Journal of Labelled Compounds and Radiopharmaceuticals
J Label Compd Radiopharm 2007; 50: 521–522.
Published online in Wiley InterScience
JLCR
(www.interscience.wiley.com). DOI: 10.1002/jlcr.1238
Short Research Article
Synthesis of stable deuterium labelled lignan derivatives and
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studies of H/D exchange at the aromatic sites
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MONIKA POHJOISPAA*, EIJA LEPPALA and KRISTIINA WAHALA
Department of Chemistry, Laboratory of Organic Chemistry, P.O. Box 55, 00014 University of Helsinki, Finland
Received 30 August 2006; Revised 21 December 2006; Accepted 21 December 2006
Keywords: deuterium; isotope exchange; labelling; lignans
Introduction
H/D exchange reactions within the lignan molecule
framework.
The lignans are a large group of compounds found in
the plant kingdom from where they end up as
mammalian metabolic products. They vary widely in
structure, but most of the lignans appear as polyphe-
nols.
All our aromatic region lignan labelling methods are
based on H/D exchange reactions under acidic condi-
tions. In our earlier work, enterolactone was refluxed
0
0
0
3 2 6
with a mixture of PBr /D O to give [2,4,6,2 ,4 ,6 -D ]-
4
enterolactone. In this method, as in other former
methods, aromatic hydrogens ortho and para to the
phenolic hydroxy group are exchanged to deuteriums
while the less active meta sites remain intact.
The growing interest in these compounds is based on
1
their possible health effects. Quantitation and quali-
fication of lignans require good resolution and sensi-
tivity because lignan concentrations are quite low in
biological samples. Thus, the analytical techniques
used for lignans are based on HPLC-MS and ID-GC-
Results and discussion
2
MS. In these methods stable isotope polylabelled
compounds are needed as internal standards.
In our recent work the deuterium labelling is carried
out under strongly acidic conditions by deuterated
phosphoric acid–boron trifluoride complex, prepared in
Materials and methods
5
,6
situ.
The method is found to be expedient for various
butyrolactone-type lignans. In this method all aromatic
protons are exchanged to deuteriums, even from the
inactivated positions, but no exchange occurs at the
benzylic or a-carbonyl sites (Scheme 1).
However, at very highly activated positions the
deuterium labels may undergo back exchange. Hence,
we have established de-deuteration conditions to
remove the less stable D labels so as to obtain
stable, isotopically homogenously labelled derivatives
Deuterium labels, available from the relatively inex-
pensive D2 and D O, have been commonly used for
2
butyrolactone-type lignans. Deuterium atoms have
been attached either to the aliphatic region of the
lignan skeleton or to the aromatic region. Dibenzylbu-
tyrolactone-type lignans are readily accessed by a
tandem Michael addition–alkylation reaction followed
by desulfurization and debenzylation with Raney nick-
3
el. Wanting to avoid synthetic labelling schemes
(
Figure 1). These polylabelled compounds can be
relying on laborious and expensive total synthesis
using prelabelled starting materials, we have studied
used safely as internal standards in isotope dilution
methods.
We have also studied the order of H/D exchange at
the aromatic sites. This was done by comparing the
empirical exchange observations with electron density
calculations to estimate the relative reactivities of the
aromatic protons (Figure 1). The effect of aromatic ring
substituents on the stability of the deuterium labels is
also examined.
*
Correspondence to: Monika Pohjoisp a¨ a¨ , Department of Chemistry,
Laboratory of Organic Chemistry, P.O. Box 55, 00014 University of
Helsinki, Finland. E-mail: monika.pohjoispaa@helsinki.fi
Contract/grant sponsor: University of Helsinki
Contract/grant sponsor: Jenny and Antti Wihuri Foundation
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Proceedings of the Ninth International Symposium on the Synthesis
and Applications of Isotopically Labelled Compounds, Edinburgh,
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6–20 July 2006.
Copyright # 2007 John Wiley & Sons, Ltd.
Pohjoispaeae, Monika
