Asymmetric Synthesis of Tetracyclic Pyrroloindolines and Constrained Tryptamines by a Switchable Cascade Reaction

Abstract

The interrupted Fischer indole synthesis of arylhydrazines and biocatalytically generated chiral bicyclic imines selectively affords either tetracyclic pyrroloindolines or tricyclic tryptamine analogues depending on the reaction conditions.Wedemonstrate that the reaction is compatible with av ariety of functional groups.T he products are obtained in high optical purity and in reasonable to good yield. We present ap lausible reaction mechanism to explain the observed reaction outcome depending on the stoichiometry of the acid mediator.T od emonstrate the synthetic utility of our method, pharmaceutically relevant examples of both product classes were synthesized in highly efficient reaction sequences,including ap henserine analogue as ap otential cholinesterase inhibitor and constrained tryptamine derivatives as selective inhibitors of the 5-HT 6 serotonin receptor and the TRPV1 ion channel.

Switchable [3+2] and [4+2] Heteroannulation of Primary Propargylamines with Isonitriles to Imidazoles and 1,6‐Dihydropyrimidines: Catalyst Loading Enabled Reaction Divergence

“…With lower loading of TfOH (0.1 equiv), 16 a was isolated in 73 % yield together with a trace amount of 17 a (entry 9). Increasing the loading of TfOH to 0.5 equiv, 1,6‐dihydropyrimidine 17 a was formed in 78 % isolated yield (entry 13) . It is worth noting that both Lavilla and Hulme have previously demonstrated that acid‐catalyzed isocyanide insertion into the NH bond, while effective with anilines, failed with aliphatic amines.…”

Pyrroloindoles as Therapeutically Invaluable Agents: A Review on their Diverse Synthetic Methodologies

“…The synthesis was initiated by the reaction of ethynyl indoloxazolidone and carboxylic acids using TsCl as an activation agent in presence of synergistic catalysis of CuÀ L1 complex and BTMtype Lewis base B1 to afford the desired products. [56] Karin Pchalek et al reported the formation of pyrroloindole derivatives (84) from indole-2-carbaldehydes (82). The method involved the reaction of 4,6-dimethoxyindole-2-carbaldehyde with triphenylphosphine and DMAD (83) which afforded pyrrolo[1,2-a]indoles in high yields as highly fluorescent yellow compounds (Scheme 24).…”

“…Under the optimized reaction conditions, TMSOTf afforded the desired product of yield 74 %. [82] Ping Li et al have developed the palladium catalyzed one pot synthesis of pyrroloindolines (212) from the reaction of thioacetamides with 3H-indol-3-ones (211) generated in situ from 2-alkynyl arylazides (209) (Scheme 51). Palladium, referred to as Lindlar's palladium, plays a role in formation of CÀ C bond, thus used in various reactions pathways.…”

“…Among them, Lewis acids exhibited improved yields, with TMSOTf proving to be superior to BF 3 OEt 2 . Under the optimized reaction conditions, TMSOTf afforded the desired product of yield 74 % [82] …”

Chemo‐Enzymatic One‐Pot Two‐Step Functionalization of 1,2,3,4‐Tetrahydroisoquinolines by Monoamine Oxidase‐Ugi‐Joullié Reaction Sequence

“…[21] Beside deracemization, the functionalization of the α-position of cyclic amines was the focus of many research projects including the industrial synthesis of a key intermediate en route to boceprevir. [22] MAOs have been used to generate precursors for multi-component reactions (Ugi-Joullié-and Ugi-Smiles-reactions) [23][24][25][26] and Fischer indole synthesis with aryl-hydrazines [27] in consecutive steps, interrupted by the isolation of the imine intermediate. In contrast, one-pot functionalization of cyclic amines via imines was achieved with cyanide [22,28] and pyrroles [29] as nucleophiles, as well as via gold-catalyzed alkynylation [30] and metal-or enzyme-catalyzed oxidation to the corresponding lactams (Figure 1).…”