Synthesis of 1-azaspiro[4.4]nonan-1-oxyls via intramolecular 1,3-dipolar cycloaddition

Khoroshunova, Yulia V.; Morozov, Denis A.; Taratayko, Andrey I.; Gladkikh, Polina D.; Glazachev, Yuri I.; Kirilyuk, Igor A.

doi:10.3762/bjoc.15.200

Cited by 6 publications

(11 citation statements)

References 26 publications

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“…To avoid overoxidation to oxoammonium cations with possible affection of the hydroxymethyl groups (cf. [42,43]), the amines were treated with ca. one equivalent of the oxidant.…”

Section: Resultsmentioning

confidence: 99%

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

Zhurko,

Dobrynin,

Glazachev

et al. 2024

Molecules

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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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“…To avoid overoxidation to oxoammonium cations with possible affection of the hydroxymethyl groups (cf. [42,43]), the amines were treated with ca. one equivalent of the oxidant.…”

Section: Resultsmentioning

confidence: 99%

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

Zhurko,

Dobrynin,

Glazachev

et al. 2024

Molecules

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“…1,3-dipolar cycloaddition, isoxazolidine ring opening and oxidation [27,30]. The literature protocol implies multi-step synthesis with low overall yield (ca.…”

Section: Synthesismentioning

confidence: 99%

“…This parameter is very important for distance measurement using Saturation Recovery (SR) method, another pulsed EPR technique widely used in structural biology [2,21]. The nitroxide 1 was prepared from 3,4-di-tert-butoxypyrroline 1-oxide [31] via repetitive sequence of procedures: pent-4-en-1-ylmagnesium bromide addition, intramolecular The nitroxide 1 was prepared from 3,4-di-tert-butoxypyrroline 1-oxide [31] via repetitive sequence of procedures: pent-4-en-1-ylmagnesium bromide addition, intramolecular 1,3dipolar cycloaddition, isoxazolidine ring opening and oxidation [27,30]. The literature protocol implies multi-step synthesis with low overall yield (ca.…”

Section: Introductionmentioning

confidence: 99%

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Synthesis and Properties of (1R(S),5R(S),7R(S),8R(S))-1,8-Bis(hydroxymethyl)-6-azadispiro[4.1.4.2]tridecane-6-oxyl: Reduction-Resistant Spin Labels with High Spin Relaxation Times

Khoroshunova

Morozov

Kuznetsov

et al. 2023

IJMS

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Site-directed spin labeling followed by investigation using Electron Paramagnetic Resonance spectroscopy is a rapidly expanding powerful biophysical technique to study structure, local dynamics and functions of biomolecules using pulsed EPR techniques and nitroxides are the most widely used spin labels. Modern trends of this method include measurements directly inside a living cell, as well as measurements without deep freezing (below 70 K), which provide information that is more consistent with the behavior of the molecules under study in natural conditions. Such studies require nitroxides, which are resistant to the action of biogenic reductants and have high spin relaxation (dephasing) times, Tm. (1R(S),5R(S),7R(S),8R(S))-1,8-bis(hydroxymethyl)-6-azadispiro[4.1.4.2]tridecane-6-oxyl is a unique nitroxide that combines these features. We have developed a convenient method for the synthesis of this radical and studied the ways of its functionalization. Promising spin labels have been obtained, the parameters of their spin relaxation T1 and Tm have been measured, and the kinetics of reduction with ascorbate have been studied.

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“…Later, the same researchers suggested that the presence of electron-withdrawing tert -butoxy groups at positions 3 and 4 of the pyrrolidine ring of 221 can strongly affect the rate of nitroxide reduction; therefore, the removal of these groups should cause a further decrease in the reduction rate of the corresponding nitroxide. In this regard, they developed a method for the synthesis of SNRs of C 1 -symmetric racemic 3,4-unsubstituted pyrrolidine nitroxides 236a–c with only one spiro (2-hydroxymethyl) cyclopentane moiety ( Scheme 41 ) [ 151 ]. Before the step of oxidation of the secondary amino group to a radical in this sequence, acyl protection of the primary alcohol group ( 237 → 238 ) is carried out.…”

Section: 25-dihydropyrrole (3-pyrroline)- and Pyrrolidine (Proxylmentioning

confidence: 99%

Spirocyclic Nitroxides as Versatile Tools in Modern Natural Sciences: From Synthesis to Applications. Part I. Old and New Synthetic Approaches to Spirocyclic Nitroxyl Radicals

Zaytseva

Mazhukin

2021

Molecules

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Spirocyclic nitroxyl radicals (SNRs) are stable paramagnetics bearing spiro-junction at α-, β-, or γ-carbon atom of the nitroxide fragment, which is part of the heterocyclic system. Despite the fact that the first representatives of SNRs were obtained about 50 years ago, the methodology of their synthesis and their usage in chemistry and biochemical applications have begun to develop rapidly only in the last two decades. Due to the presence of spiro-function in the SNRs molecules, the latter have increased stability to various reducing agents (including biogenic ones), while the structures of the biradicals (SNBRs) comprises a rigid spiro-fused core that fixes mutual position and orientation of nitroxide moieties that favors their use in dynamic nuclear polarization (DNP) experiments. This first review on SNRs will give a glance at various strategies for the synthesis of spiro-substituted, mono-, and bis-nitroxides on the base of six-membered (piperidine, 1,2,3,4-tetrahydroquinoline, 9,9′(10H,10H′)-spirobiacridine, piperazine, and morpholine) or five-membered (2,5-dihydro-1H-pyrrole, pyrrolidine, 2,5-dihydro-1H-imidazole, 4,5-dihydro-1H-imidazole, imidazolidine, and oxazolidine) heterocyclic cores.

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Synthesis of 1-azaspiro[4.4]nonan-1-oxyls via intramolecular 1,3-dipolar cycloaddition

Cited by 6 publications

References 26 publications

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

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

Synthesis and Properties of (1R(S),5R(S),7R(S),8R(S))-1,8-Bis(hydroxymethyl)-6-azadispiro[4.1.4.2]tridecane-6-oxyl: Reduction-Resistant Spin Labels with High Spin Relaxation Times

Spirocyclic Nitroxides as Versatile Tools in Modern Natural Sciences: From Synthesis to Applications. Part I. Old and New Synthetic Approaches to Spirocyclic Nitroxyl Radicals

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