Catalytic Asymmetric Reactions of 4-Substituted Indoles with Nitroethene: A Direct Entry to Ergot Alkaloid Structures

Abstract

A domino Friedel-Crafts/nitro-Michael reaction between 4-substituted indoles and nitroethene is presented. The reaction is catalyzed by BINOL-derived phosphoric acid catalysts, and delivers the corresponding 3,4-ring-fused indoles with very good results in terms of yields and diastereo- and enantioselectivities. The tricyclic benzo[cd]indole products bear a nitro group at the right position to serve as precursors of ergot alkaloids, as demonstrated by the formal synthesis of 6,7-secoagroclavine from one of the adducts. DFT calculations suggest that the outcome of the reaction stems from the preferential evolution of a key nitronic acid intermediate through a nucleophilic addition pathway, rather than to the expected "quenching" through protonation.

Keywords: Brønsted acids; asymmetric synthesis; indoles; nitroalkenes; organocatalysis.

Figure 1

Ergot alkaloid structures and domino reaction of indoles 1 with nitroethene 2. a) Some naturally occurring and semisynthetic ergot alkaloid derivatives (the 1,3,4,5‐tetrahydrobenzo[cd]indole framework is highlighted); b) Friedel–Crafts (FC)‐triggered nitro‐Michael reaction en route to ergot alkaloids; c) preliminary results: thioureas do not promote the reaction. Phosphoric acids can catalyze the reaction, by two competing pathways (nitro‐Michael vs. intermediate “quench”).

Figure 2

Free energy profile for the formation of products 3 d and 3′ d from the reaction between (E)‐4‐(1H‐indol‐4‐yl)but‐3‐en‐2‐one (1 d) and nitroethene 2. See the Supporting Information for optimized ball‐and‐stick structures.

Scheme 1

Representative screening results.

Scheme 2

Reaction with substrate 1 n and elaboration of product 3 n.