A General Pyrrolidine Synthesis via Iridium-Catalyzed Reductive Azomethine Ylide Generation from Tertiary Amides & Lactams

A new iridium-catalyzed reductive generation of both stabilized and unstabilized azomethine ylides and their application to functionalized pyrrolidine synthesis via [3+2] dipolar cycloaddition reactions is described. Proceeding under mild reaction conditions from both amide and lactam precursors possessing a suitably positioned electron-withdrawing or a trimethylsilyl group, using catalytic Vaska’s complex [IrCl(CO)(PPh3)2] and tetramethyldisiloxane (TMDS) as a terminal reductant, a broad range of (un)stabilized azomethine ylides were accessible. Subsequent, regio- and diastereoselective, inter- and intramolecular, dipolar cycloaddition reactions with variously substituted electron-poor alkenes enabled ready and efficient access to structurally complex pyrrolidine architectures. Density functional theory (DFT) calculations of the dipolar cycloaddition reactions uncovered an intimate balance between asynchronicity and interaction energies of transition structures which ultimately control the unusual selectivities observed in certain cases.

A General Pyrrolidine Synthesis via Iridium-Catalyzed Reductive Azomethine Ylide Generation from Tertiary Amides & Lactams

A new iridium-catalyzed reductive generation of both stabilized and unstabilized azomethine ylides and their application to functionalized pyrrolidine synthesis via [3+2] dipolar cycloaddition reactions is described. Proceeding under mild reaction conditions from both amide and lactam precursors possessing a suitably positioned electron-withdrawing or a trimethylsilyl group, using catalytic Vaska’s complex [IrCl(CO)(PPh3)2] and tetramethyldisiloxane (TMDS) as a terminal reductant, a broad range of (un)stabilized azomethine ylides were accessible. Subsequent, regio- and diastereoselective, inter- and intramolecular, dipolar cycloaddition reactions with variously substituted electron-poor alkenes enabled ready and efficient access to structurally complex pyrrolidine architectures. Density functional theory (DFT) calculations of the dipolar cycloaddition reactions uncovered an intimate balance between asynchronicity and interaction energies of transition structures which ultimately control the unusual selectivities observed in certain cases.

A General Pyrrolidine Synthesis via Iridium-Catalyzed Reductive Azomethine Ylide Generation from Tertiary Amides & Lactams

A new iridium-catalyzed reductive generation of both stabilized and unstabilized azomethine ylides and their application to functionalized pyrrolidine synthesis via [3+2] dipolar cycloaddition reactions is described. Proceeding under mild reaction conditions from both amide and lactam precursors possessing a suitably positioned electron-withdrawing or a trimethylsilyl group, using catalytic Vaska’s complex [IrCl(CO)(PPh3)2] and tetramethyldisiloxane (TMDS) as a terminal reductant, a broad range of (un)stabilized azomethine ylides were accessible. Subsequent, regio- and diastereoselective, inter- and intramolecular, dipolar cycloaddition reactions with variously substituted electron-poor alkenes enabled ready and efficient access to structurally complex pyrrolidine architectures. Density functional theory (DFT) calculations of the dipolar cycloaddition reactions uncovered an intimate balance between asynchronicity and interaction energies of transition structures which ultimately control the unusual selectivities observed in certain cases.

Design, Synthesis and In Vitro Mechanistic Investigation of Novel Hexacyclic Cage-Like Hybrid Heterocycles

Novel hexacyclic cage-like hybrid heterocycles have been synthesized in excellent yields employing a relatively less explored non-stabilized azomethine ylides derived from acenaphthenequinone and tyrosine with functionalized dipolarophiles using [3 + 2] cycloaddition strategy. The synthesized hexacyclic cage-like hybrid heterocycles were characterized by spectroscopic analysis. Following the physical characterization, these cage-like hybrid heterocycles were tested for their biological activity by means of different cancer (A549 and Jurkat cells) and non-cancer (BRL-3A and PCS-130) in vitro cell culture systems. The results of the study under tested concentrations (up to 100 μM) indicated that these compounds are not affecting any viability to the cell growth of non-cancer cells, while providing significant anticancer activity against both of the cancer cells. Further analysis of in-depth mechanistic study for the cell death indicated that these compounds are exhibiting late apoptosis or early necrosis pathway to the cells where it is operated by the induction of caspases.

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

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.