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

ARTICLE https://doi.org/10.1038/s42004-019-0188-2 OPEN 1234567890():,; Carbene-catalyzed asymmetric Friedel–Crafts alkylation-annulation sequence and rapid synthesis of indole-fused polycyclic alkaloids Muhammad Anwar1, Shuang Yang1,2, Weici Xu1, Jinggong Liu3, Saima Perveen1, Xiangwen Kong1, Syeda Tazeen Zehra1 & Xinqiang Fang 1,2 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. 1 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. 2 Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, 200032 Shanghai, China. 3 Orthopedics Department, Guangdong Provincial Hospital of Traditional Chinese Medicine, 510120 Guangzhou, China. Correspondence and requests for materials should be addressed to X.F. (email: ) COMMUNICATIONS CHEMISTRY | (2019)2:85 | https://doi.org/10.1038/s42004-019-0188-2 | www.nature.com/commschem 1 ARTICLE COMMUNICATIONS CHEMISTRY | https://doi.org/10.1038/s42004-019-0188-2 I economy5–7. 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 purpose8–12. Carbonyl activation of enones by Lewis/ Brønsted acids and activation of enals via iminiums are prevalent activation modes (Fig. 2a)8–12. However, exploiting new 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)1–4. However, multiple steps have been used to make the key skeletons of these molecules, thus resulting in relatively low efficiency and atom O OH Cl HO O H Cl N H CN H H H H MeS NH N H H N N N N H H H Paxilline NC H H H Fischerindole L Yuehchukene Pergolide H Hapalindole G Fig. 1 Selected indole-fused natural products and pharmaceuticals a X + N H R1 N O R2 O or R2 Many reports and reviews N H R1 R1 Activated enone Iminium R2 = H, aryl, alkyl, CO2R, etc O R1 N + N H N R1 O N Products N (not achieved) N N H α,β -unsaturated α,β-unsaturated acyl azolium N α,β-unsaturated -unsaturated acyl azolium: Challenges of using α,β 106 lower than iminiums) Much lower electrophilicity (103 −10 Catalyst recycling N-acylation Aza-Michael addition b O O H R3 O R1 R1 N O H H NH N O or R1 R1 N N 21 examples > 20:1 dr 91–99% ee O O H R3 R1 N H Side reactions suppressed Mechanistic insights disclosed H Two indole alkaloids formed Derivatizations conducted 22 examples > 20:1 dr NH 85–99% ee Fig. 2 Activation of enone/enals in indole Friedel–Crafts alkylation. a Activation modes of enones or enals in asymmetric indole Friedel–Crafts alkylation. b This work: NHC-catalyzed indole Friedel–Crafts alkylation and annulation 2 COMMUNICATIONS CHEMISTRY | (2019)2:85 | https://doi.org/10.1038/s42004-019-0188-2 | www.nature.com/commschem ARTICLE COMMUNICATIONS CHEMISTRY | https://doi.org/10.1038/s42004-019-0188-2 O O O Ph Ph Ph H 2a 1a O N A, Ar = Mes B, Ar = Ph C, Ar = C6F5 D, Ar = 4-BrC6H4 E, Ar = 2,4,6-Cl3C6H2 Ph Bn H 3a > 20:1 dr NH O O N BF4 N Ar Oxidant, base solvent, 4 Å M.S. O BF4 N O Cat. NH N H N N iPr Mes F BF4 N Ph N BF4 Ph t Bu t Bu N t N I Ph Bu C6F5 N Ph t N G TMSO N N H BF4 Ph Bu O Oxidant Fig. 3 Model system used for reaction optimization. Conditions used for optimization of the catalyst, base, solvent, and temperature can be found in Table 1 activation modes of enones/enals holds great importance to further promote the influence of this strategy. On the other side, Nheterocyclic carbene (NHC)-catalyzed reactions13–25 mediated by α,β-unsaturated acyl azoliums19,26–29 have attracted increasing research interests owing to the great value in chiral cyclic molecule synthesis. Annulations of a series of carbon-based nucleophiles30–51 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 disclosed52–56. Despite these elegant reports, using α,βunsaturated 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 addition52–54,56 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 A60–62 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 catalysts60–62 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 th (...truncated)