Asymmetric synthesis, stereochemistry and rearrangement reactions of naturally occurring 7′-hydroxylignano-9,9′-lactones

Article abstract of DOI:10.1039/b513303c

The asymmetric synthesis of a series of (7′S,8R,8′R)-7′- hydroxylignano-9,9′-lactones is presented, among them the mammalian lignan (7′S)-hydroxyenterolactone and (7′S)-parabenzlactone, allowing the stereochemistry of natural occurring (-)-parabenzlactone

Full text of DOI:10.1039/b513303c

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Asymmetric synthesis, stereochemistry and rearrangement reactions
of naturally occurring 7ꢀ-hydroxylignano-9,9ꢀ-lactones
Barbara Raffaelli, Kristiina Wa¨ha¨la¨* and Tapio Hase
Received 20th September 2005, Accepted 17th November 2005
First published as an Advance Article on the web 12th December 2005
DOI: 10.1039/b513303c
The asymmetric synthesis of a series of (7ꢀS,8R,8ꢀR)-7ꢀ-hydroxylignano-9,9ꢀ-lactones is presented,
among them the mammalian lignan (7ꢀS)-hydroxyenterolactone and (7ꢀS)-parabenzlactone, allowing
the stereochemistry of natural occurring (–)-parabenzlactone to be re-assigned. A hydroxylactone
rearrangement and its possible mechanisms are discussed. Finally a brief survey of the current naming
and numbering variants of 7ꢀ-hydroxylignano-9,9ꢀ-lactones is presented, along with a suggestion for
harmonization of the nomenclature.
viously assigned.16,17 Also for the natural compound 3 the configu-
Introduction
ration at the 7ꢀ position was recently re-assigned as being 7ꢀR.12 The
configuration of naturally occurring (–)-parabenzlactone has been
inferred18,19 as 7ꢀR, after the absolute configurations at C-7 of the 7-
hydroxylignanolactone podorhizol and its 7-epimer epipodorhizol
were established as S and R, respectively.20 The latter assignments
were based on the intramolecular 7-OH hydrogen bonding to
the lactone carbonyl, which was observed (and possible) in the
epi compound only. The podorhizol and epipodorhizol 7-CH
1H-NMR parameters (d and J) were applied18,19 to show that
(–)-parabenzlactone possesses the 7ꢀR configuration. Obviously
this analysis is inherently prone to errors because of the different
environment of the 7- and 7ꢀ-sites.
Compounds 5 and 6 have been both detected in human plasma,
and being derived from the plant lignan 1 and/or 2, are likely to
have retained the trans 8R/8ꢀR configuration, but they have never
been isolated, synthesized nor characterized as pure isomers.
Several synthetic procedures exist in literature12,21,22 for the
formation of the trans 8R/8ꢀR configuration leading to optically
active lignanolactones, either lacking benzylic functionalities
altogether or with a hydroxyl group at the C-7 position. The
recent asymmetric synthesis12 of (7ꢀS,8R,8ꢀR)- and (7ꢀR,8R,8ꢀR)-
HLLs relied on a radical carboxylation approach. Enantiopure
7ꢀ-hydroxyarctigenin has also been obtained via a semi-synthetic
route, by benzylic oxidation at C-7ꢀ of arctigenin monoacetate, but
at that time the stereochemistry of 7ꢀ-HLLs was still uncertain
and in fact in the paper the R and S configurations are incorrectly
assigned.19
In this paper we present a general approach for the stereoselec-
tive synthesis of several (7ꢀS,8R,8ꢀR)-HLLs. Thus, we report the
first asymmetric synthesis of lignans 5, 9 and 10, together with
the synthesis of 1 and 8, which also serves to clarify the absolute
configuration of naturally occurring (–)-parabenzlactone, which
in our opinion has been erroneously assigned.18 Additionally, we
report the formation of a new HLL-related hydroxylactone arising
from a rearrangement reaction in a hydride ketone reduction. The
presumed mechanism of formation is presented and discussed,
together with other possible mechanisms which may be responsible
of the formation of related lactones described in literature. Finally
we would like to point out the confusing naming and numbering
systems used at present in the literature for the 7- and 7ꢀ-HLLs.
(8R,8ꢀR)-Dibenzylbutyrolactones [or (8R,8ꢀR)-lignano-9,9ꢀ -
lactones, according to IUPAC recommendations]1 represent a
large class of naturally occurring lignans,2 but only six compounds
bearing a hydroxyl groupatthe 7ꢀ position (7ꢀ-hydroxylignano-9,9ꢀ-
lactones, 7ꢀ-HLL) are known up today (1–6, Fig. 1). Compounds
1–4 are plant lignans,3,4,5 while 5 and its isomer 6 are so-called
mammalian lignans,6,7 products of intestinal bacterial metabolism.
The current interest in 1–6 stems from their biological activities.
For example, (7ꢀS)-hydroxymatairesinol 1 [(7ꢀS,8R,8ꢀR)-4,4ꢀ,7ꢀ-
trihydroxy-3,3ꢀ-dimethoxylignano-9,9ꢀ-lactone] and its 7ꢀ-epimer
(7ꢀR)-hydroxymatairesinol 2 [also called allo-hydroxymatairesinol,
(7ꢀR,8R,8ꢀR)-4,4ꢀ,7ꢀ-trihydroxy-3,3ꢀ-dimethoxylignano-9,9ꢀ-lactone]
have been in the last years under biological and clinical studies,8,9
since it was discovered that they are precursors of the mammalian
lignan enterolactone 7 (Fig. 1), which possesses antitumor
activity.9,10 (7ꢀR)-parabenzlactone 4 [(7ꢀR,8R,8ꢀR)-7ꢀ-hydroxy-4,4ꢀ,
5,5ꢀ-dimethylenedioxylignano-9,9ꢀ-lactone] showed immunosup-
pressive properties on certain human lymphocytes.11 Biological
effects of (7ꢀR)-hydroxyarctigenin 3 [(7ꢀR,8R,8ꢀR)-4,7ꢀ-dihydroxy-
3,3ꢀ,4ꢀ-trimethoxylignano-9,9ꢀ-lactone], (7ꢀS)-hydroxyenterolactone
5
[(7ꢀS,8R,8ꢀR)-4,4ꢀ,7ꢀ-trihydroxylignano-9,9ꢀ-lactone] and its
7ꢀ-epimer (7ꢀR)-hydroxyenterolactone
6
[(7ꢀR,8R,8ꢀR)-4,4ꢀ,7ꢀ-
trihydroxylignano-9,9ꢀ-lactone] are not known at present, but
compounds 5 and 6 are metabolites of 1 and/or 2 and possible
precursors and/or metabolites of enterolactone 7.7
Lack of synthetic enantiopure compounds has obstructed the
assignment of absolute configuration of the molecules. In fact the
first stereoselective synthesis of 1–3 and 8 appeared12 only last year,
while compounds 4–6 and 9 have been only prepared as a mixture
of enantiomers.13,14
The plant derived lignans possess a trans 8R/8ꢀR configuration,
while the stereochemistry at 7ꢀ has long been unclear owing to
conflicting literature reports. The configurations of 1 and 2 were
only recently indirectly determined as 7ꢀS and 7ꢀR,15 respectively,
by X ray analysis of the corresponding diols, opposite to those pre-
Department of Chemistry, Laboratory of Organic Chemistry, University
of Helsinki, P.O. Box 55, FIN-00014, Finland. E-mail: kristiina.wahala@
helsinki.fi; Fax: +358 9191 50357
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Fig. 1 Naturally (1–6) and non-naturally occurring (8–10) 7ꢀ-hydroxylignano-9,9ꢀ-lactones. The metabolite enterolactone (7) is also shown. Note that
the (7ꢀR) configuration assigned in literature to (–)-parabenzlactone (4) is incorrect as shown in this work, and the true structure for the (–)-enantiomer
is (9).
dithio attachment.23,24 It would appear an attractive possibility to
first carry out a deketalization on the tandem product 14 and then
perform a double stereoselective reduction (on the ketone and the
Results and discussion
For establishing the trans 8R/8ꢀR stereochemistry, we first ex-
amined the well known tandem Michael addition–alkylation
ring-opened lactone aldehyde), but such a streamlined sequence
sequence,23,24 employing a lithiated dithiane 11 as nucleophile, 5-
is frustrated by the two competing relactonization modes, i.e., via
(–)-menthyloxybutenolide 1225 as a chiral auxiliary and Michael
acceptor, and a benzylic bromide 13 as an alkylating agent
(Scheme 1).
either the primary or the secondary hydroxyl (see below). This
is why in our experience also the silanyloxy–nitrile alternative
(used in place of the dithiane moiety)26 was not satisfactory due to
the silanyloxy–nitrile hydrolysis which occurs in the menthyloxy
removal step.
However, the menthyloxy auxiliary is easily removed before
alkylation.27 Thus the Michael addition of lithiated dithianes
11a–e28 to the chiral butenolide 12 afforded 16a–e in 75–88%
yield as single isomers (Scheme 2), provided 1,3-dimethyl-3,4,5,6-
tetrahydro-2(1H)-pyrimidinone (DMPU)29 was used as a co-
solvent and complexing reagent (DMPU was also essential in the
tandem Michael addition–alkylation reaction). The menthyloxy
moiety was then smoothly detached by a basic lactone hydrolysis
followed by the in situ NaBH4 reduction of the aldehyde formed,
giving the chiral lactones 17a–e (60–82% yield) on ordinary acidic
1
workup (pH 5–6). No isomerization was detected by H NMR,
Scheme 1
using the chiral shift reagent Eu(hfc)3 (ee ≥ 98%). Alkylation
of 17a–e with the appropriate benzylic bromides 13a–d gave the
lignanolactone derivatives 15a–e in acceptable yields (66–78%) and
with the wanted trans 8R/8ꢀR configuration.30
Unfortunately the product 14, obtained in 56% yield as a single
isomer, resisted all attempts at removing the menthyloxy auxiliary
to give 15. The successful outcomes reported in the literature for
certain related cases apparently all require the prior removal of the
For the unmasking of the 7ꢀ keto group via dithiane hydrolysis,
several literature methods were tested, but in our experience
Scheme 2 Reagents and conditions: (i) n-BuLi, THF, DMPU, 12, −78 ◦C; (ii) (a) NaBH4, KOH, EtOH, 0 ◦C, then rt, (b) 0.1 N HCl (pH 5–6); (iii) LDA
or LHMDS, THF, DMI, −78 ◦C to rt; (iv) (CF3COO)2IPh, CH3CN–H2O, rt.
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Table 1 L-SelectrideꢀR reduction of 18
dsa (%) H-7ꢀS
type lactone lignans from the treatment of 7ꢀ-hydroxymatairesinols
1 and 2 with base. Comparison of NMR data suggested that
the major compound (ratio between isomers was 5 : 1) found
by Eklund et al. possesses the same skeleton and stereochemistry
as our byproduct 20a. In particular, the NMR signal for H-7ꢀ,
Entry Ketone Alcohol
H-7ꢀR Yieldb (%)
1
2
3
4
5
18a
18b
18c
18d
18e
19a
19b
19c
19d
9
97
93
83
88
96
4.57
4.62
4.60
4.53
4.61
4.37
4.38
4.38
4.35
4.38
70
75
77
68
80
ꢀ
ꢀ
which for both compounds is found at about d 5.4 (JH-7
= 2.6
-H-8
Hz), is diagnostic for a trans 7ꢀ/8ꢀ configuration, which derives
from the S configuration of the 7ꢀ-OH group of 19a. The second
lactone described by Eklund and coworkers is the 7ꢀ-epimer with
a Determined by 1H NMR of crude products (7ꢀS/7ꢀR). b After flash
chromatography (7ꢀS +7ꢀR).
a H-7ꢀ signal at about d 5.1, with a coupling constant of JH-7
=
ꢀ
ꢀ
-H-8
9.3 Hz, characteristic of a cis 7ꢀ/8ꢀ configuration. The formation
of our compound 20a can be assumed to be the result of a
translactonization reaction, where the 7ꢀ-alkoxyborane from the
only (CF3CO2)2IPh31 served satisfactorily, providing 7ꢀ-
oxolignanolactones 18a–e in 50–80% yield.
R
Selectrideꢀ reaction may act as nucleophile towards the lactone
R
The reduction of the ketone moiety of 18a–e by L-Selectrideꢀ
ring, with the formation of a primary alcohol as a consequence
(Scheme 4).
produced 9,19a–d in high enantiomeric excess (Scheme 3, Table 1).
As expected of a hydride attack from the less hindered face of
the ketone 18, (7ꢀS)-OH compounds were obtained in all cases
(spectroscopic data of compound 19a in agreement with those
reported12), but considerable variations in the stereoselectivity
were encountered with values of ds up to 97% in case of 19a
(Table 1, entry 1) and as low as 83% for compound 19c (entry
3). The ds values were based on 1H-NMR of the crude mixtures,
confirming the trend previously described12 for 7ꢀ-HLL derivatives,
i.e. that the H-7ꢀS signal is at about d 4.6, while that of H-7ꢀR is at
about d 4.4 (Table 1) irrespective of the aromatic substituents (OH,
OMe, OTBDMS, OCH2O). It is not immediately obvious why this
reduction was so stereoselective for certain compounds, but less so
for others, as the differences in structures reside at relatively remote
locations. We are presently doing modelling studies to elucidate
this question.
Scheme 4 Presumed mechanism of translactonization and formation of
20a.
Eklund et al. suggest that their lactones are formed by a p-
quinone methide mechanism (Scheme 5), only available when
a free p-phenol moiety is present. In our case, the phenols are
TBDMS protected, therefore this mechanism is unlikely, and
in fact we did not detect any further rearranged lactones by
NMR of the crude mixture, from the treatment of 18a with
R
L-Selectrideꢀ reduction of 18e provided (7ꢀS)-parabenzlactone
R
9, one of the target molecules. The physical and spectroscopic
data obtained for synthetic 9 were in good agreement with
those reported for the natural product,5,18 confirming that the
stereochemistry of (–)-parabenzlactone had been erroneously
assigned as 7ꢀR instead of 7ꢀS.
L-Selectrideꢀ.
In literature two other examples of formation of compounds
similar to 20a can be found. Niwa et al.18 reported the forma-
tion of a rearranged lactone obtained as a side product from
the treatment of natural acetylparabenzlactone with KOH. The
R
In the L-Selectrideꢀ reduction of 18a a byproduct was isolated
authors suggested the structure 21 (Scheme 6) for this compound,
1
which according to H NMR (H-7ꢀ, d 5.13, d, JH-7
= 8.0 Hz)
ꢀ
ꢀ
in about 10% yield. Spectroscopic data (IR, 1- and 2D NMR, MS)
suggested that this compound was the rearranged hydroxylactone
20a (Scheme 3). At the same time a paper by Eklund et al.32
reported the isolation and characterization of two lariciresinol-
-H-8
is analogous with the minor isomer obtained by Eklund et al.32
However there is a problem in that the configuration of natural
parabenzlactone, as shown above, is 7ꢀS, while the configuration
Scheme 3 Reagents and conditions: (i) L-SelectrideꢀR , THF, −78 ◦C; (ii) TBAF–CH3COOH, THF, 0 ◦C.
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Scheme 5 Hydroxylactone rearrangement via a quinone methide intermediate.32
Scheme 6 Niwa’s rearranged lactone18 and possible mechanism of formation of 21.
of the rearranged lactone could only come from a 7ꢀR center,
assuming the same mechanism of translactonization presumed
for 20a (attack by 7ꢀ-O− on the lactone ring). This discrepancy
may be resolved by taking into account that the starting material
is acetylparabenzlactone and that AcO, in contrast to OH, is a
sufficiently good leaving group. In competition with the hydrolysis
of the AcO group, the lactone also may undergo hydrolysis with
the formation of a primary alcohol and a carboxyl group. The
COO− generated can now act as a nucleophile and attack the
7ꢀ center via a SN2 mechanism, with simultaneous detachment
of the AcO group. The final result would be a new lactone
ring with inversion of configuration at 7ꢀ position, in agreement
with Niwa’s paper and our own results. One should notice that
for acetylparabenzlactone mere AcO hydrolysis is not sufficient
to trigger the lactone rearrangement, and no other rearranged
lactones were mentioned.
Moritani et al.33 obtained a rearranged lactone 22 by treating a
(7ꢀS*,8R*,8ꢀR*)-7ꢀ-HLL 23 with NaH in DMF (Scheme 7). The
authors assumed that during this reaction complete epimerization
had occurred at the b-carbon of the new lactone ring to give a
trans 8/8ꢀ-trans 7ꢀ/8ꢀ configuration, determined by X-ray crystal-
lography. However looking at the NMR data of this compound,
one notes that H-7ꢀ is reported to appear at d 5.16, with a
Scheme 7 Lactone isomerization reported by Moritani et al.33
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ꢀ
ꢀ
ꢀ
ꢀ
JH-7
= 9.2 Hz, which however indicates a cis 7 /8 configuration
the synthesis of several (7ꢀS)-HLLs, irrespective of their aro-
matic substituents. This has allowed the preparation of (7ꢀS)-
hydroxymatairesinol 1, (7ꢀS)-hydroxyarctigenin 8 and for the
first time (7ꢀS)-hydroxyenterolactone 5, (7ꢀS)-parabenzlactone 9,
and (7ꢀS)-hydroxyprestegane B 10, a previously unknown isomer
of (7ꢀS)-hydroxymatairesinol. In connection with this work we
demonstrated that the reported (R) configuration for the 7ꢀ
position in the natural (–)-parabenzlactone was erroneous.
In one step of our synthetic procedure, performing a hydride re-
duction of a keto group, a rearranged hydroxylactone was formed
as a byproduct, presumably by a translactonization mechanism.
Altogether, three different mechanisms may be responsible for the
formation of similar lactones reported in literature, depending on
the aromatic substituents, the configuration of the 7ꢀ center and the
reaction conditions, giving an explanation for all observed cases
except one, which remained unsolved.
-H-8
according to Eklund’s results. Therefore in our opinion Moritani’s
finding is incompatible with our results and those of Eklund et al.32
and this discrepancy remains unexplained at present.
Thus three different mechanisms may operate in the lactone
isomerisations, depending on finely tuned substituent effects and
reaction conditions, one of them involving the quinone methide
route. The expected stereochemical consequences at C-7ꢀ of
the three alternatives are: retention (7ꢀ-OH), inversion (7ꢀ-OAc)
and racemization (via quinone methide). Concerning Moritani’s
lactone, none of the three possible mechanisms can explain the
formation of a trans/trans configured lactone, as reported.
R
Treatment of 18b–e with L-Selectrideꢀ furnished the 7ꢀ-HLLs
19b–e, and in all cases, except for oxo-parabenzlactone 18e, small
quantities of the rearranged lactones 20b–d were detected by H
NMR of the crude mixture (doublet at about d 5.4), but were
not isolated. Finally, the TBDMS ethers 19a–d were deprotected
with TBAF–AcOH34 (Scheme 3) to furnish compounds 1, 8
and, for the first time, (7ꢀS)-hydroxyenterolactone 5 together with
the previously unknown (7ꢀS)-hydroxyprestegane B 10, also fully
characterized.
1
Finally, in a discussion of the nomenclature of the HLL lignans,
we examine the many confusing or misleading variants in the
naming and numbering systems used in literature, and suggest the
adoption of an unequivocal naming system for these compounds,
as recommended by the IUPAC.
Nomenclature of 7ꢀ-hydroxylignano-9,9ꢀ-lactones
Experimental
The nomenclature and numbering of carbon atoms in the 7ꢀ-
HLL series, as used in the literature, is often confusing or
misleading, or even quite erroneous at times. This situation largely
arises from the fact that these compounds may be considered
as derived from any of a number of parent structures, with
different numbering being applied for example to the benzylic
carbon atoms. A naturally occurring lactone lignan where the two
arylpropyl units are joined at their 8/8ꢀ sites usually possesses a
trivial name. However, such a compound may also be named as
a lignano-9,9ꢀ-lactone (IUPAC recommendations),1 dibenzylbu-
tyrolactone, or 2(3H)-dihydrofuranone (Chemical Abstracts), or
tetrahydrofuranone (preferably avoided). The site of the benzylic
hydroxy group of hydroxymatairesinols 1 and 2 is variously given
as matairesinol C-7,6,8,12,15,17 or 7ꢀ,1,4,14,16 or even 5.19 Speaking
in terms of a butyrolactone parent, the hydroxybenzyl moiety
may be viewed as a lactone 3-35 or 4-36 substituent. Other
papers using the butyrolactone framework assign the benzylic
sites variously as 5/6,37 or 6/7,24 or 7ꢀ/7ꢀꢀ.38 Furthermore, some
authors including ourselves have changed their nomenclature in
their more recent work without actually alerting unwary readers to
this effect. If one adheres to lignano-9,9ꢀ-lactone based numbering
(IUPAC recommendations),1 there is the obvious advantage that
the hydroxybenzyl site of hydroxymatairesinol is 7ꢀ because the
alternative benzylic site, being closer to the carbonyl, has priority
and is thus 7. It would undoubtedly be very helpful if this
numbering would be more generally adopted. This numbering
may of course be used for hydroxymatairesinol and other similar
trivial names as well.
General
THF and Et2O were freshly distilled from sodium ben-
zophenone ketyl, DMPU (1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-
pyrimidinone) and DMI (N,N-dimethyl-2-imidazolidinone) from
CaH2 under reduced pressure. Lithium diisopropylamide (LDA)
was prepared from freshly distilled diisopropylamine and n-
butyllithium in THF. Other commercially available chemicals
were used as supplied by the manufacturers. 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 ethanol. Silica gel 60 (230–400 mesh, Merck) was used for
flash column chromatography. Compounds were homogeneous on
TLC. Optical rotation values were measured with a JASCO DIP-
1000 digital polarimeter at ambient temperature. NMR spectra
were recorded on a 200 MHz Varian GEMINI 2000, or a 500 MHz
Bruker Avance 500 spectrometer. Chemical shifts are given in d and
J values in Hz, using tetramethylsilane (TMS) as internal standard.
Mass spectra were obtained using a JEOL JMS-SX102 mass
spectrometer operating at 70 eV. Melting points were determined
in open capillary tubes with an electrothermal melting point
apparatus and are uncorrected. IR spectra were recorded on
a Perkin-Elmer Spectrum One FTIR instrument equipped with
ATR reflection top plate. HPLC separations were performed using
Waters 600 pump, CYCLOBOND I RSP 2000 (10 lm) column
(250 × 10 mm), Waters 996 UV photodiode array detector and
Waters 717 plus autosampler. Compounds 11b, 11e,39 1240 and
13a–d41 were prepared according to literature procedures.
2-(4-tert-Butyldimethylsilanyloxy-3-methoxyphenyl)-1,3-dithiane
(11a). 4-tert-Butyldimethylsilanyloxy-3-methoxybenzaldehyde
(1.94 g, 7.29 mmol) in dry Et2O (8.0 ml) was added at rt to a
stirred solution of propane-1,3-dithiol (0.8 ml, 8.0 mmol) and
MgBr2 (2.0 g, 1.10 mmol) in dry Et2O (10 ml) under Ar, and the
mixture was stirred overnight. The reaction was then diluted with
Conclusions
Asymmetric synthesis of optically active 7ꢀ-hydroxylignano-9,9ꢀ-
lactones concerns a subclass of lignans which possess or may
possess certain interesting biological properties. We report here
a general asymmetric synthesis route that can be applied for
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Et2O and washed with 10% NaOH, saturated NH4Cl solution
and brine. The organic phase was dried over anhydrous Na2SO4,
filtered, evaporated and the crude product purified by flash
chromatography (eluent hexane–EtOAc 4 : 1) to obtain 11a as
122.4, 132.2, 144.7, 151.2, 175.5; EIMS m/z (relative intensity):
594 (M+, 1%), 579 (9), 537 (100), 399 (50) 355 (80), 299 (60), 210
(40); HRMS (EI) m/z calcd for C27H41O5SiS2 (M-57)+, 537.2165;
found, 537.2134.
1
a viscous oil (2.4 g, 92%): H NMR (200 MHz, CDCl3) d 0.15
(3R,4R)-3-[(Propane-1,3-diyldithio)-(3,4-dimethoxyphenyl)-
methyl]-4-[(1R,2S,5R)-2-(1-methylethyl)-5-methyl-1-cyclohexyl-
oxy]butano-4-lactone (16b). Following the same procedure
as for 16a, compound 16b was prepared in 82% yield as an
amorphous solid after flash chromatography (eluent CH2Cl2 to
(s, 6H), 0.99 (s, 9H), 1.88–2.21 (m, 2H), 2.85–3.14 (m, 4H), 3.82
(s, 3H), 5.12 (s, 1H), 6.77 (d, J = 8.0 Hz, 1H), 6.92 (dd, J =
2.0, 8.0 Hz, 1H), 6.98 (d, J = 2.0 Hz, 1H). 13C NMR (50 MHz,
CDCl3) d −4.6, 18.4, 25.1, 25.7, 32.2, 51.4, 55.5, 111.6, 120.1,
120.8, 132.4, 145.1, 150.9. EIMS m/z (relative intensity): 356
(M+, 5%), 299 (100), 284 (20), 210 (80) 179 (10). HRMS (EI) m/z
calcd for C13H19O2SiS2 (M-57)+, 299.0596; found, 299.0610.
CH2Cl2–EtOAc 15 : 1): [a]26 −71.4◦ (c 1.0, CHCl3); IR (thin film)
D
mmax 1786 cm−1; 1H NMR (500 MHz, CDCl3) d 0.60–0.96 (m, 3H),
0.71 (d, J = 6.5 Hz, 3H), 0.81 (d, J = 7.0 Hz, 3H), 0.87 (d, J
= 6.5 Hz, 3H), 1.07–1.12 (m, 1H), 1.24–1.29 (m, 1H), 1.55–1.61
(m, 2H), 1.79–1.99 (m, 4H), 2.60 (dd, J = 10.5, 18.5 Hz, 1H),
2.65–2.77 (m, 5H), 2.84 (dd, J = 3.8, 18.5 Hz, 1H), 3.39 (dt, J
= 4.0, 10.6 Hz, 1H), 5.75 (s, 1H), 6.87 (d, J = 9.0 Hz, 1H), 7.47
(d, J = 2.0 Hz, 1H), 7.50 (dd, J = 2.0, 9.0 Hz, 1H); 13C NMR
(125 MHz, CDCl3) d 15.5, 20.8, 22.1, 23.0, 24.5, 25.3, 26.9, 27.10,
30.0, 31.2, 34.2, 39.6, 47.6, 54.1, 55.8, 56.1, 60.7, 77.6, 101.2,
110.8, 112.3, 122.3, 131.2, 148.5, 149.2, 175.3; EIMS m/z (relative
intensity): 494 (M+, 100%), 310 (60), 256 (100), 236 (100), 208
(100), 176 (90), 139 (40). HRMS (EI) m/z calcd for C26H38O5S2
(M+), 494.2160; found, 494.2155.
2-(3-tert-Butyldimethylsilanyloxyphenyl)-1,3-dithiane
(11c).
Following the same procedure as for 11a, compound 11c was
prepared in 90% yield as a viscous oil. 1H NMR (200 MHz,
CDCl3) d 0.24 (s, 6H), 0.98 (s, 9H), 1.83–2.22 (m, 2H), 2.84–3.13
(m, 4H), 5.10 (s, 1H), 6.77 (ddd, J = 1.2, 2.4, 8.0 Hz, 1H), 6.97
(t, J = 2.0 Hz, 1H), 7.05 (dt, J = 1.2, 8.0 Hz, 1H), 7.19 (t, J =
8.0 Hz, 1H). 13C NMR (50 MHz, CDCl3) d −4.4, 18.2, 25.1, 25.7,
32.1, 51.3, 119.6, 120.1, 120.6, 129.6, 140.4, 155.8. EIMS m/z
(relative intensity): 326 (M+, 80%), 269 (60), 195 (90). HRMS (EI)
m/z calcd for C16H26OSiS2 (M+), 326.1194; found, 326.1183.
2-(3-tert-Butyldimethylsilanyloxy-4-methoxyphenyl)-1,3-dithiane
(11d). Following the same procedure as for 11a, compound 11d
was prepared in 89% yield as a white solid: mp 101 ◦C (hexane).
1H NMR (200 MHz, CDCl3) d 0.17 (s, 6H), 0.99 (s, 9H), 1.81–2.21
(m, 2H), 2.83–3.12 (m, 4H), 3.78 (s, 3H), 5.07 (s, 1H), 6.79 (d, J =
8.0 Hz, 1H), 6.97 (d, J = 2.0 Hz, 1H), 7.02 (dd, J = 2.0, 8.0 Hz,
1H). 13C NMR (50 MHz, CDCl3) d −4.6, 18.4, 25.1, 25.7, 32.2,
50.8, 55.5, 112.0, 120.5, 120.9, 131.6, 145.0, 151.0. EIMS m/z
(relative intensity): 356 (M+, 5%), 299 (100), 284 (15), 210 (60) 179
(10). HRMS (EI) m/z calcd for C13H19O2SiS2 (M-57)+, 299.0596;
found, 299.0585.
(3R,4R)-3-[(Propane-1,3-diyldithio)-(3-tert-butyldimethylsilanyl-
oxyphenyl)methyl]-4-[(1R,2S,5R)-2-(1-methylethyl)-5-methyl-1-
cyclohexyloxy]butano-4-lactone (16c). Following the same
procedure as for 16a, compound 16c was prepared in 75% yield as
an amorphous solid after flash chromatography (eluent CH2Cl2):
[a]2D6 −70◦ (c 1.0, CHCl3); IR (thin film) mmax 1789 cm−1; 1H NMR
(500 MHz, CDCl3) d 0.22 (s, 6H), 0.60–0.98 (m, 3H), 0.72 (d, J =
7.0 Hz, 3H), 0.82 (d, J = 7.0 Hz, 3H), 0.88 (d, J = 7.1 Hz, 3H),
1.00 (s, 9H), 1.08–1.13 (m, 1H), 1.26–1.32 (m, 1H), 1.56–1.64
(m, 2H), 1.84–2.00 (m, 4H), 2.63 (dd, J = 10.0, 18.4 Hz, 1H),
2.65–2.78 (m, 5H), 2.87 (dd, J = 3.5, 18.4 Hz, 1H), 3.39 (dt, J =
4.2, 10.7 Hz, 1H), 5.73 (d, J = 1.5 Hz, 1H), 6.79 (ddd, J = 0.9,
2.4, 8.6 Hz, 1H), 7.27 (t, J = 8.0 Hz, 1H), 7.46 (t, J = 2.0 Hz, 1H),
7.55 (ddd, J = 0.9, 2.0, 8.0 Hz, 1H); 13C NMR (125 MHz, CDCl3)
d −4.3, 15.6, 18.3, 20.8, 22.2, 23.1, 24.5, 25.4, 25.7, 27.0, 27.1,
30.1, 31.3, 34.3, 39.6, 47.6, 54.0, 60.6, 77.6, 101.1, 119.7, 121.1,
122.5, 129.8, 140.7, 156.4, 175.4; EIMS m/z (relative intensity):
564 (M+, 1%), 507 (100), 369 (80), 325 (70), 217 (50). HRMS (EI)
m/z calcd for C26H39O4SiS2 (M-57)+, 507.2059; found, 507.2044.
(3R,4R)-3-[(Propane-1,3-diyldithio)-(4-tert-butyldimethylsilanyl-
oxy-3-methoxyphenyl)methyl]-4-[(1R,2S,5R)-2-(1-methylethyl)-5-
methyl-1-cyclohexyloxy]butano-4-lactone (16a). To a solution of
thioacetal 11a (750 mg, 2.10 mmol) in THF (20 ml) at −78 ◦C
under Ar, a solution of n-BuLi in hexane (1.3 M, 1.80 ml, 2.34
mmol) was added dropwise and the mixture was stirred for 1 h.
Then DMPU (0.40 ml, 4.65 mmol) was added dropwise followed
by slow addition of 12 (550 mg, 2.31 mmol) in THF (5 ml). The
reaction was stirred for 2 h at the same temperature and then
quenched with saturated NH4Cl and extracted with Et2O. Organic
phase was dried over anhydrous Na2SO4, filtered, evaporated and
the crude compound purified by flash chromatography (eluent
CH2Cl2 to CH2Cl2–EtOAc 15 : 1) to obtain 16a as an amorphous
solid (1.10 g, 88%): [a]D27 −57.0◦ (c 1.0, CHCl3); IR (thin film) mmax
1788 cm−1; 1H NMR (500 MHz, CDCl3) d 0.17 (s, 6H), 0.67–0.98
(m, 3H), 0.73 (d, J = 7.0 Hz, 3H), 0.83 (d, J = 7.0 Hz, 3H), 0.90
(d, J = 6.6 Hz, 3H), 1.00 (s, 9H), 1.10–1.15 (m, 1H), 1.30–1.32
(m, 1H), 1.56–1.60 (m, 2H), 1.81–2.02 (m, 4H), 2.60 (dd, J =
9.9, 18.4 Hz, 1H), 2.65–2.78 (m, 5H), 2.84 (dd, J = 3.6, 18.4 Hz,
1H), 3.42 (dt, J = 4.2, 10.7 Hz, 1H), 3.82 (s, 3H), 5.79 (d, J =
1.4 Hz, 1H), 6.85 (d, J = 8.4 Hz, 1H), 7.41 (dd, J = 2.4, 8.4 Hz,
1H), 7.46 (d, J = 2.4 Hz, 1H); 13C NMR (125 MHz, CDCl3) d
−4.5, 15.6, 18.4, 20.9, 22.3, 23.1, 24.6, 25.4, 25.7, 27.0, 27.2, 30.2,
31.3, 34.3, 39.6, 47.7, 54.2, 55.8, 60.9, 77.4, 101.1, 113.3, 120.7,
(3R,4R)-3-[(Propane-1,3-diyldithio)-(3-tert-butyldimethylsilan-
yloxy-4-methoxyphenyl)methyl]-4-[(1R,2S,5R)-2-(1-methylethyl)-
5-methyl-1-cyclohexyloxy]butano-4-lactone (16d). Following the
same procedure as for 16a, compound 16d was prepared in 81%
yield as an amorphous solid after flash chromatography (eluent
CH2Cl2 to CH2Cl2–EtOAc 15 : 1): [a]26 −76.6◦ (c 1.0, CHCl3);
D
1
IR (thin film) mmax 1789 cm−1; H NMR (500 MHz, CDCl3) d
0.16 (s, 3H), 0.17 (s, 3H), 0.63–0.99 (m, 3H), 0.72 (d, J = 7.0 Hz,
3H), 0.82 (d, J = 7.0 Hz, 3H), 0.88 (d, J = 6.6 Hz, 3H), 1.00 (s,
9H), 1.09–1.14 (m, 1H), 1.25–1.32 (m, 1H), 1.56–1.62 (m, 2H),
1.83–2.00 (m, 4H), 2.63 (dd, J = 10.0, 18.4 Hz, 1H), 2.65–2.77 (m,
5H), 2.85 (dd, J = 3.4, 18.4 Hz, 1H), 3.39 (dt, J = 4.2, 10.6 Hz,
1H), 3.82 (s, 3H), 5.74 (d, J = 1.4 Hz, 1H), 6.85 (d, J = 8.6 Hz,
1H), 7.44 (d, J = 2.5 Hz, 1H), 7.48 (dd, J = 2.5, 8.6 Hz, 1H);
13C NMR (125 MHz, CDCl3) d −4.5, 15.7, 18.5, 20.9, 22.2, 23.1,
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24.7, 25.4, 25.8, 27.0, 27.1, 31.0, 31.3, 34.3, 39.7, 47.7, 54.0, 55.5,
60.3, 77.5, 101.1, 111.7, 122.0, 123.2, 131.0, 145.3, 150.6, 175.5;
EIMS m/z (relative intensity): 594 (M+, 1%), 579 (3), 537 (100),
399 (70), 355 (40), 247 (20), 203 (10). HRMS (EI) m/z calcd for
C27H41O5SiS2 (M-57)+, 537.2165; found, 537.2199.
18.0 Hz, 1H), 2.65–2.79 (m, 4H), 2.87 (dd, J = 9.3, 18.0 Hz, 1H),
2.99–3.10 (m, 1H), 3.90 (s, 3H), 3.91 (s, 3H), 4.19 (dd, J = 8.2,
9.5 Hz, 1H), 4.43 (dd, J = 8.0, 9.5 Hz, 1H), 6.89 (d, J = 9.0 Hz,
1H), 7.48–7.52 (m, 2H). 13C NMR (125 MHz, CDCl3) d 24.8,
27.2, 30.2, 48.2, 55.9, 56.1, 60.8, 68.6, 111.1, 112.3, 122.0, 131.3,
148.5, 149.3, 175.8; EIMS m/z (relative intensity): 340 (M+, 90%),
255 (100), 181 (80); HRMS (EI) m/z calcd for C16H20O4S2 (M+),
340.0803; found, 340.0796.
(3R,4R)-3-[(Propane-1,3-diyldithio)-(3,4-methylenedioxyphenyl)-
methyl]-4-[(1R,2S,5R)-2-(1-methylethyl)-5-methyl-1-cyclohexyloxy]-
butano-4-lactone (16e). Following the same procedure as for
16a, compound 16e was prepared in 80% yield as a white solid
after flash chromatography (eluent CH2Cl2 to CH2Cl◦2–EtOAc
15 : 1) and trituration with hexane–Et2O: mp 118–120 C, (lit.27
128 ◦C): [a]D25 −73.6◦ (c 1.0, CHCl3), (lit.27 −71.8, c 0.96, CHCl3);
(3R)-3-[(Propane-1,3-diyldithio)-(3-tert-butyldimethylsilanyloxy-
phenyl)methyl]butano-4-lactone (17c). Following the same
procedure as for 17a, compound 17c was prepared in 64% yield as
a viscous oil after flash chromatography (eluent CH2Cl2–MeOH
100 : 1): [a]2D8 +13.2◦ (c 0.09, CHCl3); IR (thin film) mmax 1789 cm−1;
1H NMR (500 MHz, CDCl3) d 0.21 (s, 6H), 0.99 (s, 9H), 1.87–1.97
(m, 2H), 2.41 (dd, J = 9.1, 17.9 Hz, 1H), 2.66–2.75 (m, 4H), 2.83
(dd, J = 9.4, 17.9 Hz, 1H), 2.98–3.05 (m, 1H), 4.18 (dd, J = 8.3,
9.4 Hz, 1H), 4.41 (dd, J = 8.3, 9.4 Hz, 1H), 6.80 (dd, J = 2.0,
8.0 Hz, 1H), 7.28 (t, J = 8.0 Hz, 1H), 7.46 (t, J = 2.0 Hz, 1H),
7.54 (ddd, J = 0.8, 2.0, 8.0 Hz, 1H). 13C NMR (125 MHz, CDCl3)
d −4.3, 18.3, 24.8, 25.7, 27.2, 30.2, 48.0, 60.6, 68.5, 119.7, 120.7,
122.0, 130.1, 140.9, 156.5, 175.7; EIMS m/z (relative intensity):
410 (M+, <1%), 353 (65), 325 (50), 249 (90), 216 (80), 149 (30);
HRMS (EI) m/z calcd for C16H21O3SiS2 (M-57)+, 353.0701;
found, 353.0693.
1
IR (thin film) mmax 1784 cm−1; H NMR (500 MHz, CDCl3) d
0.62–0.99 (m, 3H), 0.71 (d, J = 7.0 Hz, 3H), 0.81 (d, J = 7.0 Hz,
3H), 0.88 (d, J = 6.0 Hz, 3H), 1.08–1.12 (m, 1H), 1.25–1.32 (m,
1H), 1.55–1.62 (m, 2H), 1.78–1.98 (m, 4H), 2.63 (dd, J = 10.5,
18.5 Hz, 1H), 2.64–2.77 (m, 5H), 2.85 (dd, J = 3.5, 18.5 Hz, 1H),
3.38 (dt, J = 4.0, 10.6 Hz, 1H), 5.71 (s, 1H), 5.99 (s, 2H), 6.81
(d, J = 8.0 Hz, 1H), 7.46 (d, J = 2.0 Hz, 1H), 7.47 (dd, J = 2.0,
8.0 Hz, 1H); 13C NMR (125 MHz, CDCl3) d 15.6, 20.8, 22.1,
23.0, 24.4, 25.3, 26.9, 27.0, 30.0, 31.2, 34.2, 39.6, 47.6, 54.1, 60.6,
77.6, 101.1, 101.4, 108.0, 109.6, 123.4, 132.8, 147.1, 148.5, 175.3;
EIMS m/z (relative intensity): 478 (M+, 60%), 294 (40), 256 (60),
239 (90), 220 (60), 166 (95), 149 (100). HRMS (EI) m/z calcd for
C25H34O5S2 (M+), 478.1847; found, 478.1828.
(3R)-3-[(Propane-1,3-diyldithio)-(3-tert-butyldimethylsilanyloxy-
4-methoxyphenyl)methyl]butano-4-lactone (17d). Following the
same procedure as for 17a, compound 17d was prepared in 63%
yield as an amorphous solid after flash chromatography (eluent
(3R)-3-[(Propane-1,3-diyldithio)-(4-tert-butyldimethylsilanyloxy-
3-methoxyphenyl)methyl]butano-4-lactone (17a). To a solution
of 16a (720 mg, 1.21 mmol) and NaBH4 (320 mg, 8.47 mmol) in
EtOH (98%) at 0 ◦C under Ar, a solution of KOH in 98% EtOH
(0.4 M, 4.5 ml, 1.80 mmol) was slowly added via syringe. The
mixture was stirred at 0 ◦C for 1 h and then at room temperature
for a further 2 h. The mixture was then gently poured into a
saturated NH4Cl solution containing ice and acidified (pH 5–6)
with 0.1 N HCl. The mixture was extracted with EtOAc and
the organic phase was dried over anhydrous Na2SO4, filtered
and evaporated. The crude compound was dissolved in CH2Cl2
and allowed to cyclize overnight. After solvent removal, the
crude compound was purified by flash chromatography (eluent
CH2Cl2–MeOH 100 : 1) to obtain 17a as an amorphous solid
(410 mg, 71%): [a]D24 +6.6◦ (c 1.0, CHCl3); IR (thin film) mmax
CH2Cl2–MeOH 100 : 1): [a]24 +6.9◦ (c 1.0, CHCl3); IR (thin
D
film) mmax 1779 cm−1; 1H NMR (500 MHz, CDCl3) d 0.17 (s, 6H),
1.00 (s, 9H), 1.84–1.98 (m, 2H), 2.41 (dd, J = 9.1, 17.9 Hz, 1H),
2.64–2.76 (m, 4H), 2.83 (dd, J = 9.2, 17.9 Hz, 1H), 2.98–3.05
(m, 1H), 3.83 (s, 3H), 4.18 (dd, J = 8.3, 9.5 Hz, 1H), 4.40 (dd,
J = 8.2, 9.5 Hz, 1H), 6.87 (d, J = 8.5 Hz, 1H), 7.45 (d, J =
2.5 Hz, 1H), 7.48 (dd, J = 2.5, 8.5 Hz, 1H). 13C NMR (125 MHz,
CDCl3) d −4.6, 18.5, 24.9, 25.7, 27.2, 30.2, 48.2, 55.6, 60.3, 68.6,
112.0, 121.7, 122.8, 131.2, 145.3, 150.5, 175.8; EIMS m/z (relative
intensity): 440 (M+, <1%), 425 (2), 383 (100), 355 (70), 263 (70),
247 (65), 209 (30), 149 (20), 73 (15); HRMS (EI) m/z calcd for
C17H23O4SiS2 (M-57)+, 383.0807; found, 383.0782.
1
1780 cm−1; H NMR (500 MHz, CDCl3) d 0.18 (s, 6H), 1.00 (s,
(3R)-3-[(Propane-1,3-diyldithio)-(3,4-methylenedioxyphenyl)-
methyl]butano-4-lactone (17e). Following the same procedure
as for 17a, compound 17e was prepared in 82% yield as an
amorphous solid after flash chromatography (eluent CH2Cl2–
MeOH 100 : 1): [a]D28 +10.5◦ (c 1.0, CHCl3), (lit.27 [a]D25 +10.2◦,
c 0.51, CHCl3); 13C NMR (125 MHz, CDCl3) d 24.7, 27.2, 30.2,
48.2, 60.6, 68.5, 101.5, 108.3, 109.3, 123.1, 132.9, 147.2, 148.6,
175.7; IR, 1H NMR and EIMS were in agreement with reported
data.27; HRMS (EI) m/z calcd for C15H16O4S2 (M+), 324.0490;
found, 324.0503.
9H), 1.87–1.98 (m, 2H), 2.41 (dd, J = 9.1, 17.9 Hz, 1H), 2.66–2.74
(m, 4H), 2.85 (dd, J = 9.2, 17.9 Hz, 1H), 3.00–3.05 (m, 1H), 3.82
(s, 3H), 4.18 (dd, J = 8.2, 9.5 Hz, 1H), 4.42 (dd, J = 8.1, 9.5 Hz,
1H), 6.87 (d, J = 8.4 Hz, 1H), 7.40 (dd, J = 2.4, 8.4 Hz, 1H), 7.47
(d, J = 2.4 Hz, 1H). 13C NMR (125 MHz, CDCl3) d −4.6, 18.4,
24.8, 25.7, 27.2, 30.2, 48.2, 55.7, 60.8, 68.6, 113.0, 120.9, 121.9,
132.2, 144.7, 151.2, 175.8; EIMS m/z (relative intensity): 440
(M+, <1%), 425 (6), 383 (100), 355 (70), 283 (65), 235 (60), 209
(60), 149 (40), 73 (50); HRMS (EI) m/z calcd for C17H23O4SiS2
(M-57)+, 383.0807; found, 383.0821.
(8R,8ꢀR)-4,4ꢀ-Bis(tert-butyldimethylsilanyloxy)-3,3ꢀ-dimethoxy-
7ꢀ-(propane-1,3-diyldithio)lignano-9,9ꢀ-lactone (15a). A solution
of 17a (394 mg, 0.90 mmol) in THF (2 ml) was added dropwise
to a solution of LDA (0.98 mmol, 1.1 eq.) in THF (1 ml) under
Ar at −78 ◦C. The reaction mixture was stirred for 2 h and then
DMI (0,11 ml, 0.98 mmol) was added dropwise followed by a
solution of benzylic bromide 13a (324 mg, 0.98 mmol) in THF
(3R)-3-[(Propane-1,3-diyldithio)-(3,4-dimethoxyphenyl)methyl]-
butano-4-lactone (17b). Following the same procedure as for
17a, compound 17b was prepared in 60% yield as an amorphous
solid after flash chromatography (eluent CH2Cl2–MeOH 100 :
1): [a]2D8 +10.2◦ (c 1.0, CHCl3); IR (thin film) mmax 1775 cm−1; H
1
NMR (500 MHz, CDCl3) d 1.85–1.99 (m, 2H), 2.43 (dd, J = 9.3,
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(2 ml). The reaction mixture was stirred at the same temperature
for 3 h and then left to reach the ambient temperature overnight.
The reaction was quenched with saturated NH4Cl and extracted
with Et2O. Organic phase was dried over anhydrous Na2SO4,
filtered, evaporated and the crude compound was purified by flash
chromatography (eluent CH2Cl2–MeOH 100 : 1) to obtain 15a as
an amorphous solid (340 mg, 68%): [a]2D5 +60.2◦ (c 1.0, CHCl3);
155.8, 156.5, 178.3; EIMS m/z (relative intensity): 630 (M+, 2%),
573 (70), 449 (60), 325 (100), 251 (15), 149 (20); HRMS (EI) m/z
calcd for C29H41O4Si2S2 (M-57)+, 573.1984; found, 573.1971.
(8R,8ꢀR)-3,3ꢀ-Bis(tert-butyldimethylsilanyloxy)-4,4ꢀ-dimethoxy-
7ꢀ-(propane-1,3-diyldithio)lignano-9,9ꢀ-lactone (15d). Following
the same procedure as for 15a, compound 15d was prepared
from 17d and 13c in 65% yield as an amorphous solid after flash
1
IR (thin film) mmax 1769 cm−1; H NMR (500 MHz, CDCl3) d
0.12 (s, 3H), 0.13 (s, 3H), 0.18 (s, 3H), 0.18 (s, 3H), 0.98 (s, 9H),
1.00 (s, 9H), 1.83–1.95 (m, 2H), 2.30 (dd, J = 5.7, 14.0 Hz, 1H),
2.58–2.72 (m, 5H), 3.19 (dd, J = 4.5, 14.0 Hz, 1H), 3.18–3.21 (m,
1H), 3.72 (dd, J = 9.1, 9.8 Hz, 1H), 3.75 (s, 3H), 3.80 (s, 3H),
4.45 (dd, J = 5.6, 9.8 Hz, 1H), 6.40 (dd, J = 2.0, 8.0 Hz, 1H),
6.56 (d, J = 2.0 Hz, 1H), 6.70 (d, J = 8.0 Hz, 1H), 6.88 (d, J =
8.4 Hz, 1H), 7.40 (dd, J = 2.4, 8.4 Hz, 1H), 7.44 (d, J = 2.4 Hz,
1H); 13C NMR (125 MHz, CDCl3) d −4.7, −4.6, 18.4, 24.8, 25.7,
27.1, 27.2, 35.7, 42.6, 49.9, 55.4, 55.7, 62.3, 67.6, 113.3, 113.4,
120.6, 121.0, 122.0 122.1, 130.3, 132.6, 143.9, 144.7, 150.9, 151.2,
178.7; EIMS m/z (relative intensity): 690 (M+, 10%), 675 (5), 633
(100), 513 (50), 355 (80), 179 (90); HRMS (EI) m/z calcd for
C31H45O6Si2S2 (M-57)+, 633.2196; found, 633.2224.
chromatography (eluent CH2Cl2–MeOH 100 : 1): [a]24 +67.5◦ (c
D
1
1.0, CHCl3); IR (thin film) mmax 1771 cm−1; H NMR (500 MHz,
CDCl3) d 0.14 (s, 6H), 0.17 (s, 3H), 0.18 (s, 3H), 0.99 (s, 9H),
1.01 (s, 9H), 1.82–1.95 (m, 2H), 2.35 (dd, J = 5.5, 13.9 Hz, 1H),
2.58–2.72 (m, 5H), 3.00 (dd, J = 4.7, 13.9 Hz, 1H), 3.16–3.19 (m,
1H), 3.63 (dd, J = 9.0, 9.8 Hz, 1H), 3.76 (s, 3H), 3.83 (s, 3H), 4.43
(dd, J = 5.1, 9.8 Hz, 1H), 6.59 (dd, J = 2.1, 8.2 Hz, 1H), 6.62 (d,
J = 2.1 Hz, 1H), 6.71 (d, J = 8.2 Hz, 1H), 6.87 (d, J = 8.5 Hz,
1H), 7.44 (d, J = 2.5 Hz, 1H), 7.47 (dd, J = 2.5, 8.5 Hz, 1H);
13C NMR (125 MHz, CDCl3) d −4.6, 18.4, 18.5, 24.8, 25.7, 27.0,
27.1, 35.5, 42.8, 50.0, 55.4, 55.5, 61.8, 67.4, 111.9, 112.0, 121.9,
122.3, 122.9, 123.0, 129.2, 131.4, 144.9, 145.2, 150.0, 150.4, 178.5;
EIMS m/z (relative intensity): 690 (M+, 15%), 675 (10), 633 (80),
513 (60), 355 (60), 251 (50), 179 (100); HRMS (EI) m/z calcd for
C31H45O6Si2S2 (M-57)+, 633.2196; found, 633.2225.
(8R,8ꢀR)-4-(tert-Butyldimethylsilanyloxy)-3,3ꢀ,4ꢀ-trimethoxy-7ꢀ-
(propane-1,3-diyldithio)-lignano-9,9ꢀ-lactone (15b). Following
the same procedure as for 15a, but using lithium hexamethyl-
disilazide (LHMDS, 1.6 M in THF, 1.1 eq.) in place of LDA,
compound 15b was prepared from 17b and 13a in 78% yield as
an amorphous solid after flash chromatography (eluent CH2Cl2);
(8R,8ꢀR)-4,4ꢀ,5,5ꢀ-Bis(methylenedioxy)-7ꢀ-(propane-1,3-diyldithio)-
lignano-9,9ꢀ-lactone (15e). Following the same procedure as for
15a, but using LHMDS (1.6 M in THF, 1.1 eq.) in place of
LDA, compound 15e was prepared from 17e and 13d in 66%
yield as an amorphous solid after flash chromatography (eluent
[a]2D8 +68.9◦ (c 0.66 CHCl3); IR (thin film) mmax 1770 cm−1; H
1
NMR (500 MHz, CDCl3) d 0.12 (s, 6H), 0.98 (s, 9H), 1.82–1.96
(m, 2H), 2.45 (dd, J = 5.2, 14.0 Hz, 1H), 2.58–2.74 (m, 5H), 2.98
(dd, J = 5.0, 14.0 Hz, 1H), 3.15–3.19 (m, 1H), 3.73 (s, 3H), 3.77
(dd, J = 9.0, 10.0 Hz, 1H), 3.88 (s, 3H), 3.92 (s, 3H), 4.52 (dd,
J = 5.2, 10.0 Hz, 1H), 6.40 (dd, J = 2.0, 8.0 Hz, 1H), 6.53 (d,
J = 2.0 Hz, 1H), 6.71 (d, J = 8.0 Hz, 1H), 6.85 (d, J = 8.0 Hz,
CH2Cl2): [a]27 +35◦ (c 0.5, CHCl3); IR (thin film) mmax 1769 cm−1;
D
1H NMR (500 MHz, CDCl3) d 1.81–1.97 (m, 2H), 2.58 (dd, J =
5.2, 14.0 Hz, 1H), 2.60–2.75 (m, 5H), 2.84 (dd, J = 6.5, 14.0 Hz,
1H), 3.04–3.08 (m, 1H), 3.95 (dd, J = 8.5, 10.0 Hz, 1H), 4.62 (dd,
J = 5.0, 10.0 Hz, 1H), 5.91 (part A of AB system, J = 1.5 Hz,
1H), 5.94 (part B of AB system, J = 1.5 Hz, 1H), 6.00 (part A
of AB system, J = 1.5 Hz, 1H), 6.03 (part B of AB system, J =
1.5 Hz, 1H), 6.45 (dd, J = 1.5, 8.0 Hz, 1H), 6.48 (d, J = 1.5 Hz,
1H), 6.66 (d, J = 8.0 Hz, 1H), 6.78 (d, J = 8.0 Hz, 1H), 7.35
(d, J = 2.0 Hz, 1H), 7.39 (dd, J = 2.0, 8.0 Hz, 1H); 13C NMR
(125 MHz, CDCl3) d 24.6, 26.9, 27.1, 36.2, 42.9, 50.4, 62.3, 67.7,
101.9, 101.6, 108.0, 108.1, 109.5, 109.7, 122.6, 123.3, 130.4, 133.0,
146.4, 147.1, 147.6, 148.5, 178.3; EIMS m/z (relative intensity):
458 (M+, 40%), 383 (10), 239 (100), 192 (30), 135 (50); HRMS
(EI) m/z calcd for C23H22O6S2 (M+), 458.0857; found, 458.0880.
1H), 7.43 (dd, J = 2.0, 8.0 Hz, 1H), 7.45 (d, J = 2.0 Hz, 1H); 13
C
NMR (125 MHz, CDCl3) d −4.7, 18.4, 24.7, 25.7, 27.0, 27.1, 35.9,
42.8, 50.1, 55.3, 55.9, 60.0, 62.2, 67.6, 111.0, 112.4, 113.1, 120.6,
122.0, 122.1, 130.2, 131.5, 143.9, 148.4, 149.1, 150.9, 178.7; EIMS
m/z (relative intensity): 590 (M+, 30%), 533 (100), 255 (100), 179
(60); HRMS (EI) m/z calcd for C26H33O6SiS2 (M-57)+, 533.1487;
found, 533.1461.
(8R,8ꢀR)-3,3ꢀ -Bis(tert-butyldimethylsilanyloxy)-7ꢀ -(propane-
1,3-diyldithio)lignano-9,9ꢀ-lactone (15c). Following the same
procedure as for 15a, but using LHMDS (1.6 M in THF, 1.1 eq.)
in place of LDA, compound 15c was prepared from 17c and 13b
in 71% yield as viscous oil after flash chromatography (eluent
(8R,8ꢀR)-4,4ꢀ-Bis(tert-butyldimethylsilanyloxy)-3,3ꢀ-dimethoxy-
7ꢀ-oxolignano-9,9ꢀ-lactone (18a). (CF3CO2)2IPh (470 mg,
1.09 mmol) was added to a solution of 15a (250 mg, 0.36 mmol)
in 10% aq. CH3CN (5 ml) at room temperature. The mixture was
stirred for 30 min and then quenched with saturated NaHCO3
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 80 : 1)
to obtain 18a (118 mg, 55%) as a viscous oil: [a]2D4 +19.3◦ (c 0.28,
CH2Cl2–MeOH 100 : 1): [a]24 +54.5◦ (c 0.19, CHCl3); IR (thin
D
film) mmax 1771 cm−1; 1H NMR (500 MHz, CDCl3) d 0.17 (s, 3H),
0.18 (s, 3H), 0.21 (s, 6H), 0.97 (s, 9H), 1.0 (s, 9H), 1.82–1.96 (m,
2H), 2.40 (dd, J = 5.7, 13.8 Hz, 1H), 2.59–2.72 (m, 5H), 3.04
(dd, J = 4.8, 13.8 Hz, 1H), 3.22–3.25 (m, 1H), 3.67 (dd, J = 8.9,
9.8 Hz, 1H), 4.45 (dd, J = 5.3, 9.8 Hz, 1H), 6.58 (t, J = 1.9 Hz,
1H), 6.62 (br d, J = 7.6 Hz, 1H), 6.69 (ddd, J = 0.8, 2.4, 8.0 Hz,
1H), 6.80 (ddd, J = 0.8, 2.4, 8.0 Hz, 1H), 7.09 (t, J = 8.0 Hz,
1H), 7.28 (t, J = 8.0 Hz, 1H), 7.46 (t, J = 2.0 Hz, 1H), 7.53 (ddd,
J = 0.8, 2.0, 8.0 Hz, 1H); 13C NMR (125 MHz, CDCl3) d −4.4,
−4.3, 18.2, 18.3, 24.6, 25.7, 27.0, 27.1, 36.0, 42.6, 49.8, 62.1, 67.3,
118.9, 119.6, 121.0, 121.3, 122.2, 122.9, 129.4, 130.0, 138.2, 141.0,
CHCl3), (lit.12: [a]20 +16.7◦ c 0.96, CHCl3); EIMS m/z (relative
D
intensity): 600 (M+, 2%), 543 (100), 291 (10), 193 (40), 179 (35);
HRMS (EI) m/z calcd for C32H48O7Si2 (M+), 600.2939; found,
1
600.2901; H NMR and 13C NMR (CDCl3) were in agreement
with reported data.12
338 | Org. Biomol. Chem., 2006, 4, 331–341
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(8R,8ꢀR)-4-tert-Butyldimethylsilanyloxy-3,3ꢀ,4ꢀ -trimethoxy-7ꢀ -
oxolignano-9,9ꢀ-lactone (18b). Following the same procedure
as for 18a, compound 18b was prepared in 50% yield as an
amorphous solid after flash chromatography (eluent CH2Cl2–
(500 MHz, CDCl3) d 2.91 (dd, J = 7.5, 14.0 Hz, 1H), 3.05 (dd,
J = 5.5, 14.0 Hz, 1H), 3.40–3.48 (m, 1H), 3.98–4.04 (m, 1H),
4.13 (apparent t, J = 8.5 Hz, 1H), 4.39 (apparent t, J = 8.5 Hz,
1H), 5.89 (d, J = 1.5 Hz, 2H), 6.06 (s, 2H), 6.52 (dd, J = 1.0,
8.0 Hz, 1H), 6.60 (d, J = 1.0 Hz, 1H), 6.61 (d, J = 8.0 Hz, 1H),
6.80 (d, J = 7.5 Hz, 1H), 7.20 (d, J = 1.5 Hz, 1H), 7.27 (dd, J =
1.5, 7.5 Hz, 1H); 13C NMR (125 MHz, CDCl3) d 24.9, 34.6, 44.8,
46.7, 68.1, 101.0, 102.1, 107.9, 108.0, 108.2, 109.6, 122.5, 124.8,
130.3, 130.7, 146.6, 147.9, 148.5, 152.6, 176.7, 194.5; EIMS m/z
(relative intensity): 368 (M+, 30%), 192 (40), 149 (40), 81 (50), 69
(100); HRMS (EI) m/z calcd for C20H16O7 (M+), 368.0896; found,
368.0879.
Et2O 20 : 1): [a]27 +13.8◦ (c 1.0, CHCl3); IR (thin film) mmax 1772,
D
1
1671 cm−1; H NMR (500 MHz, CDCl3) d 0.09 (s, 3H), 0.10 (s,
3H), 0.97 (s, 9H), 3.00 (dd, J = 7.5, 14.0 Hz, 1H), 3.05 (dd, J =
5.5, 14.0 Hz, 1H), 3.50–3.54 (m, 1H), 3.65 (s, 3H), 3.91 (s, 3H),
3.95 (s, 3H), 4.05 (apparent t, J = 8.2 Hz, 1H), 4.08–4.13 (m,
1H), 4.35 (apparent t, J = 8.2 Hz, 1H), 6.53 (dd, J = 1.8, 8.0 Hz,
1H), 6.60 (d, J = 1.8 Hz, 1H), 6.67 (d, J = 8.0 Hz, 1H), 6.80 (d,
J = 8.0 Hz, 1H), 7.20 (dd, J = 1.8, 8.0 Hz, 1H), 7.37 (d, J =
1.8 Hz, 1H); 13C NMR (125 MHz, CDCl3) d −4.8, −4.7, 18.4,
25.7, 34.5, 44.5, 46.4, 55.2, 56.0, 56.1, 68.2, 109.9, 110.3, 113.0,
120.8, 121.7, 122.9, 128.7, 130.5, 144.0, 149.5, 151.0, 154.2, 177.3,
194.9; EIMS m/z (relative intensity): 500 (M+, 5%), 443 (100),
236 (80), 179 (90), 165 (50); HRMS (EI) m/z calcd for C27H36O7Si
(M+), 500.2230; found, 500.2245.
(7ꢀS,8R,8ꢀR)-4,4ꢀ-Bis(tert-butyldimethylsilanyloxy)-7ꢀ-hydroxy-
3,3ꢀ-dimethoxylignano-9,9ꢀ-lactone (19a) and (2R,3R,4S)-2-(4-tert-
butyldimethylsilanyloxy-3-methoxyphenyl)methyl-3-hydroxymethyl-
4-(4-tert-butyldimethylsilanyloxy-3-methoxyphenyl)butano-4-
R
lactone (20a). L-Selectrideꢀ (1 M in THF, 0.10 ml, 0.10 mmol)
was added dropwise to a solution of◦16a (50 mg, 0.083 mmol) in
dry THF (1.5 ml) under Ar at −78 C and the reaction mixture
was stirred at the same temperature for 2 h. The reaction was
then stopped with saturated NH4Cl and extracted with EtOAc.
Organic phase was washed with oxalic acid 0.1 N, dried over
anhydrous Na2SO4, evaporated and the crude product was
purified by flash chromatography (eluent CH2Cl2–EtOAc 5 : 1) to
yield 35 mg (70%) of compound 19a (ds 97%) as a viscous oil and
4.5 mg (9%) of compound 20a as an amorphous solid.
(8R,8ꢀR)-3,3ꢀ -Bis(tert-butyldimethylsilanyloxy)-7ꢀ -oxolignano-
9,9ꢀ-lactone (18c). Following the same procedure as for 18a,
compound 18c was prepared in 70% yield as a viscous oil after
flash chromatography (eluent CH2Cl2–Et2O 80 : 1): [a]24 +25.9◦
D
1
(c 1.77, CHCl3); IR (thin film) mmax 1778, 1684 cm−1; H NMR
(500 MHz, CDCl3) d 0.13 (s, 3H), 0.15 (s, 3H), 0.21 (s, 6H), 0.95
(s, 9H), 0.99 (s, 9H), 3.01 (dd, J = 6.5, 14.0 Hz, 1H), 3.07 (dd,
J = 6.0, 14.0 Hz, 1H), 3.51–3.55 (m, 1H), 4.01–4.06 (m, 1H),
4.10 (apparent t, J = 8.5 Hz, 1H), 4.36 (apparent t, J = 8.5 Hz,
1H), 6.63–6.70 (m, 3H), 7.03–7.07 (m, 2H), 7.22–7.29 (m, 3H);
13C NMR (125 MHz, CDCl3) d −4.5, −4.4, 18.1, 18.2, 25.5, 25.6,
34.8, 43.8, 47.0, 68.0, 118.8, 119.4, 120.9, 121.3, 122.3, 129.7,
129.9, 136.8, 138.4, 156.0, 156.3, 177.1, 196.0; EIMS m/z (relative
intensity): 540 (M+, 20%), 483 (100), 275 (80), 235 (70), 73 (80);
HRMS (EI) m/z calcd for C26H35O5Si2 (M-57)+, 483.2023; found,
483.2027.
Compound 19a: [a]D27 −0.8◦ (c 0.4, CHCl3), lit.12 [a]D19 −1.5◦ (c
0.95, CHCl3); EIMS m/z (relative intensity): 602 (M+, 2%), 600
(2), 585 (5), 543 (100), 277 (20), 179 (50); HRMS (EI) m/z calcd
1
for C32H50O7Si2 (M+), 602.3095; found, 602.3116; IR, H NMR
and 13C NMR (CDCl3) were in agreement with reported data.12
Compound 20a: [a]D24 +37.5◦ (c 0.3, CHCl3); IR (thin film) mmax
3486, 1769 cm−1; 1H NMR (500 MHz, CDCl3) d 0.14 (s, 6H), 0.15
(s, 6H), 0.98 (s, 9H), 0.99 (s, 9H), 2.59–2.63 (m, 1H), 2.75 (dd, J =
10.6, 15.1 Hz, 1H), 3.09 (ddd, J = 4.5, 8.2, 10.6 Hz, 1H), 3.23 (dd,
J = 4.5, 15.1 Hz, 1H), 3.73–3.78 (m, 1H), 3.76 (s, 3H), 3.79 (s, 3H),
3.93 (dd, J = 4.0, 10.5 Hz, 1H), 5.45 (d, J = 2.6 Hz, 1H), 6.65 (dd,
J = 2.0, 8.0 Hz, 1H), 6.71–6.73 (m, 2H), 6.74–6.77 (m, 2H), 6.82
(d, J = 8.1 Hz, 1H); 13C NMR (125 MHz, CDCl3) d −4.6, 18.4,
25.7, 30.8, 41.3, 47.6, 55.6, 55.6, 60.7, 81.1, 109.0, 112.4, 117.3,
120.2, 120.9, 120.9, 132.0, 132.3, 143.8, 145.0, 151.0, 151.2, 178.1;
EIMS m/z (relative intensity): 602 (M+, 5%), 545 (90), 543 (50),
277 (20), 179 (100); HRMS (EI) m/z calcd for C32H50O7Si2 (M+),
602.3095; found, 602.3124.
(8R,8ꢀR)-3,3ꢀ -Bis(tert-butyldimethylsilanyloxy)-4,4ꢀ-dimethoxy-
7ꢀ-oxolignano-9,9ꢀ-lactone (18d). Following the same procedure
as for 18a, compound 18d was prepared in 57% yield as a viscous
oil after flash chromatography (eluent CH2Cl2–Et2O 80 : 1): [a]D24
+28.4◦ (c 0.45, CHCl3); IR (thin film) mmax 1775, 1674 cm−1; H
1
NMR (500 MHz, CDCl3) d 0.09 (s, 3H), 0.11 (s, 3H), 0.16 (s, 6H),
0.96 (s, 9H), 1.00 (s, 9H), 2.96 (dd, J = 5.7, 14.2 Hz, 1H), 3.00
(dd, J = 6.3, 14.2 Hz, 1H), 3.49 (apparent dt, J = 6.0, 8.5 Hz,
1H), 3.74 (s, 3H), 3.87 (s, 3H), 3.99–4.04 (m, 1H), 4.08 (apparent
t, J = 8.6 Hz, 1H), 4.30 (apparent t, J = 8.6 Hz, 1H), 6.64–6.68
(m, 3H), 6.81 (d, J = 8.5 Hz, 1H), 7.29 (dd, J = 2.2, 8.5 Hz,
1H), 7.33 (d, J = 2.2 Hz, 1H); 13C NMR (125 MHz, CDCl3) d
−4.7, −4.6, 18.3, 18.4, 25.6, 25.7, 34.0, 44.0, 46.3, 55.4, 55.5, 68.1,
110.9, 112.2, 120.3, 122.2, 122.5, 123.5, 128.7, 145.1, 145.4, 150.0,
156.2, 177.4, 194.6; EIMS m/z (relative intensity): 600 (M+, 2%),
585 (3), 543 (100), 305 (20), 179 (45); HRMS (EI) m/z calcd for
C32H48O7Si2 (M+), 600.2939; found, 600.2955.
(7ꢀS,8R,8ꢀR)-4-tert-Butyldimethylsilanyloxy-7ꢀ-hydroxy-3,3ꢀ,4ꢀ-
trimethoxylignano-9,9ꢀ-lactone (19b). Following the same
procedure as for 19a, compound 19b was prepared in 75% yield
(ds 93%) after flash chromatography (eluent CH2Cl2–Et2O 8 : 1)
1
as a viscous oil: IR (thin film) mmax 3497, 1746 cm−1; H NMR
(500 MHz, CDCl3, major diastereomer 7ꢀS) d 0.14 (s, 6H), 0.99
(s, 9H), 2.60–2.65 (m, 1H), 2.92 (dd, J = 5.5, 13.5 Hz, 1H),
2.95–2.98 (m, 1H), 3.08 (dd, J = 5.2, 13.5 Hz, 1H), 3.75 (s, 3H),
3.82 (apparent t, J = 9.0 Hz, 1H), 3.87 (s, 3H), 3.88 (s, 3H), 3.90
(dd, J = 6.5, 9.5 Hz, 1H), 4.61 (dd, J = 2.8, 6.8 Hz, 1H), 6.58 (dd,
J = 2.0, 8.5 Hz, 1H), 6.68 (d, J = 1.0 Hz, 1H), 6.73 (dd, J = 2.0,
8.0 Hz, 1H), 6.74 (d, J = 8.0 Hz, 1H), 6.77 (d, J = 2.0 Hz, 1H),
6.80 (d, J = 8.0 Hz, 1H); 13C NMR (125 MHz, CDCl3, major
diastereomer 7ꢀS) d −4.7, 18.4, 25.7, 35.2, 43.9, 45.1, 55.4, 55.9,
(8R,8ꢀR)-4,4ꢀ,5,5ꢀ-Bis(methylenedioxy)-7ꢀ-oxolignano-9,9ꢀ-lactone
(18e). Following the same procedure as for 18a, compound
18e was prepared in 80% yield as a white solid after flash
chromatography (eluent CH2Cl2–Et2O 20 : 1) and trituration
◦
◦
with hexane: mp 90–92 C, (lit.5 113–115 C); [a]D28 +26.5◦ (c
0.33, CHCl3); IR (thin film) mmax 1769, 1670 cm−1; 1H NMR
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68.3, 75.4, 109.0, 111.2, 113.4, 118.4, 120.6, 122.0, 131.0, 134.0,
143.8, 149.1, 149.3, 150.9, 179.1; EIMS m/z (relative intensity):
502 (M+, 10%), 445 (100), 193 (40), 179 (70), 167 (40); HRMS (EI)
m/z calcd for C23H29O7Si (M-57)+, 445.1682; found, 445.1674.
(7ꢀS,8R,8ꢀR)-4,4ꢀ,7ꢀ -Trihydroxy-3,3ꢀ -dimethoxylignano-9,9ꢀ -
lactone, [(7ꢀS)-hydroxymatairesinol (1)]. A solution of TBAF–
AcOH (1 : 1, 1.0 M in THF, 0.30 ml, 0.30 mmol) was added
dropwise to a solution of 19a (18 mg, 0.03 mmol) in dry THF
(0◦.4 ml) under Ar at 0 ◦C. The reaction mixture was stirred at
0 C for 30 min and then for a further 3 h at room temperature.
The reaction was quenched with saturated NH4Cl and extracted
with EtOAc. Organic phase was dried over anhydrous Na2SO4,
evaporated and the crude product was purified by flash
chromatography (eluent CH2Cl2–Et2O 1 : 1) to yield compound
1 (9 mg, 80%) as an amorphous solid: [a]2D4 −9.3◦ (c 0.1, THF),
(lit.3 [a]D25 −11.0◦, c 4, THF); HRMS (EI) m/z calcd for C20H22O7
(M+), 374.1366; found, 374.1345; IR, MS, 1H NMR and 13C
NMR (CDCl3) were in agreement with reported data.12,16
(7ꢀS,8R,8ꢀR)-3,3ꢀ -Bis(tert-butyldimethylsilanyloxy)-7ꢀ-hydroxy-
lignano-9,9ꢀ-lactone (19c). Following the same procedure as for
19a, compound 19c was prepared in 77% yield (ds 83%) after flash
chromatography (eluent CH2Cl2–EtOAc 5 : 1) as a viscous oil:
IR (thin film) mmax 3473, 1756 cm−1; 1H NMR (500 MHz, CDCl3,
major diastereomer 7ꢀS) d 0.19 (s, 6H), 0.20 (s, 6H), 0.98 (s, 9H),
0.99 (s, 9H), 2.59–2.65 (m, 1H), 2.87 (dd, J = 6.0, 13.5 Hz, 1H),
2.97–3.01 (m, 1H), 3.11 (dd, J = 5.2, 13.5 Hz, 1H), 3.77 (apparent
t, J = 9.0 Hz, 1H), 3.90 (dd, J = 6.8, 9.0 Hz, 1H), 4.60 (dd, J
= 2.8, 7.2 Hz, 1H), 6.69–6.83 (m, 4H), 7.11 (t, J = 7.8 Hz, 1H),
7.20 (t, J = 7.8 Hz, 1H). 13C NMR (125 MHz, CDCl3, major
diastereomer 7ꢀS) d −4.5, −4.4, 18.2, 25.6, 25.7, 35.3, 45.0, 68.1,
75.3, 117.8, 118.6, 119.0, 120.1, 121.4, 122.8, 129.4, 129.9, 139.0,
143.0, 155.8, 156.2, 178.8; EIMS m/z (relative intensity): 542
(M+, 5%), 485 (100), 437 (30), 307 (10), 221 (30); HRMS (EI) m/z
calcd for C26H37O5Si2 (M-57)+, 485.2180; found, 485.2152.
(7ꢀS,8R,8ꢀR)-4,7ꢀ -Dihydroxy-3,3ꢀ,4ꢀ -trimethoxylignano-9,9ꢀ -
lactone, [(7ꢀS)-hydroxyarctigenin (8)]. Following the same
procedure as for 1, compound 8 was prepared in 65% yield.
Flash chromatography (eluent CH2Cl2–Et2O 4 : 1) and HPLC
purification gave (7ꢀS)-8 as a glassy material: [a]2D2 −23.9◦ (c 0.56,
◦
1
CHCl3), (lit.12 [a]D21 −22.4 , c 1.1, CHCl3); H NMR (500 MHz,
CDCl3) d 2.59–2.67 (m, 1H), 2.90–2.96 (m, 2H), 3.00–3.08 (m,
1H), 3.82 (s, 3H), 3.85 (s, 3H), 3.88 (s, 3H), 3.91 (apparent t, J =
8.8 Hz, 1H), 3.96 (dd, J = 7.0, 9.5 Hz, 1H), 4.66 (dd, J = 1.5,
6.0 Hz, 1H), 6.61 (dd, J = 2.0, 8.0 Hz, 1H), 6.65 (d, J = 2.0 Hz,
1H), 6.73 (d, J = 2.0 Hz, 1H), 6.75 (dd, J = 2.0, 8.5 Hz, 1H),
6.79 (d, J = 8.0 Hz, 1H), 6.81 (d, J = 8.0 Hz, 1H); 13C NMR
(125 MHz, CDCl3) d 35.0, 43.7, 45.0, 55.8, 55.9, 55. 9, 68.4,
75.2, 108.9, 111.0, 111.9, 114.0, 118.1, 122.5, 129.4, 134.0, 144.4,
146.5, 149.0, 149.3, 179.2; EIMS m/z (relative intensity): 388
(M+, 100%), 370 (10), 194 (50), 167 (100), 137 (90); HRMS (EI)
m/z calcd for C21H24O7 (M+), 388.1366; found, 388.1519; IR and
13C NMR in agreement with reported data.12
(7ꢀS,8R,8ꢀR)-3,3ꢀ -Bis(tert-butyldimethylsilanyloxy)-7ꢀ-hydroxy-
4,4ꢀ-dimethoxylignano-9,9ꢀ-lactone (19d). Following the same
procedure as for 19a, compound 19d was prepared in 68% yield
(ds 88%) after flash chromatography (eluent CH2Cl2–EtOAc 5 :
1) as a viscous oil: IR (thin film) mmax 3487, 1761 cm−1; 1H NMR
(500 MHz, CDCl3, major diastereomer 7ꢀS) d 0.14 (s, 6H), 0.15
(s, 6H), 0.99 (s, 9H), 1.00 (s, 9H), 2.57–2.63 (m, 1H), 2.83 (dd,
J = 5.5, 13.7 Hz, 1H), 2.93 (dt, J = 5.3, 6.9 Hz, 1H), 3.07 (dd,
J = 5.1, 13.7 Hz, 1H), 3.70 (dd, J = 8.4, 9.3 Hz, 1H), 3.77 (s,
3H), 3.80 (s, 3H), 3.83 (dd, J = 6.8, 9.4 Hz, 1H), 4.51 (dd, J =
1.9, 7.4 Hz, 1H), 6.70–6.74 (m, 4H), 6.75–6.77 (m, 2H), 6.78–6.79
(m, 2H). 13C NMR (125 MHz, CDCl3, major diastereomer 7ꢀS)
d −4.7, −4.6, 18.4, 25.7, 34.7, 44.1, 45.1, 55.4, 55.4, 68.1, 75.2,
112.0, 112.1, 118.8, 119.5, 122.3, 122.9, 130.1, 134.0, 145.0, 145.3,
149.9, 151.0, 179.0; EIMS m/z (relative intensity): 602 (M+, 4%),
585 (2), 545 (70), 543 (100), 305 (20), 179 (60).
(7ꢀS,8R,8ꢀR)-3,3ꢀ,7ꢀ -Trihydroxylignano-9,9ꢀ -lactone, [(7ꢀS )-
hydroxyenterolactone (5)]. Following the same procedure as for
1, compound (7ꢀS)-5 was prepared in 60% yield after flash
chromatography (eluent CH2Cl2–Et2O 1 : 1) and HPLC as an
amorphous solid: [a]2D4 −1.32 (c 0.31, acetone); HRMS (EI) m/z
calcd for C18H18O5 (M+), 314.1154; found, 314.1149; IR, MS, 1H
NMR and 13C NMR (acetone-d6) were in agreement with reported
data (for the racemic material).14
(7ꢀS,8R,8ꢀR)-7ꢀ -hydroxy-4,4ꢀ,5,5ꢀ -bis(methylenedioxy)lignano-
9,9ꢀ-lactone, [(7ꢀS)-parabenzlactone (9)]. Following the same
procedure as for 19a, compound 9 was prepared in 80% yield
(ds 96%) after flash chromatography (eluent CH2Cl2–Et2O 8 : 1).
Trituration with hexane gave a white solid: mp 155–158 ◦C, (lit.5
(7ꢀS,8R,8ꢀR)-3,3ꢀ,7ꢀ -Trihydroxy-4,4ꢀ -dimethoxylignano-9,9ꢀ -
lactone, [(7ꢀS)-hydroxyprestegane B (10)]. Following the same
procedure as for 1, compound (7ꢀS)-10 was prepared in 81% yield
after flash chromatography (eluent CH2Cl2–Et2O 1 : 1) and HPLC
as an amorphous solid: [a]D24 −1.50 (c 0.12, CHCl3); IR (thin film)
◦
◦
159–161 C); [a]2D2 −15.0 C (c 0.3, CHCl3), (lit.5-11.0◦, c 1.15,
CHCl3); IR (thin film) mmax 3457, 1754 cm−1; 1H NMR (500 MHz,
CDCl3) d 2.54–2.60 (m, 1H), 2.90 (dd, J = 6.0, 12.0 Hz, 1H),
2.94–3.00 (m, 2H), 3.91 (m, 2H), 4.61 (dd, J = 2.8, 6.2 Hz, 1H),
5.91 (part A of AB system, J = 1.5 Hz, 1H), 5.93 (part B of
AB system, J = 1.5 Hz, 1H), 5.96 (part A of AB system, J =
1.5 Hz, 1H), 5.97 (part B of AB system, J = 1.5 Hz, 1H), 6.58
(dd, J = 1.5, 8.0 Hz, 1H), 6.61 (d, J = 1.0 Hz, 1H), 6.67 (dd, J =
1.0, 8.0 Hz, 1H), 6.68 (d, J = 8.0 Hz, 1H), 6.70 (d, J = 1.5 Hz,
1H), 6.74 (d, J = 8.0 Hz, 1H); 13C NMR (125 MHz, CDCl3)
d 35.1, 43.7, 45.1, 68.4, 75.5, 100.9, 101.3, 106.2, 108.1, 108.2,
109.9, 119.4, 122.7, 131.2, 135.3, 146.3, 147.5, 147.6, 148.1, 178.9;
EIMS m/z (relative intensity): 370 (M+, 90%), 352 (10), 175 (20),
151 (100), 135 (80); HRMS (EI) m/z calcd for C20H18O7 (M+),
370.1052; found, 370.1035.
1
mmax 3440, 1752 cm−1; H NMR (500 MHz, CDCl3) d 2.60–2.66
(m, 1H), 2.89–2.95 (m, 2H), 3.01 (dd, J = 8.0, 15.5 Hz, 1H),
3.85–3.88 (m, 1H), 3.87 (s, 3H), 3.89–3.92 (m, 1H), 3.90 (s, 3H),
4.57 (dd, J = 2.3, 6.7 Hz, 1H), 6.66 (dd, J = 2.0, 8.5 Hz, 1H), 6.72
(d, J = 2.0 Hz, 1H), 6.73–6.75 (m, 2H), 6.79 (d, J = 2.0 Hz, 1H),
6.80 (d, J = 8.5 Hz, 1H); 13C NMR (125 MHz, CDCl3) d 34.9,
44.0, 45.1, 55.9, 56.0, 68.2, 75.4, 110.6, 110.7, 112.1, 115.9, 117.8,
121.2, 130.8, 134.6, 145.4, 145.5, 145.9, 146.6, 178.9; EIMS m/z
(relative intensity): 374 (M+, 50%), 356 (20), 298 (10), 232 (10),
177 (15), 153 (80), 137 (100); HRMS (EI) m/z calcd for C20H22O7
(M+), 374.1366; found, 374.1349.
340 | Org. Biomol. Chem., 2006, 4, 331–341
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17 J. Mattinen, R. Sjo¨holm and R. Ekman, ACH Models Chem., 1998,
135, 583–590.
Acknowledgements
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We thank the Finnish Academy (48931, 2100633), Bioorganic and
Medicinal Chemistry Graduate School and University Research
Funds for financial support. BR thanks the Research Foundation
of the University of Helsinki and the Research Foundation of
Orion Corporation for grants. This work was partially carried out
within the EU project PHYTOHEALTH no QLRT-2001-02453.
This study does not necessarily reflect the views of the Commission
and in no way anticipates the Commission’s future policy in this
area.
20 M. Kuhn and A. von Wartburg, Helv. Chim. Acta, 1967, 50, 1546–
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22 M. P. Sibi, P. Liu, J. Ji, S. Hajra and J. Chen, J. Org. Chem., 2002, 67,
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