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

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.Indole-fused polycyclic alkaloids are present in numerous bioactive natural products. Here an enantioselective N-heterocyclic carbene-catalysed Friedel–Crafts alkylation/annulation cascade using acyl azolium salts as the electrophile provides access to these products with high stereoselectivity.

I ndole-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 economy [5][6][7] . Therefore, developing a protocol that can rapidly construct these polycyclic indole units is still highly desirable.
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 A 60-62 with Cs 2 CO 3 in CH 2 Cl 2 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 ( 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-C 6 H 4 -substituted enal, affording 3t in 67% yield with  All ee values were determined via HPLC analysis on a chiral stationary phase 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 singlediastereoisomers, and the absolute configuration of 3b was determined by the single crystal X-ray structure analysis (Fig. 4).
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 Nmethyl 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 Cs 2 CO 3 and Na 2 CO 3 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-d 1 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-d 3 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 ratedeterming 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 3position 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.

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.