N,N-Diethyl-(R)-[3-(2-aminopropyl)-1H-indol-7-yloxy]acetamide:  Its Process Chemistry Ranging from Enantiocontrolled Construction of the Chiral Amine Side Chain to Regioselective Functionalization of the Aromatic Starting Materials

To access N,N-diethyl-(R)-[3-(2-aminopropyl)-1H-indol-7-yloxy]acetamide (3), a key intermediate for AJ-9677 (2) acting as a potent and selective agonist for β3-adrenergic receptors, the (R)-configured 2-aminopropyl side chain of 3 is elaborated in three distinct ways: (1) chiral pool synthesis featuring the C-3 acylation of 7-benzyloxy-1H-indole (4a) with N-(9-fluorenylmethoxycarbonyl)-d-alanyl chloride (6); (2) resolution of (±)-3-(2-aminopropyl)-7-benzyloxy-1H-indole (8) via diastereomeric salt formation with O,O-di-p-toluoyl l-(2R,3R)-tartaric acid (21) to obtain (R)-8; and (3) crystallization-induced dynamic resolution (CIDR) by entrainment which transforms N,N-diethyl-(±)-[3-(N-phthaloyl-2-aminopropanoyl)-1H-indol-7-yloxy]acetamide (26) entirely into (R)-26. As regards 4a and 7-hydroxy-1H-indole (4b), the molecular scaffolds on which the above-mentioned chiral maneuvers are being executed, their synthetic approaches are explored threefold: (1) indole-ring construction on 3-benzyloxy-2-nitrotoluene [28; prepared from m-cresol (31)] by the modified Leimgruber−Batcho method; (2) direct microbial hydroxylation of indole (34) at its C-7 position; and (3) indirect hydroxylation of indoline (35) at its C-7 position via a K2S2O8-mediated Baeyer−Villiger oxidation of the tricyclic product arising from the intramolecular Friedel−Crafts acylation of N-succinyl indoline (36).