Synthesis of (-)-matairesinol, (-)-enterolactone, and (-)-enterodiol from the natural lignan hydroxymatairesinol.

Article abstract of DOI:10.1021/ol0273598

[reaction: see text] We describe here a four-step semisynthetic method for the preparation of enantiomerically pure (-)-enterolactone starting from the readily available lignan hydroxymatairesinol from Norway spruce (Picea abies). Hydroxymatairesinol was

Full text of DOI:10.1021/ol0273598

ORGANIC
LETTERS
2003
Vol. 5, No. 4
491-493
Synthesis of (−)-Matairesinol,
(−)-Enterolactone, and (−)-Enterodiol
from the Natural Lignan
Hydroxymatairesinol
,†
Patrik Eklund,* Anna Lindholm, J.-P. Mikkola,‡ Annika Smeds, Reko Lehtila1, and
Rainer Sjo1holm†
Department of Organic Chemistry, Åbo Akademi UniVersity, Biskopsgatan 8,
20500-FIN, Åbo, Finland
paeklund@abo.fi
Received November 27, 2002
ABSTRACT
We describe here a four-step semisynthetic method for the preparation of enantiomerically pure (−)-enterolactone starting from the readily
available lignan hydroxymatairesinol from Norway spruce (Picea abies). Hydroxymatairesinol was first hydrogenated to matairesinol. Matairesinol
was esterified to afford the matairesinyl 4,4′-bistriflate, which was deoxygenated by palladium-catalyzed reduction to 3,3′-dimethylenterolactone.
Demethylation of 3,3′-dimethylenterolactone and reduction with LiAlH yielded (−)-enterolactone and (−)-enterodiol, respectively.
4
Lignans have attracted much interest over the years because
of their widespread occurrence in various plant species1 and
their broad range of biological activity.1b,2 Two lignans,
unique in lacking para substitution in the benzylic groups,
enterolactone (ENL) [2,3-bis(3-hydroxybenzyl)-γ-butyro-
lactone] (5) and enterodiol (END) [2,3-bis(3-hydroxybenzyl)-
butane-1,4-diol] (6), have been found in human and animal
urine.2,3 Enterolactone is a mammalian lignan, which has
recently been shown to form by the metabolization of plant
lignans such as matairesinol (2), secoisolariciresinol, 7-hy-
droxymatairesinol (HMR) (1), and lariciresinol by intestinal
bacteria.4 The detection of the mammalian lignans ENL and
END in human urine has led to much discussion about their
biological function.2,3,5 They have been suggested to have a
role as antiestrogens and anticarcinogens among other
possible biological activities.6 In recent studies, HMR, the
(2) Setchell, K. D. R.; Lawson, A. M.; Mitchell, F. L.; Adlercreutz, H.;
Kirk, D. N.; Axelson, M. Nature 1980, 287, 740-742.
(3) Setchell, K. D. R.; Lawson, A. M.; Conway, E.; Taylor, N. F.; Kirk,
D. N.; Cooley, G.; Farrant, R. D.; Wynn, S.; Axelson, M. Biochem. J. 1981,
197, 447-458.
(4) Heinonen, S.; Nurmi, T.; Liukkonen, K.; Poutanen, K.; Wa¨ha¨la¨, K.;
Deyama, T.; Nishibe, S.; Adlercreutz, H. J. Agric. Food Chem. 2001, 49,
3178-3186.
† Process Chemistry Group, Department of Organic Chemistry, Åbo
Akademi University. Phone: + 358 2 215 4502. Fax: +358 2 215 4866.
‡ Process Chemistry Group, Laboratory of Industrial Chemistry, Åbo
Akademi University.
(1) (a) Cole, J. R.; Wiedhopf, R. M. In Chemistry of Lignans; Rao, C.
B. S., Ed.; Andhra University Press: Waltair, India, 1978; pp 39-64. (b)
Ayres, D. C.; Loike, J. D. Lignans, Chemical, Biological and Clinical
properties; Cambridge University Press: Cambridge, 1990.
(5) (a) Stitch, S. R.; Toumba, J. K.; Groen, M. B.; Funke, C. W.;
Leemhuis, J.; Vink, J.; Woods, G. F. Nature 1980, 287, 738-740. (b)
Setchell, K. D. R.; Adlercreutz, H. J. Steroid Biochem. 1979, 11, 15-16.
(c) Jacobs, E.; Metzler, M. J. Agric. Food Chem. 1999, 47, 1071-1077
and refs therein. (d) Ma¨kela¨, T. H.; Wa¨ha¨la¨, K. T.; Hase, T. Steroids 2000,
65, 437-441 and refs therein. (e) Niemeyer, H. B.; Honig, D.; Lange-
Bo¨hmer, A.; Jacobs, E.; Kulling, S. E.; Metzler, M. J. Agric. Food Chem.
2000, 48, 2910.
10.1021/ol0273598 CCC: $25.00 © 2003 American Chemical Society
Published on Web 01/18/2003

most abundant lignan in Norway spruce (Picea Abies) wood,
was shown to metabolize mainly to ENL in rats.7 Also, both
HMR and ENL have been shown to inhibit the growth of
7,12-dimethylbenz[a]anthracene-induced mammary carci-
noma in rats.7-9 Numerous metabolites of ENL have been
characterized, but little is known about their possible
biological effects.5c,e According to some older sources, ENL
and END found in humans and in vervet monkeys are
essentially racemic.3,5a However, in more recent papers, it
seems accepted that the metabolically formed ENL is mainly
(-)-(8R,8′R)-enterolactone (5, Scheme 1).10,11
semisynthesis of (-)-ENL starting from the readily available
natural lignan HMR.
HMR is found in exceptionally high concentrations (>10%
of the dry weight) in knots of Norway spruce (Picea abies).12
Methods for the separation of knots and isolation of HMR
in large scale have been developed, making HMR the first
butyrolactone lignan available in large scale.13 Knots are
dried, ground, and extracted with acetone-water. The raw
extract is purified by flash chromatography to yield pure
HMR. Alternatively, the formation of a K-acetate adduct of
(-)-HMR described by Freudenberg et al.14 is used to isolate
HMR. Knots are extracted with ethanol and K-acetate is
added to the extract to yield a HMR-K-acetate adduct,
which is separated by precipitation and filtration. Undoubt-
edly, this method is superior in large-scale isolation.
Natural HMR comprises of two diastereomers, namely,
(7S,8R,8′R)-(-)-7-hydroxymatairesinol (major isomer) and
(7R,8R,8′R)-(-)-7-allo-hydroxymatairesinol (minor isomer),
whose absolute configurations were determined recently.15
The stereochemical structure and the good availability of
HMR make it an excellent precursor for synthesis of (-)-
matairesinol, (-)-ENL, and (-)-END.
Scheme 1
In this work, HMR was first submitted to pressurized
hydrogenolysis over Pd/C in dichloroethane or the K-acetate
adduct of HMR was hydrogenolyzed with RaNi or Pd/C in
ethanol to afford (8R,8′R)-(-)-matairesinol (2) in almost
quantitative yields. In a typical experiment, 15 g of adduct
was dissolved in ethanol; catalyst was added, and the mixture
was hydrogenated under pressure for 200 min (Figure 1).
Matairesinol was then deoxygenated to 3,3′-dimethylentero-
lactone (4) according to a procedure that has been described
for hindered phenols but, to our knowledge, never been
applied to natural lignans.16,17
Two different methods for palladium-catalyzed phenolic
reduction/deoxygenation of 2 under mild conditions were
studied, deoxygenation via triflate derivatives and deoxy-
genation via 1-phenyl-tetrazyl ether derivatives. The latter
method showed promising results for the first step; etheri-
fication of the phenolic hydroxyl groups was successful, and
the product was obtained by crystallization. However,
deoxygenation of the 1-phenyl-tetrazyl derivatives was
unsuccessful. Despite several attempts by catalytic deoxy-
*Yields depend on the starting material used (HMR or HMR-
KAc) and the purity thereof.
(10) Sibi, M. P.; Liu, P.; Johnson, M. D. Can. J. Chem. 2000, 78, 133-
138.
Because of the significant biological activity of this
compound, it has been an interesting target for synthetic
chemists and several synthetic routes to enantiomerically pure
ENL have been reported.10,11 We here report an alternative
(11) (a) Sibi, M. P.; Liu, P.; Ji, J.; Hajra, S.; Chen, J.-X. J. Org. Chem.
2002, 67, 1738-1745. (b) Chenevert, R.; Mohammad-Ziarani, G.; Caron,
D.; Dasser, M. Can. J. Chem. 1999, 77, 223. (c) Bode, J. W.; Doyle, M.
P.; Protopopova, M. N.; Zhou, Q.-L. J. Org. Chem. 1996, 61, 9146. (d)
Doyle, M. P.; Protopopova, M. N.; Zhou, Q.-L.; Bode, J. W.; Simonsen, S.
H.; Lynch, V. J. Org. Chem. 1995, 60, 6654. (e) Van Oeveren, A.; Jansen,
J. F. G. A.; Feringa, B. L. J. Org. Chem. 1994, 59, 5999. (f) Yoda, H.;
Kitayama, H.; Katagiri, T.; Takabe, K. Tetrahedron 1992, 48, 3313. (g)
Asaoka, M.; Fujii, N.; Shima, K.; Takei, H. Chem. Lett. 1988, 805.
(12) Willfo¨r, S.; Hemming, J.; Eckerman, C.; Holmbom, B. Holzforchung
2002, in press.
(13) Eckerman, C.; Holmbom B. PCT WO 0209893 A1, 2001.
(14) Freudenberg, K.; Knof, L. Chem Ber. 1957, 2857.
(15) Eklund, P. C.; Sillanpa¨a¨, R.; Sjo¨holm R. J. Chem. Soc., Perkin Trans.
1 2002, 16, 1906.
(16) Saa´, J. M.; Dopico, M.; Martonell, G.; Garcia-Raso, A. J. Org. Chem.
1990, 55, 991.
(6) Setchell, K. D. R.; Adlercreutz. H. In Role of the Gut Flora Toxicity
and Cancer, Mammalian Lignans and Phytoestrogens: Recent Study on
the Formation, Metabolism and Biological Role in Health and Disease;
Rowland, I. R., Ed.; Academic Press: London, 1988; pp 315-345.
(7) Saarinen, N. M.; Wa¨rri, A.; Ma¨kela¨, S. I.; Eckerman, C.; Reunanen,
M.; Ahotupa, M.; Salmi, S. M.; Franke, A. A.; Kangas, L.; Santti, R.
Nutrition Cancer 2000, 36 (2), 207-216.
(8) Saarinen, N. M.; Huovinen, R.; Wa¨rri, A.; Ma¨kela¨, S. I.; Valent´ın-
Blasini, L.; Needham, L.; Eckerman, C.; Collan, Y. U.; Santti, R. Nutrition
Cancer 2001, 41, 82-90.
(9) Saarinen, N. M.; Huovinen, R.; Wa¨rri, A.; Ma¨kela¨, S. I.; Valent´ın-
Blasini, L.; Sjo¨holm, R.; A¨ mma¨la¨, J.; Lehtila¨, R.; Eckerman, C.; Collan,
Y. U.; Santti, R. Mol. Cancer Ther. 2002, 1, 869-876.
(17) Muslimer, W. J.; Gates J. W. J. Am. Chem. Soc. 1966, 88, 4271-
4273.
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Org. Lett., Vol. 5, No. 4, 2003

Table 1. Enantiomeric Composition of ENL in Human Serum
and Urine
sample
(-)-ENL (%)
(+)-ENL (%)
serum 1
serum 2
serum 3
urine
49
46
78
67
51
54
22
33
MS/MS using multiple reaction monitoring techniques
(MRM). Three blood serum samples, one being an average
sample of three persons (Serum 3), and one urine sample
were analyzed, using the semisynthetic (-)-ENL as a
reference compound. The enantiomeric composition shown
in Table 1 showed some differences between samples.
According to our results and the results of Saarinen et al.,
it seems reasonable to assume that ENL in mammalian
samples is neither racemic nor enantiomerically pure but that
its stereochemistry correlates with the dietary intake of
enantiomerically different precursors. Variations in the
enantiomeric composition in humans are therefore to be
expected. It may vary between individuals and populations
and/or be geographically related. It also seems most probable
that no configurational changes are introduced during the
microbial metabolism. However, to finally establish the
enantiomeric variations in humans, as well as possible
different biological properties for the two enantiomers of
ENL, a more comprehensive study is necessary.
In summary, we have developed a new approach for the
synthesis of enentiopure (-)-ENL and (-)-END. The method
of synthesis described in this work may also be used for
other lignans as well as for other phenolic natural com-
pounds. The simplicity of the reactions and the good yields
give an efficient semisynthetic route to enantiomerially pure
deoxygenated lignan derivatives, also in large scale. These
derivatives may be well suited for metabolization studies of
plant lignans.
Figure 1. Conversion of HMR-KAc adduct to matairesinol using
RaNi as a catalyst in EtOH, 130 °C, 700 PSI.
genation using Pd/C and PtO with H2, satisfactory yields
could not be obtained. The former method was undoubtedly
favorable to the latter and could be used for the phenolic
deoxygenation.
Matairesinol (2) was esterified with triflic anhydride in
lutidine to afford matairesinyl 4,4′-bistriflate (3) in good
yields. Compound 3 was then converted to 4 with 1,3-bis-
(diphenylphosphino)propane and PdCl2(PPh3)2 in DMF/TEA
using formic acid as a hydrogen donor. Demethylation of 4
was carried out using BBr3 in dichloromethane to yield 5
(overall yield ∼55%, calculated from HMR), which was
reduced with LiAlH4 to 6 (overall yield ∼40%, calculated
from HMR) (Scheme 1). The products were identified using
NMR spectroscopy, HRMS, and chiral HPLC-MS.
Although several works identifying ENL in mammalian
body fluids have been published, the enantiomeric composi-
tion has not been discussed. Preliminary results based on
optical rotation and circular dichroism showed that mam-
malian ENL is essentially racemic.3,5a However, Saarinen et
al. recently showed (by using our semisynthetic (-)-ENL
as reference) that the excretion of the two enantiomeric forms
of ENL in rats after administration of a single dose of lignan
precursors depends on the enantiomeric compositions of the
precursors.18
Acknowledgment. We gratefully acknowledge Hormos
Nutraceutical for financing this work. We also thank Markku
Reunanen for the HRMS analysis, Outi Ja¨rvinen for some
of the HPLC-analysis, and Niina Saarinen for the serum and
urine samples.
To study the enantiomeric composition of ENL in humans,
human serum and urine were analyzed by chiral HPLC-ESI-
Supporting Information Available: Experimental pro-
cedures and complete analytical data. This material is
available free of charge via the Internet at http://pubs.acs.org.
(18) Saarinen, N. M.; Smeds, A.; Ma¨kela¨, S.; A¨ mma¨la¨, J.; Hakala, K.;
Pihlava, J.-M.; Ryha¨nen, E.-L.; Sjo¨holm, R.; Santti, R. J. Chromatogr., B
2002, 777, 321-327.
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