Rapid Cascade Synthesis of Poly-Heterocyclic Architectures from Indigo

Abstract

The base-induced propargylation of the dye indigo results in the rapid and unprecedented one-pot synthesis of highly functionalized representatives of the pyrazino[1,2-a:4,3-a′]diindole, pyrido[1,2-a:3,4-b′]diindole and benzo [b]indolo [1,2-h]naphthyridine heterocyclic systems, with the last two reflecting the core skeleton of the anticancer/antiplasmodial marine natural products fascaplysin and homofascaplysins and a ring Bhomologue, respectively. The polycyclic compounds 6-8, whose structures were confirmed through singlecrystal X-ray crystallographic analysis, arise from sequential inter/intramolecular substitution-addition reactions, and in some cases, ring rearrangement reactions. Preliminary studies on controlling the reaction path selectivity, and the potential reaction mechanisms, are also described. Initial biological activity studies with these new heterocyclic derivatives indicated promising in vitro antiplasmodial activity as well as good anticancer activity. The chemistry described is new for the indigo moiety and cascade reactions from this readily available and cheap starting material should be more broadly applicable in the synthesis of additional new heterocyclic systems difficult to access by other means. Preliminary studies on controlling the reaction path selectivity, and the potential reaction mechanisms, are also described. Initial biological activity studies with these new heterocyclic derivatives indicated promising in vitro anti-plasmodial activity as well as good anti-cancer activity. The chemistry described is new for the indigo moiety and cascade reactions from this readily available and cheap starting material should be applicable more broadly in the synthesis of additional new heterocyclic systems difficult to access by other means.

A cascade synthetic route to new bioactive spiroindolinepyrido[1,2-a]indolediones from indirubin

“…This initial reaction indicated that indirubin is significantly less reactive than the corresponding indigo. The use of substituted allyl bromides continued the trend with the pink mono allylated derivatives (Type B) being produced in yields from 20-49% in 16 hour reactions (entries [1][2][3][4], with an extended 20 hour reaction required to produce the N'-cinnamylindirubin 13 (21%).…”

“…This surprising result revealed a new arena in the previously unreported chemistry of indigo, allowing access to unique, relatively complex heterocycles in one pot. [1][2][3] The structural isomers of indigo 1, indirubin 2 and isoindigo 3 ( Figure 2), are known, 4 but knowledge of their chemistry is still limited. Indirubin is the most well studied due to the reported biological activity of derivatives, known to suppress the metastatic ability of human head and neck cancer cells 5 and to reduce the invasion of glioma cells both in vitro and in vivo.…”

Novel base-initiated cascade reactions of hemiindigos to produce dipolar γ-carbolines and indole-fused pentacycles

“…Recently, S. Yamabe showed that the related benzilic type rearrangement of a-diketones involving a carbanion [1,2] migration 55 included both alkyl and aryl groups as migrating units. Surprisingly, in alkaline conditions, we managed to obtain the target g-carbolines and to avoid the formation of the rearrangement byproducts 4, 5 as the major products.…”

“…[29][30][31] Our research in the eld of cascade reactions began with the discovery of a cationic domino reaction of hemiindigos that afford pentacyclic 3-hydroxyindolenines related to indolenine alkaloids in a diastereoselective fashion under the NMR experiment conditions. 32 This is the rst example of the acid-catalyzed domino reaction that involved homocoupling of hemiindigos 1 followed by a reverse Wagner-Meerwein [1,2] type rearrangement of the intermediate 2-spiropseudoindoxyls. 32 We also described novel cationic domino reactions of hemiindigos 1 in the absence or in the presence of an external nucleophile.…”

An easy synthetic protocol for imidazo‐1,4‐oxazines and evaluation of their toxicities

“…The design and synthesis of desired and tolerable methods to attain complex molecules from appropriate starting materials are still challenging work for lots of scientific areas such as modern synthetic and medicinal chemistry. The methods which include synthesis of compounds containing nitrogen and oxygen are of growing importance due to the importance of some biological activities [1a-c]. Some important heterocyclic compounds such as antituberculosis agent 1 (PA‐824), antibiotic, sold under the trade name Levaquin 2 , and acortatarin A 3 which is an inhibitor for the production of reactive oxygen species (ROS) include oxazine cores (Figure ).…”