Stereoselective Intermolecular Radical Cascade Reactions ... - PubMed

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Abstract

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.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1

Fig. 1. Syntheses of trans -fused hexahydrocarbazoles…

Fig. 1. Syntheses of trans -fused hexahydrocarbazoles and 1,3,5-trisubstituted cyclohexanes through stereoselective intermolecular radical cascade…

Fig. 1. Syntheses of trans-fused hexahydrocarbazoles and 1,3,5-trisubstituted cyclohexanes through stereoselective intermolecular radical cascade reaction under visible light photocatalysis. A Natural products containing a hexahydrocarbazole ring. B Previous works. C Hypothesis. D Reaction of Boc-Trp and diethylethylidenemalonate. E Reaction of Boc-Trp and ɑ-CF3-alkene. F This work. PC photocatalyst, Trp tryptophan.
Fig. 2

Fig. 2. The substrate scope.

a Reaction…

Fig. 2. The substrate scope.

a Reaction conditions: 1 mol% of Ir[dF(CF 3 )ppy] 2 …
Fig. 2. The substrate scope. a Reaction conditions: 1 mol% of Ir[dF(CF3)ppy]2(dtbbpy)PF6, 0.3 mmol of Na2CO3, 0.15 mmol of 1, 0.1 mmol of 2 in DMA (2.0 mL) for 12 h under blue LEDs irradiation at 30 °C. Isolated yields of major diastereomers are reported. The dr was determined by crude 1H NMR analysis. b The combined yield of both diastereomers. c The reaction was conducted at 40 °C.
Fig. 3

Fig. 3. Diastereoselective syntheses of chiral trans …

Fig. 3. Diastereoselective syntheses of chiral trans -fused hexahydrocarbazoles with five contiguous stereogenic centers.

a Reaction…
Fig. 3. Diastereoselective syntheses of chiral trans-fused hexahydrocarbazoles with five contiguous stereogenic centers. a Reaction conditions: 1 mol% of Ir[dF(CF3)ppy]2(dtbbpy)PF6, 0.1 mmol of 2, 0.15 mmol of 7 and 0.3 mmol of Na2CO3 in DMA (2.0 mL) for 12 h under blue LEDs irradiation at 30 °C. Combined isolated yields of the diastereomers are reported. b The dr was determined by crude 1H NMR analysis. c Enantiomeric excess (ee) of the major diastereomer was reported. The ee value was determined by HPLC analysis on a chiral stationary phase.
Fig. 4

Fig. 4. Syntheses of tetrahydrocarbazoles.

a Reaction…

Fig. 4. Syntheses of tetrahydrocarbazoles.

a Reaction conditions: 1 mol% of Ir[dF(CF 3 )ppy] 2 …
Fig. 4. Syntheses of tetrahydrocarbazoles. a Reaction conditions: 1 mol% of Ir[dF(CF3)ppy]2(dtbbpy)PF6, 0.15 mmol of 1, 0.1 mmol of 2, and 0.3 mmol of Na2CO3 in DMA (2.0 mL) for 6 h under blue LEDs irradiation at 30 °C. Isolated yields of compound 9 are reported. b The dr was determined by crude 1H NMR analysis. c The ratio was determined by crude 1H NMR analysis.
Fig. 5

Fig. 5. Stern–Volmer quenching experiments of * …

Fig. 5. Stern–Volmer quenching experiments of * Ir[dF(CF 3 )ppy] 2 (dtbbpy)PF 6 with compounds…

A solution…

Fig. 5. Stern–Volmer quenching experiments of *Ir[dF(CF3)ppy]2(dtbbpy)PF6 with compounds 1a, 2a, and K1. A solution of Ir[dF(CF3)ppy]2(dtbbpy)PF6 in N,N-dimethylacetamide was excited at 380 nm and the emission intensity at 481 nm was observed.
Fig. 6

Fig. 6. Mechanistic experiments.

A Reaction of…

Fig. 6. Mechanistic experiments.

A Reaction of enantiopure ( R )- N -Boc-tryptophan ( R …
Fig. 6. Mechanistic experiments. A Reaction of enantiopure (R)-N-Boc-tryptophan (R)-1a with substrate 2a. B Deuterium experiment. C Reaction of N-methyl substituted acrylamide 2' with substrate 1a. D Control experiments.
Fig. 7

Fig. 7. A plausible reaction pathway.

A…

Fig. 7. A plausible reaction pathway.

A plausible reaction pathway for the formation of products …

Fig. 7. A plausible reaction pathway. A plausible reaction pathway for the formation of products 3a and 9a was proposed.
Fig. 8

Fig. 8. Application to the syntheses of…

Fig. 8. Application to the syntheses of 1,3,5-trisubstituted cyclohexanes.

a Reaction conditions: 1 mol% of…
Fig. 8. Application to the syntheses of 1,3,5-trisubstituted cyclohexanes. a Reaction conditions: 1 mol% of Ir[dF(CF3)ppy]2(dtbbpy)PF6, 0.1 mmol of 2, 0.15 mmol of 10 and 0.3 mmol of K2CO3 in DMA (2.0 mL) for 12 h under blue LEDs irradiation at 30 °C. Combined isolated yields of both diastereomers are reported. The dr was determined by crude 1H NMR analysis. b The reaction was performed with 2 mol% of Ir[dF(CF3)ppy]2(dtbbpy)PF6, and 2.0 equiv of 10 h for 18 h.
Fig. 9

Fig. 9. Synthetic application.

A 1.0 mmol-scale…

Fig. 9. Synthetic application.

A 1.0 mmol-scale reaction. B Synthetic transformations of 3a . C …
Fig. 9. Synthetic application. A 1.0 mmol-scale reaction. B Synthetic transformations of 3a. C Transformation of 11d. Reaction conditions: [a] (i) CF3COOH, CH2Cl2, 0 °C → rt; (ii) 2,4,6-triphenylpyrylium tetrafluoroborate, EtOH, 140 °C, 68% yield over 2 steps, >20:1 dr. [b] (i) Bis(catecholato)diboron, DMA, blue LEDs, 30 °C; (ii) Et3N, pinacol, DMA, 30 °C, 57% yield over 2 steps, >20:1 dr. [c] Methyl 2-[(phenylsulfonyl)methyl]acrylate, diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate, DMA, blue LEDs, 40 °C, 74% yield, 1.8:1 dr. [d] Methyl acrylate, diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate, DMA, blue LEDs, 40 °C, 50% yield, 3:1 dr. [e] (i) CF3COOH, CH2Cl2, 0 °C → rt; (ii) NaOH, MeOH/H2O, 100 °C, 69% yield over 2 steps, >20:1 dr.
All figures (9) See this image and copyright information in PMC

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