Journal
ACS CATALYSIS
Volume 11, Issue 12, Pages 7489-7497Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acscatal.1c01589
Keywords
Vaska's complex; amide reduction; [3+2] cycloaddition; azomethine ylide; pyrrolidines; polycyclic amine; density functional calculations
Categories
Funding
- EPSRC Centre for Doctoral Training in Synthesis for Biology and Medicine [EP/L015838/1]
- AstraZeneca
- Diamond Light Source
- Defence Science and Technology Laboratory
- Evotec
- GlaxoSmithKline
- Janssen
- Novartis
- Pfizer
- Syngenta
- Takeda
- UCB
- Vertex
- Honjo International Scholarship Foundation
- Netherlands Organization for Scientific Research (NWO)
- SURF Cooperative
- EPSRC [EP/J013501/1] Funding Source: UKRI
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This study discusses an iridium-catalyzed method for the reductive generation of azomethine ylides and their use in pyrrolidine synthesis. The method allows for the efficient access to structurally complex pyrrolidine architectures through subsequent dipolar cycloaddition reactions with variously substituted electron-deficient alkenes. Density functional theory calculations reveal the control of unusual selectivities observed in certain cases by an intimate balance between asynchronicity and interaction energies of transition structures in the cycloaddition reactions.
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.
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