The radical cascade reaction is considered as an important method to generate complex three-dimensional cyclic compounds. However, many radical cascade reactions often require the use of hazardous reagents. In recent years, photocatalysis using visible light has emerged as a promising strategy for the development of novel radical reactions under very mild and environmentally friendly conditions. Specifically, this strategy enables the facile construction of diverse cyclic compounds in a mild and sustainable fashion. Despite these advances, plenty of radical cascade cyclization reactions still rely on either the carefully designed precursors or the intramolecular design, which tempers the appeal of their further synthetic applications. Therefore, it is highly desirable to develop stereoselective intermolecular radical cascade reactions that could produce complex cyclic compounds from readily available starting materials under visible light photocatalysis.

As a pivotal structure unit, hexahydrocarbazole motif is widely occurred in many biologically active polycyclic indoline natural products (Figure 1A). Consequently, great efforts have been devoted to the preparation of functionalized hexahydrocarbazoles. Among those, direct catalytic dearomatization reaction of indole derivatives represents a straightforward and powerful strategy. The cis-fused hexahydrocarbazoles are usually obtained through the dearomatization of substituted or pre-functionalized indole derivatives. In contrast, the syntheses of the trans-fused hexahydrocarbazoles are less explored. To date, methods to uncover the highly stereoselective synthesis of this structural motif have been limited to UV-light-induced intramolecular photocyclization of reactive enamine precursors as well as Pd-catalyzed intramolecular C–H activation/cyclization reaction (Figure 1B).

Figure 1. Syntheses of trans-fused hexahydrocarbazoles through stereoselective intermolecular radical cascade reaction.

The commercially available, non-toxic, and abundant tryptophan is often used as an α-amino alkyl radical precursor in radical addition reactions via visible-light-induced photocatalysis. Nevertheless, to the best of our knowledge, there is no general method for the generation of trans-fused hexahydrocarbazoles bearing multiple stereocenters through a one-step stereoselective radical cascade reaction of tryptophan via visible-light-induced photocatalysis. Herein, we report a facile and efficient synthesis of multi-substituted trans-fused hexahydrocarbazoles via a stereoselective intermolecular radical cascade reaction of readily available tryptophans and acrylamides enabled by visible-light induced photoredox catalysis (eq 3, Figure 1C). Intriguingly, this protocol could further be applied to the stereoselective syntheses of 1,3,5-trisubstituted cyclohexanes by simply switching the starting material from tryptophans 1 to ɤ-alkenyl substituted amino acids 10 (eq 4, Figure 1C).

After an extensive investigation of reaction conditions, it was found that the desired radical cascade cyclization product 3a was obtained in 75% yield, and >20:1 dr using conditions as shown in Figure 2. Interestingly, the probably competitive radical addition product 3-1, radical addition/β-fluoride elimination product 3-2, and nucleophilic addition/cyclization product 3-3 were not detected (Figure 2).

Figure 2. Optimal reaction conditions.

With the optimized reaction conditions in hand, various substituted tryptophan derivatives 1 and N-aryl-2-(trifluoromethyl)acrylamides 2 were tested to establish the generality of the process. We were pleased to realize that the reactions of various tryptophan derivatives 1 and N-aryl-2-(trifluoromethyl)acrylamides 2 afforded the desired products in moderate to good yields and good to excellent diastereoselectivities (Figure 3).

Figure 3. Syntheses of trans-fused hexahydrocarbazoles.

Pleasingly, the present method was able to be applied to the diastereoselective syntheses of chiral trans-fused hexahydrocarbazoles. Reactions of several chiral β-aryl-substituted or β-alkyl substituted of the ɑ-amino acid moiety all gave the corresponding chiral trans-fused hexahydrocarbazoles 8 bearing five contiguous stereocenters (Figure 4).

Figure 4. Diastereoselective syntheses of chiral trans-fused hexahydrocarbazoles with five contiguous stereogenic centers.

Interestingly, the reaction also proceeded when it was performed under air, affording tetrahydro-1H-carbazoles 9 favorably with moderate yield and excellent diastereoselectivity (Figure 5).

Figure 5. Syntheses of tetrahydrocarbazoles.

In addition, this radical cascade cyclization strategy could be applied to the synthesis of 1,3,5-trisubstituted cyclohexanes by simply switching the starting material from tryptophans 1 to the alkenyl substituted amino acids 10. Several 1,3,5-trisubstituted cyclohexanes bearing at least one quaternary carbon stereocenter were obtained in moderate yield and up to 3.5:1 dr under these photocatalytic conditions (Figure 6). This strategy provides a straightforward and efficient pathway for the construction of 1,3,5-trisubstituted cyclohexanes which are challenging to be synthesized in one step.

Figure 6. Application to the syntheses of 1,3,5-trisubstituted cyclohexanes.

Based on the mechanistic experiments, a plausible reaction pathway was proposed (Figure 7). Firstly, the α-amino alkyl radical I-1 generated by photoinduced decarboxylation adds to α,β-unsaturated amide 2a to form radical intermediate I-2. This tertiary alkyl radical intermediate would subsequently undergo a radical cyclization onto the indole ring to generate the tertiary benzylic radical intermediate I-3. Finally, the hexahydrocarbazole 3a is obtained via reduction of the benzylic radical intermediate I-3 by Ir(II) and subsequent protonation under inert atmosphere. Interestingly, when this benzylic radical intermediate I-3 is exposed to air under the reaction conditions, the tetrahydro-1H-carbazole 9a is formed favorably.

Figure 7. A plausible reaction pathway.

In summary, the development of these unique stereoselective intermolecular radical cascade reactions of tryptophans or ɤ-alkenyl-α-amino acids with acrylamides via photoredox catalysis was successfully achieved recently by our laboratory. Further investigations on the reaction mechanism and the development of other stereoselective intermolecular radical cascade reactions via visible-light-induced photoredox catalysis are underway.

More details on this work can be found here: “Stereoselective intermolecular radical cascade reactions of tryptophans or ɤ-alkenyl-α-amino acids with acrylamides via photoredox catalysis” in Nature Communications (DOI: 10.1038/s41467-022-29464-5).