Modular assembly of indole alkaloids enabled by multicomponent reaction

Abstract

Indole alkaloids are one of the largest alkaloid classes, proving valuable structural moiety in pharmaceuticals. Although methods for the synthesis of indole alkaloids are constantly explored, the direct single-step synthesis of these chemical entities with broad structural diversity remains a formidable challenge. Herein, we report a modular assembly of tetrahydrocarboline type of indole alkaloids from simple building blocks in a single step while showing broad compatibility with medicinally relevant functionality. In this protocol, the 2-alkylated or 3-alkylated indoles, formaldehyde, and amine hydrochlorides could undergo a one-pot reaction to deliver γ-tetrahydrocarbolines or β-tetrahydrocarbolines directly. A wide scope of these readily available starting materials is applicable in this process, and numerous structural divergent tetrahydrocarbolines could be achieved rapidly. The control reaction and deuterium-labelling reaction are conducted to probe the mechanism. And mechanistically, this multicomponent reaction relies on a multiple alkylamination cascade wherein an unusual C(sp³)-C(sp³) connection was involved in this process. This method could render rapid access to pharmaceutically interesting compounds, greatly enlarge the indole alkaloid library and accelerate the lead compound optimization thus facilitating drug discovery.

Fig. 1. Modular assembly of indole alkaloids through multicomponent reaction.

a Representative approved drugs with the structure of tetrahydrocarboline type of indole alkaloids. b Conventional synthetic approaches to tetrahydrocarboline type of indole alkaloids. c Modular assembly of tetrahydrocarboline type of indole alkaloids delineated in this work.

Fig. 2. Scope for the multicomponent synthesis of γ-tetrahydrocarboline type of indole alkaloids.

Conditions: 1 (0.2 mmol), 2 (1.0 mmol), 3 (0.4 mmol), DMF (1.5 mL), at 60 °C for 3 h. Isolated yields are given. Phth pathalimide, PMB para-methoxybenzyl, Boc tert-butyl carbonate. ^aCH₃CN (1.5 mL) was used as solvent, TsOH (0.1 mmol) was added as an additive and the reaction was conducted at 80 °C.

Fig. 3. Scope for the multicomponent synthesis of β-tetrahydrocarboline type of indole alkaloids.

Conditions: 1 (0.2 mmol), 2 (1.0 mmol), 3 (0.4 mmol), CH₃CN (1.5 mL), at 80 °C for 8 h. Isolated yields are given. Phth pathalimide, Boc tert-butyl carbonate. ^aTsOH (0.1 mmol) was added as an additive and the reaction was conducted at 60 °C.

Fig. 4. Applications to the concise synthesis of market drugs and drug-like molecules.

MCR multicomponent reaction, PCP para-cyanophenyl.

Fig. 5. Mechanistic studies for synthesis of γ-tetrahydrocarboline.

a Deuterium-labeling and stepwise control reaction. b Cross-over reaction. c Kinetic isotope effect experiments. d Proposed mechanism.

Fig. 6. Mechanistic studies for synthesis of β-tetrahydrocarboline.

a Deuterium-labeling and stepwise control reaction. b Cross-over reaction. c Kinetic isotope effect experiments. d Proposed mechanism.