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Yne−Enones Enable Diversity-Oriented Catalytic Cascade Reactions: A Rapid Assembly of Complexity Deyun Qian and Junliang Zhang* Cite This: https://dx.doi.org/10.1021/acs.accounts.0c00466

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CONSPECTUS: A small-molecule collection with structural diversity and complexity is a prerequisite to using either drug candidates or chemical probes for drug discovery and chemical−biology investigations, respectively. Over the past 12 years, we have engaged in developing efficient diversity-oriented cascade strategies for the synthesis of topologically diverse skeletons incorporating biologically relevant structural motifs such as O- and Nheterocycles, fused polycycles, and multifunctionalized allenes. In particular, we have highlighted the use of simple, linear, and densely functionalized molecular platforms in these reactions. This account details our efforts in the design of novel molecular platforms for use in metaland organo-catalyzed cascade reactions, which include 2-(1-alknyl)-2-alken-1-ones (yne− enones) for heterocyclization/cross-coupling cascades, heterocyclization/cycloaddition cascades, nucleophilic addition/cross-coupling cascades, nucleophilic addition/heterocyclization cascades, and so on. Moreover, this Account outlines corresponding mechanistic insights, computational information, and applications of these cascades in the construction of various highly substituted carbo- and heterocycles as well as highly functionalized acyclic compounds, e.g., allenes and dienes. In addition to yne−enones, we evolved the functional groups of our original yne−enones to provide a series of yne−enone variants, which resulted in products with complementary reactivities. The reactivity profile of the yne−enones is defined by the presence of an alkyne moiety and a conjugated enone unit and their mutual through-bond connectivity. Owing to the conceptually rapid development of carbophilic activation, we have identified a series of efficient catalytic systems consisting of metal catalysts, including Pd, Au, and Rh complexes, for diversity-oriented cascade catalysis, allowing various unprecedented reactions to be achieved through different-types of reaction intermediates, including allcarbon metal 1,n-dipoles, furan-based o-quinodimethanes (oQDMs), and allenyl-metal species. In addition to commonly known transition-metal catalytic activity, the Lewis acidity of these complexes is crucial to accomplish the corresponding transformation. In addition, highly enantioselective gold(I)-catalyzed heterocyclization/cycloaddition cascades of yne−enones and their variants were achieved by the application of bisphosphines (e.g., Cn-TunePhos), monophosphines, and our developed “Ming−Phos” as chiral ligands. Importantly, Ming−Phos ligands exhibited excellent performance in gold-catalyzed mechanistically distinct [3 + n]cycloaddition reactions, in which the chiral sulfinamide moiety is possibly responsible for the interaction with the substrate to control enantioselectivity. Subsequently, we demonstrated that the easily prepared polymer-supported Ming−Phos ligand could be applied for heterogeneously gold(I)-catalyzed asymmetric cycloaddition with good stereocontrol. With metal-free catalysis, the divergent functionalization of yne−enones provides numerous synthetic outlets for structure diversification. For example, yne− enones are particularly attractive for use as precursors of various chiral and achiral heterocycles, such as pyrazoles, isoxazoles, pyrroles, and pyrans, etc.

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KEY REFERENCES

Tandem Cyclization/[3 + 3] Cycloadditions of 2-(1Alkynyl)-2-alken-1-ones with Nitrones. Angew. Chem.

• Xiao, Y.; Zhang, J. Tetrasubstituted Furans by a Pd Catalyzed Three-Component Michael Addition/Cyclization/Cross-Coupling Reaction. Angew. Chem. Int. Ed. 2008, 47, 1903−1906.1 Our starting point was to study yne−enone chemistry; a new cascade reaction model was established. II

Received: July 21, 2020

• Liu, F.; Qian, D.; Li, L.; Zhao, X.; Zhang, J. Diastereoand Enantioselective Gold(I)-Catalyzed Intermolecular © XXXX American Chemical Society

A

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Figure 1. Diversity-oriented cascade reactions for a small-molecule collection.

Int. Ed. 2010, 49, 6669−6672.2 The f irst enantioselective transformation of yne−enones enabled by the chiral gold complex. • Zhao, W.; Zhang, J. Rhodium-Catalyzed Tandem Heterocyclization and Carbonylative [(3 + 2)+1] Cyclization of Diyne-enones. Org. Lett. 2011, 13, 688− 691.3 The evolution of yne−enones to discover new reactivities and reaction models. • Chen, M.; Zhang, Z.-M.; Yu, Z.; Qiu, H.; Ma, B.; Wu, H.-H.; Zhang, J. Polymer-Bound Chiral Gold-Based Complexes as Efficient Heterogeneous Catalysts for Enantioselectivity Tunable Cycloaddition. ACS Catal. 2015, 5, 7488−7492.4 From homogeneous catalysis to heterogeneous catalysis enabled by Ming−Phos ligands.

1. INTRODUCTION To increase the returns of modern drug and probe discovery programs, there is great interest in developing synthetic smallmolecule libraries that recapitulate the attractive structural features of natural products and drugs in various fashions.5 In the past decade, several diversity-oriented synthesis (DOS) methods have been developed to confront this challenging request.6 Among these, the most commonly used method is the reagent-based (branching) method, which aims to transform a common simple substrate (building platform) into a number of diverse and distinct structural motifs by employing either different reactants or different reaction conditions.7 On the other hand, catalytic cascade reaction sequences, in which multiple reactions occur successively in a one-pot process and molecular complexity is rapidly constructed, can dramatically enhance the efficiency of synthetic endeavors.8 In our own studies, we wondered about the possible connection and orthogonality between cascade catalysis and the DOS process, which can utilize a highly functionalized precursor to produce an array of distinct molecular scaffolds, each equipped with corresponding strategically placed functionalities for applications in a new round of complexitygenerating or branching reactions (Figure 1). To this end, a critical challenge is the identification of new strategies that alter the inherent selectivity profiles of polyfunctional substrates. Initially, we focused our attention on the development of diversity-oriented cascade reactions from readily available and highly modular polyfunctional substrates, 2-(1-alknyl)-2-alken1-ones (yne−enones), 1, to achieve molecular diversity and complexity in a one-pot process (Figure 2).9

Figure 2. Selected natural products and bioactive compounds related to this account.

Following Larock’s seminal report,10 concerted efforts have been devoted to catalytic transformations of yne−enones.11 Despite remarkable advances, great challenges remain, including the following: (1) new reaction models that can convert yne−enones to diverse-types of value-added heterocyclic molecules, and acyclic compounds remain limited; and (2) highly efficient catalytic systems that are compatible for a wide range of both yne−enones and reaction partners that enable excellent enantioselectivity in cascades and/or cycloadditions are still rare. To address these problems, we have developed new reaction models, new chiral catalysts/ligands, and novel catalytic systems. Inspired by the thriving concept of carbophilic activation,12 we can now realize a variety of unprecedented reactivities through different-types of reaction intermediates, including π-acetylene-metal, all-carbon metal 1,3-dipoles (Int-1), furan-based oQDMs (Int-2), all-carbon metal 1,5-dipoles (Int-3), and allenyl-metal species (Int-4). Interestingly, the 1,2-allenyl anion species (Int-5) can be formed in the presence of an organocatalyst with regioselective nucleophilic addition. Consequently, a large array of carboand heterocycles, fused polycycles, allenes, and dienes can be B

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synthesized with a high efficiency and excellent stereoselectivity. In this Account, we endeavor to present our recent achievements in achieving diversity-oriented cascade catalysis with yne−enones, and this work is organized by the-type of cascade reaction model.

in the reaction was not strong enough to activate the substrate. The reaction allowed us to leverage the dual-role strategy for other transformations in which activation of a multiple bond (transition-metal role) and activation of a carbonyl moiety or related functional group, such as an enone (Lewis acid), were desired to proceed simultaneously. Since then, we have performed significant studies, especially in multicomponent cascade reactions, using a great variety of nucleophiles and electrophiles. As shown in Scheme 2, the detailed scope, mechanism, and application of the Pd(II)-catalyzed cascade reaction were

2. DEVELOPMENT OF NEW REACTION MODELS 2.1. Heterocyclization/Cross-Coupling Cascades

In 2007, our great interest in highly substituted furan compounds,4 which are found in numerous bioactive natural products and important pharmaceuticals (Figure 2), led us to study the Pd-catalyzed cascade reactions of yne−enones (Scheme 1).1 Inspired by the leading work of Larock,10 we

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Scheme 2. Pd(II)-Catalyzed Heterocyclization/CrossCoupling and Heck Reactions

Scheme 1. Pd(II)-Catalyzed Heterocyclization/CrossCoupling Cascade with Allyl Chlorides

studied.13 Reagent-based divergent reactions of yne−enones with allyl nucleophiles and an allyl chloride were further developed. Notably, allyl-substituted alcohols enabled the process to cross-couple reaction products 3, while the Heck reaction was achieved with dimethyl 2-allylmalonate 4. A common furanyl-palladium intermediate, Int-1.1A, was proposed to contribute to two reaction pathways. The reaction route also relied on the length of the tethered chain. Moreover, functionalized oxygen-heterocycle 3,4-fused bicyclic furans 3 could be easily accessible through the ring-closing metathesis (RCM) of corresponding furans with CC bonds. Control experiments indicated that this cascade reaction occurs via a Pd(II) catalytic cycle. In addition to the well-known alkylating reagent, allyl chloride could be an oxidant. Given the atom economy, we documented that, in addition to the cross-coupling and Heck reaction, the furyl-Pd intermediate Int-1.1A could be intercepted with an array of electrophiles (e.g., vinyl ketones) followed by the protodepalladation step, thus leading to a net hydroarylation reaction (Scheme 3).14 On the basis of the Michael addition mode, two interconvertible intermediates, Int-1.1C and Int1.1D, would be formed by the insertion of the CC double bond of vinyl ketone 6 into the C−Pd bond of intermediate Int-1.1A. In the case of acrolein acting as an electrophile, the reaction generated a furan with an acetal by acetalization of the aldehyde group. By employing diaryliodonium salts as electrophilic coupling partners, the novel Pd(II)/Cu(I)-cocatalyzed three-component arylative cycloisomerization of yne−enones 1 for the synthesis of 3-arylated furans 8 was then developed (Scheme 4).15 The possible reaction mechanism involved the formation

envisioned that Pd(II) species might exhibit dual roles, serving simultaneously as a Lewis acid and a transition metal, to catalyze a cascade reaction of 2-(1-alknyl)-2-alken-1-ones (1) with nucleophiles and an allyl halide. As a consequence, densely functionalized tetrasubstituted furans 2 could be formed through a very efficient three-component cascade heterocyclization/allylation sequence of yne−enones 1, nucleophiles, and allyl chlorides. The mechanism of this reaction was proposed as follows: the Pd(II)-catalyzed cycloisomerization/nucleophile addition led to the furylpalladium intermediate Int-1.1A, which underwent a subsequent allylation (Int-1.1B), followed by β-halide elimination, to provide furan 2 and regenerate the PdX2 catalyst. In contrast to the cyclization step, the generation of π-allyl-Pd species was also possibly the initial step. Importantly, when allyl chloride was changed to allyl bromide (even 10 equiv), the reaction gave discouraging results, indicating that the weak Lewis acid ([PdBr2(CH3CN)2] vs [PdCl2(CH3CN)2]) that was generated C

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Scheme 3. Pd(II)-Catalyzed Cascade Reaction of Yne− Enones with Nucleophiles and Vinyl Ketones

Scheme 5. Au(I)-Catalyzed 1,3-Dipolar Cycloaddition Reaction of Yne−Enones and Nitrones

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Scheme 4. Pd(II)/Cu(I)-Cocatalyzed Three-Component Cascade Reaction

oxazines was highlighted by the selective additional transformations (bottom, Scheme 5). DFT calculations helped elucidate the mechanism of goldcatalyzed 1,3-dipolar [3 + 3]-cycloaddition reactions.19 The results suggest that the reaction occurs via the generation of a π-complex in which the gold coordinates to the alkyne moiety of the yne−enones, leading to the intramolecular cyclization of the gold intermediate to form a carbocation intermediate trapped by the nucleophilic oxygen of the nitrone to generate a furyl-gold complex. Subsequently, intermolecular cyclization provides furo[3,4-d][1,2]-oxazine as well as regenerates the gold catalyst. The highest activation barrier in the entire cycle accompanying the intramolecular cyclization step is 19.5 kcal/ mol. The same reactivity of 2-(1-alkynyl)-2-alken-1-ones 1 was revealed during our further investigation. Thus, we and others can perform the [3 + 2]-cycloaddition of such 1,3-dipolar precursors with 3-styrylindoles, [3 + 4]-cycloaddition with 1,3diphenylisobenzofuran, [3 + 4]-cycloaddition with α,βunsaturated imines, [3 + 2]-cycloaddition with diarylethenes, [3 + 2]-cycloaddition with in situ generated 1-methylene-1,3dihydroisobenzofuran, [3 + 3]-cycloaddition with azides, and [3 + 2 + 2]-cycloaddition with 1,3,5-triazines (Scheme 6).20,21 InBr3 was used as a catalyst, and interestingly, an elegant threecomponent reaction between yne−enones, aldehydes, and secondary amines was developed, resulting in cyclopenta[c]furans.22 Despite remarkable achievements in the transition-metalcatalyzed reactions of yne−enones, the development of asymmetric variants was unprecedented before us, thus limiting the synthetic utility of these viable transformations. On the other hand, the development of enantioselective gold catalysis poses considerable challenges because of the tendency of gold(I) to form linear two-coordinate complexes, in which the reacting substrate is positioned far from the potential source of chirality. To address both formidable challenges, we initiated a program to exploit the asymmetric gold(I)-catalyzed cascade heterocyclization/[3 + 3]-cycloaddition of yne−enones 1 with

of the common furyl-Pd(II) species Int-1.1A, which then reacted with iodonium salt to form Pd(IV) intermediate Int1.1E. A subsequent reductive elimination provided tetrasubstituted furan 8 and regenerated the Pd(II) catalyst. It was essential to use the Cu(I) cocatalyst to achieve higher yields of products. In addition, the steric differentiation between the two aryl groups on iodine(III) enabled the selective transfer of the smaller substituent. 2.2. Heterocyclization/Cycloaddition Cascades

In the past few years, the impressive advances of yne−enone chemistry have been fueled by parallel developments in gold catalysis.16 As strong yet air- and moisture-tolerant as well as redox-stable carbophilic Lewis acids,7 gold salts and complexes have a high affinity for π-bonds, showcasing good functional group compatibility in a number of important reactions. Gold catalysis is well-developed for both cycloisomerizations and cyclizations, but its utility for [1,n]-dipolar cycloaddition has only recently been developed by us and others.17 Chargeseparated carbon chains, i.e., all-carbon 1,n-dipoles, are often difficult to handle in cycloaddition/annulation reactions because they are usually transient species. However, the negatively charged end of such a dipole can be masked by a gold complex, thus substantially switching its nucleophilicity (e.g., intermediate Int-1.2), leading to polycyclic structures in a highly regio- and stereoselective fashion. In early 2009, we first introduced the concept of combining gold-furyl [1,3]-dipole intermediate Int-1.2 with a nitrone to promote a formal 1,3-dipolar cycloaddition reaction (Scheme 5).18 Consequently, densely substituted furo[3,4-d][1,2]oxazines 9 could be obtained smoothly with high levels of regiospecificity and diastereoselectivity under mild reaction conditions. The synthetic potential of furo[3,4-d][1,2]D

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Scheme 6. Catalytic 1,3-Dipolar Cycloaddition Reactions of Yne−Enones and Versatile Dipolarophiles

Scheme 7. Au(I)-Catalyzed Enantioselective [3 + 3]Cycloaddition Reaction

nitrones in 2010 (Scheme 7).2 After investigating various chiral bisphosphine ligands for gold, we discovered that high enantioselectivities could be obtained (up to 98% ee) by the utilization of (R)-MeO-DTBM-BIPHEP (L1) as the ligand. In some cases, ligand (R)-C1-TunePhos (L2) provided better enantioselectivities than ligand (R)-MeO-DTBM-BIPHEP, which demonstrated that two strategies of MeO-BIPHEP modification were effective, with the former being more efficient, owing to the Au−Au interaction (bond length = 2.944 Å), which could make the structure more rigid. Moreover, this is the first study to use Cn-TunePhos(AuCl)2 as a chiral catalyst in enantioselective gold-catalyzed reactions. However, the enantioselectivity largely relied on the substituent on the alkyne unit of yne−enones. Although an excellent enantioselectivity was obtained with aryl substituents, only low ee values (4−55%) could be provided for substrates with aliphatic substituents. Instead of those bicationic [L*Au2X2] species, better enantioselectivity can be obtained by using monocationic [L*Au2ClX] species (L* = bisphosphine, X = a weak counteranion formed in situ from a 1:1 mixture of [L*Au2Cl2] and an AgX activator), suggesting that the second gold site might either just exert a steric influence or be involved in a second interaction with the substrate. In this regard, a new-type of chiral ligand, namely, “Ming−Phos”, was designed, in which the chiral sulfinamide moiety might enable the interaction with the nitrone to control the enantioselectivity (Scheme 8).23 Indeed, Ming−Phos (MP) ligands exhibited excellent performances in goldcatalyzed mechanistically distinct [3 + 3]-cycloaddition reactions. In the case of the asymmetric cycloaddition reaction of yne−enones 1 with nitrones, interestingly, both enantiomers with opposite configurations could be furnished in high yields with excellent diastero- and enantioselectivity by the use of a pair of diastereomers, (R,Rs)- and (S,Rs)-MP, respectively.

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Scheme 8. Au(I)-Catalyzed Enantioselective [3 + 3]Cycloaddition Reaction Enabled by Ming−Phos Ligands

To better understand the function of the N-H bond in Ming−Phos, a control experiment was implemented by E

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utilizing N-methylated Ming−Phos as the chiral ligand (Scheme 9a).23b In contrast to those obtained from the

Scheme 10. Au(I)-Catalyzed Enantioselective [3 + 2]- and [3 + 4]-Cycloaddition Reactions by Using Ming−Phos Ligands

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Scheme 9. Further Study Based on Ming−Phos Ligands

corresponding precursor (S,Rs)-MP with free N−H bonds, cycloadduct (1S,4R)-9aa was obtained with much lower yields and enantioselectivities. Moreover, X-ray diffraction analysis of the gold complexes [(S,Rs)-MPAuCl] and [(R,Rs)-MPAuCl] revealed that the gold atom only binds to the phosphine atom instead of the other heteroatoms, thus suggesting that Ming− Phos performs as a monophosphine ligand in our reaction. On the basis of these results, a model for enantiocontrol was proposed as follows (Scheme 9b): the furyl-Au-MP 1,3-dipole species Int-1.2A or Int-1.2A′, which is inclined to show linear geometry, is rapidly trapped by the oxygen atom of the nitrone with the aid of H-bonding between the N−H of the chiral ligand (Ming−Phos) and the oxygen atom of the nitrone to provide the desired cycloadduct. Notably, the enantioselectivity of the reaction and the absolute configuration of the product highly depend on the carbon chirality of the chiral ligand. The salient features of a simple structure, an air-stable property, practical synthesis from readily available starting materials, easy modification and a good performance in terms of enantioselectivity control make Ming−Phos ligands very attractive and deserving of more attention. On the basis of the success of [3 + 3]-cycloaddition, analogous enantioselective [3 + 2]- and [3 + 4]-cycloadditions were investigated (Scheme 10).24 The Au(I)/Ming−Phos complexes proved to be effective catalysts for the catalytic asymmetric intermolecular cascade reaction of yne−enones with 3-styrylindoles, producing desired indolyl-substituted cyclopenta[c]furans 10 in high yields (up to 99%) and excellent enantioselectivities (up to 97% ee).24a However, the privileged chiral bisphosphine ligand (R)-L1-derived gold

complex resulted in very low enantioselectivity (16% ee). Similarly, the highly exo- and enantioselective gold-catalyzed cascade heterocyclization/[3 + 4]-cycloaddition of yne− enones and 1,3-diphenylisobenzofuran was then performed by using Ming−Phos, leading to chiral seven-membered oxabridged rings 11 in 50−98% yields with high exo selectivity (exo/endo up to 50:1) and up to 97% ee (Scheme 10b).24b The seven-membered oxa-bridged ring is often found in natural products and bioactive molecules. The reaction proceeding via the favored transition state TS-1 to afford exo product 11 should result from the π−π stacking interaction between the furan and the benzofuran as well as the steric demands of the naphthalene group. Furthermore, an efficient method for the preparation of a polymer-bound gold catalyst was also developed (Scheme 11).4 Under low-concentration cross-linking conditions, the chiral Ming−Phos ligand can easily copolymerize with styrene. Consequently, the same catalytic activity achieved with homogeneous catalysts could be realized by the use of polymer-supported gold catalysts. Similarly, a pair of diastereomeric catalysts delivered two enantiomers in good yields with excellent diastereo- and enantioselectivity. In addition, eight catalytic cycles without the loss of enantioselectivity could be performed by using this polymer-bound gold catalyst, and large-scale synthesis was also possible. F

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Scheme 11. Polymer-Bound Chiral Gold-Based Complexes as Efficient Heterogeneous Catalysts for Enantioselectivity Tunable Cycloaddition

excellent yields and with up to 96% ee (Scheme 12b).26 Very recently, Liu et al. reported the first successful use of anthranils in gold-catalyzed asymmetric [3 + 4]-cycloaddition reactions with chiral phosphoramidite ligand L5 (Scheme 12c).27 Although 2,3-furan fused carbocycles are ubiquitous structural skeletons in many natural products, such as pinguisone, furodysinin, and furanoeremophilanes, less attention has been paid to their synthesis. In 2014, we exhibited an unprecedented method for the in situ formation of furan-based oQDMs (Int-2.1) from 2-(1-alkynyl)-2-alken-1-ones 1 through gold-mediated dehydrogenative heterocyclization in the presence of pyridine N-oxide, including the challenging C(sp3)−H activation of the methyl moiety (Scheme 13).28

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Scheme 13. Au(I)-Catalyzed Dehydrogenative Heterocyclization/[4 + 2]-Cycloaddition Cascade

In addition, the catalytic system was successfully expanded to other dipolarophiles, which enabled the synthesis of various highly functionalized furan derivatives (Scheme 12). In 2015, Scheme 12. Au(I)-Catalyzed Enantioselective [3 + n]Cycloaddition Reactions of Yne−Enones with Other Dipolarophiles

Thus, these reactive 1,3-dienes could be well-trapped by a variety of dienophiles, such as electron-deficient alkynes and alkenes, leading to highly substituted 2,3-furan fused carbocycles 15 with high steroselectivities. It was key to employ a suitable base, which should be tolerated with the metal catalyst and be strong enough to abstract the proton. Moreover, a preliminary attempt at performing asymmetric catalysis with α,β-unsaturated aldehyde gave an acceptable ee value, albeit with low diastereoselectivity. To explore new catalytic methods, we have also developed the intriguing rhodium-catalyzed cascade heterocyclization/ formal [3 + 2]-cycloaddition of yne−enones 1 with alkynes, resulting in highly substituted 4H-cyclopenta[c]furans 16 in moderate to high yields with excellent regioselectivity (Scheme 14).29 Notably, both electron-rich and electron-deficient alkynes can be leveraged for this cascade reaction. First, an Rh species acting as a carbophilic π-acid would activate the triple bond to facilitate cyclization and furnish furyl-rhodium carbocation Int-1.3 (i.e., the 3C component). The cationic Rh(I) complex plays the roles of both a traditional transition metal (for oxidative addition and insertion) and a Lewis acid (for heterocyclization). An alternative reaction route achieved by direct oxidative cyclometalation cannot be ruled out by the given data thus far.

we demonstrated the first selective gold-catalyzed [3 + 2]cycloaddition of yne−enones with the proximal CC bond of an N-allenamide, leading to enantioenriched 3,4-ring fused furans 12.25 Interestingly, both enantiomers of the cycloadducts could be obtained in good yields with high regio-, diastereo-, and enantioselectivity (up to 99% ee) by utilizing either the diastereomer of a BINOL-derived phosphoramidite ligand (Scheme 12a). By employing a Taddol-derived phosphine-phosphite gold catalyst, a novel cascade heterocyclization/[3 + 3]-cycloaddition process of yne−enones with azomethine imines was developed, furnishing highly substituted furo[3,4-d]tetrahydropyridazines 13 in good to G

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Scheme 14. Rh(I)-Catalyzed Regioselective Cascade Heterocyclization/[3 + 2]-Cycloaddition of Yne−Enones with Alkynes

In terms of metal-free catalysis, (in)organic base catalysis and phosphine catalysis are also compatible, and organic bifunctional catalysis has recently been developed (Scheme 16).32 In these transformations, yne−enones 1 serve as novel electrophiles (electron-deficient 1,3-conjugated enynes) for regioselective nucleophilic addition. The addition models rely on the nature of nucleophiles. Functionalized 1,3-dienes 18 were generated by a 4′,5′-addition pattern if heteroatom nucleophiles were utilized, whereas functionalized 1,2-allenes 19 were formed when carbon-centered nucleophiles (e.g., malonates) were applied. In addition, a popular class of carbon- and heterocyclic compounds involving isoxazoles 20, pyrazoles 21, pyrroles 22, cyclopentanes 23, pyrans 24/25, and fused polycycles 26 were afforded by a formal [m + n] (m = 3, 4; n = 2, 3) cycloaddition reaction. Notably, the method provides mild, atom-economic, and efficient access to collect highly functionalized small molecules, which are privileged skeletons in organic synthesis. As shown in Scheme 17, we next realized an organocatalytic formal [3 + 2]-cycloaddition reaction by the use of newly designed cinchona alkaloid-derived catalysts for inducing asymmetry, resulting in highly substituted 2,3-dihydroisoxazoles 27 in low to high yields with up to 99% enantioselectivity.33 Notably, the multifunctionality consisting of a hydroxyl group, an ester group, and a basic heterocycle (pyridine, imidazole, and quinoline) is crucial for both the catalytic activity and enantioselectivity. 4H-Pyran scaffolds are often found in biological and pharmaceutical molecules. Using a cyclohexyldiamine-based thiourea-tertiary amine bifunctional as catalyst T1, we presented the first enantioselective formal [3 + 3]-cycloaddition of yne−enones with β-keto esters in 2016 (Scheme 18).34 An array of polysubstituted 4H-pyrans 28 was obtained in moderate yields with good enantioselectivities under mild and eco-friendly conditions. TS-2 should be the favored transition state, which features enolate attack from the Re-face of yne−enone 1, resulting in the allene intermediate, followed by 6-endo-trig cyclization. In the case of bifunctional catalysis, an efficient intermolecular addition of nitroalkanes to yne−enone analog 1′ could lead to the asymmetric synthesis of 2,3-allenoates 29 (Scheme 19).35 The new cinchona-derived thiourea catalyst CBT was the key to success, since it played at least three roles: (1) it enabled a highly ordered transition state (TS-3) to promote the first C−C bond formation, (2) it served as an excellent proton shuttle in the second enantioselectivity-determining step (TS-4), and (3) it could also function as an excellent isomerization catalyst for the conversion from racemic alkynoates to highly enantioenriched allenoates. Finally, these trisubstituted allenoates were versatile synthons toward other important building blocks.

2.3. Cascade Reactions Initiated by Nucleophilic Addition

In contrast to heterocyclization, if the intermolecular nucleophile attacks first, an allenyl intermediate will be formed. Guided by the above chemistry in Scheme 1, we attempted to address this issue by the use of Pd(0) species to catalyze multicomponent cascades of yne−enones 1, nucleophiles, and aryl halides, but the reaction provided 1,2-allenyl ketones 17 instead of the desired 3-arylated furans (Scheme 15).30 The Scheme 15. Pd(0)-Catalyzed Cascade Reaction of Yne− Enones with Nucleophiles and Aryl Halides

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3. EVOLUTION OF YNE−ENONES FOR NEW REACTIVITIES Generally, yne−enones are easily prepared from simple alkynes and α-bromo-α,β-unsaturated enones on the gram scale with good yields by the Sonogashira cross-coupling reaction. Thus, they can be employed as a key template for rapid structural proliferation toward all kinds of yne−enone analogs. Aside from yne−enones, we also evolved the functional groups of our original yne−enones to provide a series of yne−enone variants, such as diyne−enones and 2-(1-alkynyl)alk-2-en-1-one oximes, which produced products with complementary functionalities.

possible reaction pathway relied on the degree of Lewis acidity of the ArPdX species generated from the oxidative addition of aryl halides with a Pd(0) catalyst. By employing Lewis acid catalysis, a number of trisubstituted chiral 1,2-allenyl ketones could be obtained through the intermolecular addition of malonic esters to yne−enones.31 H

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Scheme 16. Metal-Free Catalytic Cascade Reactions of Yne−Enones Initiated by Nucleophilic Addition

Scheme 17. Organocatalytic Formal [3 + 2]-Cycloaddition

Scheme 18. Organocatalytic Enantioselective Formal [3 + 3]-Cycloaddition

C(sp2)−Pd bond of Int-1.1F to the unconjugated alkyne would form a bicylic vinyl-palladium intermediate Int-3.1A, followed by the conjugate addition of the vinylpalladium species to vinyl ketone 6 to produce intermediate Int-3.1B with two convertible forms, but palladium enolate is the major form, which would prefer protonation by the in situ generated HX to provide the final product 30 instead of the Heck-type product via the β-H elimination of Int-3.1B. To extend the scope of the reaction, the cyclization of diyne−enone 1−1 with indoles by employing air as the clean oxidant was also examined (Scheme 21).37 This oxidative cascade reaction, involving the direct C−H functionalization of indoles, provided rapid access to novel indole-furan polyheterocycles 31. The formed vinyl-palladium species would release one proton and give Int-3.1A, followed by direct C−H activation at the 2-position of indoles to form palladacycle Int-

3.1. Diyne−Enones

The toolbox of yne−enones was further expanded to include diyne−enones, and we found a novel atom-economic Pd(II)catalyzed multicomponent cascade reaction with nucleophiles and vinyl ketones, resulting in highly functional 2,3-cyclo[b]furan 30 combined with a stereodefined tetrasubstituted alkene (Scheme 20).36 On the basis of our previous studies, [PdCl2(CH3CN)2] should play a dual role, i.e., as a transition metal and Lewis acid. First, [PdCl2(CH3CN)2], acting as a πacid, coordinates to the alkyne function of diyne−enone 1−1 to generate a metal intermediate, thus leading to cascade heterocyclization and nucleophilic addition to form furylpalladium species Int-1.1F and release HX. syn-Addition of the I

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Scheme 19. Organocatalytic Enantioselective Synthesis of 2,3-Allenoates

Scheme 21. Pd(II)-Catalyzed Oxidative Cascade Reaction Involving Direct C−H Functionalization

Scheme 20. Pd(II)-Catalyzed Cascade Reaction of Diyne− Enones, Nucleophiles, and Vinyl Ketones

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have exhibited extremely unrivaled abilities to construct polycyclic carbocycles and heterocycles. The coupling of cycloisomerization of yne−enones with oxidative addition, migratory insertion, and reductive elimination processes may result in ample new chances for the design of new reactions. In 2011, we developed a novel and highly efficient rhodiumcatalyzed cascade heterocyclization/carbonylative [(3 + 2)+1] reaction of diyne−enones 1−1 and carbon monoxide, producing fascinating polycyclic furan scaffolds 32 (top, Scheme 22).3 On the basis of D-labeling, carbocation intermediate Int-3.2A, which had proven to be rapidly trapped by various alcohols, participated in subsequent protodemetalation to provide bicyclic furan compound 34 and regenerate the rhodium catalyst (bottom, Scheme 22).39 In the absence of nucleophiles, the resulting metallacycle intermediate Int-3.2B would be trapped by CO, resulting in tricyclic product 32. Moreover, synthetically useful highly substituted phenols 33 could also be easily prepared via a straightforward one-pot synthetic oxidation strategy. Furthermore, the above chemistry was expanded to include the Rh(I)-catalyzed two-component cascade heterocyclization/cycloaddition reaction between diyne−enones 1−1 and external alkynes, leading to a net formal [(3 + 2) + 2] process and providing furan-derived 5,6,7-tricycles 35 (Scheme 23).40 The regioselectivity of the reaction relied on both the tether atom and the nature of the alkyne substituents. The high regioselectivity of alkyne insertion was obtained with “push− pull” tolanes. Two pathways have been proposed for the reaction, both featuring the formation of a rhodacycle analogous to Int-3.2B (from Int-3.2C) followed by the migratory insertion of the alkyne into one of the Rh−C bonds and subsequent reductive elimination. In general, the migratory insertion of the Rh−vinyl bond was more favorable.

3.1C and release HX. Subsequent reductive elimination led to the final product and generated Pd(0) species. An alternative, less likely Heck-like process was the insertion of the double C−C bond of indole into the vinyl-Pd intermediate of Int3.1A, followed by β-H elimination to afford the desired product. Compared with palladium, rhodium catalysts are more studied in all kinds of cycloaddition reactions and carbonylation reactions (i.e., Pauson−Khand reactions).38 Rhodiumcatalyzed cyclization/cycloaddition reactions, in particular, J

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Scheme 22. Rh(I)-Catalyzed Cascade Heterocyclization/ Carbonylative [(3 + 2) + 1] Reaction of Diyne−Enones

Scheme 24. Au(I)-Catalyzed Cascade Reactions of 2-(1Alkynyl)alk-2-en-1-one Oximes

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trapped by a variety of O- and C-based nucleophiles (bottom, Scheme 24).42 Then, we turned our attention to asymmetric variants. In 2018, we developed the analogous cascade heterocyclization/ [3 + 3]-cycloaddition of 2-(1-alkynyl)alk-2-en-1-one oximes 1−2 and nitrones for the synthesis of heterobicyclic pyrrolo[3,4-d][1,2]oxazines 38 with excellent stereoselectivity (Scheme 25).43 This method could be expanded to the gram Scheme 25. Au(I)-Catalyzed Enantioselective [3 + 3]Cycloaddition Reaction of 2-(1-Alkynyl)alk-2-en-1-one Oximes Scheme 23. Rh(I)-Catalyzed Cascade Heterocyclization/[(3 + 2) + 2]-Cycloaddition of Diyne−Enones and Alkynes

Compared with the stereoelectronic effect of alkynes, the regioselectivity was much more likely to be consistent with migratory insertion. 3.2. 2-(1-Alkynyl)alk-2-en-1-one Oximes

scale, maintaining the yield and enantioselectivity under the optimal reaction conditions. The reaction was also fascinating due to its extensive substrate scope and good functionality tolerance.

Similar to 2-(1-alkynyl)alk-2-en-1-ones, we discovered that 2(1-alkynyl)alk-2-en-1-one oximes 1−2 behaved as synthetic equivalents of the 1,3-dipolar synthon of gold−furyl intermediates Int-1.2 to undergo various cycloaddition reactions, such as [3 + 3]-cycloaddition with nitrones and [3 + 4]cycloaddition with α,β-unsaturated imines (Scheme 24).41 As a result, the approach provided relatively simple, mild, and safe access to an array of highly substituted pyrroles 36, which is one of the most popular scaffolds in many materials, natural products, and medicinal agents, such as Lipitor. In terms of the mechanisms, gold−pyrryl intermediates Int-7 could indeed be

3.3. Cascade Reaction Involving 1,5-H shifts

Upon the fruitful implementation of heterocyclization/crosscoupling and cycloaddition cascades, we investigated the expansion of these reactivities to cascade cyclization/[1,5] hydride shift/cyclization reactions (Scheme 26). Treatment of yne−enone acceptor substrates 1−3 with the L1(AuCl)2/ AgOTf catalyst led to the generation of furan-fused K

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Scheme 26. Au(I)- and Sc(III)-Catalyzed Cascade Reactions Involving [1,5] Hydride Shifts

interesting and urgent. In particular, the ability to use attractive noncovalent interactions for rate acceleration and enantiocontrol would significantly expand the current arsenal for yne− enone chemistry and asymmetric catalysis. To this end, new strategies such as multifunctional organocatalysis, counteranion-directed catalysis, dual metal catalysis, and relay catalysis are highly desirable.46 We hope this Account draws the attention of the synthetic community to these new catalyst/ ligands and cascade models, and their productive implementation for small-molecule collection and drug discovery.

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AUTHOR INFORMATION

Corresponding Author

Junliang Zhang − Shanghai Key Laboratory of Green Chemistry and Chemical Processes, Department of Chemistry, East China Normal University, Shanghai 200062, China; Department of Chemistry, Fudan University, Shanghai 200433, China; orcid.org/0000-0002-4636-2846; Email: junliangzhang@ fudan.edu.cn Author

Deyun Qian − Shanghai Key Laboratory of Green Chemistry and Chemical Processes, Department of Chemistry, East China Normal University, Shanghai 200062, China Complete contact information is available at: https://pubs.acs.org/10.1021/acs.accounts.0c00466

benzazepines 39 in high yields and excellent enantioselectivity.44 Mechanistically, activation of the alkyne moiety in 1−3 by Au(I) generated the zwitterionic furan species Int-1.2B. Then, 1,5-hydride transfer rather than the traditional protodeauration pathway occurred to deliver Int-1.2C, which was primed for intramolecular cyclization to produce furan fused benzazepine 39. This was the first case of an enantioselective redox-neutral-domino reaction catalyzed by gold(I) that leads to the direct functionalization of inert C(sp3)−H bonds. In the case of oxophilic Sc(OTf)3, the reaction proceeded with a cascade 1,5-hydride shift/cyclization to provide multifunctionalized ring-fused tetrahydroquinolines 40 with moderate to excellent yields with low to high diastereoselectivity (bottom, Scheme 26).45

Notes

The authors declare no competing financial interest. Biographies Deyun Qian received his Ph.D. degree from East China Normal University (ECNU) in 2015 under the supervision of Professor Junliang Zhang. Currently, he is performing postdoctoral research with Professor Xile Hu at EPFL, Switzerland. Junliang Zhang obtained his Ph.D. in 2002 from the Shanghai Institute of Organic Chemistry under the guidance of Professor Shengming Ma. After his postdoctoral training at the University of Cologne (Humboldt Fellowship) and the University of Chicago, he joined ECNU as a full professor in 2006. Since October 2017, he has been a professor of chemistry at Fudan University. His research interests include developing novel synthetic methodologies, designing novel chiral phosphine ligands, and asymmetric catalysis.

4. SUMMARY AND OUTLOOK In this Account, we have summarized our recent efforts to develop new diversity-oriented cascade methods for efficiently converging diverse small molecules with unique three-dimensional structures. The distinct reactivity of yne−enones and their variants allow these reactions to deliver an array of novel acyclic, polycyclic, and heterocyclic structures, in particular, polysubstituted furan derivatives frequently observed in natural products and bioactive small molecules and these yne−enones are useful platforms for further transformations. Furthermore, the rapid rise in interest in yne−enone chemistry has been accompanied by efforts to exploit enantioselective versions to further enhance the synthetic utility of these transformations. However, significant challenges remain unaddressed. For instance, the linear geometry of gold(I) complexes largely limits their capability to transfer chirality because the active reaction site is usually far from the chiral ligand. To solve this problem, Au(I)/Ming−Phos- and organocatalyst-based catalytic systems have exhibited enhanced activity and levels of stereochemical control in asymmetric cascade reactions. While the advances made to date are remarkable, further inventing novel and efficient transformations of yne−enones to synthesize diverse cyclic and acyclic molecules is still

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ACKNOWLEDGMENTS The financial support from the National Natural Science Foundation of China (Grant Nos. 21672067 and 21921003) is appreciated.

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https://dx.doi.org/10.1021/acs.accounts.0c00466 Acc. Chem. Res. XXXX, XXX, XXX−XXX