Stereoselective intermolecular radical cascade reactions of tryptophans or ɤ-alkenyl-α-amino acids with acrylamides via photoredox catalysis

The radical cascade reaction is considered as one of the most powerful methods to build molecular complexity. However, highly stereoselective intermolecular radical cascade reactions that can produce complex cyclic compounds bearing multiple stereocenters via visible-light-induced photocatalysis have been challenging yet desirable. 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. The trans-fused hexahydrocarbazoles with up to five stereocenters including two quaternary ones can be accessed in up to 82% yield, >20/1 diastereoselectivity, and 96% ee. Interestingly, the tetrahydrocarbazoles are favorably formed when the reaction is performed under air. Moreover, by simply switching the starting material from tryptophans to ɤ-alkenyl substituted α-amino acids, this protocol can be further applied to the stereoselective syntheses of 1,3,5-trisubstituted cyclohexanes which are otherwise challenging to access. Preliminary mechanistic studies suggest that the reaction goes through radical addition cascade and radical-polar crossover processes.

I n the pharmaceutical industry, the growing demand for complex three-dimensional cyclic compounds urges the synthetic chemists to develop novel and efficient strategies to construct these motifs 1,2 . Radical cascade reactions are considered as one of the most powerful methods to meet this demand [3][4][5][6] . This protocol, which allows the rapid syntheses of valuable complex cyclic molecules, has been widely applied in the total syntheses of natural products [7][8][9] . However, many radical transformations involving alkyl radical species usually requires the use of organic halides as substrates, the addition of toxic stannanes as the halogen or hydrogen atom transfer agents, and the use of unstable initiators 10,11 . In recent years, photocatalysis using visible light has emerged as a promising strategy for the development of novel radical reactions due to its high efficiency and convenience in the generation of various reactive radical species under mild and environmentally friendly conditions [12][13][14][15][16][17][18][19] . Specifically, the visible-light-induced radical cascade reactions enable the facile construction of diverse cyclic compounds under sustainable conditions 3,20,21 . 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 via visible-light-induced photocatalysis.
Tryptophan is a commercially available, non-toxic, abundant, and naturally occurring α-amino acid. Accordingly, we questioned whether this readily available material could be directly used to synthesize the trans-fused hexahydrocarbazole through a one-step visible-light-induced photocatalytic radical cascade reaction (Fig. 1C). In practice, tryptophan was often used as an α-amino alkyl radical precursor in radical addition reactions via visiblelight-induced photocatalysis [51][52][53][54][55][56][57][58] . In pioneer work, MacMillan and coworkers reported an elegant radical Michael addition reaction of N-Boc-tryptophan and diethylethylidenemalonate via photocatalysis (Fig. 1D) 54 . In 2016, Zhou and coworkers described an interesting photocatalytic decarboxylative/defluorinative reaction of N-Boc-tryptophan and α-trifluoromethyl alkenes (Fig. 1E) 56 . 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, Fig. 1F). The trans-fused hexahydrocarbazoles with up to five stereocenters including two quaternary ones could be accessed in up to 82% yield, >20/1 diastereoselectivity, and 96% ee. Intriguingly, this protocol could further be applied to the stereoselective syntheses of 1,3,5- trisubstituted cyclohexanes, which are otherwise challenging to access in a single operation, by simply switching the starting material from tryptophans 1 to ɤ-alkenyl substituted amino acids 10 (eq 4, Fig. 1F).

Results
Reaction optimization. Our studies were initiated with an exploration of reaction conditions for the intermolecular coupling of commercially available N-(tert-butoxycarbonyl)tryptophan (1a) and N-phenyl-2-(trifluoromethyl)acrylamide (2a) ( Table 1). After an extensive investigation of reaction conditions, it was found that the desired radical cascade cyclization product trans-fused hexahydro-1H-carbazole 3a was obtained in 75% yield and >20:1 dr when the reaction was performed with 1 mol% of Ir[dF(CF 3 )ppy] 2 (dtbbpy)PF 6 as the photocatalyst, 3 equiv of Na 2 CO 3 as the base and blue LEDs as the light source (entry 1, for the experimental setup, see Supplementary Fig. 1). Notably, 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 under these photocatalytic conditions, which demonstrated the unique selectivity of the current reaction. The reaction could also proceed when the organic dye 4-CzIPN was used as the photocatalyst (entry 2). However, the use of a ruthenium-based photocatalyst led to low yield of the desired product (entry 3). The reaction also proceeded smoothly when different inorganic bases such as NaHCO 3 and K 2 CO 3 were used (entries [4][5]. When the reaction was performed in the absence of base, the desired product was obtained with a significantly lower yield (entry 6). Control experiments demonstrated that the photocatalyst and light were indispensable for the product formation (entry 7). Interestingly, when the reaction was performed under air, 4% of the desired product was observed along with 61% of the tetrahydro-1H-carbazole 9a (entry 8, yields were determined by crude 1 H NMR analysis. For details, see Fig. 4). Evaluation of the substrate scope. 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 (Fig. 2). Reactions of N-aryl-2-(trifluoromethyl)acrylamides 2 containing either electrondonating or electron-withdrawing groups on the aromatic ring (R 4 ) attached to amide moiety all gave the corresponding products in moderate to good yields and good to excellent diastereoselectivities (3a − 3j). In addition, the tryptophan derivatives 1 containing either electron-donating or electron-withdrawing groups on the phenyl ring of the indole moiety (R 1 ) were probed. The reactions occurred smoothly, affording the corresponding transfused hexahydrocarbazoles 3 in moderate to good yields and moderate to excellent diastereoselectivities (3k-3v). Moreover, substrates 1 containing different substituents on the nitrogen atom (R 2 ) of the amino acid moiety were also tested. It was found that the carbamates, simple amides, and sulfonamide were all tolerated under these reaction conditions, affording the corresponding cyclization products in moderate to good yields and good to excellent diastereoselectivities (3w-3aa). Furthermore, reactions of ɑ, ɑ-disubstituted ɑ-amino acids also occurred, providing the trans-fused hexahydrocarbazoles 3ab-3ac with two quaternary carbon centers in moderate yields. Finally, the present method was applied to the late-stage functionalization of the derivatives of drug molecules, providing easy access to two hexahydrocarbazolecontaining complex molecules (3ad-3ae) in moderate yields and excellent diastereoselectivities. The structure and relative configuration of both diastereomers of the hexahydrocarbazole products were assigned by X-ray crystallographic analyses of compounds 3k and 3ab (major diastereomers, see Supplementary Figs. 8 and 9), and compounds 3k' and 3ab' (minor diastereomers, see Supplementary Figs. 10 and 11) respectively. Pleasingly, the present method was able to be applied to the diastereoselective syntheses of chiral trans-fused hexahydrocarbazoles with five contiguous stereogenic centers (Fig. 3).  Reactions of chiral β-aryl-substituted tryptophan derivatives 7 containing either electron-withdrawing or electron-donating groups on the aromatic ring (R 1 ) attached to β-carbon of the ɑamino acid moiety all gave the corresponding chiral trans-fused hexahydrocarbazoles bearing five contiguous stereocenters (8a-8f). In addition, reaction of the β-alkyl-substituted ɑ-amino acid also occurred smoothly, affording the desired product 8g in moderate yield and excellent diastereoselectivity. Notably, the enantiomeric purity of the starting material 6, which could be easily prepared via a simple Ag-catalyzed enantioselective reaction of glycine derivatives 5 with sulfonylindoles 4 59 , was well-preserved under these photocatalytic conditions (8a-8g). The structure and absolute configuration of the major diastereomers of the hexahydrocarbazole products were assigned by an X-ray crystallographic analysis of compound 8a (Supplementary Fig. 12). The absolute configuration was determined as (1 S, 3 S, 4 R, 5 S, 6 S).
Interestingly, the reaction also proceeded when it was performed under air, affording tetrahydro-1H-carbazole 9a favorably (9a:3a = 14:1) with moderate yield and excellent diastereoselectivity (Fig. 4, for the experimental setup, see Supplementary Fig. 2). Several substituted tryptophan derivatives 1 and N-aryl-2-(trifluoromethyl)acrylamides 2 were tested to establish the generality of the process. Reactions of tryptophan derivatives 1 and N-aryl-2-(trifluoromethyl)acrylamides 2 containing either electron-donating or electron-withdrawing groups on the aromatic ring (R 1 or R 2 ) attached to the indole or amide moiety all led to the tetrahydro-1H-carbazoles 9 favorably in moderate yields and excellent diastereoselectivities (9b-9f). The structure and relative configuration of the tetrahydrocarbazole products were assigned by an X-ray crystallographic analysis of compound 9a (see Supplementary Fig. 13).
Mechanistic studies. To probe the reaction pathway, preliminary mechanistic studies were carried out (Figs. 5 and 6). It was found that the excited photocatalyst * Ir[dF(CF 3 )ppy] 2 (dtbbpy)PF 6 could be quenched by acrylamide 2a, N-Boc-tryptophan 1a, and its sodium salt K1 respectively according to the Stern-Volmer luminescence quenching studies (Fig. 5, for experimental details, see Supplementary Fig. 7). However, the reductive quenching of * Ir[dF(CF 3 )ppy] 2 (dtbbpy)PF 6 by either N-Boc-tryptophan 1a or its sodium salt K1 was more efficient than the oxidative quenching of the excited photocatalyst by substrate 2a, which indicates the former process is possibly the initiation step of the photoredox catalytic cycle (for the cyclic voltammetry measurement experiments of compounds 1a, 2a, and K1, see the Supplementary Figs. 3-6). In addition, when the enantiopure (R)-N-Boc-tryptophan (R)-1a was utilized under the reaction conditions, the racemic product 3a was obtained (Fig. 6A). These results suggest that the α-aminoalkyl radical is formed via photoinduced decarboxylation. Furthermore, 93% of deuterium incorporation at the C3-position of the hexahydrocarbazole product was observed when D 2 O was added to the reaction mixture (Fig. 6B). These results suggest that the carbon anion in the benzylic position of indoline moiety is plausibly generated via radical-polar crossover 60,61 . Interestingly, when the N-methyl substituted acrylamide 2' was used as a substrate for the reaction, the competitive radical addition/β-fluoride elimination product 3' was obtained instead of the hexahydrocarbazole 56 , which indicates that the N-H bond of the amide moiety is very crucial for this unique radical cascade cyclization reaction (Fig. 6C). The plausible hydrogen bonding effect between the amide N-H bond and the CF 3 moiety might benefit the intramolecular cyclization. Moreover, in order to figure out whether the tetrahydrocarbazole 9a was formed via oxidation of trans-hexahydrocarbazole 3a, two control experiments were performed. Either low conversion or no reaction was observed when this transformation was carried out using the same conditions as shown in Fig. 4 or the conditions without photocatalyst (Fig. 6D). These results suggest that benzylic radical species I-3 might be involved as an intermediate during the oxidation process (for details, see Fig. 7) 62,63 .
Based on the above experimental observations, a plausible reaction pathway was proposed, as shown in Fig. 7. Firstly, the αaminoalkyl 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  Rational expansion of the method. To further test the generality of the current method, this radical cascade cyclization strategy was applied to the synthesis of 1,3,5-trisubstituted cyclohexanes (Fig. 8). To our delight, 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 the photocatalytic conditions (11a-11h). Notably, the 1,3,5-trisubstituted cyclohexane with two quaternary carbon stereogenic centers (11h) could also be accessed via this one-step radical cascade cyclization reaction. 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. The structure and relative configuration of both diastereomers of the 1,3,5-trisubstituted cyclohexane products were assigned by X-ray crystallographic analyses of the derivative of compound 11a (major diastereomer, see Supplementary Fig. 14) and compound 11d' (minor diastereomer, see Supplementary Fig. 15) respectively.
Synthetic applications. Finally, in order to demonstrate the synthetic utility of the present method, a 1.0 mmol-scale reaction and several transformations of the multi-substituted trans-fused   hexahydrocarbazoles and cyclohexanes were carried out. Under the photocatalytic conditions, 1.0 mmol-scale reaction of substrates 1a and 2a occurred smoothly, providing product 3a in excellent diastereoselectivity and moderate yield (Fig. 9A). In addition, these radical cascade cyclization products are readily transformed to other valuable building blocks. Treatment of the trans-fused hexahydrocarbazole 3a with 2,2,2-trifluoroacetic acid and then 2,4,6-triphenylpyrylium tetrafluoroborate furnished Katritzky pyridinium salt K2 in excellent diastereoselectivity and moderate yield (path a, Fig. 9B) [64][65][66] . This pyridinium salt could be further transformed to other structural motifs bearing a trans-fused hexahydrocarbazole core through the mild, catalystfree visible-light-induced deaminative functionalization reactions (paths b-d, Fig. 9B) 67,68 . Notably, the trans-fused hexahydrocarbazole product 12, bearing a Bpin group that could be readily applied in the following functionalization, could be easily accessed through this mild photoinduced deaminative borylation in excellent diastereoselectivity and moderate yield (path b, Fig. 9B) 67 . Interestingly, the bridged lactam-containing product 15 could be prepared in excellent diastereoselectivity and  , Fig. 9C).

Discussion
In this work, we have achieved the stereoselective intermolecular radical cascade reactions of readily available tryptophans and acrylamides via visible-light-induced photoredox catalysis, thus providing easy access to an array of trans-fused hexahydrocarbazoles with up to five stereogenic centers including two quaternary ones in up to 82% yield, >20/1 diastereoselectivity, and 96% ee. The reaction is distinguished by its broad substrate scope, its power in the rapid generation of molecular complexity from simple starting materials, environmentally friendly reaction conditions, and application to the late-stage functionalization. In addition, the reaction can be diverted to the syntheses of tetrahydrocarbazoles when it is performed under air. Moreover, this radical cascade protocol can further be applied to the stereoselective syntheses of 1,3,5-trisubstituted cyclohexanes by simply switching the starting material from tryptophans to ɤ-alkenyl substituted α-amino acids. This strategy allows the rapid preparation of trans-fused hexahydrocarbazoles and cyclohexanes with multiple stereocenters from simple amino acids and acrylamides. Further studies on the reaction mechanism and the development of other stereoselective intermolecular radical cascade reactions via visible-light-induced photoredox catalysis are ongoing in our laboratory.

Methods
Representative procedure for the synthesis of trans-fused hexahydrocarbazole 3a. To a Young Schlenk tube (10 mL) were added Ir[dF(CF 3 ) ppy] 2 (dtbbpy)PF 6 (1.1 mg, 0.001 mmol, 1 mol%), 1a (45.7 mg, 0.15 mmol, 1.5 equiv), 2a (21.5 mg, 0.1 mmol, 1.0 equiv), Na 2 CO 3 (31.8 mg, 0.3 mmol, 3.0 equiv), and N,N-dimethylacetamide (DMA, 2.0 mL). Subsequently, the reaction mixture was degassed through several freeze-pump-thaw cycles until no bubbles were released. The reaction mixture was stirred under argon at 30°C, and irradiated by a 5 W blue LED lamp (λ = 450-460 nm, the tube was placed at~2 cm away from the light source). After 12 h, the reaction mixture was passed through a short pad of celite and washed with ethyl acetate. The solvents were evaporated under reduced pressure to give the crude mixture, which was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate = 40:1 to 15:1, silica gel was soaked with a solution of petroleum ether and triethylamine (1000/1, v/v) before use) to afford the title compound 3a as a white solid (35.7 mg, 75% yield).

Data availability
The X-ray crystallographic coordinates for structures reported in this article have been deposited at the Cambridge Crystallographic Data Centre (CCDC), under deposition number CCDC 2108643 (3k), 2108649 (3ab), 2108644 (3k'), 2108650 (3ab'), 2108651 (8a), 2108652 (9a), 2108653 (the derivative of compound 11a), and 2108655 (11d'). The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via http://www.ccdc.cam.ac.uk/data_request/cif. Complete experimental procedures and compound characterization data are available in the Supplementary Information or from the corresponding author upon request.