).42 According to the mass spectrometry experiments and DFT calculations, a dual H-bonding activation mode was proposed (Scheme 19), which differs from the traditional phosphoric acid catalysis. Later, the authors further developed the phosphoric acidcatalyzed asymmetric [3 + 2] cycloaddition of methyleneindolinones with azlactones.43 Additionally, with a chiral bisthiourea as the H-bonding catalyst, a highly stereoselective [3 + 2] cycloaddition of 1832


Review

ACS Catalysis Scheme 22. Asymmetric 1,3-Dipolar Cycloaddition of 83 and Isatylidene Malononitriles

Scheme 23. Asymmetric 1,3-Dipolar Cycloaddition Catalyzed by a PTC

nitrones 77 and methyleneindolinones 7 was documented by Zhu and Cheng in 2013.44 A plethora of enantioenriched spiro[isoxazolidine-3,3′-oxindole] derivatives 78 with three contiguous stereocenters, including one spiro quaternary carbon stereocenter, could be accessed in 45−80% yield with 9:1 to >20:1 dr and 80−99% ee (Scheme 20). Bisthiourea 24 was identified as a multiple-H-bonding catalyst that activated both substrates simultaneously, as depicted in the transition state. Utilizing a chiral thiourea−tertiary amine catalyst, Sun, Wang, and Hong published an asymmetric [3 + 2] cycloaddition of methyleneindolinones 18 with azlactones 79 as latent 1,3-dipoles for the construction of spirocyclic quaternary oxindoles (Scheme 21).45 In the presence of 20 mol % bifunctional thiourea catalyst 80, C4 of azlactones 79 is deprotonated by the tertiary amine moiety of catalyst 80 to form activated azlactone enolate intermediates, which undergo a [3 + 2] cycloaddition with methyleneindolinones 18 to give the corresponding products 81 in moderate to high yields and dr and ee values.

In 2015, Peng and co-workers developed an asymmetric 1,3dipolar cycloaddition of the Seyferth−Gilbert reagent 83 with isatylidene malononitriles 82 catalyzed by cinchona-alkaloidbased tertiary amine H-bonding catalyst 84 (Scheme 22).46 The utilization of 10 mol % catalyst 84 enabled the preparation of a series of optically active spiro[phosphonylpyrazoline oxindoles] 85 in 73−99% yield with 91−98% ee. Notably, this represents the first example of organocatalytic enantioselective 1,3-dipolar cycloaddition with a phosphorus-containing αdiazo compound. A synergistic activation transition state was proposed in which isatylidene malononitrile 82 is activated by the hydroxyl group through H-bonding interactions; meanwhile, 83 is deprotonated by the tertiary amine of catalyst 84. The activated 83 then attacks C3 of isatylidene malononitrile 82 from the Si face in an intramolecular manner, followed by cyclization and intramolecular hydrogen transfer to produce the target products 85. In the same report, the authors developed a catalytic enantioselective three-component domino reaction of isatin, malononitrile, and 83 through a Knoevenagel condensation/1,3-dipolar cycloaddition se1833


Review

ACS Catalysis Scheme 24. Pd-Catalyzed TMM [3 + 2] Cycloaddition and Its Synthetic Application

Scheme 25. Asymmetric 1,3-Dipolar Cycloadditions of Imino Esters with Methyleneindolinones

In parallel to organocatalytic asymmetric [3 + 2] cycloadditions of cyclic substrates bearing an external olefin, chiral metal-catalyzed protocols have also achieved considerable success in the creation of spiro quaternary carbon stereocenters. Early in 2007, Trost et al.49 reported an asymmetric Pd-catalyzed trimethylenemethane (TMM) [3 + 2] cycloaddition of cyano-substituted TMM precursor 89 and methyleneindolinones 90 for the stereoselective synthesis of spirocyclic oxindolic cyclopentane derivatives 92 (Scheme 24). It was found that the combination of 2.5 mol % Pd2dba3 with 10 mol % chiral ligand 91a efficiently mediated the cycloaddition to afford the desired spirooxindole 92a in excellent yield and ee with moderate dr. As described in Scheme 24, the reactive Pd−TMM complex I, generated from 89 and the chiral Pd catalyst, equilibrated rapidly to form the stabilized complex II. The subsequent [3 + 2] cycloaddition of complex II with methyleneindolinone 90 proceeded smoothly

quence, which gave the corresponding spirocyclic products 85 with a similar levels of enantioselectivity. Additionally, the tertiary amine H-bonding bifunctional catalyst has been widely applied to a variety of asymmetric [3 + 2] cycloaddition reactions for the synthesis of chiral quaternary spirooxindole derivatives.47 With 5 mol % thiourea−quaternary ammonium salt 87a as a phase-transfer catalyst (PTC), Shang and Zhao reported a highly enantioselective 1,3-dipolar cycloaddition of methyleneindolinones 18 with imino esters 86, allowing for efficient installation of a wide range of chiral spiro[pyrrolidin-3,3′oxindoles] 88 in good yields with excellent enantioselectivities (Scheme 23).48 It should be noted that both the thiourea and the quaternary ammonium salt moiety of catalyst 87a were indispensable for high yield and diastereo- and enantioselectivity, as demonstrated by control experiments. 1834


Review

ACS Catalysis Scheme 26. Chiral N,N′-Dioxide/Metal Complex-Catalyzed Asymmetric 1,3-Dipolar Cycloaddition

Scheme 27. Enantioselective [3 + 2] Cycloaddition through Bimetallic Relay Catalysis

2010, Waldmann and co-workers combined 1−3 mol % κN,κPferrocenyl ligand 99 with Cu(CH3CN)4PF6 to develop a highly stereoselective 1,3-dipolar cycloaddition of imino esters 97 with substituted 3-methylene-2-oxindoles 96, which rendered the synthesis of enantioenriched 3,3′-pyrrolidinyl spirooxindoles 98 in excellent yield, dr, and ee (Scheme 25).52 A transition state was proposed wherein the chiral Cu(I) complex generated in situ first coordinates with 97. The resulting intermediate is deprotonated by Et3N to form an activated azomethine ylide, which then attacks 96 from the less hindered face to undergo 1,3-dipolar cycloaddition. Notably, H-bonding interactions between the carbonyl group of 96 and the amino moiety of ligand 99 might form to stabilize the transition state. Moreover, the 1,3-dipolar cycloaddition was further applied to the enantioselective synthesis of the spirotryprostatin A scaffold by the same group.53 Soon after,

to produce the corresponding spirooxindole. Notably, the opposite diastereomer could be easily achieved by using chiral ligand 91b bearing a 2-naphthyl group instead of 1-naphthylsubstituted ligand 91a. Furthermore, the Pd-catalyzed TMM [3 + 2] cycloaddition was successfully identified as the key step in the asymmetric total synthesis of (−)-marcfortine C by the same group.50 Later, Xiao and Lu presented a chiral Pdcatalyzed asymmetric [3 + 2] cycloaddition reaction of methyleneindolinones with chiral palladium-containing 1,3dipoles produced in situ from vinyl aziridine, which allowed the efficient synthesis of 3,3′-pyrrolinyl quaternary spirooxindoles in up to 93% yield with 19:1 dr and >99% ee.51 Later, metal Lewis acid-catalyzed asymmetric 1,3-dipolar cycloadditions of methyleneindolinones with azomethine ylides were also realized and used to install a wide range of chiral quaternary spirooxindole derivatives. For instance, in 1835


Review

ACS Catalysis Scheme 28. Rh-Catalyzed Enantioselective [2 + 2 + 2] Cycloaddition of Diynes and Alkenes

Wang and co-workers disclosed that the combination of TFBiphamPhos 100 with AgOAc could be used to catalyze the same 1,3-dipolar cycloaddition, affording the corresponding products 98 with moderate enantioselectivity.54 Later in 2015, Arai and Yamanaka employed a 10 mol % loading of the Cu(II) complex of their chiral bis(imidazolidine)pyridine (PyBidine) ligand 101 in the same cycloaddition reaction, providing an array of spirooxindoles 98 in excellent yields with excellent diastereo- and enantioselectivities.55 Subsequently, Feng, Liu, and co-workers found that metal complexes of their chiral N,N′-dioxide ligand 103 could be applied in the asymmetric 1,3-dipolar cycloaddition with methyleneindolinones (Scheme 26).56 In the presence of 5 mol % chiral N,N′-dioxide 103/Mg(OTf)2 complex, the highly stereoselective 1,3-dipolar cycloaddition of methyleneindolinones 18 with N,N′-cyclic azomethine imines 102 enabled the formation of enantioenriched pyrazolidine-based spirooxindole derivatives 104 in up to 99% yield with up to >20:1 dr and 99% ee (Scheme 26, eq 1). Two years later, the authors reported an asymmetric [3 + 2] cycloaddition of methyleneindolinones 7 with nitrones 105 using the combination of 10 mol % chiral N,N′-dioxide 106 with 10 mol % Co(BF4)2· H2O, which afforded spirooxindoles 107 in 45−99% yield with 9:1 to >20:1 dr and 90−99% ee (Scheme 26, eq 2).57 More recently, through the use of bimetallic relay catalysis, the Waldmann group developed a catalytic asymmetric 1,3dipolar cycloaddition of methyleneindolinones 7 with azomethine ylides formed in situ from (E)-oximino α-diazo ketones 108 toward the stereoselective synthesis of various spirotropanyl oxindoles 110 (Scheme 27).58 The authors found that the reaction began with the formation of transient azomethine ylides I from a new class of (E)-oximino α-diazo ketones 108 through an intramolecular Rh(II) carbenoid transfer to the oxime in the presence of 2 mol % Rh2(esp)2

complex. The resulting ylides I subsequently underwent an asymmetric 1,3-dipolar cycloaddition with methyleneindolinones 7 under the catalysis of 10 mol % chiral N,N′-dioxide 109/Nd(OTf)3 complex to give the desired cycloadducts 110 in up to 96% yield with up to >20:1 dr and 99% ee. The authors proposed a transition state model to rationalize the observed stereochemistry, as depicted in Scheme 27. The chiral NdIII/N,N′-dioxide complex first coordinates to the 1,3dicarbonyl moiety of oxindole 7 to form a distorted octahedral complex; the resulting azomethine ylide I then approaches preferentially from the top face of 7, with its larger cyclic part pointing away from the ester group, thereby delivering the exo products 110 as major products. In addition to methyleneindolinones, other classes of dipolarophiles, such as α,α,β-trisubstituted 2-alkylidenecycloketones,59 α-methylene-γ-butyrolactone,60 and α-alkylidenesuccinimides,61 have proven to be viable substrates in the chiral metal Lewis acid-catalyzed asymmetric [3 + 2] cycloaddition with imino esters, enabling the synthesis of various spiro compounds featuring a spiro quaternary carbon stereocenter. 2.1.3. Miscellaneous. Apart from the catalytic asymmetric [4 + 2] and [3 + 2] cycloadditions, preliminary success has been achieved with other types of enantioselective cycloadditions for the construction of spiro quaternary carbon stereocenters. For example, in 2006 Shibata and co-workers developed a Rh-catalyzed enantioselective [2 + 2 + 2] cycloaddition of diynes 111 and exo-methylene cyclic compounds 112 for the synthesis of quaternary spirocycles 114 (Scheme 28).62 It was found that 5 mol % (S)-xylylBINAP 113 and Rh(cod)BF4 complex turned out to be powerful catalysts for the transformation, which afforded a broad range of spirocyclic products 114 in good to excellent yields and enantioselectivities. In this cycloaddition, an oxidative coupling of diyne 111 first occurs to generate bicyclic metal1836


Review

ACS Catalysis Scheme 29. Enantioselective Cycloaddition of Cyclopropanes and Alkenes by Enamine Catalysis

Scheme 30. Cascade Double Michael Addition Enabled by Enamine/Iminium Sequential Catalysis

formal [2 + 2] cycloaddition of the resulting dienamine II with the 3-olefinic oxindole gives the spiro cyclobutane 117. 2.2. Michael Addition-Initiated Cascade Reaction. Catalytic asymmetric Michael addition-initiated cascade reactions of cyclic substrates bearing an external olefin represent an alternative powerful strategy for the construction of spiro quaternary carbon stereocenters and have recently attracted much attention from the chemical community.64 Although the use of chiral metal catalysis has met with limited success, asymmetric organocatalysis has been shown to be a powerful approach for the exploration of new cascade reactions, and a variety of activation models, including enamine/iminium catalysis, tertiary amine H-bonding catalysis, tertiary phosphine H-bonding catalysis, and chiral Nheterocyclic carbene (NHC) catalysis, have all proven fruitful. Nevertheless, the achievements have mainly been limited to Michael addition-initiated cascade reactions of special 3olefinic oxindole derivatives.

lacyclopentadiene I, followed by the enantioselective insertion of alkene 112 along with reductive elimination to give the spirocycle 114. In 2015, Jørgensen and co-workers reported an enantioselective [2 + 2] cycloaddition of exo-methylene cyclic compounds 116 and activated cyclopropanes 115 by enamine catalysis. The combination of 10 mol % Hayashi−Jørgensen catalyst 35 and 10 mol % PhCO2H enabled the synthesis of a diverse range of biologically relevant spirocyclobutaneoxindole and spirocyclobutanebenzofuranone derivatives 117 in good yields with high to excellent diastereo- and enantioselectivities (Scheme 29).63 It was noteworthy that the presence of both the diester group on cyclopropanes 115 and an electronwithdrawing substituent on the 3-olefinic oxindoles 116 played a critical role for high reactivity and selectivity. On the basis of mechanistic studies, a reaction pathway was proposed in which iminium ion intermediate I, generated from the reaction of cyclopropane 115 with catalyst 35, produces the activated dienamine intermediate II by deprotonation, after which a 1837


Review

ACS Catalysis Scheme 31. Three-Component Reaction by Enamine−Iminium−Enamine Sequential Catalysis

Scheme 32. Formal [4 + 2] Cycloaddition of Nazarov Reagents and Methyleneindolinones

96, aliphatic aldehydes 121, and enals 122 (Scheme 31).65 In this case, aliphatic aldehydes 121 first react with Hayashi− Jørgensen catalyst 35 to produce the corresponding activated enamine intermediates, which undergo Michael addition with 96, as illustrated in Scheme 31. The resulting 3-substituted oxindolic intermediates II then work with α,β-unsaturated iminium ions III, which are generated in situ from enals 122 and catalyst 35 through a Michael/aldol sequential process. Finally, after dehydration, a diverse range of desired spirocyclic oxindoles 123 are obtained. In addition to enals, Chen and co-workers found that nitroolefins, N-benzylmaleimide, and aldehyde imide were all viable substrates in this type of three-component cascade reaction.69 Later, Zhong and Zeng identified another molecule of aliphatic aldehyde as a competent electrophile to trap the intermediate II in the cascade reaction.70 Furthermore, a quadruple iminium/enamine/iminium/enamine catalysis was further established by the Chen group in a three-component domino reaction of methyleneindolinones with two molecules of enals, which afforded various polycyclic molecules bearing a spirooxindole motif with excellent diastereo- and enantioselectivities.71 A similar quadruple-cascade reaction between (E)3-(2-hydroxybenzylidene)oxindoles and enals was recently realized by Wang and co-workers.72

With enamine/iminium sequential catalysis, in 2009 Melchiorre and co-workers developed a facile synthesis of spirocyclic quaternary oxindoles 120 through a Michael/ Michael cascade reaction of methyleneindolinones 96 and α,βunsaturated ketones 118 (Scheme 30).65 A wide arrange of spirocyclic oxindoles 120 were obtained in good yield with high ee values in the presence of 20 mol % chiral amine catalyst 119 and 30 mol % OFBA. Later, Tao and Wang reported a similar double Michael reaction employing the combination of a cinchona-based chiral primary amine with a BINOL phosphoric acid.66 Ramachary and co-workers further realized the asymmetric double Michael reaction of methyleneindolinones with α,β-acetylenic ketones through amino enyne catalysis, allowing access to various enantioenriched spirooxindoles.67 In addition, also by enamine/iminium sequential catalysis, the double Michael cascade of α,β-unsaturated ketones with unsaturated pyrazolones was accomplished by the groups of R. Wang68a and X.-W. Wang;68b this provided a practical protocol for the assembly of optically enriched spirocyclic pyrazolones, which are an important class of molecules with significant pharmaceutical and biological activities. In the same report, Melchiorre and co-workers adopted an enamine−iminium−enamine sequential activation to establish a three-component cascade reaction of methyleneindolinones 1838


Review

ACS Catalysis Scheme 33. Tandem Michael/Cyclization Reaction of 1,3-Diones and Isatylidene Malononitriles

Scheme 34. Michael−Michael Cascade Using a Bifunctional Chiral PTC

isatins, malononitriles, and 1,3-diones involving a domino Knoevenagel/Michael/cyclization sequence with cupreine 130 as the catalyst. Subsequently, the scope of nucleophiles in this Michael/cyclization cascade with isatylidene malononitriles was broadened to include α-keto esters,82 4-hydroxycoumarin, naphthol,83 and 2-substituted thiazol-4-ones.84 Additionally, isatylidene malononitriles could be used as 2C synthons in the Michael addition-initiated cascade reaction for the construction of spiro quaternary carbon stereocenters under the catalysis of a chiral tertiary amine H-bonding catalyst.85 Multifunctional chiral phase-transfer catalysis was recently employed by Zhao and Shang and by Jørgensen to install chiral spirocycles bearing a spiro quaternary center via a Michael addition-initiated cascade reaction. In 2016, Zhao and Shang established an efficient asymmetric Michael/Michael cascade of 3-alkenyloxindoles 55 with γ-malonate-substituted α,βunsaturated esters 132 using their developed dipeptide-based multifunctional quaternary phosphonium salt catalyst 133a (Scheme 34).86 The combination of 5 mol % PTC 133a and 2.0 equiv of K2CO3 effectively promoted a double Michael reaction, giving a number of five-membered spirocyclic oxindoles 134 in high to excellent yields and selectivities. On the basis of a series of control experiments, a transition state model was proposed in which the malonate carbanion of 132 generated in situ interacts with an amide N−H and the phosphonium center of the catalyst 133a via H-bonding and

By using chiral tertiary amine−urea bifunctional catalysis, in 2010 Wei and Gong73 developed a stereoselective formal [4 + 2] annulation of Nazarov reagents 124 and methyleneindolinones 70 through a double Michael addition sequence (Scheme 32). In the presence of 10 mol % chiral catalyst 125, the double Michael addition proceeded smoothly, providing spirocyclohexanoneoxindole derivatives 126 with excellent enantioselectivities. Remarkably, further transformation of the product 126a in a three-step reaction led to the formation of spirocyclohexanoneoxindole 127, derivatives of which have found applications in the discovery of antitumor agents.74 Since then, a plethora of Michael addition-initiated cascade reactions with cyclic compounds bearing an external olefin catalyzed by chiral tertiary amine H-bonding catalysts, such as Michael/aldol,75 Michael/cyclization,76 Michael/ Mannich,77 Michael/hemiketalization,78 and Michael/alkylation,79 have been developed.80 Also in 2010, Yuan and co-workers disclosed a chiral tertiary amine H-bonding-catalyzed tandem Michael/cyclization reaction of 1,3-diones 129 with isatylidene malononitriles 128 as 3C synthons for the synthesis of spirocyclic quaternary oxindole derivatives (Scheme 33).81 Furthermore, 10 mol % cupreine 130 catalyzed the Michael/cyclization cascade efficiently to give the desired spiro[4H-pyran-3,3′-oxindole] derivatives 131 with moderate to good ee values. At the same time, the authors developed a three-component reaction of 1839


Review

ACS Catalysis Scheme 35. [4 + 2] Annulation of Isatylidene Malononitriles and α-Substituted Allenoates

Scheme 36. NHC-Catalyzed Switchable Reaction of Isatin-Derived Enals with N-Sulfonyl Ketimines

annulation with α-substituted allenoates by chiral tertiary phosphine catalysis, affording an array of spiropyrazolone derivatives in moderate to high yields and diastereo- and enantioselectivities.89 Recently, Enders and co-workers published a novel NHCcatalyzed annulation of isatin-derived enals 139 with α,βunsaturated N-sulfonyl ketimines 140 toward structurally diversified spirocyclopentane oxindoles (Scheme 36).90 It is noteworthy that the use of chiral NHC catalyst 141 led to the formation of various spirocyclic oxindoles 142 bearing an enaminone moiety with good to excellent stereoselectivities, while spirocylic oxindoles 144 bearing an α,β-lactam motif could be easily accessed from the same starting materials by using a slightly different NHC catalyst 143, base, and solvent. As illustrated in Scheme 36, a plausible reaction pathway was demonstrated to account for the observed stereochemical and divergent annulation. In the case of catalyst 141, along with the use of N,N-diisopropylethylamine (DIPEA) and the nonpolar solvent CH2ClCH2Cl, the NHC homoenolate intermediates A, generated from enals 139, first undergo Michael addition with α,β-unsaturated ketimines 140 to form the corresponding

electrostatic interactions. Meanwhile, another amide N−H bond activates electrophile 55 through coordination with the ester carbonyl group, as shown in Scheme 34. In the same year, Jørgensen and co-workers presented a highly stereoselective Michael/alkylation sequence of benzofulvenes and dimethyl bromomalonate catalyzed by a new cinchona alkaloid-based bifunctional PTC, which provided an efficient approach for the preparation of cyclopropane spiroindene derivatives.87 In the Michael addition-initiated cascade reaction, chiral nucleophilic catalysis, such as tertiary phosphine catalysis and NHC catalysis, was found to be an efficient covalent bond activation mode to create spiro quaternary carbon stereocenters. In 2012, the Lu group successfully reported an asymmetric [4 + 2] annulation of isatylidene malononitriles 128 and α-substituted allenoates 136 utilizing amino acidderived bifunctional phosphine 137 (Scheme 35).88 Various biologically important 3-spirocyclohexene-2-oxindoles 138 could be obtained in 53−96% yield with 84−93% ee and 6:1 to >20:1 dr using 5 mol % phosphine 137 as the catalyst. Subsequently, Guo and co-workers discovered that unsaturated pyrazolones were also viable substrates in the [4 + 2] 1840


Review

ACS Catalysis Scheme 37. Chiral NHC-Catalyzed Asymmetric Michael/Aldol/Lactonization Cascade

Scheme 38. Chiral Sc(III) Complex-Catalyzed [3 + 2] Annulation of Allylsilanes 149 and Methyleneindolinones 18

hydroxyphenyl-substituted p-quinone methides also participate in the NHC-catalyzed annulation with isatin-derived enals, furnishing a variety of spirooxindole-ε-lactones.91 In the same year, Wang and co-workers developed an asymmetric Michael/intramolecular aldol/lactonization cascade reaction of oxindolyl β,γ-unsaturated α-keto esters 145 with enals 146 by chiral NHC catalysis (Scheme 37).92 Under the catalysis of 10 mol % aminoindanol-derived triazoliumbased NHC catalyst 147, a variety of spirooxindoles 148 featuring four contiguous stereocenters were obtained in 52−

intermediates B, which subsequently proceed through an azaDieckmann-type cyclization to deliver the desired spirocycles 142. However, when NHC catalyst 143 together with the inorganic base K3PO4 and polar solvent MeCN are used, the resulting intermediates I also undergo a Michael addition to produce intermediates II through a proton transfer process, followed by a Mannich-type reaction to yield the acyl azolium species III, which afford the corresponding spirocyclic products 144 and regenerate the active NHC catalyst through lactamization. One year later, the authors found that o1841


Review

ACS Catalysis Scheme 39. N,N′-Dioxide 103/Mg(OTf)2-Catalyzed Michael/Friedel−Crafts/Mannich Cascade

Scheme 40. Chiral PyBidine 101/Ni(OAc)2 Complex-Catalyzed Michael/Aldol Cascade Reaction

roles in the annulation process: one is to enhance the catalytic activity by forming a cationic (R,S)-indaPyBOX·Sc(OTf)2BArF complex, and the other is to facilitate the generation of a transient β-silyl carbocation. In 2015, Feng and co-workers reported an efficient asymmetric Michael/Friedel−Crafts/Mannich cascade of NBoc-3-alkenyloxindoles 7 with 2-isocyanoethylindoles 152 catalyzed by the N,N′-dioxide 103-derived Mg(OTf)2 complex (Scheme 39).94 Various polycyclic 3-spirooxindoles 153 with four contiguous stereocenters were produced in up to 96% yield with >20:1 dr and 93% ee. As shown in TS-I of Scheme 39, the isocyanide group of the 2-isocyanoethylindole attacks the methyleneindolinone from the β-Si face because it is shielded by the amide group under the ligand. This is followed by a Friedel−Crafts/dearomative annulation sequence to give the desired product 153.

71% yield with >20:1 dr and 73−99% ee. Similarly, a possible reaction mechanism is illustrated in Scheme 37. Along with the significant achievements of the organocatalyzed Michael addition-initiated cascade reactions of cyclic substrates bearing an external olefin, chiral metal catalysis only recently demonstrated initial potency in the assembly of enantioenriched spirocycles featuring spiro quaternary centers. For instance, in 2014 Franz and co-workers presented a chiral Sc(III) complex-catalyzed asymmetric [3 + 2] annulation of allylsilanes 149 and methyleneindolinones 18 through a Michael/1,2-silyl shift/cyclization process (Scheme 38).93 They found that a 10 mol % loading of the chiral PyBOXderived Sc(III) complex generated in situ from (R,S)indaPyBOX 150, Sc(OTf)3, and NaBArF smoothly mediated this annulation and provided an array of functionalized spirooxindolic cyclopentanes 151 in good to excellent yields and selectivities. Notably, the additive NaBArF might play two 1842


Review

ACS Catalysis Scheme 41. N,N′-Dioxide 16/Sc(OTf)3 Complex-Catalyzed Domino 1,5-H Shift/Ring-Closure Reaction

Scheme 42. Chiral Zirconium Complex-Catalyzed Diene Cyclization

One year later, Arai and co-workers accomplished an asymmetric Michael/aldol reaction of methyleneindolinones 96 and thiosalicylaldehydes 154 catalyzed by their developed chiral PyBidine 101/Ni(OAc)2 complex, which was an effective method to generate a variety of thiochromanyl spirooxindoles having three contiguous stereogenic centers (Scheme 40).95 On the basis of initial HRMS analysis and control experiments, the authors proposed that the PyBidine/Ni(II) complex interacts with thiosalicylaldehyde 154 and concurrently activates methyleneindolinone 96 through the Hbonding interaction with the N−H bond of the imidazolidine ring. The enantioselective Michael addition of thiolate with 96 then occurs to give intermediate II, which undergoes an intramolecular aldol reaction to provide 155 as the major

product. In addition, the Feng group realized a catalytic asymmetric thia-Michael/aldol cascade of 1,4-dithiane-2,5diols with 3-alkenyloxindoles employing a chiral N,N′-dioxide/ Ni(II) complex, allowing access to a series of spirocyclic oxindole-fused tetrahydrothiophenes in good yields with excellent ee and dr.96 The Feng group established a practical synthesis of chiral spirooxindole−tetrahydroquinolines 157 through a chiral Sc(III) complex-catalyzed asymmetric domino 1,5-hydride shift/ring-closure reaction with well-designed methyleneindolinones 156 (Scheme 41).97 The use of 10 mol % N,N′-dioxide 16/Sc(OTf)3 complex as the catalyst was identified to be effective for this transformation, rendering the synthesis of various spirocyclic products 157 in 57−97% yield with >20:1 dr and 82−94% ee. On the basis of kinetic isotope effect 1843


Review

ACS Catalysis Scheme 43. Chiral Palladium Complex-Catalyzed 1,6-Enyne Cyclization

Scheme 44. Chiral Palladium Complex-Catalyzed 1,7-Enyne Cyclization

have been developed to install various chiral spirocycles containing a spiro quaternary center. Although chiral metal catalysis has dominated these reactions, the potential of organocatalysis has been demonstrated. 3.1. Ene-Type Cyclizations. Transition-metal-promoted ene-type cyclizations of dienes, enynes, and diynes are very useful in synthetic organic chemistry98 and have not only been applied to the synthesis of various natural products99 but also serve as a promising strategy to construct spiro quaternary carbon stereocenters by the choice of rationally designed substrates. For instance, in their study of chiral zirconium complex-catalyzed asymmetric diene cyclization to access heterocycles in 1997, Mori and co-workers realized the first example of diene cyclization for the synthesis of chiral spiro heterocycles featuring a spiro quaternary carbon stereocenter by using as substrates the suitable dienes 158 having a cyclic moiety bearing an internal olefin. The use of 10 mol % chiral zirconium complex (S)-(EBTHI)ZrBINOL 159 effectively mediated the cyclization of diene 158, providing the desired spirocyclic products 160 in good yield and enantioselectivity

experiments, the 1,5-H transfer process was considered the rate-determining step. Interestingly, in the presence of 10 mol % chiral N,N′-dioxide 16/Sc(OTf)3 complex, the cascade reactions of (R)-156a and (S)-156b with 99% ee delivered (2R,3R)-157a and (2S,3S)-157b, respectively, which indicated a clear chiral memory effect in this chiral N,N′-dioxide-derived Sc(III) complex-catalyzed cascade reaction.

3. VIA CYCLIC COMPOUNDS BEARING AN INTERNAL OLEFIN Catalytic asymmetric reactions involving cyclic compounds bearing an internal olefin are an important alternative strategy toward spiro quaternary carbon stereocenters that has attracted much interest from synthetic chemists. In contrast to the use of cyclic compounds bearing an external olefin functionality, a greater diversity of optically enriched spirocycles could be built because they have much greater structural diversity. Through much effort from the synthetic community, a series of stereoselective reactions, such as ene-type cyclizations, semipinacol-type rearrangements, and dearomatization reactions, 1844


Review

ACS Catalysis Scheme 45. Organocatalytic Semipinacol-Type Rearrangement of Hydroxy Enones 168

Scheme 46. Semipinacol-Type Rearrangement through Direct Allylic C−H Activation

Compared with the formation of chiral five-membered spiro rings from 1,6-enyne cyclization, the formation of sixmembered spiro rings through catalytic enantioselective enetype cyclizations with 1,7-enynes was thought to be challenging, possibly because of the increased difficulty of forming six-membered ring systems over five-membered ones. Even so, Hatano and Mikami102 applied a chiral cationic Pd(II) complex to realize a highly efficient and enantioselective ene-type cyclization of 1,7-enynes 165, which allowed sixmembered spirocycles featuring a spiro quaternary carbon stereocenter to be forged (Scheme 44). It was found that the combination of 10 mol % (S)-BINAP and 5 mol % Pd(MeCN)4(BF4)2 was optimal for the current 1,7-enyne cyclization, furnishing various spirocyclic quinolines 166 or 167 in good to excellent yields and ee values. 3.2. Semipinacol-Type Rearrangements. The catalytic asymmetric semipinacol-type rearrangement is also an efficient strategy for the construction of spiro quaternary carbon stereocenters, which was first established in 2009 by Tu and co-workers through chiral iminium catalysis (Scheme 45).103

(Scheme 42).100 Interestingly, substrate 158a having a cyclohexene moiety delivered only the cis product 160a in 47% yield with 94% ee (eq 1), whereas substrate 158b featuring a cyclopentene moiety produced cis- and trans-160b in a ratio of almost 2:1 (eq 2). Later, in 2003, Hatano and Mikami101 found that the combination of a 10 mol % loading of their own developed phosphine−oxazoline 162 and a 5 mol % loading of Pd(MeCN)4(BF4)2 enabled the 1,6-enyne cyclization of various allyl propargyl sulfonamides 161 to proceed smoothly to produce a series of chiral spirocyclic alkaloids 163 featuring five- to 15-membered rings in good yields with high enantioselectivities, albeit accompanied by olefin migration products 164 in some cases (Scheme 43). Notably, the ratio of olefin migration significantly depended on the ring size of the cyclic olefin, as depicted in the selected examples shown in Scheme 43. Meanwhile, this cationic Pd(II) catalyst could also catalyze the asymmetric ene-type spirocyclization of allyl propargyl ethers with similar results, providing a variety of heterocycles bearing a spiro quaternary carbon stereocenter. 1845


Review

ACS Catalysis Scheme 47. Semipinacol-Type Rearrangement via Nazarov Cyclization Intermediate

Scheme 48. Intramolecular CADA Reaction of Tryptamine-Derived Indol-3-yl Allylic Carbonates

dr and ee. Notably, both the Pd(II) species and (S)-TRIP were essential for the semipinacol rearrangement, as no reaction occurred in the absence of either one. In addition, 1,4benzoquinone (BQ) as the oxidant and noncoordinating aromatic solvents also proved to be critical for high levels of enantiocontrol. According to preliminary mechanistic studies, a reaction pathway was proposed in which cyclobutanols 171 first coordinate to the active Pd(II) species to form the corresponding complexes I, which undergo rate-limiting C−H activation to generate π-allyl−Pd intermediates II. Subsequent semipinacol ring expansion of II affords 172 and a Pd(0) species, which is reoxidized to Pd(II) by BQ. Recently, Tu and co-workers reported a chiral Brønsted acid-catalyzed asymmetric tandem Nazarov cyclization/semipinacol rearrangement reaction toward quaternary spirocyclic diketones (Scheme 47).105 Under the catalysis of 10 mol % chiral N-triflylphosphoramide 174, a variety of well-designed 2hydroxyalkyl-1,4-dien-3-one derivatives 173 underwent an asymmetric Nazarov cyclization to generate the corresponding

The authors found that the combination of cinchona-based primary amine 169 and N-Boc-L-phenylglycine was a powerful catalyst system for the asymmetric vinylogous α-ketol rearrangement of hydroxy enones 168 through semipinacoltype rearrangement, allowing the preparation of spirocyclic diketones 170 featuring a spiro quaternary carbon stereocenter in 57−99% yield with 48−97% ee. A possible transition state was demonstrated for the transformation, through which primary amine 169 reacts with hydroxy enone 168 in the presence of N-Boc-L-phenylglycine to generate the activated iminium intermediate, which subsequently undergoes a semipinacol-type rearrangement to give the desired diketone 170. Later, in 2012, Chai and Rainey104 developed a highly enantioselective semipinacol rearrangement of indenyl-substituted cyclobutanols 171 through direct allylic C−H activation (Scheme 46). The use of 10 mol % Pd(OAc)2 and 20 mol % phosphoric acid (S)-TRIP delivered various spirocyclic indenes 172 in 22−78% yield with good to high 1846


Review

ACS Catalysis Scheme 49. Intramolecular CADA Reaction of Indole Derivative 179

Scheme 50. Intramolecular CADA Reactions of N-Alkyl-Tethered Indol-3-yl Allylic Carbonates 184 and 188

oxyallyl intermediates I, which then went through a semipinacol ring expansion to furnish a series of chiral spiro[4.4]nonane-1,6-diones 175 in 69−96% yield with >20:1 dr and 84−97% ee. Furthermore, this represents the first direct example of the preparation of optically pure cyclopentanones 175 with up to four consecutive stereocenters by means of Nazarov cyclization. 3.3. Dearomatization Reactions. Over the past few decades, catalytic asymmetric dearomatization (CADA) reactions have gained considerable attention because they can enable direct transformations from readily available aromatic compounds to enantiopure polycycles and spirocycles, which are frequently found in natural products and are also key structural motifs in pharmaceuticals and biologically active molecules.106 Furthermore, CADA also offers a straightforward protocol for the construction of spiro quaternary carbon stereocenters through a dearomatization process. In this context, an array of indole, phenol, and βnaphthol derivatives have been applied to the CADA reaction, allowing a highly efficient synthesis of structurally diversified quaternary spirocyclic scaffolds. With a dearomatization strategy, in 2010 You and coworkers disclosed the first example of a highly efficient Ircatalyzed intramolecular allylic C3 alkylation reaction of indoles 176, which enabled the synthesis of spiroindolenine

derivatives 178 featuring two contiguous stereocenters, with one being a spiro quaternary center (Scheme 48).107 With the combination of [Ir(cod)Cl]2 and their developed chiral phosphoramidite ligand Me-THQphos 177,108 tryptaminederived allylic carbonates 176 effectively underwent intramolecular allylic dearomatization reactions, delivering sixmembered spiroindolenines 178 in good to excellent yields and selectivities. In addition, substrates having a substituent at C2 of the indole moiety also afforded the corresponding products in excellent yield and ee, albeit with modest dr values. Two years later, the same group further presented a highly enantioselective synthesis of five-membered spiroindolenines using Ir-catalyzed asymmetric allylic dearomatization of indole derivatives 179. The use of a 4 mol % loading of the chiral Ir complex prepared from [Ir(cod)Cl]2 and ligand 180 turned out to be a powerful approach, furnishing a series of spiro cyclopentane-1,3′-indolines 182 in up to 96% yield with up to 16:1 dr and 99% ee after treatment of the resulting spiroindolenines with NaBH3CN (Scheme 49).109 More interestingly, under the catalysis of 30 mol % TsOH, spiroindolenines 181 underwent stereospecific allylic migration to produce the corresponding tetrahydrocarbazoles 183. Comprehensive DFT calculations supported a concerted mechanism involving a “three-center−two-electron”-type transition state, as depicted in Scheme 49.110 1847


Review

ACS Catalysis Scheme 51. Intramolecular CADA Reaction of Racemic Indole Derivatives 191

Scheme 52. Desymmetrizing Allylic Dearomatization of Prochiral Indole-Derived Allylic Carbonates

highly stereoselective allylic dearomatization of C2-substituted N-alkyl-tethered indol-3-yl allylic carbonate 188 for the synthesis of five-membered aza-spiroindolenines 190 without any migration (Scheme 50, eq 2).112 With 2 mol % [Ir(cod)Cl]2 and 4 mol % ligand 180, a variety of azaspiroindolines 190 could be obtained in high yields and stereoselectivities after reduction of aza-spiroindolenine intermediates 189 with LiAlH4 in a one-pot fashion. One year later, by tuning the electronic properties of the Nlinker in the indol-3-yl allylic carbonates, You and co-workers reported the chiral Ir complex-catalyzed asymmetric allylic dearomatization of N-substituted N-tethered indol-3-yl allylic

Subsequently, in 2013 You and co-workers found that only chiral tetrahydro-β-carbolines 187 were obtained in the allylic dearomatization of N-Bn-tethered indol-3-yl allylic carbonates 184 in the presence of a chiral Ir complex (Scheme 50, eq 1). This result possibly occurred because sequential methylene migration via a three-center−two-electron-type transition state was more prone to proceed when substrates 186 contained a functional group with a strong ability to stabilize the positive charge; indeed, the aza-spiroindolenine intermediate was observed in situ by infrared spectroscopy, but it was difficult to isolate.111 On this basis, by installing a substituent group at C2 of the indole ring, the authors successfully achieved a 1848


Review

ACS Catalysis Scheme 53. Chiral Phosphoric Acid-Catalyzed CADA Reactions

Scheme 54. Formal [3 + 2] Cycloaddition of Arylsulfonyl Indoles and Vinylcyclopropanes

carbonate 191 without a substituent at C2 of the indole moiety (Scheme 51).113 When racemic indole derivatives 191 containing an electron-withdrawing N-protecting group and an aryl substituent at C8 were employed, the three isolable azaspiroindolenine diastereomers 192a−c were obtained with excellent ee values under the catalysis of the chiral Ir complex generated in situ from 2 mol % [Ir(cod)Cl]2 and 4 mol % ligand 180. Notably, the resulting aza-spiroindolenine diastereomers 192 could be converted into the corresponding tetrahydro-β-carbolines 193 in 77% yield with 5:1 dr and 94% ee through a one-pot dearomatization/migration sequence. Very recently, You and co-workers also developed an iridium-catalyzed stereoselective desymmetrizing allylic dearomatization of prochiral bis(indol-3-yl)-substituted allylic carbonates 194, allowing efficient access to various enantioenriched six-membered spiroindolenines featuring three con-

tiguous stereocenters, including one spiro quaternary center (Scheme 52).114 The combination of 2 mol % [Ir(dbcot)Cl]2 and 4 mol % ligand 195 was identified as a powerful catalyst for this reaction, giving rise to the target spirocyclic spiroindolenines 196 in up to 99% yield with 20:1 dr and 99% ee. An unprecedented six- to seven-membered ring expansion of spiroindolenines 196 proceeded smoothly under the catalysis of 30 mol % TsOH to yield hexahydroazepino[4,5-b]indoles 197 with almost no loss of enantioselectivity. Apart from chiral iridium catalysis, You and colleagues recently disclosed that chiral phosphoric catalysis can also be used to mediate the CADA reactions of indole derivatives. The use of 10 mol % chiral phosphoric acid 199 was effective for the enantioselective intramolecular dearomative Michael addition of indolyl enones 198, affording various enantioenriched spiroindolenines 200 in good yields and enantioselec1849


Review

ACS Catalysis Scheme 55. CADA Reaction of Para-Substituted Phenol Derivatives

Scheme 56. Pd-Catalyzed Enantioselective Arylative Dearomatization of Phenol Derivatives

tivities (Scheme 53, eq 1).115 More recently, chiral phosphoric acid 199 was used by the same group to catalyze the stereoselective dearomatization of indolyl dihydropyridines 201 through an enamine isomerization/spirocyclization/transfer hydrogenation sequence (Scheme 53, eq 2).116 In addition, Liu and He established a practical synthesis of enantioenriched five-membered spiroindolenines using a chiral Pd complex-catalyzed formal [3 + 2] cycloaddition of vinylcyclopropane derivative 205 and α,β-unsaturated imines generated in situ from arylsulfonyl indoles 204 through an intramolecular allylic dearomatization process (Scheme 54).117 The use of 5 mol % Pd(dba)2 and ligand 94 enabled a series of spiroindolenines 206 to be obtained in good to high yields and ee values with excellent dr values. As demonstrated in Scheme 54, a catalytic cycle was proposed in which 1,3-dipole

intermediate A is generated from dimethyl vinylcyclopropane diester 205 in the presence of the chiral palladium complex. Arylsulfonyl indole 205 is then deprotonated by the carbanion of 1,3-dipole species A to produce the corresponding α,βunsaturated imine B and benzenesulfinate D. Subsequently, the nucleophilic addition of 1,3-dipole A to α,β-unsaturated imine B yields indole-tethered allylic palladium C, which then undergoes intramolecular allylic dearomatization to afford the desired spiroindolenine 206 and regenerate chiral Pd complex. On the basis of this analysis, an excess of vinylcyclopropane 205 is required for this cyclization because 1 equiv of 205 is consumed to give byproduct F. Aside from indoles, phenol derivatives, which are an important class of feedstocks in organic synthesis, can also be employed as C-nucleophiles in the CADA reaction to create 1850


Review

ACS Catalysis Scheme 57. Hypervalent Iodine-Mediated Oxidative Dearomatization of Phenol Derivatives

only avoided the generation of diaryl ethers through a competitive intermolecular C−O cross-coupling but also favored reductive elimination of the resulting six-membered palladacycle intermediate to give the desired product over the rearomatization process, as shown in Scheme 56. Later, in 2015, Gong and co-workers developed a chiral hypervalent iodine-catalyzed enantioselective oxidative dearomatization reaction of naphthol derivatives 216 that allowed quaternary spirooxindoles 218 to be forged (Scheme 57).122 The oxidative dearomatization of 1-hydroxy-N-aryl-2-naphthamide derivatives 216 proceeded smoothly when chiral iodobenzene catalyst 217 was employed as the precatalyst and m-chloroperoxybenzoic acid (m-CPBA) was used as the stoichiometric oxidant, giving various spirooxindoles 218 in 42−80% yield with 80−92% ee. As illustrated in Scheme 57, the authors proposed that chiral iodobenzene catalyst 217 is oxidized by m-CPBA to give hypervalent phenyl-λ3-iodane A. Subsequently, substitution of A with the hydroxy group of 216 gives chiral iodoenol-type intermediate B, which then undergoes ligand exchange with either trifluoroethanol or water to generate associative intermediate C. Finally, an intramolecular SN2′-like Friedel−Crafts substitution of intermediate C occurs through Si-face attack, affording the desired product 218 and releasing chiral iodobenzene 217. Notably, the addition of both trifluoroethanol and H2O was identified to be beneficial for achieving high yield and enantioselectivity by facilitating the associative pathway. In the same year, Luan and co-workers reported the first Pdcatalyzed dynamic kinetic asymmetric spiroannulation of

spiro quaternary carbon stereocenters, although they are wellknown to serve as O-nucleophiles. In 2010, by the use of rationally designed substrates, Hamada and co-workers reported a Pd-catalyzed enantioselective intramolecular ipsoFriedel−Crafts allylic alkylation of para-substituted phenol 207 through an allylic dearomatization process. With the combination of Pd(dba)2 and Trost ligand 208, quaternary spiro cyclohexadienone 209 was isolated in 80% yield with 9:1 dr and 89% ee (Scheme 55, eq 1).118 In parallel with this work, You and co-workers published an improved result for the same dearomatization reaction using the chiral Ir complex generated from phosphoramidite ligand 211 and [Ir(cod)Cl]2 (Scheme 55, eq 2).119 Subsequently, You and co-workers successfully applied a chiral phosphoramidite-derived Ir catalytic system to realize the allylic dearomatization reaction of α-substituted βnaphthol derivatives, which are a more challenging class of substrates.120 The CADA reactions of phenol derivatives for the construction of spiro quaternary carbon stereocenters were not limited to asymmetric allylic substitution reactions. In 2011, as part of their research on the palladium-catalyzed arylative dearomatization of phenol derivatives 213, Buchwald and co-workers realized a catalytic enantioselective version of this transformation by combining Pd(OAc)2 with chiral monophosphine ligand 214 (Scheme 56).121 The target molecules 215 containing a spiro quaternary carbon stereocenter were obtained in good to high yields and enantioselectivities. Notably, the key to success for this arylative dearomatization was the selection of a catalyst system that not 1851


Review

ACS Catalysis Scheme 58. Chiral Pd-Catalyzed Intermolecular Spiroannulation of Phenols 219 with Alkynes

Scheme 59. Pd-Catalyzed Asymmetric Intermolecular Carbocyclization of Phenols 223 with 224

naphthol 223 undergoes oxidative addition with the Pd(0) complex and the resulting intermediate then reacts with diyne 224 through carbopalladation to generate intermediate I. Subsequent intramolecular carbopalladation of the aryl-Pd(II) species to the alkyne moiety forms the corresponding intermediate II, which finally undergoes an asymmetric dearomatization process to provide the target polycycle 226. In addition to the use of prefunctionalized phenol derivatives in intermolecular dearomatization reactions, the You group described a Rh-catalyzed asymmetric dearomatization of 2naphthol derivatives 227 with internal alkynes 228 using a C− H activation strategy, which provided a new straightforward entry for the synthesis of polycyclic molecules bearing a spiro quaternary carbon stereocenter (Scheme 60).125 With 5 mol % chiral Rh catalyst 229 together with Cu(OAc)2 and K2CO3, the C−H functionalization/dearomatization reaction afforded an array of polycyclic compounds with good to excellent enantioselectivities. On the basis of mechanistic studies and comprehensive DFT calculations,126 a catalytic cycle was proposed (Scheme 60). Deprotonation of the naphthol by chiral Rh catalyst occurs first to give intermediate I, which then undergoes C−H activation as the turnover-limiting step. The resulting six-membered rhodacyclic intermediate II coordinates with the alkyne and subsequently undergoes regio- and enantioselective migratory insertion of the alkyne, leading to

phenol derivatives with alkynes using an axial-to-central chirality transfer strategy, allowing access to a new class of spirocycles 222 featuring a spiro quaternary carbon stereocenter (Scheme 58).123 The chiral NHC−Pd complex generated from NHC 221 and Pd(OAc)2 was found to be the best choice for the current spiroannulation of racemic axial biaryls 219 and alkynes 220, providing various spirocycles 222 in 55−95% yield with 84−96% ee. It should be noted that the addition of potassium iodide was crucial to obtain high yields. As shown in Scheme 58, oxidative addition of the C−Br bond in 219 with the Pd(0) catalyst takes place first to afford intermediate I, which slows the rotation of the biaryl moiety. Subsequently, intermediate I is coupled with alkyne 220, and subsequent dearomatizative spiroannulation of the phenol moiety in a highly enantioselective manner delivers the product 222. One year later, Luan and co-workers reported a Pd-catalyzed asymmetric intermolecular carbocyclization of naphthol derivatives 223 with tethered diynes 224 for the construction of chiral polycyclic molecules bearing a spiro quaternary carbon stereocenter (Scheme 59).124 With 5 mol % Pd(OAc)2 and TADDOL-derived phosphoramidite 225, the desired polycyclic product 226 was obtained in 83% yield with 66% ee through a cross-coupling/dearomatization process. A reaction pathway was proposed in which the C−Br bond of 1852


Review

ACS Catalysis Scheme 60. Rh-Catalyzed Asymmetric C−H Functionalization/Dearomatization of 2-Naphthols

Scheme 61. Pd-Catalyzed Asymmetric Heck Reaction of 231

method for carbon−carbon bond formation, was first used to construct spiro quaternary carbon stereocenters by Overman and co-workers in 1992 (Scheme 61).128 The authors found that the asymmetric Heck cyclizations of aryl iodides 231 proceeded smoothly under catalysis by the (R)-BINAP/ Pd2(dba)3 complex. Remarkably, by the use of Ag3PO4 or 1,2,2,6,6-pentamethylpiperidine (PMP) to scavenge HI, the 3,3-spirooxindole enantiomers (S)- and (R)-232, respectively, could be accessed using the same (R)-BINAP ligand. In addition, Takao and co-workers described an intramolecular Friedel−Crafts-type 1,4-addition of designed cyclic compounds 233 bearing an internal olefin by imine catalysis (Scheme 62).129 A wide range of quaternary spiroindanes 235

the eight-membered rhodacyclic intermediate IIIa. Although an equilibrium exists between rhodacycle IIIa and high-energy π-oxaallyl-Rh intermediate IIIb, only the former can participate in the next dearomatization process through [1,3′]-reductive elimination, giving rise to intermediate IV, which releases the dearomatized product and regenerates the active catalytic species under the interaction with Cu(OAc)2. Shortly after, with a similar strategy, Lam and co-workers developed a C−H functionalization/spiroannulation of enol derivatives and internal alkynes for the enantioselective synthesis of quaternary spiroindenes.127 3.4. Miscellaneous. Apart from the three types of reaction discussed above, the asymmetric Heck reaction, as a versatile 1853


Review

ACS Catalysis Scheme 62. Organocatalyzed Intramolecular Friedel−Crafts-Type 1,4-Addition

Scheme 63. Synergistic Ring Contraction/Formal [6 + 2] Cycloaddition of Pyrazolones 236 with Enals

might deprotonate another phenolic hydroxy group of substrate 233 in the intermediate, thereby increasing the reactivity and forming an advanced asymmetric reaction site. Most importantly, this organocatalytic intramolecular Friedel− Crafts-type 1,4-addition was applied to the asymmetric formal synthesis of the spirocyclic natural products (−)-cannabispirenone A and B and the total synthesis of (−)-misramine.130 Inspired by the formal ring expansion of vinyl cyclopropanes with enals for the construction of spiro compounds through synergistic catalysis,131 Rios and co-workers recently designed a new class of pyrazolone derivatives 236 as equivalents of

were prepared with excellent enantioselectivity in the presence of cinchonidine-based primary amine 234 together with the addition of water and p-bromophenol. On the basis of control experiments, a plausible reaction pathway for the spirocyclization was proposed (Scheme 62). First, primary amine catalyst 234 reacts with the ketone group of substrate 233 to generate imine intermediate I, in which the phenolic hydroxy group of 233 is deprotonated at the same time by the tertiary amine part of 234. The resultant intermediate II undergoes intramolecular 1,4-addition and subsequent hydrolysis to give the spiro product 235. Meanwhile, a second molecule of catalyst 234 1854


Review

ACS Catalysis Scheme 64. Michael/Aldol Cascade of 3-Substituted Oxindoles 238 and Methyleneindolinones 70

Scheme 65. Synthesis of Spirocyclopentaneoxindoles from 3-Allyloxindoles

intermediate E. Finally, hydrolysis of the iminium and decoordination of palladium furnishes [5,5]-spiropyrazolone derivative 237 and regenerates both catalysts.

vinyl cyclopropanes and realized a ring-contraction/formal [6 + 2] cycloaddition process of 236 with enals 122 for the construction of various spiropyrazolones featuring a spiro quaternary center (Scheme 63).132 Under the synergistic catalysis of Pd(0) with chiral secondary amine 35, a wide range of [5,5]-spiropyrazolone derivatives 237 were obtained in excellent yields and stereoselectivities. On the basis of computational predictions and experimental evidence, a catalytic cycle was proposed (Scheme 63). The reactant 236 and enal 122 are activated by Pd(0) catalysis and chiral amine 35, respectively, to produce the corresponding reactive πallylpalladium complex B and iminium intermediate C. Palladium intermediate B then reacts as a nucleophile with C to give intermediate D, wherein the resulting enamine then attacks the palladium-coordinated allyl cation to produce

4. VIA CYCLIC METHINE COMPOUNDS During the past several years, a variety of asymmetric cascade sequences and intramolecular cyclizations involving cyclic methine compounds have emerged as promising protocols for the synthesis of a diverse range of spirocyclic molecules featuring a spiro quaternary stereogenic center. In this section, representative achievements are introduced according to the class of substrates used. Intermolecular cascade reactions with cyclic methine compounds were first achieved using organocatalysis. In 1855


Review

ACS Catalysis Scheme 66. Synthesis of Spirocyclopenteneoxindoles from 3-Alkynyloxidoles

2011, with rationally designed 3-substituted oxindoles 238 as cyclic methine compounds, the Barbas group reported a Michael/aldol cascade reaction for the installation of enantiomerically enriched bispirooxindole derivatives 240 having four stereogenic centers, two of which are spiro quaternary centers (Scheme 64).133 It was found that the utilization of the new multifunctional cinchona alkaloid catalyst 239 bearing thiourea and tertiary and primary amine moieties enabled the efficient domino Michael/aldol reaction of 3substituted oxindoles 238 and methyleneindolinones 70, producing an array of bispirooxindoles 240 with high levels of diastereo- and enantioselectivity. Notably, the opposite enantiomer could also be readily obtained with excellent selectivity simply by varying the thiourea and tertiary amine configuration of the cinchona alkaloid while keeping the axial chirality of the (S)-binaphthyl diamine scaffold. As demonstrated in Scheme 64, a dual-activation transition state was postulated in which 3-substitued oxindole 238 is activated by the thiourea moiety of catalyst 239 through multiple Hbonding interactions while the protonated tertiary amine and primary amine coordinate with the carbonyl groups of methyleneindolinone 70, thereby inducing the high selectivity. Following this work, Wang and Hong reported the stereoselective construction of bispirooxindoles using a tertiary amine−squaramide-catalyzed Michael/alkylation sequence on methyleneindolinones with 3-bromoethyl-substituted oxindoles.134

Subsequently, the Barbas group developed a stereoselective Michael/Henry cascade reaction of 3-substituted oxindoles 238 with nitrostyrenes using a bifunctional quinidine derivative as the catalyst, which provided a facile protocol for access to highly substituted spirocyclopentane oxindoles.135 Later, by means of an iminium/enamine activation strategy, a domino Michael/aldol condensation of 238 with enals and a 1,6conjugate addition/aldol cascade reaction between 238 and βsubstituted cyclic dienones were independently accomplished by the groups of Barbas136 and Melchiorre,137 allowing for the direct preparation of enantiomerically pure spirocyclic quaternary oxindole derivatives. Also in 2011, Shao and co-workers described a highly efficient synthesis of optically active spirocyclopentaneoxindoles by an organocatalytic enantio- and diastereoselective Michael addition/intramolecular silyl nitronate−olefin cycloaddition (ISOC)/fragmentation sequence of N-Boc-3-allyl oxindoles 241 with nitroolefins 242 (Scheme 65, eq 1).138 In the presence of a 10 mol % loading of their developed tertiary amine−thiourea catalyst 243, the asymmetric Michael addition of N-Boc-3-allyloxindoles 241 to nitroolefins proceeded smoothly to afford chiral 3,3′-disubstituted oxindoles 245, which is a key element for the stereocontrol of the sequence. Subsequently, the desired spirocyclic oxindoles 244 were obtained in up to 85% yield with up to 99% ee after an ISOC and fragmentation process. Notably, the complete transfer of chirality in the ISOC/fragmentation sequence might be attributed to the preferred nitronate 1856


Review

ACS Catalysis Scheme 67. Synthesis of Spirocyclopropyl Oxindoles from 3-Chlorooxindoles

Scheme 68. Michael/Acylation Cascade of Β-Keto Amides 255 and α,β-Unsaturated Acyl Cyanides 256

sequence of 3-propargyloxindoles 249 and enals 122 using iminium/enamine−Pd(II) synergistic catalysis. It was found that the combination of Hayashi−Jørgensen catalyst 35 and PdCl2 was effective for the Michael/cyclization sequence, providing a wide range of spirocyclopentene oxindoles 250 in 60−92% yield with 5:1 to >20:1 dr and 93−99% ee. Remarkably, in stark contrast to the stepwise catalytic protocols, a clear 1 + 1 > 2 synergistic effect was observed, as much higher diastereo- and enantioselectivities were achieved in this sequence. In line with initial mechanistic studies, the authors proposed a synergistic reaction pathway to explain the observed stereochemistry and chemoselectivity, as outlined in Scheme 66. The reaction begins with the generation of iminium intermediate A, which then undergoes a Michael addition to give the corresponding enamine intermediate B followed by a dynamic kinetic asymmetric transformation through chiral enamine−Pd(II) synergistic catalysis, which contributes to the stereocontrol. Finally, a subsequent cycloisomerization of the obtained chiral inter-

conformation I driven by a 1,3-allylic strain interaction, thus furnishing a transient isoxazolidine intermediate II in a highly diastereoselective manner. At same time, the authors documented an asymmetric Michael/Michael cascade reaction between nitroolefins 242 and novel Michael donor−acceptor 3-allyloxindoles 247, which were prepared from N-Boc-3-allyloxindoles 241 with vinyl ester through Ru-catalyzed cross-metathesis (Scheme 65, eq 2).139 A diverse range of spirocyclopentaneoxindoles 248 with four contiguous stereocenters were obtained in 73−87% yield with 16:1 to >20:1 dr and 93−99% ee when the same catalyst 243 was used. Since then, a variety of cascade reactions with 3-allyloxindole derivatives, including Michael/Michael,140 Michael/Povarov,141 Michael/allylation,142 and Mannich/ deprotection/Michael143 cascades, have been developed toward quaternary spirooxindoles. Besides the 3-allyloxindole derivatives, 3-propargyloxindoles have also been applied for the construction of spiro quaternary carbon stereocenters by Wang and Hong (Scheme 66).144 They developed a highly stereoselective Michael/cyclization 1857


Review

ACS Catalysis Scheme 69. Michael/Hemiaminalization Reaction of β-Keto Amides and Enals

Scheme 70. Intramolecular Carbocyclization Cascade of Allene-Linked Keto Amides

squaramide bifunctional-catalyzed asymmetric Michael/intramolecular cyclization sequence with methyleneoxindoles and arylidenepyrazolones by Kanger145 and Du,147 respectively. In addition to 3-substituted oxindole scaffolds, cyclic β-keto amides were also used recently as cyclic methine substrates to construct spiro quaternary carbon stereocenters because they have two nucleophilic reactive sites, as opposed to 3substituted oxindoles, which have both nucleophilic and electrophilic reactive sites. In 2014, Rodriguez and Bonne presented a practical approach that provides access to optically active spirocyclic lactams through a chiral tertiary amine−thiourea bifunctionalcatalyzed stereoselective formal [3 + 3] spiroannulation of cyclic β-keto amides 255 with α,β-unsaturated acyl cyanides 256 as biselectrophiles.148 Under the catalysis of 10 mol % catalyst 257, a broad range of spiroglutarimide derivatives 258 were obtained in 71−87% yield with 1:1 to 10:1 dr and 34− 92% ee (Scheme 68). On the basis of a series of mechanistic studies, the authors speculated that the reaction starts with the formation of the enolate of β-keto amide 255 through deprotonation by the tertiary amine of catalyst 257; the

mediate C leads to the product 250 and regenerates catalyst 35 and the Pd(II) species. In 2013, Kanger, Malkov, and co-workers demonstrated an enantioselective synthesis of chiral spirocyclopropyl oxindoles using as the cyclic methine substrates 3-chlorooxindoles 251 bearing both nucleophilic and electrophilic sites at C3 of the oxindole scaffold (Scheme 67).145 The use of 20 mol % chiral secondary amine 253 effectively promoted the Michael/ cyclization cascade reaction of 3-chlorooxindoles 251 with enals 252, furnishing the target spirocyclopropyl oxindoles 254 in good yields and stereoselectivities. The proposed reaction pathway is shown Scheme 67, in which iminium intermediate I is formed from chiral amine 253 and enal 252 and then is attacked by the 3-chlorooxindole in a Michael addition process. The resultant enamine intermediate II undergoes an intramolecular SN2 alkylation to deliver the product 254. One year later, the Melchiorre group reported the 1,6-addition/ cyclization sequence of 3-chlorooxindoles 251 with dienals under dienamine catalysis.146 Additionally, 3-chlorooxindoles were utilized to synthesize polycyclic compounds containing a spirocyclopropyl oxindole motif by means of a tertiary amine− 1858


Review

ACS Catalysis Scheme 71. Intramolecular α-Arylation of α-Substituted Cyclic Ketones 265

Scheme 72. Intramolecular Direct C-Acylation of α-Substituted Indanone Derivatives 269

allene-linked pronucleophiles 261 first reacted with iodides 262 under the catalysis of 10 mol % chiral Pd(II) complex, formed in situ from Pd(OAc)2 and chiral bis(oxazoline) ligand 263, to produce allyl intermediates I, which then underwent intramolecular alkylation to furnish various spirolactam products 264 in good yields with excellent dr and good ee values. Subsequently, Takizawa and Sasai reported a chiral Pdcatalyzed asymmetric intramolecular α-arylation of α-substituted cyclic ketones 265 tethered to a bromobenzene moiety at the α-position (Scheme 71).152 The combination of 5 mol % Pd(OAc)2 with 7.5 mol % Josiphos ligand 266 enabled various chiral spirocyclic ketones 267 to be formed in 28−91% yield with 12−83% ee. Furthermore, the obtained spirocyclic ketone 267a was elaborated in five simple operations to obtain a new chiral spirocyclic tertiary phosphine catalyst 268, which could be used to catalyze the aza-MBH reaction of N-Ts imines and methyl vinyl ketone with moderate enantioselectivity. Apart from using chiral Pd complexes as transition metal catalysts, chiral PTCs have also received some attention for the construction of spiro quaternary carbon stereocenters by means of intramolecular reactions involving cyclic methine compounds. For example, Smith and co-workers demonstrated an intramolecular direct C-acylation with rationally designed α-substituted indanone derivatives 269 for the synthesis of enantioenriched quaternary spirobiindanones 271 (Scheme 72).153 With chiral ammonium salt 270 as the PTC and K3PO4 as the base, ketone enolates were generated in situ from indanone derivatives 269 and subsequently underwent direct

resulting enolate is stabilized and orientated by H-bonding interactions with the thiourea moiety. Meanwhile, α,βunsaturated acyl cyanide 256 is activated by the ammonium part of the catalyst through H-bonding activation, and subsequent Michael addition and intramolecular acylation cyclization give the target molecule, as demonstrated in Scheme 68. Later, in 2017, Meazza, Rios, and Veselý developed an asymmetric Michael addition/hemiaminalization cascade sequence of cyclic β-keto amides 259 with α,β-unsaturated aldehydes 122 by chiral iminium catalysis.149 An array of αspiro-δ-lactams 260 were obtained in 37−90% yield with 1.2:1 to >20:1 dr and 55 to >99% ee in the presence of 20 mol % secondary amine 253 and 2,4-(NO2)2C6H3CO2H (Scheme 69). More recently, Biju and co-workers accomplished a highly efficient chiral NHC-catalyzed enantioselective formal [3 + 3] spiroannulation of cyclic β-keto amides 259 with α-bromo-α,βunsaturated aldehydes, which enabled the assembly of a series of biologically and synthetically important spiroglutarimide derivatives in high yields and stereoselectivities.150 In pace with the advance of intermolecular cascade reactions involving cyclic methine substrates in the creation of spiro quaternary carbon stereocenters, a variety of intramolecular cyclizations utilizing well-designed cyclic methine compounds have also been realized. In 2013, Dixon and co-workers documented a Pd-catalyzed asymmetric intramolecular carbocyclization cascade of allenelinked keto amides 261 for the synthesis of highly functionalized spirolactams 264 featuring a spiro quaternary center (Scheme 70).151 In the presence of silver phosphate, the 1859


Review

ACS Catalysis Scheme 73. Intramolecular Enolate C-Acylation of 3-Substituted Oxindole Derivatives 272

Scheme 74. Michael/Michael/Aldol Reaction of 3-Unsubstituted Oxindoles with Enals

assembly of spiro quaternary stereogenic centers. Distinct activation modes, such as iminium catalysis, tertiary amine Hbonding catalysis, and tertiary phosphine catalysis, have been used to conduct various asymmetric cascade reactions with cyclic methylene compounds as dinucleophiles. In 2010, Rios and co-workers pioneered the asymmetric Michael/Michael/aldol cascade reaction involving cyclic methylene compounds and iminium catalysis, which rendered the synthesis of chiral spirocyclic molecules featuring a spiro quaternary carbon stereocenter (Scheme 74).155 The authors found that the combination of 20 mol % Hayashi−Jørgensen catalyst 35 with PhCO2H efficiently catalyzed the Michael/ Michael/aldol cascade of 3-unsubstituted oxindoles 275 and enals 276 to furnish an array of quaternary spirocyclic oxindoles 277 in up to 90% yield with up to >20:1 dr and 99% ee. Moreover, other types of cyclic methylene substrates, such as pyrazolones and benzofuran-2(3H)-ones, were also competent substrates under the standard conditions, leading to the corresponding spirocyclic products with excellent dr and ee values. As illustrated in Scheme 74, oxindole 275 undergoes two sequential Michael addition reactions with two molecules of enal 276 through iminium catalysis, followed by an intramolecular aldol reaction and irreversible dehydration to render the spirocyclic product. Notably, the utilization of benzoic acid was essential for the production of the target

C-acylation with a pentafluorophenyl ester to give spirobiindanones 271 in 71−99% yield with 86−98% ee. In addition, a new type of doubly quaternized cinchona alkaloid-based PTC developed by Xiang and Yasuda was identified as a powerful catalyst for the installation of optically active spirocyclic quaternary oxindoles through an intramolecular alkylation of 3-substituted oxindole derivatives 272 bearing a benzyl chloride scaffold (Scheme 73).154 At a loading of only 1 mol %, catalyst 273 enabled the current reaction to proceed efficiently to afford the desired spirooxindoles 274 in excellent yields and ee values. Notably, the authors found that the leaving group has a significant effect on the selectivity because the ee of the product decreased greatly when the Cl substituent was replaced with either a Br or OTs group. More importantly, the quaternized quinolone moiety plays a crucial role in achieving high reactivity and enantioselectivity, although detailed reasons are not currently clear, as demonstrated by the control experiments shown in Scheme 73.

5. VIA CYCLIC METHYLENE COMPOUNDS With the development of asymmetric organocatalysis in the past two decades, a diverse range of organocatalytic stereoselective cascade reactions involving cyclic methylene compounds, including 3-unsubstituted oxindoles and 4-unsubstituted pyrazolones, have gained considerable interest for the 1860


Review

ACS Catalysis Scheme 75. Direct Enantioselective Cyclopropanation of Oxindoles

Scheme 76. Formal [5 + 1] Cyclization of Oxindoles with Ester-Linked Bisenones

278 with bromonitroolefins 279 that allowed access to 3spirocyclopropyl-2-oxindoles (Scheme 75). In the presence of a 10 mol % loading of their developed multifunctional catalyst 280 incorporating an amino acid, oxindoles 278 first proceed through a Michael addition reaction with bromonitroolefins 279 to give intermediates I, which go through an intramolecular H-shift and subsequent SN2 substitution to deliver the desired spirocyclopropanes 281 in up to 76% yield with up to >20:1 dr and 99% ee, accompanied by the formation of 282 (Scheme 75, eq 1). Most importantly, another diastereoisomer of 282 could be readily accessed in up to 95% yield with up to >20:1 dr and 98% ee simply by treating the resultant 281 with

spirooxindoles; no product formed in the absence of PhCO2H, likely because it mediated the irreversible dehydration step, thereby avoiding the occurrence of a retro-Michael reaction. Three years later, the Veselý group reported a similar Michael/ Michael/aldol sequence in which the oxindoles were replaced with benzothiophenones as cyclic methylene substrates, which afforded a series of optically pure spirocyclic benzothiophenones in good yields with excellent selectivity.156 With tertiary amine H-bonding multifunctional catalysis together with 3-unsubstituted oxindoles as dinucleophilic reagents, in 2012 Dou and Lu157 developed a direct enantioselective cyclopropanation of 3-unsubstituted oxindoles 1861


Review

ACS Catalysis Scheme 77. Domino Michael/Conia-Ene Reactions Involving Pyrazolones 287

Scheme 78. Michael/Aldol Sequence for the Reaction of Pyrazolones with Nitroalkenes

transition state I, followed by an intermolecular Michael addition to give the enone-tethered intermediate II. Finally, intramolecular Michael addition of oxindole 283 to enone 284 affords the target product 286. Two years later, also using tertiary amine H-bonding catalysis, Schoenebeck and Enders reported a facile stereoselective synthesis of multifunctionalized chiral spiropyrazolones 290 by means of a domino Michael/Conia-ene reaction involving pyrazolones 287 (Scheme 77).159 The use of 1 mol % tertiary amine−squaramide catalyst 289 with 3 mol % Ag2O mediated the Michael/Conia-ene cascade of pyrazolones 287 with alkyne-tethered nitroalkenes 288, giving spiropyrazolones 290 in 27−99% yield with 8:1 to >20:1 dr and 42−99% ee. Furthermore, the internal alkynes bearing aliphatic and aromatic substituents (R3 = c-hexyl, n-Bu, Ph) were also competent substrates, and their use led to comparable results. On the basis of control experiments and computational studies, an asymmetric Michael addition of 287 to the nitroalkene moiety of 288 catalyzed by catalyst 289 first occurs, and then

1.0 equiv of 1,4-diazabicyclo[2.2.2]octane (DABCO) through a stereochemically retentive conversion. Furthermore, diastereomer 282 was also prepared directly from oxindole 278 with bromonitroolefin 279 in a stepwise manner (Scheme 75, eq 2). Notably, the final products 282 resulted from two pathways in this case, including direct cyclopropanation and epimerization from 281, thereby providing higher yields and slightly different ee values. Later, in 2014, Xu, Liang, and co-workers developed a stereoselective formal [5 + 1] cyclization of dinucleophilic 3unsubstituted oxindoles 283 with ester-linked bisenones 284 catalyzed by a bifunctional tertiary amine−thiourea catalyst (Scheme 76).158 A wide range of trisubstituted spirooxindole δ-lactones with three contiguous stereocenters were prepared in high yields with excellent dr and ee. The authors proposed that the tertiary amine moiety of bifunctional catalyst 285 deprotonates oxindole 283 to form an enolate, while the enone is activated by the thiourea part through H-bonding interactions with one of the carbonyl groups, as shown in 1862


Review

ACS Catalysis Scheme 79. Michael/Michael/Aldol Cascade Reaction by Synergistic Catalysis

Scheme 80. [4 + 1] Annulation of Pyrazolones with Allenoate-Derived MBH Acetates

94% ee under the catalysis of 2 mol % tertiary amine− squaramide catalyst 293. The sequence commenced with the asymmetric Michael addition of pyrazolone 291 to nitroalkene 292 catalyzed by the squaramide catalyst 293. A diastereoselective intramolecular aldol reaction of the resulting chiral adduct I then proceeded in the presence of DIPEA to deliver the final products 294. Utilizing the synergistic activation of chiral tertiary amine Hbonding catalysis with iminium catalysis, Zhou, Li, and co-

an intramolecular Conia-ene reaction of the resultant intermediate I proceeds smoothly under the catalysis of Ag2O to provide spirocycle 290. Soon after, the asymmetric one-pot Michael/aldol sequential reaction of pyrazolones 291 with nitroalkenes 292 decorated with an alkyl ketone moiety was developed by the Chen group (Scheme 78).160 A variety of functionalized spiropyrazolone derivatives 294 featuring four consecutive stereogenic centers were obtained in 37−80% yield with 15:1 to >20:1 dr and 70− 1863


Review

ACS Catalysis Scheme 81. Asymmetric Desymmetrization of Spiro Cyclohexadienone Oxindoles

tional catalyst 302, providing access to a variety of enantioenriched 4-spiro-5-pyrazolones 303 in good yields with high ee values (Scheme 80).163 To gain a clearer understanding of this [4 + 1] annulation pathway and stereocontrol, a plausible reaction mechanism was demonstrated (Scheme 80). The reaction starts with nucleophilic attack of tertiary phosphine 302 to allenoate 301, and the resulting intermediate A undergoes a subsequent elimination of acetate to generate intermediate B, which is then attacked at the γ-position by the pyrazolone enolate 300. Proton transfer from the thus-formed phosphonium ylide C then occurs to give intermediate D, followed by an intramolecular Michael addition and elimination of the catalyst 302 to yield the desired cycloadduct 303. Additionally, the authors proposed that a water molecule participates in the 1,3-proton transfer process according to their preliminary studies. Moreover, the H-bonding interaction between the amide N−H bond of catalyst 302 and the pyrazolone enolate is essential for high reactivity and enantioselectivity, as exemplified by the control experiments shown in Scheme 80.

workers designed a one-pot asymmetric Michael/Michael/ aldol tandem reaction of 3-unsubstituted N-Boc-oxindoles 295 and nitroolefins 242 with enals 122 (Scheme 79).161 The combination of 15 mol % chiral tertiary amine−thiourea catalyst 296 with Hayashi−Jørgensen catalyst 35 proved to be optimal, leading to a wide array of highly functionalized spirocyclic oxindoles 297 featuring five consecutive stereogenic centers in up to 94% yield with up to 7:2:1 dr and >99% ee (Scheme 79, eq 1). More interestingly, the spirocyclic oxindoles 299, one major alternative diastereomer of the products 297, could be obtained in up to 92% yield with 9:2.5:1 dr and >99% ee by changing the TMS group on the secondary amine catalyst to a tert-butyldimethylsilyl (TBS) group (Scheme 79, eq 2), which was likely due to the different steric effects of catalysts 35 and 298. On the basis of a series of control experiments, a proposed mechanistic pathway is illustrated in Scheme 79. Nitroolefins 242 are activated by the thiourea part of catalyst 296 through intermolecular Hbonding interactions. Meanwhile, the tertiary amine moiety acts as a Brønsted base to deprotonate oxindoles 295, thereby facilitating the first Michael addition with activated nitroolefins 242. The thus-produced Michael adducts I then undergo the second nitro-Michael reaction with the enals, which are activated by the secondary amine catalyst through iminium catalysis, to deliver intermediates II, followed by an intramolecular aldol reaction to afford the corresponding products. Three years later, using the same strategy, Du and co-workers accomplished the stereoselective synthesis of cyclohexanonefused spiropyrazolones containing four continuous stereocenters through an asymmetric Michael/Michael/aldol cascade reaction with dinucleophilic pyrazolones.162 Additionally, Lu and co-workers achieved a highly enantioselective [4 + 1] annulation of pyrazolones 300 with α-substituted allenoate 301 catalyzed by a 20 mol % loading of their own L-threonine-derived O-silylated phosphine bifunc-

6. VIA COMPOUNDS WITH A PROCHIRAL SPIROCENTER Catalytic asymmetric desymmetrization of compounds with a prochiral spirocenter is a straightforward strategy for the generation of a diverse range of enantiomerically enriched spirocyclic molecules featuring a quaternary carbon stereocenter, which have received increased attention in the past 5 years. Nonetheless, most of the methods focus on the synthesis of spirocyclic oxindole derivatives. In 2013, Wang and co-workers applied a desymmetrization strategy in the synthesis of chiral quaternary spirooxindoles for the first time and developed an asymmetric desymmetrization of prochiral spiro cyclohexadienone oxindoles 304 through an organocatalyzed enantioselective sulfa-Michael addition 1864


Review

ACS Catalysis Scheme 82. Desymmetric Enantioselective C−H Oxygenation of Spirooxindole Derivatives 306

Scheme 83. Carbonyl-Directed Heck−Matsuda Desymmetrization of Prochiral Spirocycles

(Scheme 81).164 The sulfa-Michael addition was efficiently facilitated by a 5 mol % loading of tertiary amine H-bonding multifunctional catalyst 306, giving the desired spirooxindoles 307 in 77−95% yield with >20:1 dr and 82−95% ee. Notably, the enone functionality of spirooxindoles 307 not only could be selectively reduced by NaBH4 to give the allylic alcohol and by Pd(OH)2/C to give the ketone but also readily underwent a secondary sulfa-Michael reaction under the catalysis of K2CO3. This provided an opportunity to access both 307a and epi307a under the same conditions simply by varying the addition

sequence of the two different thiols, as exemplified in Scheme 81. Also employing desymmetrization of prochiral spirocyclic oxindole derivatives, in 2015 Bach and co-workers reported an enantioselective benzylic C−H oxygenation of rationally selected prochiral spirooxindoles 308 to allow access to optically active quaternary spirooxindoles 311 (Scheme 82).165 By the use of 1.0 mol % chiral supramolecular ruthenium metalloporphyrin complex 310 as the catalyst, the enantioselective C−H oxygenation of 308 could be performed effectively with 2,6-dichloropyridine N-oxide (309) as an 1865


Review

ACS Catalysis Scheme 84. Desymmetric Dehydrogenation of Prochiral Spiro Cyclohexanones

spirooxindoles 315 in 78−95% yield with >20:1 dr and 87− 99% ee (Scheme 83, eq 1). Furthermore, a diverse variety of simpler five- and six-membered prochiral spirolactones/ spirolactams 316 were also suitable substrates, furnishing chiral spirolactones/spirolactams 318 with excellent stereoselectivity when chiral ligand 317 was used with ZnCO3 as the base (Scheme 83, eq 2). Control experiments demonstrated that the carbonyl group of 316 was essential to achieve high reactivity and selectivity; 318d was obtained in only 45% yield with 1:1 dr with 20:1 dr (Scheme 86).170 Notably, treatment of the obtained α-spirocyclopropyl lactone 331d with LiAlH 4 provided a useful protocol for the generation of highly optically active hydroazulene 332, which is a member of an important class of seven-membered carbocycles in natural product synthesis. Later, in 2009, Katsuki and co-workers improved and broadened the same cyclopropanation by using 1 mol % iridium−salen complex 334 (Scheme 87).171 A broad variety of trans-selective α-spirocyclopropyl lactones 335 were achieved in excellent yields with excellent diastereo- and enantioselectivities. It should be noted that the addition of 4 Å

MS suppressed well the formation of byproducts resulting from O−H insertion of water. Moreover, 1,1-disubstituted αmethylstyrene was also a viable substrate under the standard conditions, affording the product 335f in 99% yield with 99% ee, albeit with 5:1 trans selectivity. Ultimately, the corresponding chiral 1,4-cycloheptadiene derivatives, which are widely present in many natural products, could be readily accessed stereospecifically through Cope rearrangement. Diazooxindoles, as an alternative cyclic diazo compound, have also recently received increasing attention in the stereoselective synthesis of structurally diversified spirocyclopropyl oxindoles.172 At the end of 2012, Awata and Arai173 pioneered the enantioselective cyclopropanation of diazooxindoles 337 and monosubstituted alkenes 329 by employing 1 mol % Rh2(S-PTTL)4 as the chiral catalyst, which allowed access to the desired spirocyclopropyl oxindoles 338 in 65− 99% yield with 7:1 to >20:1 dr and 48−74% ee (Scheme 88). Moreover, both 1-aryl- and 1-alkyl-substituted alkenes were suitable substrates under the optimal conditions. Meanwhile, we reported the first highly diastereo- and enantioselective cyclopropanation of diazooxindoles 339 and alkenes (Scheme 89).174 It was found that the utilization of 2.0−5.0 mol % (R)-difluorphos 341/Hg(II) complex allowed 1868


Review

ACS Catalysis Scheme 89. Enantioselective Cyclopropanation with Diazooxindoles Catalyzed by a Hg(II) Catalyst

spirocyclopropyl oxindoles with vicinal quaternary carbon stereocenters. Interestingly, mechanistic studies indicated that the formation of strong C−F···H−N interactions between the solvent (PhF) and the N−H bond of the 339-derived Au(I)− carbenoid intermediate effectively lowered the reaction barrier. This was the first demonstration that C−F···H−X interactions177 between fluorinated solvents and the reactive intermediates might be helpful to improve both the reactivity and stereoselectivity of a catalytic asymmetric reaction.

the preparation of various spirocyclopropyl oxindoles 342 in 40−99% yield with >20:1 dr and 60−99% ee. Additionally, 1,1and 1,2-disubstituted alkenes could also be used to deliver the corresponding products, albeit in moderate to good yields and ee values, as shown in the selected examples. Interestingly, a significant ligand acceleration effect was observed in this Hgcatalyzed cyclopropanation because employing even 0.2 mol % ligand 341 with 2.0 mol % Hg(OTf)2 enabled cyclopropanation in 74% yield with 83% ee; in stark contrast, less than 7% yield was obtained in the absence of chiral ligand. Most importantly, the results demonstrated for the first time that the catalytic properties of Hg(II) could be modulated by varying the ligand. Along with our interest in gold catalysis,175 we further made an unprecedented breakthrough in the asymmetric cyclopropanation involving diazooxindoles for the assembly of structurally diversified chiral spirocyclopropyl oxindoles (Scheme 90).176 By using the chiral cationic Au(I) complex derived from Ding’s SKP ligand 344, we found that a wide range of cis- and trans-1,2-disubstituted, 1,1-disubstituted, and trisubstituted alkenes 343 all worked very well with diazooxindoles 339 to provide various spirocyclopropyl oxindoles 345 in up to 98% yield with >20:1 dr and 95% ee. Notably, in general it is difficult to develop a general catalytic system that offers full stereocontrol for the cyclopropanation with trans- or cis-1,2-disubstituted and trisubstituted alkenes because of the high sensitivity of metallocarbenes to the steric hindrance and geometry of alkenes, which highlights the significant advantages of this Au(I)-catalyzed approach. Moreover, the results represent the first example of highly stereoselective Au(I)-catalyzed asymmetric cyclopropanation of diazo reagents. Most recently, we also found that an SKPderived chiral digold catalyst could realize highly stereoselective cyclopropanation of unprotected diazooxindoles with α-CH2F or α-CHF2 styrenes to furnish fluorinated 3-

8. MISCELLANEOUS Aside from the six major classes of synthetic strategies reviewed above, several asymmetric reactions with other rationally designed acyclic and cyclic substrates have also emerged as tools with which to construct spirocyclic compounds bearing a spiro quaternary carbon stereocenter. We summarize these advancements in this section. Gong and co-workers developed an asymmetric direct intramolecular C(sp2)−H/C(sp3)−H oxidative cross-coupling of N1,N3-diphenylmalonamides 346 catalyzed by a chiral organoiodine reagent, which provides an alternative straightforward approach toward optically active quaternary spirooxindoles (Scheme 91).178 The combination of a 15 mol % loading of their newly synthesized chiral organoiodine catalyst 347 with 2.0 equiv of CF3CO2H and 4.0 equiv of the oxidant MeCO3H was found to be effective for the two sequential aryl C−H activations of various N1,N3-diphenylmalonamides 346, affording spirocyclic bisoxindoles 348 in moderate yields with good enantioselectivities. As demonstrated in Scheme 91, a reaction transition state was proposed to account for the origin of the stereochemistry. The oxidation cyclization reaction involves a syn addition−elimination process via an iodonium intermediate with trifluoroacetate counterion,179 and an intramolecular Friedel−Crafts addition of anilide to the 1869


Review

ACS Catalysis Scheme 90. Enantioselective Cyclopropanation with Diazooxindoles Catalyzed by a Au(I) Catalyst

Scheme 91. Asymmetric Direct Intramolecular C(sp2)−H/C(sp3)−H Oxidative Cross-Coupling of 346

mono-oxindole, followed by a similar addition−elimination to yield (S)-348 as the major product. In 2014, Shi and co-workers reported a straightforward entry to an optically enriched spiro[cyclopenta[b]indole-1,3′-oxindole] scaffold through an organocatalytic asymmetric [3 + 2]

iodoenol in the associative intermediate is preferentially performed from the less sterically hindered Si face of the 2indololate moiety, creating the stereogenic center. Subsequently, elimination of the iodine catalyst results in the acyclic 1870


Review

ACS Catalysis Scheme 92. Asymmetric [3 + 2] Cycloaddition of 3-Hydroxyoxindoles 349 and 2-Vinylindoles 350

Scheme 93. [3 + 2] Annulation of Isatin-Derived MBH Carbonates with Electron-Deficient Alkenes

cycloaddition of 3-methyl-2-vinylindoles 350 with isatinderived 3-indolylmethanols 349 (Scheme 92).180 The authors found that 10 mol % chiral phosphoric acid 351 was an effective catalyst, affording a wide range of spiro[cyclopenta[b]indole-1,3′-oxindoles] 352 in good yields with excellent stereoselectivities. On the basis of control experiments, the authors proposed that the reaction starts with an acid-catalyzed dehydration of 3-indolylmethanols 349 to produce the corresponding vinyliminium intermediates, which subsequently undergo a vinylogous Michael addition with 350 via the Hbonding activation model of transition state I. The thusobtained transient intermediates II rapidly undergo an intramolecular Friedel−Crafts reaction triggered by the force of restoring the stable indole moiety, giving the target molecules 352. It should be noted that the N−H bond of the indole moiety in both reacting partners is crucial for high enantioselectivities. Later on, the authors further reported the synthesis of structurally diverse chiral quaternary spirocyclic oxindole derivatives through the asymmetric cascade reactions

of isatin-derived 3-indolylmethanols 349 with isatin-derived imines generated in situ181 or 7-vinylindoles.182 Isatin-derived MBH carbonates 353, produced from isatins and acrylates, have also recently been applied in the synthesis of various quaternary spirooxindole derivatives. For example, a catalyst-controlled diastereodivergent synthesis of chiral polycyclic quaternary spirooxindoles was developed by Chen and Ouyang using a chiral Lewis base-catalyzed asymmetric [3 + 2] annulation of isatin-derived MBH carbonates 353 with electron-deficient alkenes 354 (Scheme 93).183 A variety of polycyclic spirooxindoles 356 were prepared with excellent diastereo- and enantioselectivities under the catalysis of 10 mol % H-bond-donor tertiary phosphine bifunctional catalyst 355. Interestingly, the use of 10 mol % tertiary phosphine catalyst 357 rendered various diastereomers 359 in good to excellent yields and stereoselectivities. Moreover, in the presence of a 10 mol % loading of their newly designed chiral DMAP-type catalyst 358, spirooxindoles 359 could also be obtained with better results. On the basis of DFT calculations, the authors 1871


Review

ACS Catalysis Scheme 94. Chiral Phosphoric Acid-Catalyzed Cyclization Reaction of Ketals 360

Scheme 95. Asymmetric [3 + 3] Annulation of N-Diethoxyphosphoryl Oxindoles 363 with Aldonitrones

ligands.188 However, the rigid structure makes their catalytic asymmetric synthesis very difficult.189 For example, the general synthetic approach for the preparation of chiral 1,1′spirobiindane-7,7′-diols (SPINOLs), a class of versatile synthetic precursors for the preparation of various chiral catalysts and ligands, involves chiral resolution of the corresponding racemates.190 In 2016, Tan and co-workers reported the first example of catalytic enantioselective synthesis of chiral SPINOLs by means of chiral phosphoric acid-

proposed that the origin of the diastereoselectivity might be the steric hindrance effect of the catalysts. Additionally, a number of asymmetric [3 + 2] annulations of isatin-derived MBH carbonates with propargyl sulfones,184 N-phenylmaleimide,185 1-azadienes,186 and α-cyano-α,β-unsaturated ketones187 have also been realized to access a diverse range of quaternary spirooxindole derivatives. Optically active 1,1′-spirobiindanes have recently emerged as a privileged framework of axially chiral organocatalysts and 1872


Review

ACS Catalysis Scheme 96. Asymmetric [3 + 3] Annulation of N-Diethoxyphosphoryl Oxindoles 363 with Ketonitrones

Scheme 97. Kinugasa/Michael Domino Reaction of Prochiral Cyclohexadienones with Nitrones

catalyzed spirocyclization of ketones or ketals (Scheme 94).191 The use of 1 mol % chiral phosphoric acid 361 could effectively catalyze the cyclization of ketals 360, affording a wide array of optically active SPINOL derivatives 362 in 50− 99% yield with 83−96% ee. Notably, the practicality of this methodology was further demonstrated by a multigram-scale synthesis that proceeded without loss of yield or enantioselectivity. On the basis of control experiments, the authors

proposed a possible reaction pathway, as illustrated in Scheme 94. The reaction starts with the formation of intermediates A catalyzed by 361, which then generate intermediates B in situ. Subsequently, active o-quinodimethane intermediates C are formed in the presence of acid 361, which finally deliver the target SPINOLs 362 under the action of chiral catalyst 361. The double H-bonding interaction between the phosphoric 1873


Review

ACS Catalysis

be accessed with excellent stereoselectivity (up to >20:1 dr and 97% ee) in the presence of 1.0 equiv of iBu2NH. To understand the reaction mechanism pathway, a catalytic cycle was proposed in which the reaction begins with the production of copper acetylide intermediate I from alkyne 370 to generate the active Cu(I) species in situ. Subsequently, a catalytic stereoselective Kinugasa [3 + 2] cycloaddition with the nitrone occurs smoothly to give copper-bound isoxazoline intermediate II, which undergoes a rearrangement to afford tethered four-membered copper enolate intermediate III. Subsequent desymmetric Michael addition forms the desired spirocyclic βlactam 373 and regenerates the active Cu catalyst.

acid and intermediate C is the key to control of the stereoselectivity. Early in 1999, Carreira and co-workers pioneered the ring expansion of spirocyclopropyl oxindoles, a class of monoactivated donor−acceptor cyclopropanes, as a promising straightforward approach toward spirocyclic quaternary oxindoles.192 However, no catalytic enantioselective version involving spirocyclopropyl oxindoles has been reported in the past 20 years, likely because of their low reactivity. Recently, however, we reported a highly diastereo- and enantioselective [3 + 3] cycloaddition of spirocyclopropyl oxindoles 363 with nitrones 364 (Scheme 95).193 It was found that use of 10 mol % chiral BOX/Ni(II) complex, generated in situ from BOX ligand 365 and Ni(OTf)2, could efficiently catalyze the [3 + 3] cycloaddition, and kinetic resolution of N-diethoxyphosphoryl spirocyclopropyl oxindoles (±)-363 and aldonitrones 364 allowed the preparation of a plethora of enantiomerically enriched oxindole-based spirocyclic tetrahydro-1,2-oxazines 366 with excellent dr and ee, accompanied by the recovery of chiral spirocyclopropyl oxindoles (1R,2S)-363 with excellent enantioselectivities. Notably, the N-diethoxyphosphoryl protecting group of the spirocyclopropyl oxindoles proved to be crucial for securing high reactivity and diastereoselectivity; the use of other Nprotecting groups, such H, Bn, ketone, or Ts, all gave inferior results, as illustrated in Scheme 95. Control experiments and NMR analysis, together with previous studies, led to the proposal of a stepwise mechanistic pathway and reaction transition state to explain the observed stereochemistry and high reactivity. This [3 + 2] annulation begins with coordination of N-diethoxyphosphoryl oxindole 363 to the chiral Ni(II) complex, which facilitates the O-attack of nitrone 364 to the cyclopropane moiety. An intramolecular Mannich cyclization of the resulting intermediate I then occurs through a favored boatlike transition state II, affording the 3,6-transtetrahydro-1,2-oxazine-based spirooxindole 366 as the major product. Moreover, the N-diethoxyphosphoryl group of the product 366 can be readily removed in the presence of 1.0 equiv of KOH. Interestingly, the same catalyst could enable a catalytic enantioselective one-pot sequential [3 + 3] dipolar cycloaddition reaction of aldehyde, N-alkyl hydroxylamine, and spirocyclopropyl oxindole, affording the desired product 366 with up to 97% ee, albeit with a diminished dr value.193b Remarkably, under the catalysis of the same chiral BOX/ Ni(II) complex at a loading of 10 mol %, a highly stereoselective [3 + 3] annulation of N-diethoxyphosphoryl oxindoles 363 with acetophenone-derived ketonitrones 368 was further established by the same group, providing a variety of spirooxindoles with consecutive quaternary and tetrasubstituted carbon stereocenters in 78−88% yield with 10:1 to 18:1 dr and 94−98% ee (Scheme 96).192 Furthermore, the result represents the first example of enantioselective catalytic reactions based on such unactivated ketonitrones 368 to forge tetrasubstituted carbon stereocenters, which showcases a new synthetic opportunity through which ketonitrones can be used to create tetrasubstituted carbon stereocenters. Very recently, Enders and co-workers reported an enantioselective Kinugasa/Michael domino reaction of prochiral alkyne-tethered cyclohexadienones 370 with nitrones 371, providing a powerful protocol for the synthesis of versatile, highly functionalized spirocyclic β-lactams (Scheme 97).194 The employment of 20 mol % Cu(OTf)2 and 22 mol % BOX ligand 372 allowed an array of chiral spirocyclic lactams 373 to

9. CONCLUSIONS AND OUTLOOK Over the past few decades, tremendous achievements in the catalytic enantioselective construction of spiro quaternary carbon stereocenters have been made. As summarized here, a variety of elegant approaches based on the six major strategies outlined in Figure 2 have exhibited their power and advantages for the facile synthesis of a diverse range of chiral threedimensional (3D) spirocyclic molecules featuring a spiro quaternary center. During this process, the values and different activation modes of chiral metal Lewis acid catalysis, transition metal catalysis, and organocatalysis have all been demonstrated. Despite significant progress, many limitations remain, and this field of research is full of synthetic opportunities for further development. First, although six major strategies involving six different types of substrates have been explored, the reaction classes and substrate types of each strategy remain very limited. For example, in spite of the significant attention that has been paid to catalytic asymmetric reactions involving cyclic compounds bearing internal olefin functionality, most of them are limited to special oxindole scaffolds and use either cycloaddition or Michael addition-initiated cascade reactions. Therefore, the development of various new types of substrates having sufficient structural diversity and more reaction classes would be a promising direction for the efficient creation of spiro quaternary carbon stereocenters. Moreover, other asymmetric catalytic models, such as photoredox catalysis, electric catalysis, and enzyme catalysis, still have no application in this area, which is another direction that needs to be explored in the future. We believe that more practical and efficient protocols for the catalytic enantioselective construction of spirocyclic scaffolds featuring a spiro quaternary carbon stereocenter will continue to be exploited, along with the emergence of a range of new catalytic systems and structurally diversified substrates. Such 3D quaternary spirocycles will also find an increasing number of applications in the fields of pharmaceuticals, agrochemicals, materials science, and other related areas.

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AUTHOR INFORMATION

Corresponding Authors

*E-mail for J.-S.Y.: [email protected]. *E-mail for J.Z.: [email protected]. ORCID

Feng Zhou: 0000-0002-6729-1311 Jian Zhou: 0000-0003-0679-6735 Notes

The authors declare no competing financial interest. 1874


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ACS Catalysis

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ACKNOWLEDGMENTS The financial support from the National Natural Science Foundation of China (21725203) is appreciated.

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ACS Catalysis

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(179) Sreenithya, A.; Sunoj, R. B. Mechanistic insights on iodine(III) promoted metal-free dual C−H activation involved in the formation of a spirocyclic bis-oxindole. Org. Lett. 2014, 16, 6224− 6227. (180) Tan, W.; Li, X.; Gong, Y.-X.; Ge, M.-D.; Shi, F. Highly diastereo- and enantioselective construction of a spiro[cyclopenta[b]indole-1,3′-oxindole] scaffold via catalytic asymmetric formal [3 + 2] cycloadditions. Chem. Commun. 2014, 50, 15901−15904. (181) Dai, W.; Lu, H.; Li, X.; Shi, F.; Tu, S.-J. Diastereo- and enantioselective construction of a bispirooxindole scaffold containing a tetrahydro-β-carboline moiety through an organocatalytic asymmetric cascade reaction. Chem. - Eur. J. 2014, 20, 11382−11389. (182) Shi, F.; Zhang, H.-H.; Sun, X.-X.; Liang, J.; Fan, T.; Tu, S.-J. Organocatalytic asymmetric cascade reactions of 7-vinylindoles: diastereo- and enantioselective synthesis of C7-functionalized indoles. Chem. - Eur. J. 2015, 21, 3465−3471. (183) Zhan, G.; Shi, M.-L.; He, Q.; Lin, W.-J.; Ouyang, Q.; Du, W.; Chen, Y.-C. Catalyst-controlled switch in chemo- and diastereoselectivities: annulations of Morita−Baylis−Hillman carbonates from isatins. Angew. Chem., Int. Ed. 2016, 55, 2147−2151. (184) Peng, J.; Huang, X.; Jiang, L.; Cui, H.-L.; Chen, Y.-C. Tertiary amine-catalyzed chemoselective and asymmetric [3 + 2] annulation of Morita-Baylis-Hillman carbonates of isatins with propargyl sulfones. Org. Lett. 2011, 13, 4584−4587. (185) Wang, Y.; Liu, L.; Zhang, T.; Zhong, N.-J.; Wang, D.; Chen, Y.-J. Diastereo- and enantioselective [3 + 2] cycloaddition reaction of Morita−Baylis−Hillman carbonates of isatins with N-phenylmaleimide catalyzed by Me-DuPhos. J. Org. Chem. 2012, 77, 4143−4147. (186) Wang, K.-K.; Jin, T.; Huang, X.; Ouyang, Q.; Du, W.; Chen, Y.-C. α-Regioselective asymmetric [3 + 2] annulations of MoritaBaylis-Hillman carbonates with cyclic 1-azadienes and mechanism elucidation. Org. Lett. 2016, 18, 872−875. (187) Wang, K.-K.; Wang, P.; Ouyang, Q.; Du, W.; Chen, Y.-C. Substrate-controlled switchable asymmetric annulations to access polyheterocyclic skeletons. Chem. Commun. 2016, 52, 11104−11107. (188) For a book and reviews, see: (a) Privileged Chiral Ligands and Catalysts; Zhou, Q.-L., Ed.; Wiley-VCH: Weinheim, Germany, 2011; pp 137−170. (b) Ding, K.; Han, Z.; Wang, Z. Spiro Skeletons: A class of privileged structure for chiral ligand design. Chem. - Asian J. 2009, 4, 32−41. (c) Xie, J.-H.; Zhou, Q.-L. Chiral diphosphine and monodentate phosphorus ligands on a spiro scaffold for transitionmetal-catalyzed asymmetric reactions. Acc. Chem. Res. 2008, 41, 581− 593. (d) Xie, J.-H.; Zhou, Q.-L. Magical Chiral Spiro Ligands. Huaxue Xuebao 2014, 72, 778−797. (189) Recently, Ding and coworkers established a practical protocol for the enantioselective synthesis of cyclohexyl-fused chiral spirobiindanes. See: Zheng, Z.; Cao, Y.; Chong, Q.; Han, Z.; Ding, J.; Luo, C.; Wang, Z.; Zhu, D.; Zhou, Q.-L.; Ding, K. Chiral cyclohexyl-fused spirobiindanes: practical synthesis, ligand development, and asymmetric catalysis. J. Am. Chem. Soc. 2018, 140, 10374− 10381. (190) (a) Zhang, J.-H.; Liao, J.; Cui, X.; Yu, K.-B.; Zhu, J.; Deng, J.G.; Zhu, S.-F.; Wang, L.-X.; Zhou, Q.-L.; Chung, L. W.; Ye, T. Highly Efficient and Practical Resolution of 1,1′-Spirobiindane-7,7′-diol by Inclusion Crystallization with N-Benzylcinchonidinium Chloride. Tetrahedron: Asymmetry 2002, 13, 1363−1366. (b) Lu, S.; Poh, S. B.; Zhao, Y. Kinetic Resolution of 1,1′-Biaryl-2,2′-Diols and Amino Alcohols through NHC-Catalyzed Atroposelective Acylation. Angew. Chem., Int. Ed. 2014, 53, 11041−11045. (191) Li, S.; Zhang, J.-W.; Li, X.-L.; Cheng, D.-J.; Tan, B. Phosphoric Acid-Catalyzed Asymmetric Synthesis of SPINOL Derivatives. J. Am. Chem. Soc. 2016, 138, 16561−16566. (192) Alper, P. B.; Meyers, C.; Lerchner, A.; Siegel, D. R.; Carreira, E. M. Facile, novel methodology for the synthesis of spiro[pyrrolidin3,3′-oxindoles]: catalyzed ring expansion reactions of cyclopropanes by aldimines. Angew. Chem., Int. Ed. 1999, 38, 3186−3189. Also see ref 6i. (193) (a) Xu, P.-W.; Liu, J.-K.; Shen, L.; Cao, Z.-Y.; Zhao, X.-L.; Yan, J.; Zhou, J. Diastereo- and enantioselective [3 + 3] cycloaddition 1881


Review

ACS Catalysis of spirocyclopropyl oxindoles using both aldonitrones and ketonitrones. Nat. Commun. 2017, 8, 1619. (b) Xu, P.-W.; Chen, C.; Liu, J.K.; Song, Y.-T.; Zhou, F.; Yan, J.; Zhou, J. One-pot sequential [3 + 3] dipolar cycloaddition of aldehyde or ketone and hydroxylamine with spirocyclopropyl oxindole. J. Org. Chem. 2018, 83, 12763−12774. (194) Shu, T.; Zhao, L.; Li, S.; Chen, X.-Y.; von Essen, C.; Rissanen, K.; Enders, D. Asymmetric synthesis of spirocyclic β-lactams through copper-catalyzed Kinugasa/Michael domino reactions. Angew. Chem., Int. Ed. 2018, 57, 10985−10988.

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Catalytic Enantioselective Construction of Spiro Quaternary Carbon

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