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

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.

Photoredox catalysis enabling decarboxylative radical cyclization of γ,γ-dimethylallyltryptophan (DMAT) derivatives: formal synthesis of 6,7-secoagroclavine

“…We began our investigation of the proposed decarboxylative cyclization by exposing the N -Boc derivative 8 , Ir catalyst, and K 2 HPO 4 in DMF to a 34 W blue LED lamp at room temperature ( Table 1 ) [ 93 – 97 ]. To our delight, cyclization was observed under these preliminary conditions, albeit in low yield (35% yield) and low regioselectivity (1:1) ( Table 1 , entry 1).…”

Phosphine Catalyzed Michael-Type Additions: The Synthesis of Glutamic Acid Derivatives from Arylidene-α-amino Esters

“…Considering this last approach, α-substituted glutamates have been mainly obtained via the Michael-type additions of glycine derivatives (glycine templates) onto the corresponding α,β-unsaturated reagents. This reliable strategy employs N -arylidene-α-amino acid esters [ 14 , 15 , 16 ] or tert -butyl N -benzylidieneamino glycinate [ 17 , 18 , 19 , 20 , 21 , 22 ] ( Scheme 1 a) and even activated N -arylideneaminomalonates [ 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 ] ( Scheme 1 b) as starting materials. In all cases, phase transfer catalysis (PTC) conditions or the employment of organic superbases are the most common trends to complete the reaction.…”

Kinetics of H· Transfer from CpCr(CO)3H to Various Enamides: Application to Construction of Pyrrolidines

“…α-Amino radicals are useful in the construction of natural products and drugs that contain pyrrolidines. − Their synthesis has been reviewed by Dixon and co-workers, who list three “classical” single-electron approaches: (a) oxidation and proton loss from an amine, − (b) oxidation and CO 2 loss from an amino carboxylate, , and (c) reduction and CO 2 loss from an amino ester , (Figure A). They note the recent popularity of imine reduction, often by photoredox methods (Figure B). , …”