The research group of Prof. Xiaoming Feng and associate Prof. Yangbin Liu at Shenzhen Bay Laboratory focuses on the development of strategies and methodologies to construct series of valuable organic compounds, including diverse sigmatropic rearrangements (review: Chem. Sci. 2022, 13, 12290) and visible-light-driven transformations (ACIE 2022, 61, e202203374). In this context, we note C3-prenylated and reverse-prenylated indoline scaffolds are frequently found in a variety of natural bioactive products, such as aszonalenin and flustramine, exhibiting a series of anticancer, antibacterial, and antifungal properties. Intrigued by their wide-ranging spectrum of biological activities, the construction of these dimethylallyl-related indoline derivatives has attracted intensive attention from synthetic chemists. In our recent paper published on Nature Communications, we demonstrated a visible-light-induced Giese radical dearomatization/Ireland-Claisen rearrangement, providing an alternative approach to accomplish the valuable prenylation and reverse-prenylation of electron-deficient indoles in good to excellent yields and diastereoselectivities.

    In living organisms, dimethylallyl pyrophosphate (DMAPP) and isopentenyl pyrophosphate (IPP) as the precursors are usually utilized via enzyme catalysis to selectively introduce prenyl and reverse-prenyl motifs into various biological primary and secondary metabolites (Figure 1a). For small molecule metabolites, C3-prenylated and reverse-prenylated indoline scaffolds are frequently found in a variety of natural bioactive products¹, such as aszonalenin and flustramine, exhibiting a series of anticancer, antibacterial, and antifungal properties (Figure 1b). Intrigued by their wide-ranging spectrum of biological activities, the construction of these dimethylallyl-related indoline derivatives has attracted intensive attention from synthetic chemists².

Figure 1. a, Enzyme-catalysed (reverse-)prenylation of complex molecules with isopentenyl pyrophosphate (IPP) or dimethylallyl pyrophosphate (DMAPP). b, Representative naturally occurring (reverse-)prenylated indoline products.

     In principle, catalytic dearomative prenylation of readily available indoles via allylic substituent reactions has been recognized as one of the most straightforward methods to access the dimethylallyl-related indolines in a single step^3-4 (Figure 2). However, these corresponding transformations usually depend on the use of electron-rich indoles via an intramolecular process, and the precious metals (Ir and Pd) are often necessary. By contrast, the electron-deficient indoles are rarely employed as nucleophiles in the realm of allylic alkylation reactions, owing to the mismatched electrical properties. It is challenging to achieve both intermolecular dearomatization and prenylation of electron-deficient indoles simultaneously⁵.

Figure 2. Previous work, transition metals-catalysed allylic substituent reactions of electron-rich indoles.

     Recently, photoredox-enabled Giese-type radical addition has been implemented to the dearomatization of electron-deficient indoles. In general, diverse radical precursors, such as tertiary amines, N-arylglycines, aliphatic carboxylic acids and aldehydes, are initialized by the excited photocatalysts, which undergo a radical nucleophilic-addition to the electron poor C2=C3 bond of indoles. The resulting dearomatized radicals are then reduced to give the corresponding anions, followed by a rapid protonation to deliver the hydrofunctionalized indoline derivatives^6-8 (Figure 3, top). Inspired by our continuing interest in sigmatropic rearrangements⁹, we envisage whether the incorporation of photoredox-enabled nucleophilic radical dearomatization of indoles and [3,3]-rearrangement (Ireland-Claisen type) could be developed to prepare the prenylated and reverse-prenylated indolines¹⁰ (Figure 3, bottom). When employing 1-(3,3-dimethylallyl) indole-3-carboxylates as electrophilic substrates and α-silylamines as nucleophilic radical precursors, the generated in situ carbanions can be captured by TMS⁺, leading to the formation of highly reactive silylketene acetals. Subsequent [3,3]-rearrangement takes place under mild conditions and gives the C3-reverse-prenylated and C2-aminoalkylated indoline derivatives. Similarly, only by adjusting the 1-(1,1-dimethylallyl) substituents on electrophilic indoles, the complementary C3-prenylated indoline derivatives are obtained with ease and efficiency. In addition, an array of natural products and pharmaceuticals containing an aminoalkyl group are selectively incorporated in indoline scaffolds, displaying good tolerance of diverse functional groups and excellent diastereoselectivity (>20:1 d.r.). The corresponding transformations of the secondary α-silylamines provide the biologically important lactam-fused indolines in one-pot synthesis. The preliminary bioactivity study reveals a potential anticancer property of these structurally appealing indolines.

Figure 3. This work, diastereoselective dearomative (reverse-)prenylation of electron-deficient indoles via photocatalytic tandem Giese radical addition/Ireland-Claisen rearrangement.

References

1. Tanner, M. E. Mechanistic studies on the indole prenyltransferases. Prod. Rep. 32, 88–101 (2015).
2. Hu, Y.-C., Min, X.-T., Ji, D.-W. & Chen, Q.-A. Catalytic prenylation and reverse prenylation of aromatics. Trends in Chemistry 4, 658–675 (2022).
3. Ruchti, J. & Carreira, E. M. Ir-catalyzed reverse prenylation of 3-substituted indoles: total synthesis of (+)-aszonalenin and (-)-brevicompanine B. Am. Chem. Soc. 136, 16756–16759 (2014).
4. Tu, H.-F., Zhang, X., Zheng, C., Zhu, M. & You. S.-L. Enantioselective dearomative prenylation of indole derivatives. Catal. 1, 601–608 (2018).
5. Cerveri, A. & Bandini, M. Recent advances in the catalytic functionalization of “electrophilic” indoles. J. Chem. 38, 287–294 (2020).
6. Cheng, Y.-Z., Huang, X.-L., Zhuang, W.-H., Zhao, Q.-R., Zhang, X., Mei, T. S. & You, S.-L. Intermolecular dearomatization of naphthalene derivatives by photoredox-catalyzed 1,2-hydroalkylation. Chem. Int. Ed. 59, 18062–18067 (2020).
7. Zhang, Y. , Ji, P., Guo, F., Zeng, F. X. & Wang, W. Photoredox asymmetric nucleophilic dearomatization of indoles with neutral radicals. ACS Catal. 11, 998–1007 (2021).
8. Varlet, T., Bouchet, D., Elslande, E. V. & Masson, G. Decatungstate-photocatalyzed dearomative hydroacylation of indoles: direct synthesis of 2-acylindolines. Eur. J. 28, e202201707 (2022).
9. Liu, Y. B., Liu, X. H. & Feng, X. M. Recent advances in metal-catalysed asymmetric sigmatropic rearrangements. Sci. 13, 12290–12308 (2022).
10. Kleinmans, R., Will, L. E., Schwarz, J. L. & Glorius, F. Photoredox-enabled 1,2-dialkylation of alpha-substituted acrylates via Ireland-Claisen rearrangement. Sci. 12, 2816–2822 (2021).