Asymmetric synthesis of pyrrolo[1,2-a]indoles via bifunctional tertiary amine catalyzed [3 + 2] annulation of 2-nitrovinylindoles with azlactones

Abstract

The chiral pyrrolo[1,2-a]indole skeleton represents a privileged structural motif in many natural products and pharmaceutical agents. Herein we developed an efficient [3 + 2] annulation of 2-nitrovinylindoles with azlactones via the cascade Michael addition and intramolecular acylation under the catalysis of a bifunctional tertiary amine in combination with DABCO, delivering a wide range of pyrrolo[1,2-a]indoles in good yields with high diastereo- and enantioselectivities. Alternatively, 7-nitrovinylindoles served as 4C synthons to perform enantioselective [4 + 2] annulation under identical conditions, smoothly affording pyrrolo[3,2,1-ij]quinoline skeletons with good to high stereoselectivities. Furthermore, a novel enantio-enriched indole-based tetracyclic skeleton was facilely derived from the obtained pyrrolo[1,2-a]indoles.

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Introduction

Indole-based polycyclic skeletons represent a prominent backbone in pharmaceutical chemistry and synthetic chemistry.¹ Among them, the chiral pyrrolo[1,2-a]indole skeleton is deemed as a privileged pharmacophore in various indole alkaloids and bioactive relevant compounds,² and it also acts as a desirable precursor for the construction of structurally more complex indole-fused architectures.³ For instance, flinderoles A–C, isoborreverine and dimethylisoborreverine have been demonstrated as significant antimalarial reagents (Fig. 1). JTT-10 has been proven to be an excellent protein kinase C-β-selective inhibitor.

Fig. 1 Representative natural products and bioactive reagents containing a pyrrolo[1,2-a]indole core structure.

As a result, the development of the asymmetric synthesis of such skeletons has received considerable attention in the past decades. Various facile synthetic strategies toward such skeletons have been well established, including the direct C2-functionalization/annulation sequence of indoles,⁴ [6 + 2] cycloaddition of 2-indolylmethanols,⁵ and [3 + 2] cycloaddition of C2-functionalized indoles.⁶ Of particular importance, the [3 + 2] annulation of electron-deficient 2-vinylindoles with various 2C nucleophilic synthons provides a versatile platform for the construction of densely functionalized chiral pyrrolo[1,2-a]indole skeletons.^6e–h Since the seminal work of Enders in 2013,^6e the enantioselective [3 + 2] annulation of 2-nitrovinylindoles has made significant progress during the past decade, delivering a wide range of structurally diverse enantio-enriched pyrrolo[1,2-a]indole skeletons. Besides, Deng and coworkers unveiled that indole C2-substituted enones serve as a good partner in the CPA catalyzed [3 + 2] annulation with azlactones, providing chiral pyrrolo[1,2-a]indoles comprising a quaternary stereocenter in generally good yields albeit with relatively low ee values (only 3 examples >90% ee) (Scheme 1).^6f Therefore, the highly efficient and enantioselective [3 + 2] annulation of C2-functionalized indoles toward the synthesis of enantio-enriched pyrrolo[1,2-a]indoles is still a challenging task.

Scheme 1 Overview of the asymmetric [3 + 2] annulation of electron-deficient 2-vinylindoles and our studies.

The azlactone derived from amino acids has proven to be a versatile and powerful precursor owing to its multiple reactive sites.⁷ Based on the highly reactive nucleophilic site, various asymmetric transformations such as alkylations,⁸ Michael reactions,⁹ and rearrangement reactions¹⁰ are initiated under asymmetric catalysis, affording various chiral amino acid derivatives through a facile pathway. Besides, the lactone moiety is regarded as a highly reactive acyl species, which is readily captured by a nucleophilic heteroatom to undergo an acylation reaction after the prior nucleophilic addition, thus implementing a cascade [2 + n] annulation process to afford enantio-cyclic skeletons.¹¹ However, the highly efficient asymmetric [3 + 2] annulation catalyzed by a chiral tertiary amine has been rarely reported although azlactones feature a strong acidic site.^11j–n With our continuous interest in the asymmetric synthesis of pyrrolo[1,2-a]indoles, we envisioned that 2-nitrovinylindoles would serve as an electrophilic 3C synthon for [3 + 2] annulation with azlactones via a cascade Michael reaction and intramolecular acylation under tertiary amine catalysis, giving chiral pyrrolo[1,2-a]indoles with a quaternary stereocenter. Furthermore, it is intriguing that 7-nitrovinylindoles could be engaged in this protocol to perform an asymmetric [4 + 2] cyclization to obtain the valuable pyrrolo[3,2,1-ij]quinoline skeleton based on the above principle.¹² We herein report a switchable asymmetric [3 + 2]/[4 + 2] cyclization of azlactones with 2-nitrovinylindoles and 7-nitrovinylindoles, respectively, under the catalysis of a bifunctional tertiary amine, smoothly furnishing a wide range of pyrrolo[1,2-a]indoles and pyrrolo[3,2,1-ij]quinolines in good yields with high enantio- and diastereo-selectivities.

Results and discussion

Initially, we started our investigation by employing (E)-2-(2-nitrovinyl)-1H-indole 1a and azlactone 2a as the model substrates to obtain the optimized conditions. As shown in Table 1, under the catalysis of the quinidine-derived bifunctional tertiary amine catalyst C1 in DCM at room temperature, the desired cycloadduct 3a and Michael adduct 3a′ were observed consistently after 24 h, unambiguously indicating that this cyclization proceeded via a cascade Michael reaction and intramolecular acylation process, although the acylation process was retarded. Therefore, DABCO was supplemented after 1a was consumed to accelerate the acylation process at 0 °C, affording the desired pyrrolo[1,2-a]indole 3a in a moderate yield with good enantioselectivity (entry 1). Additionally, the quinidine-derived bifunctional catalysts C2 and C3 were tested in this reaction, but they delivered the target product with lower enantioselectivities (entries 2 and 3). Pleasingly, the quinine-derived bifunctional amine-squaramide C4 in combination with DABCO delivered the product with a good yield and enantioselectivity (entry 4). Then, hydrogenated and OH-free bifunctional catalysts C5 and C6 were used in this reaction, but lower ee values were obtained (entries 5 and 6). Besides, the Brønsted acid (R)-1,1′-binaphthyl-2,2′-diylhydrogenphosphate was demonstrated to be inert in this reaction.^6f Subsequently, the examination of solvents indicated that xylene slightly increased the yield and enantiocontrol (entry 7 vs. entries 8–12). The temperature test revealed that a higher temperature (40 °C) was beneficial for the conversion and enantiocontrol (entries 13–16). Besides DABCO, other nucleophilic bases including DMAP and imidazole were tested, but they gave inferior results (entries 17 and 18). As a result, we conducted this reaction on a 0.1 mmol scale under the catalysis of C4 with the assistance of DABCO in xylene at 40 °C, delivering the desired pyrrolo[1,2-a]indole 3a in a good yield with high stereoselectivity (entry 14, 71% yield, 90% ee, >19 : 1 dr).

Table 1 Optimization of conditions for the cascade asymmetric [3 + 2] annulation^a

Entry	C	Solvent	Base	T (°C)	Yield^b (%)	ee^c (%)
a Unless noted otherwise, the reactions were carried out with 1a (0.05 mmol), 2a (0.06 mmol), amine C (10 mol%) and DABCO (30 mol%) in the solvent (1.0 mL) at room temperature; all cases >19 : 1 dr. b Isolated yield. c Determined by HPLC analysis on a chiral stationary phase.
1	C1	DCM	DABCO	25	41	−83
2	C2	DCM	DABCO	25	41	−55
3	C3	DCM	DABCO	25	63	−55
4	C4	DCM	DABCO	25	66	86
5	C5	DCM	DABCO	25	48	81
6	C6	DCM	DABCO	25	67	79
7	C4	Xylene	DABCO	25	69	89
8	C4	THF	DABCO	25	51	72
9	C4	CHCl3	DABCO	25	62	81
10	C4	CF3Ph	DABCO	25	70	75
11	C4	Dioxane	DABCO	25	58	87
12	C4	Toluene	DABCO	25	67	79
13	C4	Xylene	DABCO	0	66	86
14	C4	Xylene	DABCO	40	71	90
15	C4	Xylene	DABCO	50	71	90
16	C4	Xylene	DABCO	60	70	88
17	C4	Xylene	DMAP	40	69	89
18	C4	Xylene	Imidazole	40	—	—

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With the optimized conditions in hand, the substrate scope and limitations of this [3 + 2] cyclization protocol were evaluated as shown in Table 2. Firstly, various functionalized 1 were engaged in the reaction with 2a under the optimized conditions. A wide range of halogenated indoles at different sites were well tolerated in this protocol, giving the desired products 3b–3i in good to high yields with excellent diastereoselectivities (>19 : 1 dr) and generally high enantioselectivities (75–92% ee). Besides, electron-rich group substituted indoles were also tested and provided the products 3j–3m in good yields with excellent diastereoselectivities (>19 : 1 dr) and high ee values (77–96% ee). To our delight, the pyrrole-derived nitroolefin reacted smoothly under identical conditions, albeit giving the desirable pyrrolo[1,2-a]pyrrole 3n as a single diastereoisomer with moderate enantioselectivity (57% ee), probably due to the absence of π–π stacking interaction between the benzene moiety of the indole and the azlactone.^11g On the other hand, a spectrum of substituted azlactones were examined in the reaction with 1a under identical conditions. In general, except for the azlactone with para-F-substituted Ar¹, which gave the product 3o with 60% ee, azlactones with either an electron-rich or electron-deficient group on the phenyl ring of Ar¹ were well compatible in this reaction, delivering the products 3p–3t in good yields with excellent diastereo- and enantioselectivities (>19 : 1 dr, 90–92% ee). In addition, both electron-deficient and electron-rich substituents on the phenyl ring R² of the azlactone worked well in the reaction with 1a, smoothly affording the products 3u and 3v with outstanding ee values (90% ee). Notably, when R² was substituted with a benzyl group, the reaction proceeded well and afforded the desired product 3w in a good yield with high diastereo- and enantioselectivity (>19 : 1 dr, 91% ee). Moreover, the reaction of 5-F-substituted 1d and 4-F-substituted phenyl R² in azlactone 2i was carried out under identical conditions, affording the cycloadduct 3x with good results (76% yield, 90% ee, >19 : 1 dr) and with good crystal properties, which would be utilized to prepare a single crystal to determine the absolute configuration of these cycloadducts.

Table 2 Substrate scope and limitations of the asymmetric [3 + 2] annulation^a

Entry	R^1	Ar^1/R^2	Yield^b (%)	ee^c (%)
a Unless noted otherwise, the reactions were carried out with 1 (0.1 mmol), 2 (0.12 mmol), C4 (10 mol%) and DABCO (30 mol%) in xylene (1.0 mL) at 40 °C, >19 : 1 dr. b Isolated yield. c The ee values were determined by chiral HPLC analysis. d (E)-2-(2-Nitrovinyl)-1H-pyrrole was employed. e The structure and relative configuration of product 3x were determined by X-ray analysis. The other products were assigned analogously.
1	H	Ph/Ph	3a, 71	90
2	5-Br	Ph/Ph	3b, 70	80
3	5-Cl	Ph/Ph	3c, 69	82
4	5-F	Ph/Ph	3d, 63	87
5	6-Br	Ph/Ph	3e, 82	83
6	4,6-Cl2	Ph/Ph	3f, 81	83
7	4,6-F2	Ph/Ph	3g, 53	75
8	3-Br	Ph/Ph	3h, 81	92
9	3-Cl	Ph/Ph	3i, 78	83
10	5-CH3	Ph/Ph	3j, 82	90
11	5-OMe	Ph/Ph	3k, 75	96
12	4-OMe	Ph/Ph	3l, 63	77
13	4-Me	Ph/Ph	3m, 73	77
14^d	H	Ph/Ph	3n, 92	57
15	H	4-FC6H4/Ph	3o, 73	60
16	H	3-FC6H4/Ph	3p, 77	91
17	H	4-ClC6H4/Ph	3q, 73	92
18	H	4-NO2C6H4/Ph	3r, 81	91
19	H	4-OtBuC6H4/Ph	3s, 75	92
20	H	4-CH3C6H4/Ph	3t, 83	90
21	H	Ph/4-FC6H4	3u, 83	90
22	H	Ph/4-CH3C6H4	3v, 79	92
23	H	Ph/Bn	3w, 63	91
24^e	5-F	Ph/4-FC6H4	3x, 76	90

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Encouraged by the above excellent results and inspired by the cascade reaction process, we envisaged that the acylation step could be incorporated into a cascade [4 + 2] annulation by employing the readily available (E)-7-(2-nitrovinyl)-1H-indole 4 to react with azlactones 2, producing the valuable pyrrolo[3,2,1-ij]quinoline skeleton 5 under the established conditions (Scheme 2). Unfortunately, the Michael adduct 5a′ was smoothly formed but without the generation of the desired cycloadduct 5a under the above-optimized conditions. To our delight, the desired cycloadduct 5a was smoothly obtained in 72% yield with good stereoselectivity (77% ee, >19 : 1 dr) when DABCO was replaced by DBU. Then, further preliminary substrate scope investigation of this enantioselective [4 + 2] annulation indicated that (E)-7-(2-nitrovinyl)-1H-indoles 4 with different substituents would react well with azlactone 2a, smoothly giving the desired pyrrolo[3,2,1-ij]quinoline skeletons 5b and 5c with promising or high enantioselectivity.

Scheme 2 Asymmetric [4 + 2] annulation of 7-nitrovinylindoles with azlactone 2a.

Alternatively, N-Me protected 1a-Me might serve as another type of 3C synthon in the C3-acylation process followed by the Michael addition to the azlactone, giving the chiral indole-fused skeleton 6a (Scheme 3). However, only the Michael adduct 6a′ was observed with inferior results under the standard conditions, and further treatment of 6a′ with DBU or DMAP did not improve the results. Moreover, the indole-derived Michael acceptor (E)-3-(1H-indol-2-yl)-1-phenylprop-2-en-1-one 7a was employed in this protocol, but it delivered the cycloadduct 8a in a moderate yield without enantiocontrol.

Scheme 3 Exploration of the asymmetric [3 + 2] annulation with other types of functionalized indoles.

As the obtained cycloadduct features multiple reactive sites and useful functional groups, we conducted some derivatizations to obtain other more structurally complex indole-based skeletons using pyrrolo[1,2-a]indole 3a. As shown in Scheme 4, through hydroboration with NaBH₄ in combination with NiCl₂ and protection with (Boc)₂O in a one-pot manner, the nitro-group was smoothly hydrogenated to give the stable amine derivative 9 in an excellent yield with good enantioretention. Moreover, the NO₂-group was removed in the presence of DBU in DCM to afford the olefin derivative 10 in a good yield with high enantioselectivity. Furthermore, free-NH₂-bearing 11 could be converted into an imine intermediate by condensation with paraformaldehyde in the presence of TFA, thus initiating an intramolecular Friedel–Crafts reaction to afford a valuable chiral indole-fused tetracyclic skeleton in a high yield with good enantioretention. Notably, the secondary amine group of the tetracyclic product should be protected as amide 12 upon cyclization to avoid the retro-Friedel–Crafts reaction-induced ring-opening reaction.

Scheme 4 Synthetic transformations of the pyrrolo[1,2-a]indole 3a.

Based on the X-ray structure of the chiral product 3x and our experimental results, we have proposed a plausible transition state to rationalize the stereochemistry of this transformation. As outlined in Scheme 5, the azlactone was deprotonated by the tertiary amine of the quinuclidines to form the enolate species. Simultaneously, the nitrovinylindole was activated and orientated through the hydrogen-bonding interaction between the nitro-group and the squaramide moiety. Furthermore, the π–π stacking interaction between the benzene moiety of the indole and azlactone would be formed to further stabilize the postulated transition state,^11g which facilitated the Michael addition of the enolate from the Re-face to give the chiral intermediate 3x′. Subsequently, the base-promoted intramolecular amidation reaction delivered the observed chiral product 3x.

Scheme 5 Proposed transition state.

Conclusions

In conclusion, we have developed an elegant asymmetric [3 + 2] annulation of (E)-2-(2-nitrovinyl)-1H-indoles with azlactones under the catalysis of a bifunctional tertiary amine catalyst. A wide variety of valuable pyrrolo[1,2-a]indoles were produced in good yields with generally excellent diastereo- and enantioselectivities. Besides, using the (E)-7-(2-nitrovinyl)-1H-indole in the reaction with azlactones, novel pyrrolo[3,2,1-ij]quinoline skeletons were smoothly obtained with good yields and stereoselectivities. Furthermore, novel bioactive relevant compounds including the amine derivative and indole-fused tetracyclic architecture were smoothly obtained with remarkable stereoselectivities via simple transformations. These valuable highly-oriented three-dimensional indole-based frameworks with stereogenic complexity might find further application in medicinal chemistry.

Data availability

The data underlying this study are available in the published article and its ESI.†

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

We are grateful for the financial support from the National Natural Science Foundation of China (22001216), the Science and Technology Department of Sichuan Province, China (2022NSFSC1203, 2023NSFSC1977), the Chemical Synthesis and Pollution Control Key Laboratory of Sichuan Province (No. CSPC202315) and the Xihua University Science and Technology Innovation Competition Project for Postgraduate Students (YK20240257).

References

1. (a) S. Lancianesi, A. Palmieri and M. Petrini, Synthetic approaches to 3-(2-nitroalkyl) indoles and their use to access tryptamines and related bioactive compounds, Chem. Rev., 2014, 114, 7108–7149; (b) M. Somei and F. Yamada, Simple indole alkaloids and those with a non-rearranged monoterpenoid unit, Nat. Prod. Rep., 2005, 22, 73–103; (c) I. S. Marcos, R. F. Moro, I. Costales, P. Basabe and D. Díez, Sesquiterpenyl indoles, Nat. Prod. Rep., 2013, 30, 1509; (d) Y.-C. Zhang, F. Jiang and F. Shi, Organocatalytic Asymmetric Synthesis of Indole-Based Chiral Heterocycles: Strategies, Reactions, and Outreach, Acc. Chem. Res., 2020, 53, 425–446; (e) J. Li, Q. Zhao, C. Gou, Q. Li, H. Leng, Q. Huang and Y. Liu, Construction of Indole–Fused Heterocycles Starting from 2−Thioxoindolines, Iminoindolines, and Their Derivatives, Adv. Synth. Catal., 2021, 363, 4497–4515; (f) G.-J. Mei, W. L. Koay, C. X. A. Tan and Y. Lu, Catalytic asymmetric preparation of pyrroloindolines: strategies and applications to total synthesis, Chem. Soc. Rev., 2021, 50, 5985–6012.
2. (a) E. O. M. Orlemans, W. Verboom, M. W. Scheltinga, D. N. Reinhoudt, P. Lelieveld, H. H. Fiebig, B. R. Winterhalter, J. A. Double and M. C. Bibby, Synthesis, mechanism of action, and biological evaluation of mitosenes, J. Med. Chem., 1989, 32, 1612–1620; (b) E. O. M. Orlemans, W. Verboom, M. W. Scheltinga, D. N. Reinhoudt, P. Lelieveld, H. H. Fiebig, B. R. Winterhalter, J. A. Double and M. C. Bibby, Synthesis, mechanism of action, and biological evaluation of mitosenes, J. Med. Chem., 1989, 32, 1612–1620; (c) J. M. Liesch, O. D. Hensens, J. Springer, R. S. L. Chang and V. J. Lotti, Asperlicin, a novel non-peptidal cholecystokinin antagonist from aspergillus alliaceus structure elucidation, J. Antibiot., 1985, 36, 1638; (d) B. S. Iyengar, W. A. Remers and W. T. Bradner, Preparation and antitumor activity of 7-substituted 1,2-aziridinomitosenes, J. Med. Chem., 1986, 29, 1864–1868; (e) T. Sasase, H. Yamada, K. Sakoda, N. Imagawa, T. Abe, M. Ito, S. Sagawa, M. Tanaka and M. Matsushita, Novel protein kinase C–β isoform selective inhibitor JTT–010 ameliorates both hyper– and hypoalgesia in streptozotocin– induced diabetic rats, Diabetes, Obes. Metab., 2005, 7, 586–594; (f) J. Vepsäläinen, S. Auriola, M. Tukiainen, N. Ropponen and J. Callaway, Isolation and Characterization of Yuremamine, a New Phytoindole, Planta Med., 2005, 71, 1053–1057; (g) L. S. Fernandez, M. S. Buchanan, A. R. Carroll, Y. J. Feng, R. J. Quinn and V. M. Avery, Flinderoles A−C: Antimalarial Bis-indole Alkaloids from Flindersia Species, Org. Lett., 2009, 11, 329–332; (h) L. S. Fernandez, M. L. Sykes, K. T. Andrews and V. M. Avery, Antiparasitic activity of alkaloids from plant species of Papua New Guinea and Australia, Int. J. Antimicrob. Agents, 2010, 36, 275–279.
3. (a) R. Kim, A. J. Ferreira and C. M. Beaudry, Total Synthesis of Leuconoxine, Melodinine E, and Mersicarpine through a Radical Translocation–Cyclization Cascade, Angew. Chem., Int. Ed., 2019, 58, 12595–12598; (b) V. J. Colandrea, S. Rajaraman and L. S. Jimenez, Synthesis of the Mitomycin and FR900482 Ring Systems via Dimethyldioxirane Oxidation, Org. Lett., 2003, 5, 785–787; (c) B. P. Pritchett, J. Kikuchi, Y. Numajiri and B. M. Stoltz, Enantioselective Pd–Catalyzed Allylic Alkylation Reactions of Dihydropyrido[1,2− a ]indolone Substrates: Efficient Syntheses of (−)–Goniomitine, (+)–Aspidospermidine, and (−)–Quebrachamine, Angew. Chem., Int. Ed., 2016, 55, 13529–13532; (d) D. H. Dethe, R. D. Erande and A. Ranjan, Biomimetic Total Syntheses of Borreverine and Flinderole Alkaloids, J. Org. Chem., 2013, 78, 10106–10120; (e) H. Li, P. Cheng, L. Jiang, J. Yang and L. Zu, Bio–Inspired Fragmentations: Rapid Assembly of Indolones, 2−Quinolinones, and (−)–Goniomitine, Angew. Chem., Int. Ed., 2017, 56, 2754–2757.
4. (a) M. Zeng, W. Zhang and S. You, One–Pot Synthesis of Pyrrolo[1,2− a ]indoles by Chiral N –Triflyl Phosphoramide Catalyzed Friedel–Crafts Alkylation of 4,7−Dihydroindole with β, γ –Unsaturated α –Keto Esters, Chin. J. Chem., 2012, 30, 2615–2623; (b) H. Cheng, L. Lu, T. Wang, Q. Yang, X. Liu, Y. Li, Q. Deng, J. Chen and W. Xiao, Highly Enantioselective Friedel–Crafts Alkylation/N –Hemiacetalization Cascade Reaction with Indoles, Angew. Chem., Int. Ed., 2013, 52, 3250–3254; (c) Y. Zhang, X. Liu, X. Zhao, J. Zhang, L. Zhou, L. Lin and X. Feng, Enantioselective Friedel–Crafts alkylation for synthesis of 2-substituted indole derivatives, Chem. Commun., 2013, 49, 11311; (d) Y. Sun, Y. Qiao, H. Zhao, B. Li and S. Chen, Construction of 9 H -Pyrrolo[1,2- a ]indoles by a Copper-Catalyzed Friedel–Crafts Alkylation/Annulation Cascade Reaction, J. Org. Chem., 2016, 81, 11987–11993.
5. (a) Z.-Q. Zhu, L. Yin, Y. Wang, Y. Shen, C. Li, G.-J. Mei and F. Shi, Diastereo- and enantioselective construction of biologically important pyrrolo[1,2-a]indole scaffolds via catalytic asymmetric [3 + 2] cyclodimerizations of 3-alkyl-2-vinylindoles, Org. Chem. Front., 2017, 4, 57–68; (b) K. Bera and C. Schneider, Brønsted Acid Catalyzed [3+2]–Cycloaddition of 2−Vinylindoles with In Situ Generated 2−Methide–2 H –indoles: Highly Enantioselective Synthesis of Pyrrolo[1,2− a ]indoles, Chem. – Eur. J., 2016, 22, 7074–7078; (c) K. Bera and C. Schneider, Brønsted Acid Catalyzed [3 + 2]-Cycloaddition of Cyclic Enamides with in Situ Generated 2-Methide-2 H -indoles: Enantioselective Synthesis of Indolo[1,2- a ]indoles, Org. Lett., 2016, 18, 5660–5663.
6. (a) D. Enders, A. Greb, K. Deckers, P. Selig and C. Merkens, Quadruple Domino Organocatalysis: An Asymmetric Aza–Michael/Michael/Michael/Aldol Reaction Sequence Leading to Tetracyclic Indole Structures with Six Stereocenters, Chem. – Eur. J., 2012, 18, 10226–10229; (b) H. Lu, J. Lin, J. Liu and P. Xu, One–Pot Asymmetric Synthesis of Quaternary Pyrroloindolones through a Multicatalytic N–Allylation/Hydroacylation Sequence, Chem. – Eur. J., 2014, 20, 11659–11663; (c) D. Enders, C. Wang, X. Yang and G. Raabe, One-Pot Organocatalytic Asymmetric Synthesis of 1H-Pyrrolo[1,2a]indol-3(2H)-ones via a Michael-Hemiaminalization-Oxidation Sequence, Synlett, 2011, 469–472; (d) L. Hong, W. Sun, C. Liu, L. Wang and R. Wang, Asymmetric Organocatalytic N–Alkylation of Indole–2−carbaldehydes with α,β–Unsaturated Aldehydes: One–Pot Synthesis of Chiral Pyrrolo[1,2−a ]indole–2−carbaldehydes, Chem. – Eur. J., 2010, 16, 440–444; (e) Q. Ni, H. Zhang, A. Grossmann, C. C. J. Loh, C. Merkens and D. Enders, Asymmetric Synthesis of Pyrroloindolones by N–Heterocyclic Carbene Catalyzed [2+3] Annulation of α–Chloroaldehydes with Nitrovinylindoles, Angew. Chem., Int. Ed., 2013, 52, 13562–13566; (f) W. Yang, H. Wang, Z. Pan, Z. Li and W. Deng, Asymmetric synthesis of pyrrolo[1,2-a]indoles via organocatalytic [3 + 2] annulation of substituted 2-vinylindoles with azlactones, Chin. Chem. Lett., 2020, 31, 721–724; (g) W. Yang, Z. Sun, H. Sun and W. Deng, Nickel(II)–Catalyzed Diastereo– and Enantioselective [3+2] Cycloaddition of α–Ketoesters with 2−Nitrovinylindoles and 2−Nitrovinylpyrroles, Chin. J. Chem., 2019, 37, 216–220; (h) C.-C. Xie, R. Tan and Y.-K. Liu, Asymmetric construction of polycyclic indole derivatives with different ring connectivities by an organocatalysis triggered two-step sequence, Org. Chem. Front., 2019, 6, 919–924.
7. (a) J. S. Fisk, R. A. Mosey and J. J. Tepe, The diverse chemistry of oxazol-5-(4H)-ones, Chem. Soc. Rev., 2007, 36, 1432; (b) I. F. S. Marra, P. P. De Castro and G. W. Amarante, Recent Advances in Azlactone Transformations, Eur. J. Org. Chem., 2019, 5830–5855; (c) P. P. de Castro, A. G. Carpanez and G. W. Amarante, Azlactone Reaction Developments, Chem. – Eur. J., 2016, 22, 10294–10318.
8. (a) B. M. Trost and L. C. Czabaniuk, Palladium–Catalyzed Asymmetric Benzylation of Azlactones, Chem. – Eur. J., 2013, 19, 15210–15218; (b) X. Wei, D. Liu, Q. An and W. Zhang, Hydrogen-Bond Directed Regioselective Pd-Catalyzed Asymmetric Allylic Alkylation: The Construction of Chiral α-Amino Acids with Vicinal Tertiary and Quaternary Stereocenters, Org. Lett., 2015, 17, 5768–5771; (c) W. Chen and J. F. Hartwig, Control of Diastereoselectivity for Iridium-Catalyzed Allylation of a Prochiral Nucleophile with a Phosphate Counterion, J. Am. Chem. Soc., 2013, 135, 2068–2071; (d) H. Zhou, H. Yang, M. Liu, C. Xia and G. Jiang, Brønsted Acid Accelerated Pd-Catalyzed Direct Asymmetric Allylic Alkylation of Azlactones with Simple Allylic Alcohols: A Practical Access to Quaternary Allylic Amino Acid Derivatives, Org. Lett., 2014, 16, 5350–5353; (e) B. M. Trost and L. C. Czabaniuk, Benzylic Phosphates as Electrophiles in the Palladium-Catalyzed Asymmetric Benzylation of Azlactones, J. Am. Chem. Soc., 2012, 134, 5778–5781.
9. (a) G. Li, W. Sun, J. Li, F. Jia, L. Hong and R. Wang, Organocatalytic enantioselective formal arylation of azlactones using quinones as the aromatic partner, Chem. Commun., 2015, 51, 11280–11282; (b) M. Weber, S. Jautze, W. Frey and R. Peters, Bispalladacycle–Catalyzed Michael Addition of In Situ Formed Azlactones to Enones, Chem. – Eur. J., 2012, 18, 14792–14804; (c) M. Weber, W. Frey and R. Peters, Catalytic Asymmetric Synthesis of Functionalized α,α–Disubstituted α–Amino Acid Derivatives from Racemic Unprotected α–Amino Acids via in–situ Generated Azlactones, Adv. Synth. Catal., 2012, 354, 1443–1449.
10. (a) J. C. Ruble and G. C. Fu, Enantioselective Construction of Quaternary Stereocenters: Rearrangements of O -Acylated Azlactones Catalyzed by a Planar-Chiral Derivative of 4-(Pyrrolidino)pyridine, J. Am. Chem. Soc., 1998, 120, 11532–11533; (b) M. Xie, Y. Zhang, M. Shan, X. Wu, G. Qu and H. Guo, Chiral DMAP– N –oxides as Acyl Transfer Catalysts: Design, Synthesis, and Application in Asymmetric Steglich Rearrangement, Angew. Chem., Int. Ed., 2019, 58, 2839–2843; (c) A. Moyano, N. El-Hamdouni and A. Atlamsani, Asymmetric Organocatalytic Rearrangement Reactions, Chem. – Eur. J., 2010, 16, 5260–5273; (d) C. K. De, N. Mittal and D. Seidel, A Dual-Catalysis Approach to the Asymmetric Steglich Rearrangement and Catalytic Enantioselective Addition of O -Acylated Azlactones to Isoquinolines, J. Am. Chem. Soc., 2011, 133, 16802–16805.
11. For selected examples of asymmetric [4 + 2] annulations, see: (a) Y. Wang, J. Pan, R. Jiang, Y. Wang and Z. Zhou, Stereocontrolled Construction of 3,4−Dihydrocoumarin Scaffolds with a Quaternary Amino Acid Moiety via Chiral Squaramide–Catalyzed Cascade Michael Addition/Lactonization Reaction, Adv. Synth. Catal., 2016, 358, 195–200; (b) A. K. Simlandy, B. Ghosh and S. Mukherjee, Enantioselective [4 + 2]-Annulation of Azlactones with Copper-Allenylidenes under Cooperative Catalysis: Synthesis of α-Quaternary α-Acylaminoamides, Org. Lett., 2019, 21, 3361–3366; (c) S. Dong, X. Liu, X. Chen, F. Mei, Y. Zhang, B. Gao, L. Lin and X. Feng, Chiral Bisguanidine-Catalyzed Inverse-Electron-Demand Hetero-Diels−Alder Reaction of Chalcones with Azlactones, J. Am. Chem. Soc., 2010, 132, 10650–10651; (d) L. Zhang, Y. Liu, K. Liu, Z. Liu, N. He and W. Li, Asymmetric synthesis of dihydrocoumarins via the organocatalytic hetero-Diels–Alder reaction of ortho-quinone methides, Org. Biomol. Chem., 2017, 15, 8743–8747; (e) S. Zhang, M. Lv, S. Yin, N. Li, J. Zhang and X. Wang, Asymmetric Synthesis of Dihydrocoumarins Containing Contiguous Quaternary and Tertiary Stereogenic Centers Catalyzed by a Cinchona–Alkaloid–Based Bifunctional Thiourea Derivative, Adv. Synth. Catal., 2016, 358, 143–153; (f) H. Kim, Y. Kim and S. Kim, Asymmetric Synthesis of 3,4−Dihydroquinolin–2−ones via Organocatalytic [4+2]–Cyclization of 2−Amino–β–nitrostyrenes with Azlactones, Adv. Synth. Catal., 2024, 366, 1756–1762; (g) J. Hejmanowska, A. Albrecht, J. Pięta and Ł. Albrecht, Asymmetric Synthesis of 3,4−Dihydrocoumarins Bearing an α,α–Disubstituted Amino Acid Moiety, Adv. Synth. Catal., 2015, 357, 3843–3848; (h) J. Jiang, J. Qing and L. Gong, Asymmetric Synthesis of 3−Amino–δ–lactams and Benzo[a]quinolizidines by Catalytic Cyclization Reactions Involving Azlactones, Chem. – Eur. J., 2009, 15, 7031–7034; (i) S. Ruan, X. Lin, L. Xie, L. Lin, X. Feng and X. Liu, Asymmetric synthesis of 3-aminodihydrocoumarins via the chiral guanidine catalyzed cascade reaction of azlactones, Org. Chem. Front., 2018, 5, 32–35. For selected examples of asymmetric [3 + 2] annulations, see: (j) S. Dong, X. Liu, Y. Zhu, P. He, L. Lin and X. Feng, Organocatalytic Oxyamination of Azlactones: Kinetic Resolution of Oxaziridines and Asymmetric Synthesis of Oxazolin-4-ones, J. Am. Chem. Soc., 2013, 135, 10026–10029; (k) J. Yu, L. Yu, X. Zhao, L. Gan, W. Zhu, Z. Wang, R. Wang and X. Jiang, Organocatalytic asymmetric [3+2] annulation of 1,4-dithiane-2,5-diol with azlactones: access to chiral dihydrothiophen-2(3H-one derivatives, Org. Chem. Front., 2018, 5, 2040–2044; (l) X. Liu, Y. Wang, D. Yang, J. Zhang, D. Liu and W. Su, Catalytic Asymmetric Inverse–Electron–Demand 1,3−Dipolar Cycloaddition of C,N–Cyclic Azomethine Imines with Azlactones: Access to Chiral Tricyclic Tetrahydroisoquinolines, Angew. Chem., Int. Ed., 2016, 55, 8100–8103; (m) C. Ma, J. Zhou, Y. Zhang, G. Mei and F. Shi, Catalytic Asymmetric [2+3] Cyclizations of Azlactones with Azonaphthalenes, Angew. Chem., Int. Ed., 2018, 57, 5398–5402; (n) L. Xie, S. Dong, Q. Zhang, X. Feng and X. Liu, Asymmetric construction of dihydrobenzofuran-2,5-dione derivatives via desymmetrization of p -quinols with azlactones, Chem. Commun., 2019, 55, 87–90.
12. (a) J. Jumina, D. Wenholz, N. Kumar and D. Black, Synthesis of a Variety of Activated Pyrrolo[3,2,1-ij]quinolines, Synthesis, 2019, 51, 1989–1994; (b) X.-Y. Duan, Z. Tian, B. Liu, T. He, L.-L. Zhao, M. Dong, P. Zhang and J. Qi, Highly Enantioselective Synthesis of Pyrroloindolones and Pyrroloquinolinones via an N-Heterocyclic Carbene-Catalyzed Cascade Reaction, Org. Lett., 2021, 23, 3777–3781; (c) Y. Nie, J. Zhou and Y. Wang, Catalyst-Controlled Divergent Cycloisomerizations of N -Propargyl Indoles, Org. Lett., 2023, 25, 4350–4354.

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Footnotes

† Electronic supplementary information (ESI) available: Experimental procedures, structural proof, and CIF file of 3x. CCDC 2372776. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d4qo01557f

‡ These authors contributed equally to this work.

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