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.

Enantioselective Brønsted Acid Catalysis as a Tool for the Synthesis of Natural Products and Pharmaceuticals

“…The transformation is highly diastereoselective and delivers trans-tricyclic benzo[cd]indoles 19 in high yields and ee values up to 99 %. [19] On the other hand, the cis isomers can be easily obtained by epimerization of the NO 2 -substituted stereocenter with as olution of NaOH/MeOH. In principle, this equilibration, which is in favor of the cis isomers, allows for the use of the same catalytic system to access the whole set of diastereomers.…”

“…For instance, cascade reactions involving nitroethene 17 and indoles 18 bearing a Michael acceptor in position 4, are efficiently promoted by catalyst PA 1 (Scheme ). The transformation is highly diastereoselective and delivers trans ‐tricyclic benzo[ cd ]indoles 19 in high yields and ee values up to 99 % . On the other hand, the cis isomers can be easily obtained by epimerization of the NO 2 ‐substituted stereocenter with a solution of NaOH/MeOH.…”

A Tandem Asymmetric Friedel–Crafts Alkylation/Michael Addition: Synthesis of Novel Ergoline Derivatives

“…In 2015, Bernardi and co‐workers addressed this issue by developing an organocatalyzed asymmetric tandem Friedel‐Crafts (FC) alkylation/Michael addition to synthesize the tricyclic core of the ergoline skeleton from 4‐substituted indoles and nitroethene (Scheme a) , . Although they could install two contiguous chiral centres at the C 5 ‐ and C 6 ‐positions in excellent stereoselectivity, their method did not work to prepare products possessing C 4 substituents.…”

Application of a One‐Pot Friedel–Crafts Alkylation/Michael Addition Methodology to the Asymmetric Synthesis of Ergoline Derivatives

“…In 2015, Bernardi and co‐workers developed an organocatalysed tandem Friedel–Crafts alkylation/Michael addition to synthesise the tricyclic core of the ergoline scaffold from 4‐substituted indole derivatives and nitroethene (Scheme a) . This methodology allowed for the installation of two contiguous chiral centres at the C 5 ‐ and C 6 ‐positions, but not the C 4 ‐position.…”