Access to Indole-Annulated Medium-Sized Lactams through Protonation/Deuteration-Induced Ring-Opening of Spiroindolines

Abstract

A protocol has been developed to access indoleannulated eight-and nine-membered lactams through protonationinduced ring-opening of spiroindolines, which are dearomative Heck products of tetrahydro-β-carbolines or hexahydroazepino [3,4-b]indoles. Brønsted acids and nucleophiles were explored and compared in the transformation. A combination of deuterated hydrochloride and deuterated methanol enables deuterative ring-opening of spiroindolines to afford medium-sized lactam diastereoisomers with a deuterium content ratio around 1:1. ■ INTRODUCTIONIndole-annulated medium-sized nitrogen-containing heterocyclic rings are core structures embedded in bioactive natural alkaloids, including balasubramide, 1 deoxyisoaustamide, 2 okaramine, 3 lundurine A−D, 4 and vinblastine. 5 Generally, the construction of medium-sized compounds has been challenging in organic synthesis due to unfavorable entropy and transannular interactions. 6 It is impressive that significant strategies including cycloaddition, 7 cycloisomerization, 8 and ring expansion 9 have been invented for the generation of eightand nine-membered nitrogen-containing heterocycles.Recently, we have developed a diastereoselective protocol to prepare indole-annulated eight-membered lactams through light-driven alkylative ring-opening of spiroindolines, a type of dearomative Heck product of easily available β-carbolines. 10 DFT calculations and mechanistic experiments support that a cationic C−C fragmentation should be favorable rather than a homolytic C−C fragmentation, in which a tertiary cation intermediate might be involved (Scheme 1a). 11 Because a tertiary carbon cation could be formed regioselectively through direct protonation of an alkene, we envisioned an alternative to indole-annulated medium-sized lactams by protonationinduced ring-opening of the spiroindolines (Scheme 1b).The key issues of the transformation include the choice of Brønsted acids, the tolerance of the indole ring, and the nucleophile to trap the iminium intermediate. Furthermore, if this can be realized, a deuterative ring-opening would be feasible by employing deuterated acids and deuterated nucleophiles, which provides an unprecedented protocol to prepare deuterated indole-containing medium-sized hetero-