DOI: 10.3390/molecules29030599 ISSN: 1420-3049

2,5-Di-tert-butyl-2,5-diethylpyrrolidine-1-oxyls: Where Is a Reasonable Limit of Sterical Loading for Higher Resistance to Reduction?

Irina F. Zhurko, Sergey A. Dobrynin, Yurii I. Glazachev, Yuri V. Gatilov, Igor A. Kirilyuk
  • Chemistry (miscellaneous)
  • Analytical Chemistry
  • Organic Chemistry
  • Physical and Theoretical Chemistry
  • Molecular Medicine
  • Drug Discovery
  • Pharmaceutical Science

The pyrrolidine nitroxides with four bulky alkyl substituents adjacent to the N–O∙ group demonstrate very high resistance to reduction with biogenic antioxidants and enzymatic systems. This makes them valuable molecular tools for studying the structure and functions of biomolecules directly in a living cell and for functional EPR and NMR tomography in vivo. The first example of highly strained pyrrolidine nitroxides with both ethyl and tert-butyl groups at each of the α-carbon atoms of the nitroxide moiety with cis-configuration of the tert-butyl groups was prepared using a three-component domino reaction of tert-leucine and 2,2-dimethylpentan-3-one with dimethyl fumarate with subsequent conversion of the resulting strained pyrrolidine into 1-pyrroline-1-oxide and addition of EtLi. The nitroxide has demonstrated unexpectedly fast reduction with ascorbate, the rate constant k2 = (2.0 ± 0.1) × 10−3 M−1s−1. This effect was explained by destabilization of the planar nitroxide moiety due to repulsion with the two neighboring tert-butyl groups cis to each other.

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