Carbene-catalyzed asymmetric friedel–crafts alkylation-annulation sequence and rapid synthesis of indole-fused polycyclic alkaloids

ABSTRACT Organocatalyzed asymmetric Friedel–Craft reactions have enabled the rapid construction of chiral molecules with highly enantioselectivity enriching the toolbox of chemists for

producing complex substances. Here, we report N-heterocyclic carbene-catalyzed asymmetric indole Friedel–Crafts alkylation-annulation with α,β-unsaturated acyl azolium as the key

intermediate, affording a large variety of indole-fused polycyclic alkaloids with excellent diastereo- and enantioselectivities. The reaction mechanism is also investigated, and the reaction

products can be easily converted to highly functionalized indole frameworks with different core structures. SIMILAR CONTENT BEING VIEWED BY OTHERS ORGANOCATALYTIC CYCLOADDITION OF

ALKYNYLINDOLES WITH AZONAPHTHALENES FOR ATROPOSELECTIVE CONSTRUCTION OF INDOLE-BASED BIARYLS Article Open access 02 February 2022 ORGANOPHOTOCATALYTIC DEAROMATIZATION OF INDOLES, PYRROLES

AND BENZO(THIO)FURANS VIA A GIESE-TYPE TRANSFORMATION Article Open access 19 February 2021 CATALYTIC ENANTIOSELECTIVE REDUCTIVE ALKYNYLATION OF AMIDES ENABLES ONE-POT SYNTHESES OF

PYRROLIDINE, PIPERIDINE AND INDOLIZIDINE ALKALOIDS Article Open access 06 October 2023 INTRODUCTION Indole-fused polycyclic scaffolds are ubiquitous in a large number of bioactive molecules

and pharmacuticals, such as paxilline (potassium channel blocker), fischerindole L (antifungal activity), yuehchukene (strong anti-implantation activity), pergolide (medicine in the

treatment of Parkinson’s disease), and hapalindole G (antimycotic activities) (Fig. 1)1,2,3,4. However, multiple steps have been used to make the key skeletons of these molecules, thus

resulting in relatively low efficiency and atom economy5,6,7. Therefore, developing a protocol that can rapidly construct these polycyclic indole units is still highly desirable. Asymmetric

indole functionalization has been a field of intense focus in the recent decade. Friedel–Crafts alkylation of indoles using enones/enals has been a powerful strategy to achieve the above

purpose8,9,10,11,12. Carbonyl activation of enones by Lewis/Brønsted acids and activation of enals via iminiums are prevalent activation modes (Fig. 2a)8,9,10,11,12. However, exploiting new

activation modes of enones/enals holds great importance to further promote the influence of this strategy. On the other side, N-heterocyclic carbene (NHC)-catalyzed

reactions13,14,15,16,17,18,19,20,21,22,23,24,25 mediated by α,β-unsaturated acyl azoliums19,26,27,28,29 have attracted increasing research interests owing to the great value in chiral cyclic

molecule synthesis. Annulations of a series of carbon-based nucleophiles30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51 with α,β-unsaturated acyl azoliums have been

reported by Studer, Lupton, Bode, Enders, Chi, Ye, You, Du, Hui, Biju, and other groups. Additionally, the use of heteroatoms (N or S) as nucleophiles to react with α,β-unsaturated acyl

azoliums has also been disclosed52,53,54,55,56. Despite these elegant reports, using α,β-unsaturated acyl azolium as the basic enal activation mode to achieve indole Friedel–Crafts

alkylation remains a significant challenge to date (Fig. 2a). The difficulties arise from: (1) according to Studer and Mayr’s study, such a reaction is unfavorable because the

electrophilicity of α,β-unsaturated acyl azoliums is 103–106 lower than that of iminiums57; (2) the competitive aza-Michael addition52,53,54,56 and N-acylation58 reactions are easy to occur

under basic conditions; (3) the difficulty in regenerating NHC catalyst. Recently, Studer et al. achieved the intramolecular dearomative indole acylation via NHC catalysis59. Here we address

these challenges by installing an enone unit into indoles to trigger the following annulation, which provides additional driving force for the Friedel–Crafts alkylation, and the protocol

affords a series of indole-fused polycyclic alkaloids with excellent diastero- and enantioselectivities (Fig. 2b). RESULTS OPTIMIZATION OF THE REACTION CONDITIONS Readily available indole

enone 1A and enal 2A were selected to test our hypothesis (Fig. 3). The reaction using catalyst A60,61,62 with Cs2CO3 in CH2Cl2 led to the desired product 3A with excellent 99% ee, but in

only 15% yield, and 1A was mostly recovered, indicating the low reactivity of α,β-unsaturated acyl azolium towards 1A (Table 1, entry 1). Then we tested catalysts60,61,62 B, C, D, and E, but

in all cases, trace amount of 3A was formed (Table 1, entry 2). Catalyst F produced 3A with slightly lower yield and ee (Table 1, entry 3), and catalysts G, H, and I retarded the reaction

(Table 1, entry 4). To our delight, increasing the temperature to 40 °C enhanced the yield (Table 1, entry 5), but other bases, such as K2CO3, KOAc, KO_t_Bu, and DBU led to inferior results

(Table 1, entries 6–9). CHCl3 or DCE proved inefficient and THF and toluene impeded the reaction (Table 1, entries 10–13). Gratifyingly, using more oxidant and M.S. and higher temperature

could further enhance the yield (Table 1, entry 14), and 3A could be finally obtained in an acceptable 76% yield without affecting the enantioselectivity (Table 1, entry 15). SCOPE OF

1,2,3,4-TETRAHYDROCYCLOPENTA[_B_]INDOLE ALKALOIDS Having identified the optimal conditions, we then evaluated the generality and limitations of this protocol. We found that the reaction

could tolerate the introduction of electron-withdrawing 4-Cl, 3-Cl, 4-F, 4-Br, and electron-donating 4-Me substituents into the phenyl rings of the enone units, delivering 3B–3F with

excellent 95–99% ee (Fig. 4, 3B–3F). Then we tested aryl enals equipped with F, Cl, and Br groups at the phenyl rings, and they all worked well under the optimal conditions, releasing 3G–3J

with excellent 95–99% ee (Fig. 4, 3G–3J). Furan-substituted enal was surveyed and 3K was formed smoothly in 70% yield with 97% ee (Fig. 4, 3K). Enals with electron-rich aryl groups showed

low conversion, but adding a Cl group into the indole ring had little influence on the outcome, affording 3L with 99% ee (Fig. 4, 3L). Moreover, varying simultaneously the substituent

patterns of both enones and enals proved possible, delivering 3M–3R with 91–99% ee (Fig. 4, 3M–3R). Furthermore, methyl enone also worked well, forming 3S with 99% ee (Fig. 4, 3S).

Additionally, enone with a Cl atom at the indole moiety could also cyclize with 4-Cl-C6H4-substituted enal, affording 3T in 67% yield with 99% ee (Fig. 4, 3T). Finally, when three

substituted groups were introduced into the phenyl ring of enal, indole, and ketone unit, respectively, product 3U was also liberated with excellent 97% ee (Fig. 4, 3U). In all cases, the

products were obtained as single diastereoisomers, and the absolute configuration of 3B was determined by the single crystal X-ray structure analysis (Fig. 4). SCOPE OF

1,3,4,5-TETRAHYDROBENZO[CD]INDOLE ALKALOIDS Next we investigated the possibility of making 1,3,4,5-tetrahydrobenzo[cd]indoles, which are also key units in many bioactive molecules. Indole

enone 4A could react with 2A smoothly under slightly modified conditions, releasing 5A in 74% yield with excellent 99% ee (Fig. 5, 5A; Cs2CO3 led to 55% yield). Then we surveyed a series of

enals bearing substituents with different electronic properties, and in all cases, the corresponding products were formed with excellent ee (Fig. 5, 5B–5E). Furan-substituted enal also

worked well, affording 5F in 99% ee (Fig. 5, 5F). Aliphatic methyl enal proved amenable and 5G was formed with 85% ee in 64% yield (Fig. 5, 5G). Moreover, the reaction tolerated a variety of

enones with both electron-poor and electron-rich aryl substituents, allowing access to 5H–5N with 90–95% ee (Fig. 5, 5H–5N). The reactions using thiophene or methyl-substituted enones

proved successful, delivering 5O and 5P with excellent 93% and 97% ee, respectively (Fig. 5, 5O and 5P). Finally, we investigated the simultaneous variations of both enal and enone

substituents, and different combination modes, such as aryl/aryl, aryl/alkyl, and alkyl/alkyl were all tolerated, and good to excellent ee values of the products were observed (Fig. 5,

5Q–5V). The absolute configuration of 5A was determined by the single crystal X-ray structure analysis (Fig. 5)17. SCALE-UP SYNTHESIS AND PRODUCT DERIVATIZATIONS Scale-up synthesis of 3A and

5A proved possible, with no erosion of the ee detected (Fig. 6a, b). Furthermore, various simple reactions can be used to afford amide 6A, ester 6B/7A, and aldehyde 7B (Fig. 6c, d). The

newly formed functional groups in these compounds can be readily used for further transformations. MECHANISTIC STUDIES A series of experiments were conducted to gain more mechanistic

insights (Fig. 7). The reaction using N-methyl indole enone 1A′ or 4A′ failed to deliver any products (Fig. 7a), indicating the vital role of indole N–H in the reaction. However, both Cs2CO3

and Na2CO3 cannot deprotonate indole N–H, showing that the nitrogen anion is not involved in the reaction (Fig. 7b). With catalytic amount of base or even without base, the reaction can

still occur, albeit in lower yields (Fig. 7c). Using anion substrate 4AA we got N-acylation product 8A in 51% yield, and no annulation product was detected (Fig. 7d), which further excluded

the existence of nitrogen anion in the catalytic cycle. Then, N-deuterium 4AB and 3-deuterium 4AC were used, but the reaction only led to 5A, indicating that proton transfer from indole to

enal-derived intermediates may not occur (Fig. 7e). Furthermore, the reaction using deuterium enal 2A-D1 resulted in no erosion of D atom in the product, but the reaction was obvioulsy

sluggish, and N-acylation product was also formed (Fig. 7f). However, using 2A-D3 we observed apparent D/H exchange during the reaction and only 63% deuterium was kept at the α-position of

the ester moiety, indicating the probable equilibrium between azolium enolate and acyl azolium intermediates. Using 4M as the reference, we could estimate the KIE of the reaction to be 2.0,

indicating that indole 3-position addition/C–H bond cleavage (from I to II) is possibly involved in the rate-determing step (RDS) (Fig. 7g). A plausible mechanism was proposed in Fig. 7h.

The reaction of enal and NHC under oxidative conditions affords unsaturated acyl azolium I. The Friedel–Crafts reaction of indole enone and I results in enolate II (see the Supplementary

Material for more details of this step); II can be protonated to produce III, and the process is reversible. Then the Michael addition happens to form a new enolate IV, and after

lactonization, product 3A is produced, together with the regeneration of free carbene. Similar process happens when enone 4A is used, producing 5A as the final product. DISCUSSION In

summary, we have disclosed the NHC-catalyzed asymmetric indole Friedel–Crafts alkylation-annulation using α,β-unsaturated acyl azoliums for the first time, and the protocol afforded a large

variety of indole-fused polycyclic alkaloids with excellent diastereo- and enantioselectivities. The competitive side reactions were suppressed, and mechanistic studies revealed that indole

3-position C–H bond cleavage is involved in the rate-determing step, and rapid equilibrium between azolium enolate and acyl azolium exists. This work further expands the application of NHC

catalysis, and is also a valuable addition to the field of indole Friedel–Crafts alkylation. Further studies on NHC-catalyzed annulation reactions are ongoing in our group. METHODS GENEARL

PROCEDURE FOR THE ANNULATION REACTION OF 1 AND 2 Substrate 1A (247.10 mg 1.00 mmol), oxidant (612.45 mg, 1.50 mmol), 4 Å M.S. (2.00 g), Cs2CO3 (488.69 mg, 1.50 mmol) and catalyst (83.84 mg,

0.20 mmol) were added to CH2Cl2 (5 mL) at room temperature under argon atmosphere. After 15 min, 2A (198.09 mg, 1.50 mmol) was added into the reaction system. The reaction was stirred at 50 

°C for 20 h. After that the residue was filtered on celite, the solvent was removed under reduced pressure and the residue was purified by flash chromatography with petroleum ether/ethyl

acetate (v:v = 10:1) as eluent to afford the product 3A (271.5 mg, 72% yield). GENERAL PROCEDURE FOR THE ANNULATION REACTION OF 4 AND 2 Substrate 4A (247.10 mg 1.00 mmol), oxidant (612.45 

mg, 1.50 mmol), 4 Å M.S. (3.00 g), Na2CO3 (159.00 mg, 1.50 mmol) and catalyst (83.84 mg, 0.20 mmol) were added to CH2Cl2 (5 mL) at room temperature under argon atmosphere. After 15 min, 2A

(198.08 mg, 1.50 mmol) was added into the reaction system. The reaction was stirred at 50 °C for 20 h. After that the residue was filtered on celite, the solvent was removed under reduced

pressure and the residue was purified by flash chromatography with petroleum ether/ethyl acetate (v:v = 10:1) as eluent to afford the product 5A (279.0 mg, 74% yield). TYPICAL PROCEDURE FOR

THE PREPARATION OF SUBSTRATES See Supplementary methods for more details. PROCEDURE FOR THE PRODUCT DERIVATIZATIONS See Supplementary methods for more details. DEUTERIUM EXPERIMENTS See

Supplementary Figs. 1–6. PROPOSED INDOLE FRIEDEL–CRAFTS ALKYLATION MECHANISM See Supplementary Fig. 7. 1H NMR AND 13C NMR SPECTRA OF SUBSTRATES AND PRODUCTS See Supplementary Figs. 8–79.

HPLC SPECTRA OF PRODUCTS See Supplementary Figs. 80–126. CRYSTALLOGRAPHY The CIF files for compounds 3B and 5A are available in Supplementary Data 1 and 2. Crystal data and structure

refinement are shown in Supplementary Tables 1 and 2. DATA AVAILABILITY Data for the crystal structures reported in this paper have been deposited at the Cambridge Crystallographic Data

Centre (CCDC) under the deposition numbers CCDC 1879978 (3B) and CCDC 1879979 (5A). Copies of these data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif. All other

data supporting the findings of this study, including compound characterization, are available within the paper and its Supplementary Information files, or from the corresponding authors on

request. REFERENCES * Kong, Y.-C., Cheng, K.-F., Cambie, R. C. & Waterman, P. G. Yuehchukene: a novel indole alkaloid with anti-implantation activity. _J. Chem. Soc. Chem. Commun_.

https://doi.org/10.1039/C39850000047 (1985). * Moore, R. E., Cheuk, C., Yang, X.-Q. G. & Patterson, G. M. L. Hapalindoles, antibacterial and antimycotic alkaloids from the cyanophyte

_Hapalosiphon fontinalis_. _J. Org. Chem._ 52, 1036–1043 (1987). Article  CAS  Google Scholar  * Park, A., Moore, R. E. & Patterson, G. M. L. Fischerindole L, a new isonitrile from the

terrestrial blue-green alga fischerella muscicola. _Tetrahedron Lett._ 33, 3257–3260 (1992). Article  CAS  Google Scholar  * Sanchez, M. & McManus, O. B. Paxilline inhibition of the

alpha-subunit of the high-conductance calcium-activated potassium channel. _Neuropharmacology_ 35, 963–968 (1996). Article  CAS  Google Scholar  * Sheu, J.-H., Chen, Y.-K. & Hong, Y.-L.

V. An efficient synthesis of yuehchukene. _Tetrahedron Lett._ 32, 1045–1046 (1991). Article  CAS  Google Scholar  * Fukuyama, T. & Chen, X. Stereocontrolled synthesis of (–)-hapalindole

G. _J. Am. Chem. Soc._ 116, 3125–3126 (1994). Article  CAS  Google Scholar  * Richter, J. M. et al. Enantiospecific total synthesis of the hapalindoles, fischerindoles, and welwitindolinones

via a redox economic approach. _J. Am. Chem. Soc._ 130, 17938–17954 (2008). Article  CAS  Google Scholar  * Poulsen, T. B. & Jørgensen, K. A. Catalytic asymmetric Friedel–Crafts

alkylation reactions-copper showed the way. _Chem. Rev._ 108, 2903–2915 (2008). Article  CAS  Google Scholar  * You, S.-L., Cai, Q. & Zeng, M. Chiral Brønsted acid catalyzed

Friedel–Crafts alkylation reactions. _Chem. Soc. Rev._ 38, 2190–2201 (2009). Article  CAS  Google Scholar  * Zeng, M. & You, S.-L. Asymmetric Friedel-Crafts alkylation of indoles: the

control of enantio- and regioselectivity. _Synlett_ 2010, 1289–1301 (2010). Article  Google Scholar  * Bartoli, G., Bencivenni, G. & Dalpozzo, R. Organocatalytic strategies for the

asymmetric functionalization of indoles. _Chem. Soc. Rev._ 39, 4449–4465 (2010). Article  CAS  Google Scholar  * Dalpozzo, R. Strategies for the asymmetric functionalization of indoles: an

update. _Chem. Soc. Rev._ 44, 742–778 (2015). Article  CAS  Google Scholar  * Enders, D., Niemeier, O. & Henseler, A. Organocatalysis by N-heterocyclic carbenes. _Chem. Rev._ 107,

5606–5655 (2007). Article  CAS  Google Scholar  * Biju, A. T., Kuhl, N. & Glorius, F. Extending NHC-catalysis: coupling aldehydes with unconventional reaction partners. _Acc. Chem. Res._

44, 1182–1195 (2011). Article  CAS  Google Scholar  * Grossmann, A. & Enders, D. N-Heterocyclic carbene catalyzed domino reactions. _Angew. Chem. Int. Ed._ 51, 314–325 (2012). Article 

CAS  Google Scholar  * Bugaut, X. & Glorius, F. Organocatalytic umpolung: N-heterocyclic carbenes and beyond. _Chem. Soc. Rev._ 41, 3511–3522 (2012). Article  CAS  Google Scholar  *

Bode, J. W. An internal affair. _Nat. Chem._ 5, 813–815 (2013). Article  CAS  Google Scholar  * Chen, X.-Y. & Ye, S. Enantioselective cycloaddition reactions of ketenes catalyzed by

N-heterocyclic carbenes. _Synlett_ 24, 1614–1622 (2013). Article  CAS  Google Scholar  * Ryan, S. J., Candish, L. & Lupton, D. W. Acyl anion free N-heterocyclic carbene organocatalysis.

_Chem. Soc. Rev._ 42, 4906–4917 (2013). Article  CAS  Google Scholar  * Hopkinson, M. N., Richter, C., Schedler, M. & Glorius, F. An overview of N-heterocyclic carbenes. _Nature_ 510,

485–496 (2014). Article  CAS  Google Scholar  * Flanigan, D. M., Romanov-Michailidis, F., White, N. A. & Rovis, T. Organocatalytic reactions enabled by N-heterocyclic carbenes. _Chem.

Rev._ 115, 9307–9387 (2015). Article  CAS  Google Scholar  * Menon, R. S., Biju, A. T. & Nair, V. Recent advances in employing homoenolates generated by N-heterocyclic carbene (NHC)

catalysis in carbon–carbon bond-forming reactions. _Chem. Soc. Rev._ 44, 5040–5052 (2015). Article  CAS  Google Scholar  * Chen, X. Y., Liu, Q., Chauhan, P. & Enders, D. N-Heterocyclic

carbene catalysis via azolium denolates: an efficient strategy for remote enantioselective functionalizations. _Angew. Chem. Int. Ed._ 57, 3862–3873 (2018). Article  CAS  Google Scholar  *

Murauski, K. J. R., Jaworski, A. A. & Scheidt, K. A. A continuing challenge: N-heterocyclic carbene-catalyzed syntheses of γ-butyrolactones. _Chem. Soc. Rev._ 47, 1773–1782 (2018).

Article  CAS  Google Scholar  * Chen, X.-Y., Li, S., Vetica, F., Kumar, M. & Enders, D. N-Heterocyclic-carbene-catalyzed domino reactions via two or more activation modes. _iScience_ 2,

1–26 (2018). Article  Google Scholar  * De Sarkar, S., Biswas, A., Samanta, R. C. & Studer, A. Catalysis with N-heterocyclic carbenes under oxidative conditions. _Chem. Eur. J._ 19,

4664–4678 (2013). Article  Google Scholar  * Mahatthananchai, J. & Bode, J. W. On the mechanism of N-heterocyclic carbene-catalyzed reactions involving acyl azoliums. _Acc. Chem. Res._

47, 696–707 (2014). Article  CAS  Google Scholar  * Levens, A. & Lupton, D. W. All-carbon (4 + 2) annulations catalysed by N-heterocyclic carbenes. _Synlett_ 28, 415–424 (2017). CAS 

Google Scholar  * Zhang, C., Hooper, J. F. & Lupton, D. W. _N_-Heterocyclic carbene catalysis via the α,β-unsaturated acyl azolium. _ACS Catal._ 7, 2583–2596 (2017). Article  CAS  Google

Scholar  * Ryan, S. J., Candish, L. & Lupton, D. W. _N_-Heterocyclic carbene-catalyzed generation of α,β-unsaturated acyl imidazoliums: synthesis of dihydropyranones by their reaction

with enolates. _J. Am. Chem. Soc._ 131, 14176–14177 (2009). Article  CAS  Google Scholar  * De Sarkar, S. & Studer, A. NHC-catalyzed Michael addition to α,β-unsaturated aldehydes by

redox activation. _Angew. Chem. Int. Ed._ 49, 9266–9269 (2010). Article  Google Scholar  * Rong, Z.-Q., Jia, M.-Q. & You, S.-L. Enantioselective _N_-heterocyclic carbene-catalyzed

Michael addition to α,β-unsaturated aldehydes by redox oxidation. _Org. Lett._ 13, 4080–4083 (2011). Article  CAS  Google Scholar  * Lu, Y., Tang, W., Zhang, Y., Du, D. & Lu, T.

N-Heterocyclic carbene-catalyzed annulations of enals and ynals with indolin-3-ones: synthesis of 3,4-dihydropyrano[3,2-b]indol-2-ones. _Adv. Synth. Catal._ 355, 321–326 (2013). Article  CAS

  Google Scholar  * Chen, X.-Y. et al. N-Heterocyclic carbene catalyzed cyclocondensation of α,β-unsaturated carboxylic acids: enantioselective synthesis of pyrrolidinone and

dihydropyridinone derivatives. _Angew. Chem. Int. Ed._ 53, 11611–11615 (2014). Article  CAS  Google Scholar  * Perveen, S. et al. Enantioselective synthesis of 1,2-dihydronaphthalenes via

oxidative N-heterocyclic carbene catalysis. _Org. Lett._ 19, 2470–2473 (2017). Article  CAS  Google Scholar  * Gillard, R. M., Fernando, J. E. M. & Lupton, D. W. Enantioselective

N-heterocyclic carbene catalysis via the dienyl acyl azolium. _Angew. Chem. Int. Ed._ 57, 4712–4716 (2018). Article  CAS  Google Scholar  * Ryan, S. J., Candish, L. & Lupton, D. W.

N-Heterocyclic carbene-catalyzed (4 + 2) cycloaddition/decarboxylation of silyl dienol ethers with α,β-unsaturated acid fluorides. _J. Am. Chem. Soc._ 133, 4694–4697 (2011). Article  CAS 

Google Scholar  * Candish, L., Levens, A. & Lupton, D. W. Enantioselective all-carbon (4 + 2) annulation by _N_-heterocyclic carbene catalysis. _J. Am. Chem. Soc._ 136, 14397–14400

(2014). Article  CAS  Google Scholar  * Yetra, S. R., Mondal, S., Mukherjee, S., Gonnade, R. G. & Biju, A. T. Enantioselective synthesis of spirocyclohexadienones by NHC-catalyzed formal

[3 + 3] annulation reaction of enals. _Angew. Chem. Int. Ed._ 55, 268–272 (2016). Article  CAS  Google Scholar  * Zhang, G. et al. Enantioselective intermolecular all-carbon [4 + 2]

annulation via N-heterocyclic carbene organocatalysis. _Chem. Commun._ 53, 13336–13339 (2017). Article  CAS  Google Scholar  * Kaeobamrung, J., Mahatthananchai, J., Zheng, P. & Bode, J.

W. An enantioselective Claisen rearrangement catalyzed by N-heterocyclic carbenes. _J. Am. Chem. Soc._ 132, 8810–8812 (2010). Article  CAS  Google Scholar  * Li, G.-T., Li, Z.-K., Gu, Q.

& You, S.-L. Asymmetric synthesis of 4-aryl-3,4-dihydrocoumarins by N-heterocyclic carbene catalyzed annulation of phenols with enals. _Org. Lett._ 19, 1318–1321 (2017). Article  CAS 

Google Scholar  * Kravina, A. G., Mahatthananchai, J. & Bode, J. W. Enantioselective, NHC-catalyzed annulations of trisubstituted enals and cyclic N-sulfonylimines via α,β-unsaturated

acyl azoliums. _Angew. Chem. Int. Ed._ 51, 9433–9436 (2012). Article  CAS  Google Scholar  * Cheng, J., Huang, Z. & Chi, Y. R. NHC organocatalytic formal LUMO activation of

α,β-unsaturated esters for reaction with enamides. _Angew. Chem. Int. Ed._ 52, 8592–8596 (2013). Article  CAS  Google Scholar  * Bera, S., Samanta, R. C., Daniliuc, C. G. & Studer, A.

Asymmetric synthesis of highly substituted β-lactones through oxidative carbene catalysis with LiCl as cooperative Lewis acid. _Angew. Chem. Int. Ed._ 53, 9622–9626 (2014). Article  CAS 

Google Scholar  * Bera, S., Daniliuc, C. G. & Studer, A. Enantioselective synthesis of substituted δ-lactones by cooperative oxidative N-heterocyclic carbene and Lewis acid aatalysis.

_Org. Lett._ 17, 4940–4943 (2015). Article  CAS  Google Scholar  * Liang, Z. Q., Wang, D. L., Zhang, H. M. & Ye, S. Enantioselective synthesis of bicyclic δ-lactones via N-heterocyclic

carbene-catalyzed cascade reaction. _Org. Lett._ 17, 5140–5143 (2015). Article  CAS  Google Scholar  * Chen, X.-Y. et al. Highly enantioselective kinetic resolution of Michael adducts

through N-heterocyclic carbene catalysis: an efficient asymmetric route to cyclohexenes. _Chem. Eur. J._ 24, 9735–9738 (2018). Article  CAS  Google Scholar  * Liu, Q., Chen, X.-Y.,

Puttreddy, R., Rissanen, K. & Enders, D. N-Heterocyclic carbene catalyzed quadruple domino reactions: asymmetric synthesis of cyclopenta[c]chromenones. _Angew. Chem. Int. Ed._ 57,

17100–17103 (2018). Article  CAS  Google Scholar  * Wang, J. et al. Carbene-catalyzed enantioselective addition of benzylic carbon to unsaturated acyl azolium for rapid synthesis of

pyrrolo[3,2-c]quinolones. _ACS Catal._ 8, 9859–9864 (2018). Article  CAS  Google Scholar  * Mukherjee, S., Ghosh, A., Marelli, U. K. & Biju, A. T. N-Heterocyclic carbene-catalyzed

Michael–Michael-lactonization cascade for the enantioselective synthesis of tricyclic δ-Lactones. _Org. Lett._ 20, 2952–2955 (2018). Article  CAS  Google Scholar  * Zhang, H.-R., Dong,

Z.-W., Yang, Y.-J., Wang, P.-L. & Hui, X.-P. N-Heterocyclic carbene-catalyzed stereoselective cascade reaction: synthesis of functionalized tetrahydroquinolines. _Org. Lett._ 15,

4750–4753 (2013). Article  CAS  Google Scholar  * Wu, X. et al. Enantioselective nucleophilic β-carbon atom amination of enals: carbene-catalyzed formal [3 + 2] reactions. _Angew. Chem. Int.

Ed._ 55, 12280–12284 (2016). Article  CAS  Google Scholar  * Wu, X. et al. Construction of fused pyrrolidines and β-lactones by carbene-catalyzed C–N, C–C, and C–O bond formations. _Angew.

Chem. Int. Ed._ 56, 4201–4205 (2017). Article  CAS  Google Scholar  * Fang, C., Lu, T., Zhu, J., Sun, K. & Du, D. Formal [3 + 4] annulation of α,β-unsaturated acyl azoliums: access to

enantioenriched N–H-free 1,5-benzothiazepines. _Org. Lett._ 19, 3470–3473 (2017). Article  CAS  Google Scholar  * Mukherjee, S., Shee, S., Poisson, T., Besset, T. & Biju, A. T.

Enantioselective N-heterocyclic carbene-catalyzed cascade reaction for the synthesis of pyrroloquinolines via N–H functionalization of indoles. _Org. Lett._ 20, 6998–7002 (2018). Article 

CAS  Google Scholar  * Samanta, R. C. et al. Nucleophilic addition of enols and enamines to α,β-unsaturated acyl azoliums: mechanistic studies. _Angew. Chem. Int. Ed._ 51, 5234–5238 (2012).

Article  CAS  Google Scholar  * Ta, L. & Sundén, H. Oxidative organocatalytic chemoselective N-acylation of heterocycles with aromatic and conjugated aldehydes. _Chem. Commun._ 54,

531–534 (2018). Article  CAS  Google Scholar  * Bera, S., Daniliuc, C. G. & Studer, A. Oxidative N-heterocyclic carbene catalyzed dearomatization of indoles to spirocyclic indolenines

with a quaternary carbon stereocenter. _Angew. Chem. Int. Ed._ 56, 7402–7406 (2017). Article  CAS  Google Scholar  * Kerr, M. S., Read de Alaniz, J. & Rovis, T. A highly enantioselective

catalytic intramolecular Stetter reaction. _J. Am. Chem. Soc._ 124, 10298–10299 (2002). Article  CAS  Google Scholar  * Kerr, M. S. & Rovis, T. Enantioselective synthesis of quaternary

stereocenters via a catalytic asymmetric Stetter reaction. _J. Am. Chem. Soc._ 126, 8876–8877 (2004). Article  CAS  Google Scholar  * Lv, H., Zhang, Y.-R., Huang, X.-L. & Ye, S.

Asymmetric dimerization of disubstituted ketenes catalyzed by N-heterocyclic carbenes. _Adv. Synth. Catal._ 350, 2715–2718 (2008). Article  CAS  Google Scholar  Download references

ACKNOWLEDGEMENTS This work was supported by NSFC (21871260, 21502192, 21402199), the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB20000000), Fujian Natural

Science Foundation (2018J05035), and China Postdoctoral Science Foundation (2018M630734). AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * State Key Laboratory of Structural Chemistry, and Key

Laboratory of Coal to Ethylene Glycol and Its Related Technology, Fujian Institute of Research on the Structure of Matter, Center for Excellence in Molecular Synthesis, University of Chinese

Academy of Sciences, 350100, Fuzhou, China Muhammad Anwar, Shuang Yang, Weici Xu, Saima Perveen, Xiangwen Kong, Syeda Tazeen Zehra & Xinqiang Fang * Key Laboratory of Synthetic

Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, 200032, Shanghai, China Shuang Yang & Xinqiang Fang * Orthopedics Department, Guangdong Provincial Hospital of

Traditional Chinese Medicine, 510120, Guangzhou, China Jinggong Liu Authors * Muhammad Anwar View author publications You can also search for this author inPubMed Google Scholar * Shuang

Yang View author publications You can also search for this author inPubMed Google Scholar * Weici Xu View author publications You can also search for this author inPubMed Google Scholar *

Jinggong Liu View author publications You can also search for this author inPubMed Google Scholar * Saima Perveen View author publications You can also search for this author inPubMed Google

Scholar * Xiangwen Kong View author publications You can also search for this author inPubMed Google Scholar * Syeda Tazeen Zehra View author publications You can also search for this

author inPubMed Google Scholar * Xinqiang Fang View author publications You can also search for this author inPubMed Google Scholar CONTRIBUTIONS X.F. designed the project. M.A. conducted

most of the experiments. S.P., X.K. and S.T.Z. conducted part of the experiments. X.F. wrote the manuscript. M.A. and S.Y. prepared the Supplementary Material. J.L. tested the single crystal

structures. W.X. and S.Y. contributed to discussions. CORRESPONDING AUTHOR Correspondence to Xinqiang Fang. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no competing

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http://creativecommons.org/licenses/by/4.0/. Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Anwar, M., Yang, S., Xu, W. _et al._ Carbene-catalyzed asymmetric Friedel–Crafts

alkylation-annulation sequence and rapid synthesis of indole-fused polycyclic alkaloids. _Commun Chem_ 2, 85 (2019). https://doi.org/10.1038/s42004-019-0188-2 Download citation * Received:

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