Stereochemistry and rearrangement reactions of hydroxylignanolactones

Article abstract of DOI:10.1039/b801593g

Various conflicting data on the rearrangement and absolute stereochemistry of hydroxylignano-9,7′-lactones are resolved using ¹⁸O labeled compounds, also confirmed by an X-ray analysis of a pure lignano-9,7′- lactone enantiomer, obtained for the first time. Under NaH/DMF rearrangement conditions a silyl protected hydroxylignano-9,9′-lactone underwent an unexpected silyl migration. The Royal Society of Chemistry 2008.

Full text of DOI:10.1039/b801593g

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Stereochemistry and rearrangement reactions of hydroxylignanolactones†‡
Barbara Raffaelli,a Monika Pohjoispa¨a¨,a Tapio Hase,a Christine J. Cardin,b Yu Ganb and Kristiina Wa¨ha¨la¨*a
Received 29th January 2008, Accepted 11th April 2008
First published as an Advance Article on the web 19th May 2008
DOI: 10.1039/b801593g
Various conflicting data on the rearrangement and absolute stereochemistry of
hydroxylignano-9,7ꢀ-lactones are resolved using 18O labeled compounds, also confirmed by an X-ray
analysis of a pure lignano-9,7ꢀ-lactone enantiomer, obtained for the first time. Under NaH/DMF
rearrangement conditions a silyl protected hydroxylignano-9,9ꢀ-lactone underwent an unexpected silyl
migration.
Introduction
Lignans, as natural products widely distributed in the plant
kingdom, are the topic of many investigations due to their
numerous interesting biological properties, such as anticancer
and immunosuppressive activity.1 Besides clinical studies, much
effort has been invested into finding strategies for the synthesis
of the various subclasses.2 We have recently reported the stere-
oselective synthesis of several (7ꢀS,8R,8ꢀR)-7ꢀ-hydroxylignano-
9,9ꢀ-lactones (7ꢀ-HLLs 1a,b,d,e, Fig. 1), among which the plant
lignan (−)-parabenzlactone (1a) and the mammalian lignan 7ꢀS-
hydroxyenterolactone (1d) were obtained as enantiopure products
for the first time.3
Scheme 1 Proposed mechanism of formation of the rearranged lactone
3a (route B).3 For Ar1 see Fig 1.
et al.4 by basic hydrolysis (2% KOH–MeOH) of 2a and originally
described with a 7ꢀ/8ꢀ-cis-8/8ꢀ-cis configuration (3a). In fact,
according to the corrected stereochemistry of the starting material
2a, the rearranged product obtained by a simple translactonization
should be the 7ꢀ/8ꢀ-trans-8/8ꢀ-cis isomer 4a (Scheme 1, route A).
However the reported NMR data (in particular the 7ꢀ-H signal,
Fig. 1 7ꢀS-Hydroxylignano-9,9ꢀ-lactones and their aromatic substitution
pattern.
The total synthesis of 7ꢀ-HLLs allowed us to correct the
stereochemistry of 1a, and of its naturally occurring derivative
acetylparabenzlactone (2a, Scheme 1) as 7ꢀS,3 as opposed to the
previously reported4 configuration. This adjustment also involved
a re-examination of the lignano-9,7ꢀ-lactone obtained by Nishibe
ꢀ
ꢀ
doublet at d 5.13 ppm, JH-7 /H-8 = 8 Hz) are not well-matched with
such configuration which, as observed by Eklund et al.5 and by us,3
should have the 7ꢀ proton as a doublet at d 5.45 ppm, JH-7 /H-8
=
ꢀ
ꢀ
2.6 Hz. On the other hand, since the NMR data were anyway
consistent with a 7ꢀ/8ꢀ-cis-8/8ꢀ-cis configuration (7ꢀ-H doublet at
d 5.12 ppm, JH-7 /H-8 = 9.3 Hz),5 we suggested an SN2 mechanism
for the formation of the rearranged lactone 3a, where, with OAc
as the leaving group, an inversion of the configuration at 7ꢀ has
taken place during the relactonization (Scheme 1, route B).3
In continuation of our previous work we now present the results
of mechanistic studies we undertook in order to clarify these ques-
tions. The studies were accomplished using 18O labeled compounds
and monitoring the results by mass spectroscopy (MS). A variety
of rearrangement conditions were investigated using different
ꢀ
ꢀ
aDepartment of Chemistry, Laboratory of Organic Chemistry, Univer-
sity of Helsinki, P.O. Box 55, FIN-00014, Finland. E-mail: kristiina.
wahala@helsinki.fi.; Fax: +358 9191 50357; Tel: +358 9191 50356
bDepartment of Chemistry, University of Reading, Whiteknights, Reading,
UK. E-mail: c.j.cardin@rdg.ac.uk.; Fax: +44 118 3786331; Tel: +44 118
3788215
† Dedicated to Prof. E. J. Corey on the occasion of his 80th birthday.
‡ CCDC reference number 676372. For crystallographic data in CIF or
other electronic format see DOI: 10.1039/b801593g
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unlabeled substrates, such as 8-methylparabenzlactone, a lignan
derivative lacking a carbonyl protons, and diversely aromatic-
substituted lignanolactones.
Results and discussion
Translactonization of 18O labeled substrates
Scheme 3 Reagents and conditions: (1) 2% KOH–MeOH, rt; (2) 2 N
HCl. For Ar1 see Fig 1.
To distinguish between the translactonization and the SN2 rear-
rangement mechanism, we prepared (Scheme 2) the labeled silyl
protected 7ꢀS-hydroxymatairesinol 18O-1b and the parabenzlac-
tone derivative 18O-2a, and looked by MS for the conservation
product 18O-1a. Since spectroscopic analyses showed the presence
of a trisubstituted butyrolactone ring, two piperonyl groups and
a primary alcohol, it was evident that the lignan skeleton was
conserved and the new compound must be a stereoisomer of 3a and
4a. A NOESY experiment of the product showed no correlation
between the protons 7ꢀ and 8ꢀ (good evidence for a 7ꢀ/8ꢀ-trans
configuration), nor between H-8 and H-8ꢀ. Instead, a NOESY
correlation was detected between H-7ꢀ/8, 7ꢀ/9, 8/9ꢀ and 7/8ꢀ.
On the basis of these results it was deduced that this compound
is the previously reported (in unlabeled form)4,6 7ꢀ/8ꢀ-trans-8/8ꢀ-
trans (7ꢀS,8S,8ꢀR) isomer 18O-7a (Scheme 3), which arises from a
translactonization accompanied by an a-epimerization.
R
vs. loss of the label under the translactonization (L-Selectrideꢀ)
or the SN2 rearrangement (KOH–MeOH) conditions. In the
translactonization route, the 18O should be retained in the product,
but should be missing in the rearranged lactone derived by the SN2
mechanism.
Translactonization studies with NaH–DMF or 2% KOH–MeOH
The present findings also clarify the discrepancy between our
previous results3 and those of Iwasaki7 and Eklund.5 Iwasaki
had reported the concomitant translactonization/a-epimerization
whilst treating ( )-1c (Fig. 1) with NaH–DMF to obtain the all-
trans ( )-7c (confirmed by X-ray analysis). In our earlier paper we
assumed, supported by Eklund’s results,5 that the 7ꢀ-H doublet at d
5.1 ppm was sign of a cis 7ꢀ/8ꢀconfiguration, and could not explain
how the all-trans 7c could give such a similar signal (doublet at
d 5.16 ppm, JH-7 /H-8 = 9.2 Hz).3 It is now understandable that,
although a different mechanism of formation is involved, the same
configuration 7ꢀ/8ꢀ-trans-8/8ꢀ-trans is obtained with both NaH–
DMF and KOH–MeOH, as the similarity between the NMR of
7c and 7a clearly shows. Also it is evident that the coincidental
NMR resemblance between the all-cis and the all-trans lactones is
misleading and leads to proposal of the wrong mechanism (SN2).
To compare directly the two reactions (Table 1), 1a3 was sub-
mitted to both Nishibe’s (2% KOH–MeOH)4 and Iwasaki’s (NaH–
DMF)7 rearrangement conditions. In our hands the reaction with
NaH–DMF furnished a mixture of the starting material 1a and
ꢀ
ꢀ
Scheme 2 Reagents and conditions: (i) (CF3CO2)2IPh, CH3CN–18OH2
(for 5a,b) or CH3CN–H2O (for 5c), rt; (ii) L-SelectrideꢀR , THF, −78 ◦C;
(iii) Ac2O-Py, rt. For Ar and Arꢀ see Fig. 1.
The 18O label was introduced during the deprotection of the
dithiane moiety of 5 using 18OH2 as the co-solvent. Since no
rearranged product had been previously observed in the treatment
R
of oxoparabenzlactone 6a with L-Selectrideꢀ,3 we decided to
perform the reduction also on 18O-6b to follow the destiny of
the label in a simple translactonization. The treatment of 18O-
R
6a or 18O-6b with L-Selectrideꢀ (Scheme 2, step ii) furnished,
as expected, the 7ꢀS-HLL alcohols 18O-1a or 18O-1b, along with
the rearranged 9,7ꢀ-lactones 18O-4a or 18O-4b, in a ca. 85 : 15
ratio according to NMR and MS.§ In particular the mass spectra
showed that for a simple translactonization the 18O label is totally
conserved. The acetylated derivative 18O-2a was submitted to
hydrolytic conditions4 (Scheme 3) to reinstate 18O-1a and the
presumed rearranged lactone in a 2 : 1 ratio, as indicated by
Nishibe.4 However the MS analysis of the latter showed that the
molecule still contained the 18O label. This result was in conflict
with a possible SN2 mechanism, which therefore was ruled out. On
the other hand a simple translactonization would have furnished
the product 18O-4a, easily distinguished from the hydrolysis
Table 1
1 : 7 ratioa
1a : 7a
Yield (%)b
1c : 7c
1a
7a
1c
7c
(i) 2%KOH–MeOH
(ii) NaH–DMF
64 : 36
40 : 60
57 : 43
36 : 64
61
23
31
33
58
26
31
38c
§ The minor product 4a was not observed in our previous experiment.3 The
studies about the L-SelectrideꢀR side reaction will be the subject of another
paper of the series where full characterization of 4a will be reported.
a From the 1H NMR of the crude material. b Yields after flash chromatog-
raphy. c Reported yield of ( )-7c was 75%.7
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the rearranged lactone 7a in a 40 : 60 ratio, with a 33% yield
of the latter, very different from Iwasaki’s results7 (75% yield
with no recovery nor detection of starting material reported).
To exclude any effects due to the unlike aromatic substituents,
Nishibe’s and Iwasaki’s rearrangement conditions were repeated
on the enantiopure compound3 1c (Scheme 2). With NaH–DMF
1c gave results (1 : 7 ratio and yields) comparable to those obtained
for 1a (Table 1). Thus the nature of phenolic protection does not
play a role in these reactions. With KOH–MeOH 1a or 1c each
furnished a mixture of starting material and rearranged lactone in
a ca. 60 : 40 ratio, in agreement with the results of the hydrolysis
of 18O-2a (Scheme 3) and also as previously achieved by Nishibe4
with 2a as the substrate.
The difference in the 1 : 7 ratios under conditions (i) and (ii)
(Table 1), and a change of the predominant product in these
reactions, may be explained by the reactions mechanisms. When
NaH–DMF is employed the lactone moiety of 1 undergoes a nucle-
ophilic attack by the formed alkoxide ion and the a-epimerization
occurs more or less simultaneously to give the thermodynamically
more stable product 7. In the case of KOH–MeOH (Scheme 4) the
lactone moiety of 1 undergoes transesterification by the action of
MeO− present in the reaction medium, forming the methyl ester
diol intermediate, which can be deprotonated at the a position.
After acidification, relactonization can occur with either hydroxy
group present in the intermediate, but the preference is determined
by the selectivity of a-proton reinsertion into the molecule, prior
to relactonization. A reprotonation from the less hindered upper
face leads back to the starting material 1, whereas protonation
from the lower face will lead to the rearranged 7. From the 1 : 7
ratio values it is clear that the structure 1 is preferred. Evidence
for this equilibrium was obtained by treating 7a with 2% KOH–
MeOH. Translactonization/a-epimerization is observed and the
ratio 1a : 7a = 66 : 34 was obtained after 48 h (compared to the
1.5 h required when 1a was the starting material). Probably the 9,7ꢀ-
lactone 7a is more hindered then 1a, making transesterification
less favorable. Furthermore, when 1a and 7a were treated with 2%
KOH–t-BuOH no rearrangement was observed.
Fig. 2 Crystal structure of 8a (50% probability ellipsoids).
Translactonization studies with aq. NaOH–EtOH
Yamauchi and Kinoshita8 exploited the translactonization re-
action for the synthesis of the unnatural (7ꢀR/8S/8ꢀR)-8/8ꢀ-cis-
parabenzlactone 9a. In this case the starting material was the 7ꢀ/8ꢀ-
cis-8/8ꢀ-trans pivaloyl protected lignano-9,7ꢀ-lactone 10a, which
was treated with 1M aq NaOH–EtOH (50 : 50) to give a mixture
of deprotected 7ꢀ-HLL 9a and the lignano-9,7ꢀ-lactone 11a in a
1 : 2 ratio (Scheme 5). This mixture is also obtained using the
alcohol 11a directly as starting material. Working in an aqueous
medium, the a-epimerization cannot take place on the carboxylate
intermediate. For this reason the sterically more favored 8/8ꢀ-
trans-7ꢀ-HLL was not formed.
Scheme
5 Translactonization reaction for the synthesis of
8/8ꢀ-cis-parabenzlactone 9a.8 Reagents and conditions: (1) 1M aq
NaOH, EtOH, rt; (2) 6M HCl. For Ar1 see Fig. 1.
In trying to obtain 12a, the 7ꢀ epimer of 9a, the above
conditions were tested on 7a (Scheme 6), but surprisingly no
translactonization was observed and only 7a was recovered. Since
the only difference in the starting materials 11a and 7a is the
stereochemistry at the 7ꢀ site, this must play a crucial role in
the formation of an 8/8ꢀ-cis-7ꢀ-HLL under these conditions. To
confirm that steric hindrance is the key feature in this type
of reactions, 1a was also treated with 1M aq NaOH–EtOH
(Scheme 6). As expected this reagent did not furnish the rearranged
lactone 4a, owing to the unfavourable 8/8ꢀ-cis configuration,
which was nevertheless obtained under different conditions (L-
Scheme 4 Mechanism of translactonization/a-epimerization in 2%
KOH–MeOH. For Ar1 see Fig. 1.
R
Selectrideꢀ, Scheme 2). Thus it is evident that a-epimerization
is necessary in the translactonization of 1 and 7, due to their
configuration. In support of these considerations, 1a and 7a when
treated with 2% aq KOH–MeOH (50:50) only gave the starting
materials in both cases.
The absolute configuration of 7a was confirmed by X-ray
analysis of the 3,5-dinitrobenzoate derivative 8a (Fig. 2).
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NaOH–EtOH, the presence of the water in the reaction medium
does not prevent (as seen for 1a) the reaction from occurring,
providing the same results as with 2% KOH–MeOH, which is
in turn comparable with those obtained for 1a and 1c (Table 1).
On the other hand NaH–DMF furnished less rearranged lactone
20a when compared with the results obtained with 1a and 1c
(Table 1), likely due to steric hindrance exerted by the 8-methyl in
the nucleophilic attack.
Translactonization studies of Ar-O-silylated
7ꢀS-hydroxymatairesinol 1b
In connection with another study, we have observed that phenolic
silyl ethers can be cleaved selectively in the presence of aliphatic
silyl ethers by means of NaH in DMF.12 Thus the aryl-O-silyl
protected 7ꢀS-hydroxymatairesinol 1b3 was subjected to the NaH–
DMF translactonization conditions (Scheme 8). As anticipated
the reaction proved to be a powerful desilylating tool, and some of
the rearranged/a-epimerized product 7e with free phenolic groups
was obtained. However the major product of this reaction was
the unexpected TBDMS-derivative 21e, formed by a migration
of the silyl group to the aliphatic hydroxyl. Traces of totally and
partially silyl protected 1b were also detected by NMR, but were
not isolated. In this case the combined amount of rearranged
lactones 7e and 21e (81%) is higher than under the same reaction
conditions with 1a and 1c as starting materials. We believe that
this is due to the formation of the silyl derivative 21e, whose
aliphatic protection group is not cleaved by NaH–DMF, making
the retro-translactonization impossible. Detailed studies about the
capability of NaH to cleave silyl protecting groups will be reported
in due course.
Scheme 6 Reagents and conditions: (1) 1M aq NaOH, EtOH, rt; (2) 2 N
HCl. For Ar1 see Fig. 1.
Translactonization studies of ( )-8-methylparabenzlactone 13a
Because of the importance of a-epimerization under ba-
sic conditions, these reactions were further tested on ( )-8-
methylparabenzlactone 13a, a compound where no a protons
are available. Compound 13a was synthesized as shown in
Scheme 7. A Michael addition3 between the dithiane 14a9 and
the methylbutenolide 15 gave a mixture of the a/b-trans and
a/b-cis isomers 16a in a 2 : 1 ratio. The diastereoselective
alkylation3 with piperonyl bromide 17a10 afforded only the a/b
(8/8ꢀ)-trans compound 18a, due to the bulky substituent present
at the chiral b carbon (1,2 asymmetric induction).11 The relative
configuration was confirmed by the lack of correlation between
the methyl and the H-8ꢀ in a NOESY experiment. Ketone 19a,
obtained after removal of the dithiane functionality, was reduced
R
diastereoselectively (de 99%) with L-Selectrideꢀ, furnishing ( )-
8-methylparabenzlactone 13a and the translactonized product
20a (ratio 84 : 16). Lactone 13a was subjected to the various
conditions discussed above (2% KOH–MeOH, NaH–DMF and
1M aq. NaOH–EtOH), furnishing in all cases the rearranged
product 20a and the starting material 13a in a ca. 35 : 65 ratio.
Thus the presence of the methyl group at C-8 clearly affects the
behaviour of the rearrangement reaction. In the case of 1M aq.
Scheme 8 Reagents and conditions: (1) NaH–DMF, 0 ◦C; (2) 2 M HCl.
Scheme
7
Reagents and conditions: (i) n-BuLi, THF, DMPU,
1
−78 ◦C→rt; (ii) LHMDS, THF, DMI, −78 ◦C→rt; (iii) (CF3COO)2IPh,
CH3CN–H2O, rt; (iv) L-SelectrideꢀR , THF, −78 ◦C; (v) 1) 2%
KOH–MeOH, rt; 2) 2 M HCl; (vi) (1) NaH–DMF, 0◦C; (2) 2 N HCl;
(vii) (1) 1M aq. NaOH, EtOH, rt; (2) 2 M HCl. For Ar1 see Fig. 1.
The H NMR spectrum of 21e shows signals very similar to
those of the unprotected 7e, which in turn resembles the spectra
of 7a–d, particularly regarding the diagnostic peak of H-7ꢀ (d at
ꢀ
ꢀ
d 5.1 ppm, JH-7 /H-8 = 9 Hz). Thus the aromatic variation and
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Table 2
Starting material
Reagents
Product(s)
Outcome
1a (or 2a)
2% KOH–MeOH
NaH–DMF
1M aq NaOH–EtOH
2% KOH–t-BuOH
2% aq KOH–MeOH
NaH–DMF
1a + 7a
1a + 7a
1a
Translactonization and a-epimerization
Translactonization and a-epimerization
No reaction
No reaction
No reaction
Translactonization, a-epimerization, silyl
cleavage and silyl migration
Translactonization and a-epimerization
Translactonization and a-epimerization
Translactonization and a-epimerization
No reaction
1a
1a
1a
1a
1b
1a
1a
21e +7e
1c
2% KOH–MeOH
NaH–DMF
1c + 7c
1c + 7c
1a + 7a
7a
7a
7a
13a + 20a
13a + 20a
13a + 20a
1c
7a
2% KOH–MeOH
1M aq NaOH–EtOH
2% KOH–t-BuOH
2% aq KOH–MeOH
2% KOH–MeOH
NaH–DMF
7a
7a
No reaction
No reaction
Translactonization
Translactonization
7a
13a
13a
13a
1M aq NaOH–EtOH
Translactonization
derivatizations of the aliphatic hydroxy group of 7 (TBDMS,
benzoate, MOM7) do not produce significant changes in the NMR
chemical shift of the characteristic H-7ꢀ signal. Similarities in the
1H NMR spectra can also be observed for 4a–e. This can be useful
in determining the stereochemistry of the trisubstituted lignano-
9,7ꢀ-lactones, as previously applied to the 7ꢀ-HLLs.3,13 However,
this may not be valid for the all-cis stereoisomers. In fact the
only two reported all-cis-lignano-9,7ꢀ-lactones 3e5 and ( )-22a6
(Fig. 3) present a remarkable difference for the H-7ꢀ signals in both
resolved as summarized in Table 2. The reaction mechanisms
were studied using 18O labeled substrates and the absolute
stereochemistry of the rearranged lactone obtained by Nishibe4
was determined as 7a, thanks also to the X-ray analysis of its
dinitrobenzoate derivative 8a, obtained for the first time for this
type of lignans. Compound 7a derives from a translactonization
accompanied by an a-epimerization and not, as we earlier
proposed,3 by an SN2 mechanism. Different basic conditions
were evaluated showing that the stereochemistry of the lactone
determines whether a rearrangement or a-epimerization is ob-
served or not. Rearrangement studies were also performed on
the unnatural 8-methyl substituted lignanolactone 13a. In this
case the stereochemistry did not play a particular role in the
formation of the rearranged lactone, which was obtained under
all conditions. Finally the aromatic silyl protected lignan 1b was
treated with NaH–DMF causing rearrangement, a-epimerization
and deprotection of the aryl silyl ethers, together with an
unexpected migration of the silyl to the aliphatic hydroxy group.
The resemblance observed in the 1H NMR for this class of
compounds can be a useful expedient for the assignment of the
stereochemistries.
ꢀ
ꢀ
chemical shifts and coupling constants (d 5.12 ppm, JH-7 /H-8
=
9.3 Hz for 3e5 vs. d 5.43 ppm, JH-7 /H-8 = 5.4 Hz for ( )-22a6). The
sizeable variation of these values could be caused by the bulky
TBDMS group, which may significantly affect the conformation
of 22a and consequently modify the NMR signals, in contrast to
those previously observed for 21e and 7e.
ꢀ
ꢀ
Experimental
Experiments were monitored by TLC using aluminium based,
precoated silica gel sheets (Merck 60 F254, layer thickness
0.2 mm) and visualized under UV light and further with a
mixture of vanillin and sulfuric acid in EtOH. Compounds were
homogeneous on TLC. Silica gel 60 (230–400 mesh, Merck) was
used for flash column chromatography. Optical rotation values
were measured with a JASCO DIP-1000 digital polarimeter at
rt. NMR spectra were recorded on a 500 MHz Varian Inova
spectrometer or on a 300 MHz Varian Mercury. Chemical shifts
are given in d in ppm and J values in Hz, using TMS as an internal
standard. Mass spectra were obtained using a JEOL JMS-SX102
mass spectrometer operating at 70 eV and for the 18O compounds
were measured with Bruker MicroTofLC (ESI) using Agilent ESI
Tunemix as a calibration solution. Melting points were determined
in open capillary tubes with a Bu¨chi B-545 melting point apparatus
and are uncorrected. IR spectra were recorded on a Perkin-Elmer
Spectrum One FTIR instrument equipped with ATR reflection
Fig. 3 Reported 7ꢀ/8ꢀ-cis-8/8ꢀ-cis-lignano-9,7ꢀ-lactones.5,6
As for the compounds possessing an 8-methyl 13a and 20a,
while the H-7ꢀ signal of 13a is similar to that in the 7ꢀS-HLL series
(1a–e), the chemical shift of the H-7ꢀ signal of 20a (d 4.8 ppm) is
significantly different both from the 7a–d,21e series (d 5.1 ppm)
and from the 4a–e series (d 5.4 ppm). Thus the methyl crucially
affects both the reactivity (in 13a) and the NMR signals (in 20a).
Conclusion
In this study the rearrangement reactions of various
hydroxylignano-9,9ꢀ- and -9,7ꢀ-lactones have been investigated and
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top plate. THF, CH3CN and Py were dried by distillation from
Na, P2O5 and CaH2 respectively. Compounds 1a, 1b, 5a–c,3 14a9
and 17a10 were prepared according to reported procedures. Other
commercially available chemicals were used as supplied by the
manufacturers. The absolute configuration of 8a was determined
15% yield respectively after flash chromatography (eluent CH2Cl2–
Et2O 8 : 1). IR and NMR of 18O-1a were in agreement with data
reported for the unlabeled 1a.3 For 18O-1a: HRMS (ESI-TOF) m/z
calcd for C20H18NaO618O [M + Na]+ 395.0992, found 395.0998. For
18O-4a: HRMS (ESI-TOF) m/z calcd for C20H18NaO618O [M +
Na]+ 395.0992, found 395.0996.
˚
using Cu-Ka radiation, (k = 1.5418 A), on an Oxford Diffraction
Gemini-S-Ultra diffractometer. 17995 reflections were measured
(7ꢀS,8R,8ꢀR)-[7ꢀ-18O]-7ꢀ-Acetoxy-3,3ꢀ,4,4ꢀ-
at 150 K, and merged to give 3252 unique reflections, Rmerge
=
bis(methylenedioxy)lignano-9,9ꢀ-lactone (18O-2a)
0.0431, in space group P21. The structure was refined to an R-
factor of 0.0299 (for all data) and Flack parameter of −0.19(14).‡
A solution of 18O-1a (88 mg, 0.15 mmol) in 5 ml of Ac2O-Py (4 : 1)
was stirred overnight at rt. The residue was extracted with CHCl3
(10 ml), washed with water (3 × 10 ml). The organic phase was
dried over anhydrous Na2SO4, filtered, evaporated and the crude
product was purified by flash chromatography (eluent CH2Cl2–
(8R,8ꢀR)-[7ꢀ-18O]-4,4ꢀ-Bis(tert-butyldimethylsilyloxy)-3,3ꢀ-
dimethoxy-7ꢀ-oxolignano-9,9ꢀ-lactone (18O-6b)
(CF3COO)2IPh (100 mg, 0.23 mmol) was added to a solution of
5b3 (55 mg, 0.08 mmol) in 10 : 1 CH3CN-18OH2 (1.1 ml) at rt. The
mixture was stirred for 30 min and then quenched with saturated
NaHCO3 (10 ml) and extracted with Et2O (3 × 10 ml). The organic
phase was dried over anhydrous Na2SO4, filtered, evaporated and
the crude compound was purified by flash chromatography (eluent
CH2Cl2) to obtain 18O-6b (20 mg, 41%) as a viscous oil. IR and
NMR were in agreement with data reported for the unlabeled
6b.3 HRMS (ESI-TOF) m/z calcd for C32H49O618OSi2 [M + H]+
603.3059, found 603.3054.
Et2O 20 : 1) to yield 85 mg (86%) of 18O-2a: [a]D −26.9◦ (c 0.3,
22
dioxane), (for 2a lit.4 −19.6◦, c 0.82, dioxane); IR (thin film) mmax
1769, 1743, 1227, 1034 cm−1;1H NMR (300 MHz, CDCl3) d(ppm)
6.74–6.69 (m, 2H), 6.64–6.55 (m, 4H), 5.97 (part A of an AB
system, J = 1.5 Hz, 1H), 5.95 (part B of an AB system, J =
1.5 Hz, 1H), 5.94 (part A of an AB system, J = 1.5 Hz, 1H), 5.93
(part B of an AB system, J = 1.5 Hz, 1H), 5.71 (d, J = 6.9 Hz,
1H), 3.99 (dd, J = 8.1, 9.6 Hz, 1H), 3.92 (dd, J = 6.0, 9.6 Hz,
1H), 2.96 (dd, J = 6.9, 13.8 Hz, 1H), 2.87 (dd, J = 4.8, 13.8 Hz,
1H), 2.83–2.68 (m, 2H), 2.11 (s, 3H); 13C NMR (75 MHz, CDCl3)
d(ppm) 178.0, 169.8, 148.1, 147.8 (2×), 146.5, 131.0, 130.7, 122.6,
120.1, 109.7, 108.3, 108.2, 106.5, 101.4, 101.0, 76.3, 68.0, 43.9,
43.4, 35.1, 21.0; HRMS (ESI-TOF) m/z calcd for C22H20NaO718O
[M + Na]+ 437.1098, found 437.1093.
(8R,8ꢀR)-[7ꢀ-18O]-3,3ꢀ,4,4ꢀ-Bis(methylenedioxy)-7ꢀ-oxolignano-9,9ꢀ-
lactone (18O-6a)
Following the same procedure as for 18O-6b, compound 18O-6a
was prepared from 5a3 in 86% yield after flash chromatography
(eluent CH2Cl2-Et2O 20:1). IR and NMR were in agreement with
data reported for the unlabeled 6a.3 HRMS (ESI-TOF) m/z calcd
for C20H16NaO618O [M + Na]+ 393.0831, found 393.0836.
General procedure with 2% KOH–MeOH4 (procedure A):
(7ꢀS,8S,8ꢀR)-[7ꢀ-18O]-3,3ꢀ,4,4ꢀ-bis(methylenedioxy)-8ꢀ-
hydroxymethyl-3,3ꢀ-dimethoxylignano-9,7ꢀ-lactone (18O-7a)
A solution of 18O-2a (78 mg, 0.19 mmol) in 2% KOH–MeOH
(5 ml) was stirred for 2 h at rt. The solution was acidified (pH 3)
with 2 N HCl and extracted with CH2Cl2 (3 × 20 ml). The organic
phase was dried over anhydrous Na2SO4, filtered, evaporated and
the crude product was purified by flash chromatography (eluent
CH2Cl2–Et2O 3 : 1) to yield 33 mg (47%) of 18O-1a and 20 mg (29%)
(7ꢀS,8R,8ꢀR)-[7ꢀ-18O]-4,4ꢀ-Bis(tert-butyldimethylsilyloxy)-7ꢀ-
hydroxy-3,3ꢀ-dimethoxylignano-9,9ꢀ-lactone (18O-1b) and
(7ꢀS,8R,8ꢀR)-[7ꢀ-18O]-4,4ꢀ-bis(tert-butyldimethylsilyloxy)-8ꢀ-
hydroxymethyl-3,3ꢀ-dimethoxylignano-9,7ꢀ-lactone (18O-4b)
R
L-Selectrideꢀ (1M in THF, 0.026 ml, 0.026 mmol) was added
dropwise to a solution of 18O-6b (12 mg, 0.020 mmol) in dry THF
(1 ml) under Ar at −78◦C and the mixture was stirred at the same
temperature for 2 h. The reaction was then stopped with saturated
NH4Cl (10 ml) and extracted with EtOAc (3 × 10 ml). The organic
phase was dried over anhydrous Na2SO4, filtered, evaporated and
the crude product was purified by flash chromatography (eluent
CH2Cl2-Et2O 20:1) to yield 8.5 mg (70%) of 18O-1b and 2 mg (16%)
of 18O-4b. IR and NMR were in agreement with data reported for
the unlabeled 1b and 4b.3 For 18O-1b: HRMS (ESI-TOF) m/z
calcd for C32H50NaO618OSi2 [M + Na]+ 627.3035, found 627.3030.
For 18O-4b: HRMS (ESI-TOF) m/z calcd for C32H50NaO618OSi2
[M + Na]+ 627.3035, found 627.3030.
of 18O-7a. For 18O-7a: [a]D + 66.97 (c 0.37, THF); IR (thin film)
27
1
mmax 3339, 1765, 1249, 1035 cm−1; H NMR (500 MHz, CDCl3)
d(ppm) 6.75 (d, J = 8.0 Hz, 1H), 6.73 (d, J = 7.5 Hz, 1H), 6.72 (d,
J = 1.5 Hz, 1H), 6.69 (dd, J = 1.5, 7.5 Hz, 1H), 6.66 (dd, J = 1.5,
8.0 Hz, 1H), 6.60 (d, J = 1.5 Hz, 1H), 5.96 (s, 2H), 5.94 (s, 2H), 5.13
(d, J = 8.5 Hz, 1H), 3.55 (dd, J = 3.5, 11.0 Hz, 1H), 3.48 (dd, J =
4.0, 11.0 Hz, 1H), 3.15 (dd, J = 5.0, 14.0 Hz, 1H), 3.06 (ddd, J =
5.0, 7.0, 12.0 Hz, 1H), 2.95 (dd, J = 7.0, 14.0 Hz, 1H), 2.28–2.22
(m, 1H); 13C NMR (75 MHz, CDCl3) d(ppm) 177.5, 148.3, 148.2,
148.1, 146.8, 132.4, 131.7, 122.5, 120.5, 109.8, 108.7, 108.4, 106.7,
101.5, 101.3, 81.2, 59.8, 50.9, 43.8, 35.1; HRMS (ESI-TOF) m/z
calcd for C20H18NaO618O [M + Na]+ 395.0992, found 395.0998.
(7ꢀS,8R,8ꢀR)-[7ꢀ-18O]-7ꢀ-Hydroxy-3,3ꢀ,4,4ꢀ-bis(methylenedioxy)-
lignano-9,9ꢀ-lactone (18O-1a) and (7ꢀS,8R,8ꢀR)-[7ꢀ-18O]-8ꢀ-
hydroxymethyl-3,3ꢀ,4,4ꢀ-bis(methylenedioxy)lignano-9,7ꢀ-
lactone (18O-4a)§
(7ꢀS,8S,8ꢀR)-3,3ꢀ,4,4ꢀ-Bis(methylenedioxy)-8ꢀ-hydroxymethyl-3,3ꢀ-
dimethoxylignano-9,7ꢀ-lactone (7a)
Compound 1a3 was treated as described in the procedure A to
obtain after flash chromatography (eluent CH2Cl2–Et2O 3 : 1) a
mixture of starting material 1a (61%) and rearranged lactone 7a
(31%). For 7a: [a]D22 + 90.14◦ (c 0.4, CHCl3); IR and NMR were in
Following the same procedure as for 18O-1b and 18O-4b, com-
pounds 18O-1a and 18O-4a§ were prepared from 18O-6a in 72% and
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agreement with the data of 18O-7a; HRMS (ESI-TOF) m/z calcd
(8R,8ꢀR)-3ꢀ,4ꢀ-Dimethoxy-3,4-methylenedioxy-7ꢀ-oxolignano-9,9ꢀ-
lactone (6c)
for C20H18NaO7 [M + Na]+ 393.0950, found 393.0956.
Following the same procedure as for 18O-6b, using H2O instead
of 18OH2, compound 6c was prepared in 65% yield as a white
solid after flash chromatography (eluent CH2Cl2–Et2O 20 : 1):
mp 153–154◦C (CHCl3–Et2O) (lit.7 140–141◦C (AcOEt–acetone));
[a]D + 41.08 (c 0.1, CHCl3); 13C NMR (125 MHz, CDCl3)
d(ppm) 195.0, 177.0, 154.2, 149.4, 147.8, 146.5, 130.7, 128.9, 122.9,
122.5, 110.3, 110.0, 109.8, 108.3, 101.0, 68.3, 56.2, 56.0, 46.5, 44.8,
34.5; IR, MS and 1H NMR were in agreement with reported
data;7 HRMS (EI) m/z calcd for C21H20O7 (M+), 384.1209; found,
384.1204.
General procedure with NaH–DMF7 (procedure B)
A solution of 1a3 (50 mg, 0.13 mmol) in DMF (2 ml) was added to
a mixture of NaH (8 mg, 55–65% oil dispersion, previously rinsed
with n-hexane) in DMF (2 ml) at 0◦C under Ar. The reaction
mixture was stirred at the same temperature for 1.5 h and then
acidified (pH 3–4) with 2 N HCl. The mixture was extracted with
EtOAc (3 × 10 ml) and the organic phase was washed with water
(2 × 10 ml), dried over anhydrous Na2SO4, filtered, evaporated and
the crude product was purified by flash chromatography (eluent
CH2Cl2–Et2O 3 : 1) to yield 11.5 mg (23%) of compound 1a and
16.5 mg (33%) of compound 7a.
◦
25
(7ꢀS,8R,8ꢀR)-7ꢀ-Hydroxy-3ꢀ,4ꢀ-dimethoxy-3,4-
methylenedioxylignano-9,9ꢀ-lactone (1c) and
(7ꢀS,8R,8ꢀR)-8ꢀ-hydroxymethyl-3ꢀ,4ꢀ-dimethoxy-3,4-
methylenedioxylignano-9,7ꢀ-lactone (4c)
General procedure with 1M aq NaOH–EtOH8 (procedure C)
Following the same procedure as for 18O-1b and 18O-4b, com-
pounds 1c (de 97%) and 4c were prepared in 61% and 7% yield,
respectively, after flash chromatography (eluent CH2Cl2–Et2O 10 :
A solution of 7a (50 mg, 0.13 mmol) in 1M aq NaOH (1 ml) and
EtOH (1 ml) was stirred overnight at rt and then acidified (pH 3–4)
with 2 N HCl. The mixture was extracted with EtOAc (3 × 10 ml).
The organic phase was washed with water (2 × 10 ml), dried over
anhydrous Na2SO4, filtered, evaporated and the crude product was
purified by flash chromatography (eluent CH2Cl2–Et2O 3 : 1) to
yield only the starting material 7a (80%).
1). For 1c mp 122–124◦C (Et2O); [a]D −20.09◦ (c 0.34, CHCl3);
22
13C NMR (125 MHz, CDCl3) d(ppm) 178.8, 149.3, 149.1, 147.7,
146.4, 133.9, 131.3, 122.7, 118.1, 111.1, 109.9, 108.8, 108.0, 101.0,
75.4, 68.4, 55.9, 55.8, 45.2, 43.6, 35.2; IR, MS and 1H NMR
were in agreement with reported data;7 HRMS (EI) m/z calcd fo◦r
C21H22O7 (M+), 386.1365; found, 386.1362. For 4c: [a]D24 + 44.47
1
(c 0.54, THF); IR (thin film) mmax 3517, 1769 cm−1; H NMR
(8R,8ꢀR)-3ꢀ,4ꢀ-Dimethoxy-3,4-methylenedioxy-7ꢀ-(propane-1,3-
(500 MHz, CDCl3) d(ppm) 6.85 (d, J = 8.0 Hz, 1H), 6.82 (dd, J =
2.0, 8.0 Hz, 1H), 6.78 (d, J = 2.0 Hz, 1H), 6.71 (d, J = 8.0 Hz,
1H), 6.69 (d, J = 1.5 Hz, 1H), 6.65 (dd, J = 1.5, 8.0 Hz, 1H), 5.91
(s, 2H), 5.53 (d, J = 2.0 Hz, 1H), 3.96 (dd, J = 4.5, 11.0 Hz, 1H),
3.87 (s, 3H), 3.86 (s, 3H), 3.78 (dd, J = 7.5, 11.0 Hz, 1H), 3.20
(dd, J = 5.0, 15.0 Hz, 1H), 3.04 (ddd, J = 5.0, 8.5, 11.0 Hz, 1H),
2.74 (dd, J = 11.0, 15.0 Hz, 1H), 2.62–2.58 (m, 1H); 13C NMR
(125 MHz, CDCl3) d(ppm) 177.8, 149.3, 148.9, 147.9, 146.3, 132.3,
131.5, 121.2, 116.9, 111.3, 108.6, 108.4, 108.2, 101.0, 80.9, 60.8,
56.0, 55.9, 47.4, 41.1, 30.7; EIMS m/z (relative intensity): 386 (M+,
50%), 368 (40), 194 (20), 167 (100), 135 (70); HRMS (EI) m/z calcd
for C21H22O7 (M+), 386.1365; found, 386.1378.
diyldithio)-lignano-9,9ꢀ-lactone (5c)
LHMDS (1.6M in THF, 0.58 ml, 0.92 mmol) was added
dropwise to a solution of (3R)-[(propane-1,3-diyldithio)-(3,4-
dimethoxyphenyl)methyl]butano-4-lactone3 (286 mg, 0.84 mmol)
in THF (3 ml) at −78 ◦C under Ar. The reaction mixture was
stirred for 2 h, then DMI (0.10 ml, 0.92 mmol) was added dropwise
followed, after 30 min, by a solution of piperonyl bromide 17a10
(200 mg, 0.93 mmol) in THF (1 ml). The mixture was stirred at
the same temperature for 1 h and then allowed to reach rt in 2 h,
then quenched with saturated NH4Cl (10 ml) and extracted with
Et2O (3 × 15 ml). The organic phase was dried over anhydrous
Na2SO4, filtered, evaporated and the crude compound was purified
by flash chromatography (eluent CH2Cl2–Et2O 10 : 1) to obtain
5c as a white s◦olid (310 mg, 78%): mp 89–91◦C (Et2O–n-hexane);
(7ꢀS,8S,8ꢀR)-8ꢀ-Hydroxymethyl-3ꢀ,4ꢀ-dimethoxy-3,4-
methylenedioxylignano-9,7ꢀ-lactone (7c)
[a]D + 72.17 (c 1.0, CHCl3); IR (thin film) mmax 1766 cm−1; H
NMR (500 MHz, CDCl3) d(ppm) 7.48 (dd, J = 2.0, 8.0 Hz, 1H),
7.33 (d, J = 2.0 Hz, 1H), 6.86 (d, J = 8.0 Hz, 1H), 6.63 (d, J =
8.0 Hz, 1H), 6.41 (dd, J = 2.0, 8.0 Hz, 1H), 6.36 (d, J = 2.0 Hz,
1H), 5.95 (part A of an AB system, J = 1.5 Hz, 1H), 5.91 (part
B of an AB system, J = 1.5 Hz, 1H), 4.68 (dd, J = 5.0, 10.0 Hz,
1H), 3.99 (dd, J = 9.0, 10.0 Hz, 1H), 3.94 (s, 3H), 3.83 (s, 3H),
3.09–3.05 (m, 1H), 2.82 (dd, J = 7.0, 14.0 Hz, 1H), 2.77–2.57 (m,
5H), 2.49 (dd, J = 5.0, 14.0 Hz, 1H), 1.96–1.82 (m, 2H); 13C NMR
(125 MHz, CDCl3) d(ppm) 178.3, 149.3, 148.5, 147.7, 146.5, 131.4,
130.4, 122.6, 122.3, 112.0, 110.7, 109.5, 107.9, 101.0, 67.8, 62.5,
55.8 (2×), 50.3, 42.8, 36.1, 27.2, 27.0, 24.7; EIMS m/z (relative
intensity): 474 (M+, 80%), 399 (50), 368 (49), 255 (100), 175 (80),
135 (90); HRMS (EI) m/z calcd for C24H26O6S2 (M+), 474.1171;
found, 474.1177.
25
1
Compound 1c was treated according to the general procedures A
and B and a mixture of 1c and 7c was obtained (for ratios and
yields see Table 1). For 7c: [a]D27 + 47.45 (c 1.08, THF); 13C NMR
(125 MHz, CDCl3) d(ppm) 177.5, 149.5, 149.4, 147.9, 146.4, 131.5,
130.7, 122.4, 119.2, 110.9, 109.7, 108.9, 108.4, 101.0, 81.0, 59.6,
55.9, 55.8, 50.3, 43.6, 34.6; IR, MS and 1H NMR were in agreement
with reported data;7 HRMS (EI) m/z calcd for C21H22O7 (M+),
386.1365; found, 386.1362.
(7ꢀS,8S,8ꢀR)-3,3ꢀ,4,4ꢀ-Bis(methylenedioxy)-3,3ꢀ-dimethoxy-8ꢀ-(3,5-
dinitrobenzoyloxy)methyllignano-9,7ꢀ-lactone (8a)
3,5-Dinitrobenzoyl chloride (100 mg, 0,46 mmol) was added to a
solution of 7a (40 mg, 0.11 mmol) in Py (4 ml) and the mixture
was stirred overnight at rt. The reaction was stopped with water
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1
(10 ml) and extracted with CH2Cl2 (3 × 20 ml). The organic phase
was washed with water (2 × 10 ml), dried over anhydrous Na2SO4,
filtered, evaporated and the crude compound was purified by flash
chromatography (eluent CH2Cl2–Et2O 4 : 1) to obtain 8a as a
yellow solid (40 mg, 65%): mp 182–183◦C (CH2Cl2); [a]D25 + 66.81 ◦
120◦C (Et2O–n-hexane), IR (thin film) mmax 1766 cm−1; H NMR
(500 MHz, CDCl3) d(ppm) 7.42 (dd, J = 1.5, 8.0 Hz, 1H), 7.37 (d,
J = 1.5 Hz, 1H), 6.80 (d, J = 8.0 Hz, 1H), 6.79 (d, J = 1.5 Hz,
1H), 6.76 (dd, J = 1.5, 8.0 Hz, 1H), 6.71 (d, J = 8.0 Hz, 1H), 6.00
(s, 2H), 5.92 (s, 2H), 4.48 (app t, J = 9.5 Hz, 1H), 3.81 (app t, J =
9.0 Hz, 1H), 3.07 (d, J = 13.5 Hz, 1H), 2.86–2.61 (m, 6H), 1.96–
1.89 (m, 2H), 1.60 (s, 3H); 13C NMR (125 MHz, CDCl3) d(ppm)
181.0, 148.4, 147.6, 146.9, 146.5, 134.8, 130.4, 124.2, 123.4, 111.2,
109.7, 108.0, 107.9, 101.5, 100.9, 65.9, 61.0, 51.2, 49.3, 44.1, 28.1,
27.6, 24.8, 21.9; EIMS m/z (relative intensity): 472 (M+, 30%),
239 (80), 206 (50), 165 (20), 135 (100); HRMS (EI) m/z calcd for
C24H24O6S2 (M+), 472.1014; found, 472.1013.
1
(c 0.31, THF); IR (thin film) mmax 1771, 1733 cm−1; H NMR
(500 MHz, CDCl3) d(ppm) 9.20 (app. t, J = 2.0 Hz, 1H), 8.80 (d,
J = 2.0 Hz, 2H), 6.75 (d, J = 7.5 Hz, 1H), 6.74 (d, J = 1.5 Hz, 1H),
6.71 (dd, J = 1.5, 7.5 Hz, 1H), 6.68 (dd, J = 1.5, 7.5 Hz, 1H), 6.63
(d, J = 7.5 Hz, 1H), 6.59 (d, J = 1.5 Hz, 1H), 5.93 (s, 2H), 5.92
(m, 2H), 5.04 (d, J = 9.0 Hz, 1H), 4.23 (d, J = 6.0 Hz, 2H), 3.22
(dd, J = 4.0, 14.0 Hz, 1H), 3.00 (dd, J = 7.5, 14.0 Hz, 1H), 2.91–
2.87 (m, 1H), 2.82–2.76 (m, 1H); 13C NMR (125 MHz, CDCl3)
d(ppm) 175.8, 162.2, 148.8 (2×), 148.7, 148.5, 148.4, 147.1, 132.9,
131.2, 130.9, 129.4 (2×), 122.8, 122.5, 121.1, 109.6, 108.9, 108.4,
106.9, 101.8, 101.4, 82.9, 65.6, 47.7, 45.4, 35.3; EIMS m/z (relative
intensity): 564 (M+, 40%), 534 (20), 372 (100), 342 (40), 192 (70),
135 (90); HRMS (EI) m/z calcd for C27H20O12N2 (M+), 564.1016;
found, 564.1011.
(8R*,8ꢀR*)-8-Methyl-3,3ꢀ,4,4ꢀ-bis(methylenedioxy)-7ꢀ-oxolignano-
9,9ꢀ-lactone (19a)
Following the procedure as for 18O-6a, using H2O instead of
18OH2, compound 19a was prepared from 18a in 60% yield after
flash chromatography (eluent CH2Cl2); mp 113–114 ◦C (Et2O–n-
hexane); IR (thin film) mmax 1763, 1668 cm−1; 1H NMR (500 MHz,
CDCl3) d(ppm) 7.26 (dd, J = 1.5, 8.0 Hz, 1H), 7.20 (d, J = 1.5 Hz,
1H), 6.81 (d and d overlapping, J = 8.0 Hz, 2H), 6.74 (d, J =
8.0 Hz, 1H), 6.71 (dd, J = 1.5, 8.0 Hz, 1H), 6.07 (s, 2H), 5.99 (s,
2H), 4.58 (dd, J = 4.5, 9.0 Hz, 1H), 4.18 (dd, J = 4.5, 8.0 Hz,
1H), 3.93 (dd, J = 8.0, 9.0 Hz, 1H), 3.11 (d, J = 13.5 Hz, 1H),
2.72 (d, J = 13.5 Hz, 1H), 1.13 (s, 3H); 13C NMR (125 MHz,
CDCl3) d(ppm) 196.3, 179.9, 152.5, 148.6, 148.1, 147.2, 131.9,
129.6, 124.7, 123.3, 110.3, 108.5, 108.0, 107.9, 102.1, 101.2, 66.7,
48.2, 47.0, 44.1, 20.7; EIMS m/z (relative intensity): 380 (M+, 5%),
443 (100), 236 (80), 179 (90), 165 (50); HRMS (EI) m/z calcd for
C21H18O7 (M+), 382.1052; found, 382.1039.
(2R*,3R*)-2-Methyl-3-[(propane-1,3-diyldithio)-(3,4-
methylendioxyphenyl)methyl]-butano-4-lactone (trans-16a) and
(2S*,3R*)-2-methyl-3-[(propane-1,3-diyldithio)-(3,4-
methylendioxyphenyl)methyl]-butano-4-lactone (cis-16a)
n-BuLi (1.3M in n-hexane, 1.80 ml, 2.29 mmol) was added
dropwise to a solution of thioacetal 14a9 (500 mg, 2.08 mmol)
in THF (10 ml) at −78 ◦C under Ar. The mixture was stirred
for 1 h, then DMPU (0.28 ml, 2.29 mmol) was added dropwise
followed, after 30 min, by slow addition of 15 (225 mg, 2.29 mmol)
in THF (2 ml). The reaction mixture was stirred for 2 h at the same
temperature, then quenched with saturated NH4Cl and extracted
with Et2O. The organic phase was dried over anhydrous Na2SO4,
filtered, evaporated and the crude compound was purified by flash
chromatography (eluent CH2Cl2–Et2O 20 : 1) to obtain 547 mg
(78%) of a 2 : 1 mixture oftrans-16a and cis-16a (not separated): mp
88–90◦C (Et2O); IR (thin film) mmax 1766 cm−1; EIMS m/z (relative
intensity): 338 (M+, 60%), 239 (100), 165 (100); HRMS (EI) m/z
calcd for C16H18O4S2 (M+), 338.0646; found, 338.0653. For trans-
16a (major product): 1H NMR (500 MHz, CDCl3) d(ppm) 7.49–
7.45 (m, 2H), 6.83 (d, J = 8.5 Hz, 1H), 6.01 (s, 2H), 4.42 (dd, J =
8.5, 9.5 Hz, 1H), 4.23 (dd, J = 9.0, 9.5 Hz, 1H), 2.84–2.57 (m, 6H),
1.99–1.84 (m, 2H), 1.42 (d, J = 7.5 Hz, 3H); 13C NMR (125 MHz,
CDCl3) d(ppm) 179.0, 148.6, 147.2, 133.1, 123.3, 109.5, 108.2,
101.5, 67.0, 61.1, 55.4, 35.9, 27.2, 27.1, 24.7, 17.0. For cis-16a
(minor product): 1H NMR (500 MHz, CDCl3) d(ppm) 7.49–7.46
(m, 2H), 6.81 (d, J = 8.5 Hz, 1H), 6.00 (s, 2H), 4.54 (app. t, J =
9.5 Hz, 1H), 4.20 (dd, J = 7.0, 9.5 Hz, 1H), 2.95 (app. q J =
8 Hz, 1H), 2.84–2.57 (m, 5H), 1.99–1.84 (m, 2H), 1.42 (d, J =
8.0 Hz, 3H); 13C NMR (125 MHz, CDCl3) d(ppm) 178.8, 148.4
146.9, 134.4, 123.2, 109.4, 107.9, 101.5, 67.5, 59.2, 52.6, 38.4, 27.6,
27.5, 24.6, 13.1.
(7ꢀS*,8R*,8ꢀR*)-7ꢀ-Hydroxy-8-methyl-3,3ꢀ,4,4ꢀ-
bis(methylenedioxy)-lignano-9,9ꢀ-lactone
[( )-8-methylparabenzlactone, 13a] and
(7ꢀS*,8R*,8ꢀR*)-8ꢀ-hydroxymethyl-8-methyl-3,3ꢀ,4,4ꢀ-
bis(methylenedioxy)-3,3ꢀ-dimethoxylignano-9,7ꢀ-lactone (20a)
Following the same procedure as for 18O-1b and 18O-4b, com-
pounds 13a (de 99%) and compound 20a were obtained in 70%
and 9% respectively after flash chromatography (eluent CH2Cl2–
Et2O 20 : 1). For 13a: mp 159–160◦C (Et2O); IR (thin film) mmax
1
3510, 1762 cm−1; H NMR (500 MHz, CDCl3) d(ppm) 6.93 (d,
J = 1.5 Hz, 1H), 6.88 (dd, J = 1.5, 8.0 Hz, 1H), 6.79 (d, J =
1.5 Hz, 1H), 6.78 (d, J = 8.0 Hz, 1H), 6.75 (d, J = 8.0 Hz, 1H),
6.70 (dd, J = 1.5, 8.0 Hz, 1H), 5.97 (part A of an AB system, J =
1.5 Hz, 1H), 5.96 (s, 2H), 5.94 (part B of an AB system, J = 1.5 Hz,
1H), 4.63 (dd, J = 2.0, 10.0 Hz, 1H), 3.55 (dd, J = 9.0, 11.0 Hz,
1H), 3.44 (app. t, J = 9.0 Hz, 1H), 3.23 (d, J = 13.5 Hz, 1H),
2.99 (d, J = 13.5 Hz, 1H), 2.74 (dt, J = 9.0, 11.0 Hz, 1H), 1.45
(s, 3H); 13C NMR (125 MHz, CDCl3) d(ppm) 181.4, 148.3, 148.0,
147.5, 146.3, 136.0, 131.2, 124.4, 119.7, 111.6, 108.4, 108.0, 106.4,
101.3, 100.8, 74.0, 66.3, 47.5, 45.2, 42.4, 18.9; EIMS m/z (relative
intensity): 384(M+, 50%), 366 (20), 151 (40), 135 (100); HRMS
(EI) m/z calcd for C21H20O7 (M+), 384.1209; found, 384.1194. For
(8R*,8ꢀR*)-8-Methyl-3,3ꢀ,4,4ꢀ-bis(methylenedioxy)-7ꢀ-(propane-
1,3-diyldithio)-lignano-9,9ꢀ-lactone (18a)
1
20a: viscous oil, IR (thin film) mmax 3473, 1757 cm−1; H NMR
Following the same procedure as for 5c, compound 18a was
prepared from 16a (cis and trans) and piperonyl bromide 17a10 in
66% yield after flash chromatography (eluent CH2Cl2): mp 118–
(500 MHz, CDCl3) d(ppm) 6.81 (d, J = 1.5 Hz, 1H), 6.78 (d, J =
8.0 Hz, 1H), 6.75 (m, 2H), 6.71 (d, J = 1.5 Hz, 1H), 6.67 (dd,
J = 1.5, 8.0 Hz, 1H), 5.97 (AB system, J = 2.0 Hz, 2H), 5.94 (AB
2626 | Org. Biomol. Chem., 2008, 6, 2619–2627
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system, J = 2.0 Hz, 2H), 4.84 (d, J = 10.5 Hz, 1H), 4.01 (dd, J =
8.0, 11.5 Hz, 1H), 3.84 (dd, J = 5.5, 11.5 Hz, 1H), 2.99 (d, J =
13.5 Hz, 1H), 2.85 (d, J = 13.5 Hz, 1H), 2.44 (ddd, J = 5.5, 8.0,
10.5 Hz, 1H), 1.37 (s, 3H); 13C NMR (125 MHz, CDCl3) d(ppm)
179.1, 148.2, 148.1, 147.5, 146.7, 131.8, 129.5, 123.4, 120.3, 110.6,
108.3, 108.1, 106.6, 101.4, 101.0, 80.3, 58.9, 57.6, 48.0, 38.5, 23.7;
EIMS m/z (relative intensity): 384 (M+, 50%), 366 (20), 151 (40),
135 (100); HRMS (EI) m/z calcd for C21H20O7 (M+), 384.1209;
found, 384.1201.
J = 1.5 Hz, 1H), 6.70 (dd, J = 2.0, 8.0 Hz, 1H), 6.69 (dd, J = 1.5,
8.0 Hz, 1H), 6.49 (d, J = 2.0 Hz, 1H), 5.11 (d, J = 9.5 Hz, 1H),
3.87 (s, 3H), 3.77 (s, 3H), 3.58 (dd, J = 3.5, 11.0 Hz, 1H), 3.50
(dd, J = 4.0, 11.0 Hz, 1H), 3.14–3.05 (m, 3H), 2.32–2.27 (m, 1H);
13C NMR (125 MHz, CDCl3) d(ppm) 177.7, 146.9, 146.7, 146.2,
144.5, 130.1, 129.7, 122.3, 120.1, 114.4, 114.1, 111.9, 108.2, 81.2,
59.0, 56.0, 55.9, 50.1, 43.8, 34.4; EIMS m/z (relative intensity):
374 (M+, 80%), 356 (20), 194 (20), 180 (90), 153 (30), 151 (30), 137
(100); HRMS (EI) m/z calcd for C20H22O7 (M+) 374.1365, found
374.1360.
Compound 19a was treated according to the general procedures
A, B, and C, obtaining in all cases a mixture of starting material
13a (19–28%) and rearranged lactone 20a (41–65%).
Acknowledgements
(7ꢀS,8S,8ꢀR)-8ꢀ-tert-Butyldimethylsilyloxymethyl-4,4ꢀ-dihydroxy-
3,3ꢀ-dimethoxylignano-9,7ꢀ-lactone (21e) and (7ꢀS,8S,8ꢀR)-
4,4ꢀ-dihydroxy-8ꢀ-hydroxymethyl-3,3ꢀ-dimethoxylignano-9,7ꢀ-
lactone (7e)
The Academy of Finland is acknowledged for support (grant
210633).
Notes and references
Compound 1b3 was treated according to the general procedure B,
1 K.-H. Lee and Z. Xiao, Phytochem. Rev., 2003, 2, 341.
2 R. S. Ward, in Studies in Natural Products Chemistry, Bioactive Natural
Products, Part E, Elsevier, Amsterdam, 2000, 24, 739.
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220.
to give after flash chromatography (eluent CH2Cl2–MeOH 97 : 3)
27
21e (55%) and 7e (26%). For 21e: [a]D + 36.83 (c 0.57, THF); IR
1
(thin film) mmax 1765 cm−1; H NMR (500 MHz, CDCl3) d(ppm)
6.84 (d, J = 8.0 Hz, 1H), 6.81 (d, J = 8.0 Hz, 1H), 6.79 (d,
J = 2.0 Hz, 1H), 6.67 (dd, J = 2.0, 8.0 Hz, 1H), 6.66 (dd, J =
2.0, 8.0 Hz, 1H), 6.46 (d, J = 2.0 Hz, 1H), 5.11 (d, J = 9.0 Hz,
1H), 3.86 (s, 3H), 3.77 (s, 3H), 3.49 (dd, J = 3.5, 10.5 Hz, 1H),
3.41 (dd, J = 3.5, 10.5 Hz, 1H), 3.15–3.10 (m, 1H), 3.05 (d, J =
5.5 Hz, 2H), 2.26–2.21 (m, 1H), 0.89 (s, 9H), 0.14 (s, 6H); 13C
NMR (125 MHz, CDCl3) d(ppm) 178.1, 146.9, 146.6, 146.1, 144.5,
130.2, 129.8, 122.4, 120.1, 114.2, 114.0, 111.9, 108.2, 81.0, 59.0,
55.9, 55.8, 50.6, 43.3, 34.4, 25.8 (3×), 18.2, −5.6 (2x); EIMS m/z
(relative intensity): 488 (M+, 40%), 431 (30), 401 (20), 277 (80),
151 (30), 137 (100); HRMS (EI) m/z calcd for C26H36O7Si (M+)
10 A. van Oeveren, J. F. G. A. Jansen and B. L. Feringa, J. Org. Chem.,
1994, 59, 5999.
11 S. Hanessian and P. J. Murray, Can. J. Chem., 1986, 64, 2231.
12 P. Kiuru, and K. Wa¨ha¨la¨, unpublished results.
13 J. Fischer, A. J. Reynolds, L. A. Sharp and M. S. Sherburn, Org. Lett.,
2004, 6, 1345.
27
488.2230, found 488.2236. For 7e: [a]D +52.68 (c 0.2, THF); IR
1
(thin film) mnmax 1748 cm−1; H NMR (500 MHz, CDCl3) d(ppm)
6.84 (d, J = 8.0 Hz, 1H), 6.83 (d, J = 8.0 Hz, 1H), 6.81 (d,
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