Synthesis of new pyrrolidine nitroxide epoxides as versatile paramagnetic building blocks

Article abstract of DOI:10.1016/S0040-4039(02)01911-1

Pyrrolidine nitroxide epoxides were synthesized by oxidation of the corresponding alkene, diene and α,β-unsaturated aldehyde with m-CPBA or H₂O₂ to provide new spin labels and paramagnetic synthons.

Full text of DOI:10.1016/S0040-4039(02)01911-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 8125–8127
Synthesis of new pyrrolidine nitroxide epoxides as versatile
paramagnetic building blocks
Tama´s Ka´lai,a Cec´ılia P. Sa´r,a Jo´zsef Jekob and Ka´lma´n Hidega,*
3
aInstitute of Organic and Medicinal Chemistry, University of Pe´cs, PO Box 99, H-7643 Pe´cs, Hungary
bICN Hungary, PO Box 1, H-4440 Tiszavasva´ri, Hungary
Received 31 July 2002; revised 27 August 2002; accepted 6 September 2002
Abstract—Pyrrolidine nitroxide epoxides were synthesized by oxidation of the corresponding alkene, diene and a,b-unsaturated
aldehyde with m-CPBA or H2O2 to provide new spin labels and paramagnetic synthons. © 2002 Elsevier Science Ltd. All rights
reserved.
Nitroxides were discovered almost half a century ago1
and since then they have found diverse uses as spin
labels,2 co-oxidants3 and spin traps.4 Their medical
applications as SOD mimics,5 antioxidants6 and MRI
contrast agents7 have attracted much attention from the
scientific community over the last four decades. In our
laboratory a series of pyrroline and pyrrolidine anel-
lated five- and six-membered heterocycles were synthe-
sized very recently.8 However, it is a real challenge to
find a simple method for the synthesis of pyrrolidine
nitroxide anellated oxiranes that is capable of extra
H-bond formation (as a H acceptor with oxygen), but
still affords the possibility of covalent bond formation
with a reactive arm via a different reaction site.
Many efficient methods have been developed for the
synthesis of epoxides and they have been extensively
utilized for the synthesis of 1,2-disubstituted moieties in
natural products and drugs.9 The first paramagnetic
epoxides were synthesized by the Darzens-method1 or
as a co-product of the oxidation of the corresponding
2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridine.10
Cyclization of a chlorohydrin gave an epoxide attached
to pyrroline nitroxide11 and very recently Ozhogina
reported12 the Corey reaction of the paramagnetic alde-
hyde 1a13 with a sulfur ylide to achieve the correspond-
ing epoxide. In our laboratory we have found that
H2O2 treatment of the aldehyde 1a in the presence of
NaOH in aqueous MeOH gave the 3-oxyl-2,2,4,4-tetra-
methyl-6-oxa-3-azabicyclo[3.1.0]hexane-1-carboxylic
acid radical 2a and the carboxylic acid 3a1 in a 10:1
ratio. This reaction was extendable to other b-substi-
tuted-a,b-unsaturated aldehydes 1b and 1c,14 generating
the corresponding epoxy acids 2b and 2c and carboxylic
acids 3b and 3c as by-products. This method offers a
new reagent type (2a–c) in which the 1 and 5 sub-
Scheme 1. Reagents and conditions: (a) 30% aq. H2O2, (2.0 equiv.), 10% aq. NaOH (2.0 equiv.), MeOH, rt, 24 h, 2a–c (80–92%),
3a–c (8–20%).
Keywords: nitroxides; epoxides; spin labels; ring opening.
* Corresponding author. Tel.: +36(72)536220; fax: +36(72)536219; e-mail: khideg@main.pote.hu
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01911-1

8126
T. Ka´lai et al. / Tetrahedron Letters 43 (2002) 8125–8127
Scheme 2. Reagents and conditions: (a) ClCO2Et (1.1 equiv.), Et2O, Et3N (1.1 equiv.), 0°C, 2 h, (72%); (b) for 5a NaBH4, (3.0
equiv.), EtOH, 0°C, 2 h, (81%); (c) (i) MsCl (1.1 equiv.), Et3N (1.1 equiv.), CH2Cl2, 0°C“rt, 1 h, (ii) LiBr (2.0 equiv.), acetone,
55°C, 1 h, 47%; (d) NaSSO2CH3 (2.0 equiv.), acetone/H2O, 30 min, 55°C, 40%.
Scheme 3. Reagents and conditions: (a) m-CPBA (2.5 equiv.), CH2Cl2, rt, 24 h (7: 31%, 8: 52%); (b) m-CPBA (1.2 equiv.), benzene,
rt, 24 h, (68%); (c) NaBH4 (3.0 equiv.), EtOH, 78°C, 30 min (61%).
stituents are anchored in the cis position by the epoxide
ring. As far as we know, until now only trans 3,4-disub-
stituted paramagnetic rings were available (Scheme 1).15
In conclusion, new paramagnetic epoxides21 have been
synthesized by oxidation of the corresponding pyrroli-
nes or unsaturated pyrrolidine derivatives. These para-
magnetic epoxides open new opportunities in synthesis
of multiply functionalized spin labels. Their use and
further ring opening reactions including stereochemical
outcome are under investigation in our laboratory.
During studies of the reactions of epoxides 2a–c, we
found the epoxide ring to be rather inert, surviving the
reduction of the mixed anhydride ester 4 to the alcohol
5a. Compound 5a could be converted to the
methanethiosulfonyl compound16 5c via mesylate and
bromide 5b without opening the epoxide ring (Scheme
2).
Acknowledgements
To amass more reactive epoxides we oxidized exo- and
isolated double bond containing nitroxides. The sym-
metric paramagnetic diene 617 can be oxidized with
m-CPBA in CH2Cl2 to monoepoxide 7 and diepoxide 8
in a 3:5 ratio. The latter can be regarded as a potential
crosslinking reagent and the biological effect of its
diamagnetic analogue, 1,3-butadiene diepoxide, is well
studied.18 We believe the fate of the toxic butadiene
diepoxide in a living organism can be easily followed by
EPR spectroscopy by monitoring the paramagnetic
diepoxide 8. Oxidation of 2,2,5-trimethyl-5-vinylpyrro-
This work was supported by grant from Hungarian
National Research Foundations (OTKA T34307,
T030013 and M 028226). Bolyai fellowships for T. K.
and C. S. from Hungarian Academy of Sciences is
gratefully acknowledged. The authors thank to Dr. O.
H. Hankovszky for helpful discussions. The authors
thank to Z. Berente for NMR measurement (University
of Pe´cs, Department of Biochemistry and Medical
Chemistry), M. Balog for technical assistance, V.
Csokona for elemental analysis and M. Szabo´ for mass
spectral measurements (ICN, Hungary).
19
lidin-1-yloxy compound 9 with m-CPBA in benzene
gave
2,2,5-trimethyl-5-oxiran-2-yl-pyrrolidin-1-yloxy
radical 10 as mixture of two diastereomers in 1:5 ratio,
Rf 0.43 and 0.35, respectively (TLC, silicagel, hexane/
Et2O, 2:1).
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3
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21. Compounds were characterized by ESR, MS, NMR and
elemental analysis. Spectra were in each case consistent
with the assigned structures. All the monoradicals exhib-
ited free equidistant lines aN=14.7–15.5 G. To obtain
high resolution NMR spectra of the NO radicals were
reduced to diamagnetic N-hydroxy compounds by codis-
solving PhNHNHPh reducing agent in NMR tube. Phys-