This study was supported by the National Research Foundation of Korea (NRF) grants funded by the Korean Government (NRF-2021R1A2C1012984 and NRF-2021R1A5A6002803 (Center for New Directions in Organic Synthesis)).
2,2′-Biindolyl natural products have a long history of applications owing to their unique structural features and biological activities. In this Account, we describe the recent progress achieved by our research group in the total syntheses of several 2,2′-biindolyl natural products using the cyanide-catalyzed imino-Stetter reaction as the key reaction to construct the 2,2′-biindolyl scaffold from 2-aminocinnamic acid derivatives and indole-2-carboxaldehydes. The development of a novel protocol to access 2,2′-bisindole-3-acetic acid derivatives via the cyanide-catalyzed imino-Stetter reaction and its application to the total syntheses of class I (arcyriaflavin A), class II (iheyamines A and B), and class III (calothrixin B) 2,2′-biindolyl natural products are discussed.
1. Introduction
2. Synthesis of 2,2′-Biindolyl Compounds via Cyanide-Catalyzed Imino-Stetter Reaction
4 Several protocols have been developed to access 2,2′-biindolyl derivatives. For selected examples, see ref. 8–10.
In this Account, ‘the symmetry of 2,2′-biindolyl compounds’ was determined by the substituent pattern on each phenyl ring of the indole scaffold regardless of the substituent
5a on the pyrrole ring.
For a proposed biosynthetic pathway of calothrixins A and B, see:
6a
Yamabuki A,
Fujinawa H,
Choshi T,
Tohyama H,
Matsumoto K,
Ohmura K,
Nobuhiro J,
Hibino S.
Tetrahedron Lett. 2006; 47: 5859
2,2′-Biindolyl scaffold could be constructed via the base-catalyzed cyclization of oxalamides bearing o-toluidine derivatives. However, this protocol generally requires harsh reaction conditions, resulting in a limited substrate scope. For selected examples, see:
For selected examples of the construction of the 2,2′-biindolyl scaffold via Fisher indolization of 2-acetylindole derivatives and aryl hydrazines, see:
24 Compound 23 possesses axial chirality about the C-2–C-2′ bond owing to the presence of different protecting groups in each indole scaffold. Four peaks were observed in the chiral HPLC chromatogram. The retention times of the major diastereomer of 23 were 40.0 and 58.2 min, while those of the minor diastereomer of 23 were 48.4 and 76.6 min. The enantiomer of the major diastereomer with the second retention time (the third peak observed in the HPLC chromatogram) and that of the minor diastereomer with the first retention time (the second peak observed in the HPLC chromatogram) have the same stereochemical configuration at the α-position of the azepinone scaffold, which was confirmed using HPLC analysis after converting 23 into 19 by removing the Boc groups in 23.
25a
Scharnagel D,
Goller J,
Deibl N,
Milius W,
Breuning M.
Angew. Chem. Int. Ed. 2018; 57: 2432
26 A significant loss of enantiopurity was observed during the isolation of aldehyde 25. Therefore, we decided to use aldehyde 25 for aldimine formation without isolation.
27a
Lipshutz BH,
Hackmann C.
J. Org. Chem. 1994; 59: 7437
