Abstract
An 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 1 mol% 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-deficient 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.
Highlights
Saturated pyrrolidine heterocycles are prevalent in biologically active natural products and are among the 10 most common ring systems in small drug molecules (Scheme 1A).[1−4]new broad scope methods for their synthesis remain important
These dipoles can be prepared from the opening of an aziridine ring6i or more commonly from the activation of an imine/iminium ion species and are especially useful for the synthesis of pyrrolidines unsubstituted on the nitrogen atom.5c,6s Other methods exist, requiring the construction of finely tuned precursors.6aa Notwithstanding these many advances, to date, a general reductive strategy for azomethine ylide 1,3-dipole generation from tertiary amides and lactams enabling downstream access to desirable pyrrolidine structures remains unsolved.6af Toward this end and building on our program on reductive manipulation of amide functional groups,[7] we reasoned that iridium-catalyzed hydrosilylation of suitably functionalized tertiary amides and lactams could
Proline methyl ester benzoylamide derivative 1a was chosen as a model system to investigate the transformation, alongside oxazolidinone dipolarophile 2a, selected for its previous use in [3 + 2] cycloadditions and for its easy downstream derivatization.[8]
Summary
Saturated pyrrolidine heterocycles are prevalent in biologically active natural products and are among the 10 most common ring systems in small drug molecules (Scheme 1A).[1−4]. Proline methyl ester benzoylamide derivative 1a was chosen as a model system to investigate the transformation, alongside oxazolidinone dipolarophile 2a, selected for its previous use in [3 + 2] cycloadditions and for its easy downstream derivatization.[8] Using 1 mol % IrCl(CO)(PPh3)[2] (Vaska’s complex) and 2 equiv of tetramethyldisiloxane (TMDS) for partial amide reduction, plus additional triethylamine as a Brønsted base for the generation of the dipole, we were pleased to isolate the desired product 3a in a 50% yield as a single diastereoisomer, indicating the formation and subsequent stereoselective cycloaddition of the azomethine ylide (Scheme 2, entry 1). Using N(trimethylsilyl)methyl amides as substrates, and following standard conditions for Vaska’s complex-catalyzed hydrosilylation, with substoichiometric amounts of TMSCl as an additive to trigger the desilylation, we were pleased to observe [3 + 2] dipolar cycloaddition of unstabilized azomethine ylides taking place This approach is complementary to the one described above, as the resulting pyrrolidine ring of the cycloadduct bears no substituent a to the nitrogen atom.
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