Indolylglycines Backbones in the Synthesis of Enantiopure 3,3‐Spiroindolenines, Indolyl Tetracyclic Hemiaminals, and 3‐Indolyl‐maleimides Frameworks

Abstract

This paper describes the synthesis of novel N‐substituted 3‐indolylglycines (3IGs), in high yields and optical purity via three‐component Mannich reaction (3CR) of indole and free glyoxylic acid in the presence of primary and secondary aliphatic amines. By using this efficient approach, a series of racemic 3‐indolylglycines (3IGs) as well as the optically pure (S)‐3‐indolylglycine ((S)‐3IG) in multigram synthesis using (R‐1‐phenylethylamine ((R)‐α‐PEA) as chiral pool were synthetized. In parallel investigations, 3IGs were used as the starting material for the highly stereoselective synthesis of spiroindolenines bearing three controlled contiguous stereogenic centers. Despite our expectations, the N‐chloroacetyl esters of 3IGs did not provide the expected spiroindolenine derivatives but led us to the discovery of a new methodology for the preparation of 3‐indolylmaleimides (3IMs); compounds known for their broad range of important biological and fluorescence activities.

New Advances in the Synthetic Application of Enantiomeric 1-Phenylethylamine (α-PEA): Privileged Chiral Inducer and Auxiliary

“…Another three-component Mannich-type synthesis was developed for the simple preparation of enantiomerically pure 3-indolylglycines ( Scheme 41 ). Despite the medium diastereoselectivity of the Mannich reaction (80/20 dr), the pure diastereomer was easily separated, and the selective N -debenzylation was performed with triethylammonium formate catalyzed by Pd/C, resulting in the enantiomerically pure ( S )-indolylglycine [ 64 ].…”

“…Three-component aromatic Betti-type reaction.Another three-component Mannich-type synthesis was developed for the simple preparation of enantiomerically pure 3-indolylglycines (Scheme 41). Despite the medium diastereoselectivity of the Mannich reaction (80/20 dr), the pure diastereomer was easily separated, and the selective N-debenzylation was performed with triethylammonium formate catalyzed by Pd/C, resulting in the enantiomerically pure (S)-indolylglycine[64].Molecules 2020, 25, x FOR PEER REVIEW 21 of 36Another three-component Mannich-type synthesis was developed for the simple preparation of enantiomerically pure 3-indolylglycines (Scheme 41). Despite the medium diastereoselectivity of the Mannich reaction (80/20 dr), the pure diastereomer was easily separated, and the selective Ndebenzylation was performed with triethylammonium formate catalyzed by Pd/C, resulting in the enantiomerically pure (S)-indolylglycine[64].Scheme 41.…”