Synthesis of pyrrolizidines and indolizidines by multicomponent 1,3-dipolar cycloaddition of azomethine ylides

Abstract

Different multicomponent 1,3-dipolar cycloadditions (1,3-DC) of cyclic α-amino acid derivatives with aldehydes and dipolarophiles have been described as efficient and simple methodologies for the synthesis of the pyrrolidine unit of pyrrolizidines and indolizidines. When free cyclic α-amino acids are used, a thermal promoted decarboxylative process generates in situ the corresponding non-stabilized azomethine ylides, which afforded the corresponding pyrrolizidines and indolizidines with a hydrogen in the bicyclic units. This methodology has been employed to the synthesis of complex systems including spiro derivatives when ketones are used as carbonyl component. In addition, working with cyclic α-amino acid derived esters, the three-component 1,3-DC takes place under milder reaction conditions giving the corresponding pyrrolizidines and indolizidines with an alkoxycarbonyl group in the bridge adjacent carbon to the nitrogen. This methodology can be carried out by a double consecutive or stepwise 1,3-DC to provide pyrrolizidines via the precursor prolinates. The conformation of the azomethine ylide controls the endo/exo diastereoselectivity of the 1,3-DC.

N-tert-Butanesulfinyl imines in the asymmetric synthesis of nitrogen-containing heterocycles

“…In most cases, the pyrrolidine ring is formed from an amine with a hydrocarbon chain that also carries a functional group at the appropriate distance that allows the cyclization process to take place. In the case of substituted pyrrolidines, the stereoselective synthesis is especially interesting, highlighting the 1,3-dipolar cycloaddition reactions with azomethine ylides as an example of transformation that take place with great stereocontrol, and allow the synthesis of polyfunctionalized pyrrolidines in a single reaction step [91,92]. On the other hand, natural amino acids proline and hydroxyproline are functionalized pyrrolidines that have found great application in organic synthesis as chiral organocatalysts in stereoselective processes [93,94].…”

Substrate‐Controlled Regioselectivity Switch in a Three‐Component 1,3‐Dipolar Cycloaddition Reaction to Access 3,3′‐Pyrrolidinyl‐Spirooxindoles Derivatives

“…Multicomponent reactions (MCRs) are a valuable tool to provide higher synthetic diversity and structural complexity of important pharmaceutics in the field of synthetic chemistry [7] . This MCRs are an efficient, fast and sustainable approach to synthesize multifunctional and complex chemical structures, when compared to step‐by‐step approaches [8] . Moreover, isatin has been widely used as a starting material to construct the spirooxindole compounds via multicomponent 1,3‐dipolar cycloaddition reactions [9] .…”

Collagen-Coated Superparamagnetic Iron Oxide Nanoparticles as a Sustainable Catalyst for Spirooxindole Synthesis

“…Very useful in combinatorial chemistry, MCRs make it possible to constitute chemical libraries for high throughput screening in the pharmaceutical industry. Several evocative tags are commonly involved in MCRs such as the atomic economy, easy to implement, using very mild reaction conditions, and without recourse to toxic metals, these reactions represent a de nite step forward to ideal synthesis 29,30 .…”

“…Heterocyclic compounds represent more than 90% of the active ingredients possessing a wide range of applications in pharmaceutical industry, veterinary medicine and phytochemistry 31 . Indoles, oxindoles, and spirooxindoles are important heterocyclic compounds, and ubiquitous motifs in naturally and unnaturally occurring biologically active pharmaceutical ingredients 292, 30,314 . Some biologically active indoles, oxindoles and spirooxindoles are presented in gure 1.…”