One-Pot, Three-Component Assembly of Indoloquinolines: Total Synthesis of Isocryptolepine

Abstract

Indolo[3,2-c]quinolones have been efficiently synthesized via an acid-mediated, one-pot, three-component condensation of arylhydrazines, o-aminoacetophenones, and triazines or nitriles. The synthetic application of this method is showcased by the concise synthesis of isocryptolepine alkaloid and a series of its synthetic analogues with demonstrated cancer cell antiproliferative activities.

A Concise Synthesis of Isocryptolepine by C–C Cross-Coupling Followed by a Tandem C–H Activation and C–N Bond Formation

“…Generally, the reported syntheses of isocryptolepine utilise the following key synthetic strategies: palladium-catalysed coupling reactions, 7 Fischer indole cyclisation, 8 photochemical cyclisation, 9 Pictet-Spengler cyclisation, 10 aza-Wittig reaction 11 and a recently reported one-pot approach. 12 Herein, we present an efficient and convenient synthesis of isocryptolepine from readily available starting materials and show that the two key steps in the synthesis can also be performed in one pot. Our retrosynthetic analysis of isocryptolepine (1), which is shown in Scheme 1, was inspired by the seminal work of Buchwald and co-workers, 13 and by a recent publication by Bjørsvik and Elumalai, who reported a protocol that gave access to carbazole frameworks upon intramolecular C-N bond formation via C-H activation.…”

Synthesis of Benzofuroquinolines via Phosphine‐Free Direct Arylation of 4‐Phenoxyquinolines in Air

“…The crude mixture was purified by column chromatography over silica gel using DCM/EtOAc (7:3) as eluent to yield the product as an off‐white solid (0.030 g, 83 %); m.p. > 250 °C (lit . 340–341 °C).…”

“…Synthesis of 11 H ‐Indolo[3,2‐ c ]quinoline (4): N ‐(2‐bromophenyl)quinolin‐4‐amine 3 (1 equiv. ), Pd(OAc) 2 (5 mol‐%), PCy 3 · HBF 4 (10 mol‐%) and caesium carbonate (2 equiv.)…”

Synthesis and characterization of terbium doped TiO2 nanoparticles and their use as recyclable and reusable heterogeneous catalyst for efficient and environmentally sustainable synthesis of spiroannulated indolo[3,2‐c]quinolines‐ mimetic scaffolds of isocryptolepine

“…[1] The indoloquinoline heterocyclic system is an important privileged scaffold frequently encountered in natural products isolated from medicinal plants used in traditional medicines. [2,3] Indoloquinoline alkaloids [4] including isocryptolepine (I), cryptolepine (II), 11-isopropylcryptolepine (III), neocryptolepine (IV), 11-methylneocryptolepine (V) and isoneocryptolepine (VI), are isolated from the roots of West African plant, Cryptolepis Sanguinolenta (Figure 1). [5] Among them, isocryptolepine has been reported to exhibit promising activity, [6,7] such as antimalarial, [8,9] antiproliferative [9] and anticancer activity.…”

“…[29] The substitution of Ti +4 with Tb +3 and the formation of Ti-O-Tb bonds as a result of doping of Terbium with TiO 2 NPs increase the catalytic efficiency and facilitates the reaction to provide the products in excellent yields as compared with provided with TiO 2 NPs. [30] Indolo [3,2-c]quinolines have been synthesized by palladium-catalyzed isocyanide insertion reactions, [31] aza-Wittig reactions of isocyanates with iminophosphoranes, [32] gold catalyzed cyclizations of acyclic alkynes [33] and recently by PPA catalyzed sequential reaction of indoles with carboxylic acids/nitriles or with 1,3,5-triazine involving Fisher and Vilsmeier reactions [3] and by reaction of 2-(2-bromoaryl)-1H-indoles with aldehydes and aqueous ammonia. [6] But most of the synthetic strategies reported in the literature for the synthesis of indolo [3,2-c]quinolines have some limitations because of involving multi-step synthesis with isolation and purification of intermediates, use of expensive catalysts and volatile solvents, lower product yields, longer reaction time, or harsh reaction conditions.…”