Synthesis of (-)-conocarpan by two routes based on radical cyclization and establishment of its absolute configuration

Article abstract of DOI:10.1039/b801858h

Two independent routes for the total synthesis of the bioactive neolignan (-)-conocarpan are described. The first (98% ee) is based on formal radical cyclization onto a benzene ring, and involves a 5-exo-trigonal closure onto a double bond restrained within a 6-membered ring. The second route (88% ee), which is shorter, is based on 5-exo-trigonal cyclization of an aryl radical onto a pendant terminal double bond. The two routes differ in their degree of stereoselectivity. The absolute configuration originally assigned to (+)-conocarpan had previously been called into question on the basis of empirical chiroptical rules; the present chemical work confirms the need for revision, and the assigned absolute configurations of several compounds correlated with (+)-conocarpan must also be changed. The Royal Society of Chemistry.

Full text of DOI:10.1039/b801858h

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Synthesis of (−)-conocarpan by two routes based on radical cyclization and
establishment of its absolute configuration†
Derrick L. J. Clive* and Elia J. L. Stoffman
Received 1st February 2008, Accepted 25th February 2008
First published as an Advance Article on the web 1st April 2008
DOI: 10.1039/b801858h
Two independent routes for the total synthesis of the bioactive neolignan (−)-conocarpan are
described. The first (98% ee) is based on formal radical cyclization onto a benzene ring, and involves a
5-exo-trigonal closure onto a double bond restrained within a 6-membered ring. The second route (88%
ee), which is shorter, is based on 5-exo-trigonal cyclization of an aryl radical onto a pendant terminal
double bond. The two routes differ in their degree of stereoselectivity. The absolute configuration
originally assigned to (+)-conocarpan had previously been called into question on the basis of
empirical chiroptical rules; the present chemical work confirms the need for revision, and the assigned
absolute configurations of several compounds correlated with (+)-conocarpan must also be changed.
with the sign of the Cotton effect for a number of other compound
classes. This is an empirical method which was validated by
application to a small number of dihydrobenzofurans.10
Several compounds have been chemically13 or spectro-
scopically4h correlated with (+)-conocarpan and so their absolute
configuration is also called into question and the need for
revision is confirmed by the present work. Likewise, the absolute
configuration of natural (−)-conocarpan must also be reversed.
Introduction
(+)-Conocarpan, originally assigned the structure and absolute
configuration shown in 1,1 is a neolignan2,3 that was first isolated
from timber used for marine construction. The purpose of
that investigation was to identify substances in the timber that
conferred resistance to a variety of marine organisms. A number of
other plant sources were later also found to contain conocarpan.3–6
The compound possesses a wide range of biological activities—
some of them potentially important, such as toxicity to mosquito
larvae,4f ,g,7 antitrypanosomal,8a antibacterial,8b antifungal8c,d and
photoprotective activity.8e This broad spectrum activity is char-
acteristic of numerous neolignans,9 and their biological activity
clearly makes them a class worth examining from a synthetic point
of view.9 Although many appear to be structurally simple, those
such as conocarpan actually contain a fragile stereocenter at C(2)
that imposes some restriction on the type of synthetic approaches
that can be used.
Results and discussion
We examined (+)-conocarpan as a synthetic target14–17 that
might be accessible by using radical cyclization to construct
the dihydrofuran segment. Racemic conocarpan can be made
easily by biomimetic oxidation1 or by manganese(III)-mediated
radical cyclization,18,19 but the presence of a labile C–O bond at
an asymmetric center that is part of a para-oxygenated benzylic
subunit makes the preparation of the optically active material
a much more difficult task. In addition, Sharpless asymmetric
epoxidation, which is potentially an ideal method for setting up
the C(2) stereochemistry, does not work well20 for compounds
of type 2 that have a strongly electron-releasing para oxygen
substituent.22,23,25
The structure of (+)-conocarpan was established spectroscopi-
cally, and the absolute configuration was assigned as 2R,3R (see
1) on the basis of a comparison of the CD curve of conocarpan
acetate with the CD curves of a number of dihydrobenzofurans
that had different substitution patterns in the aromatic rings.
Some years later, the configurational assignment was called
into question as a result of chiroptical studies by the Antus
group10,11 who had extended to dihydrobenzofurans the helicity
rules proposed by Snatzke et al.12 that relate absolute configuration
As indicated above, both enantiomers of conocarpan are
known, and we arbitrarily aimed at the originally assigned
configuration 1. Our initialplan was togenerate across-conjugated
enone of type 3 (Scheme 1), in the expectation that radical closure
(3 → 4) would preferentially give the indicated C(2)–C(3) trans
stereochemistry. On the basis of prior methodology work in this
laboratory,26 we were confident that 4 could be converted via 5 or
6 into 7, which is a protected version of conocarpan.
Chemistry Department, University of Alberta, Edmonton, Alberta T6G 2G2,
Canada. E-mail: derrick.clive@ualberta.ca
† Electronic supplementary information (ESI) available: Additional exper-
imental procedures. See DOI: 10.1039/b801858h
We considered two approaches to structures of type 327 by way of
the transformations 8 → 10 and 11 → 12 (Scheme 2). Both routes
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Scheme 1 Pg = protecting group; R = Me or group convertible into Me.
Scheme 3 Reagents and conditions: (a) LiBH4; (b) t-BuMe2SiCl, ImH,
89% over two steps; (c) see text, 68% via triflate; (d) BF3·OEt2 (for selective
deprotection of the –CH2OSiMe2t-Bu unit), 66–74%; (e) Dess–Martin
periodinane; (f) Pinnick oxidation, 81% over two steps; (g) Barton
halogenative decarboxylation, 43–66% over two steps; (h) Bu4NF, AcOH,
85%; (i) PhI(OAc)2, MeOH, 88%; (j) Bu3SnH, AIBN, PhMe, 72%; (k)
˚
TsOH·H2O, 4 A molecular sieves, CH2Cl2, 92%.
At this point we decided to examine an epoxide of type 11
(see Scheme 2) with the intention of subsequently protecting the
primary OH with a bulky silyl group so as to enhance stereos-
electivity in the planned radical cyclization (see below). To this
end allylic alcohol 22 was prepared from p-hydroxybenzaldehyde
21 and Sharpless asymmetric epoxidation,24 using (−)-diisopropyl
tartrate, then gave epoxide 23 (Scheme 4). The derived Mosher
esters from this epoxide, and from corresponding racemic material,
Scheme 2 Pg, Pg1, Pg2, Pg3 = protecting groups; R = Me or group
convertible into Me.
involve displacement at a benzylic carbon28–30 with a phenolate 9
as the nucleophile.
1
With Scheme 2 in mind, we first made 14 by an Evans aldol route
(Scheme 3) but met problems with the displacement (see 14 → 15)
either under Mitsunobu conditions or after modifying the benzylic
hydroxyl to the triflate or mesylate. Nonetheless, with some of the
required displacement product 15 in hand, we generated acid 16
and used a Barton–Hunsdiecker process31 to make the iodides 17.
Desilylation and oxidation in MeOH with PhI(OAc)2 produced the
cross-conjugated ketones 18, but the radical cyclization32 (18 →
19) gave poor diastereoselectivity and, after aromatization (19 →
20), the cis : trans ratio was only ca. 33 : 67. In an effort to improve
the diastereoselectivity, we planned to prepare substrates of type
18 with other groups in place of the C(3) methyl. However, using
14 with vinyl or CH2SiPh2t-Bu in place of this methyl, we again
met serious problems in the benzylic displacement with respect to
both yield and diastereoselectivity.
were examined by H NMR to establish the er of 23 as 95 : 5.
In retrospect we should have measured the optical purity of the
commercial Mosher acid chloride, but failed to do so; nonetheless,
at the end of the synthesis the optical purity of conocarpan (ee
98%) was measured by the more reliable method of chiral HPLC
(see later). Reaction of the epoxide with the sodium salt of phenol
2433,34 in water produced diol 25, which we could obtain as a single
isomer in 76% by chromatography. The stereochemistry shown for
25 is based on the assumption that epoxide opening occurs with
inversion; prior literature35 as well as the presumed mechanism
provides a basis for this assumption. Use of a basic aqueous
solution for epoxide opening, as opposed to an organic solvent,
appeared to represent the optimum conditions. The primary
hydroxyl of 25 was protected by silylation and the remaining sec-
ondary hydroxyl was replaced by iodine using Ph3P–I2–imidazole
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Fig. 1 NOE measurements.
Scheme 5 Reagents and conditions: (a) E-1-propenyllithium; (b) cam-
phorsulfonic acid, CH2Cl2, 30 min, 54% over two steps; (c) 1-propenyl-
magnesium bromide; (d) camphorsulfonic acid, CH2Cl2, 2 h, 71% over
two steps.
Scheme 4 Reagents and conditions: (a) TsCl, Et3N; (b) (EtO)2P(O)-
CH2CO2Et, Et3N, LiBr, 81%; (c) DIBAL, 95%; (d) Sharpless asymmetric
epoxidation, 93%; (e) NaOH, water, 24, 76%; (f) t-BuMe2SiCl, ImH, 96%;
(g) Ph3P, I2, ImH, 89%; (h) Pd(PPh3)4, dimedone, 99%; (i) PhI(OAc)2,
MeOH, 91%; (j) Bu3SnH, AIBN, PhMe, 80◦C, 72% yield of 28 and 29.
the E-isomer we decided to treat the slower-eluting compound
29 with 1-propenylmagnesium bromide, which is commercially
available and also gives an E : Z mixture (32). With both reagents
a double bond isomerization (Z → E) would be required, as we
were unable to effect separation of the geometrical isomers, even
by argentic chromatography.
(25 → 26). Oxidation with PhI(OAc)2 in MeOH generated the key
cross-conjugated ketones 27 and these underwent 5-exo-trigonal
radical cyclization under standard conditions (slow addition of
stannane and AIBN to a hot solution of 27 in PhMe) to
afford three fractions after chromatography. The fastest eluting
compound was 28 (26%) and the slowest eluting was 29 (45%).
The middle fraction was the isomer mixture 30 (10.5%). This latter
material had the two substituents on the dihydrofuran cis and was
discarded. We did not characterize the ring fusion stereochemistry
of 30, but expect36 that it was a mixture of the two possible cis-
fused compounds. The relative stereochemistry of 28 and 29 was
established by the NOE measurements summarized in Fig. 1.
Compounds 28 and 29 were processed individually (Scheme 5).
The former was treated with E-1-propenyllithium, generated by
the action of t-BuLi on commercial E-1-bromopropene (labeled
99% E). This experiment gave alcohol 31 with an E : Z ratio of
97 : 3, as estimated by 1H NMR. Since we did not obtain exclusively
In both cases, treatment with CSA effected aromatization (31 →
33; 32 → 33). We then equilibrated the E/Z isomers originating
from 31, using PdCl2(PhCN)2,37 to obtain 34 with an E : Z ratio
of ca. 97 : 3 (Scheme 6). Removal of the silicon protecting group
and replacement of the resulting hydroxyl by iodine38 (34 → 35 →
36), followed by hydride displacement of the iodine (Et3BHLi39)
gave 37. At this time, using the second route described below,
we had discovered that prolonged exposure to the palladium
catalyst during double bond equilibration improved the E : Z
ratio to a level where the Z-isomer was not detectable by high
1
field H NMR. Accordingly, compound 37 was treated with the
isomerization catalyst37 for 48 h to afford geometrically pure
material (74% from the iodide). Desulfonylation [Na(Hg), MeOH,
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Scheme 6 Reagents and conditions: (a) PdCl2(PhCN)2, CH2Cl2, 3.5 days,
95%; (b) Bu4NF, 100%; (c) Ph3P, I2, ImH (82%) or MsCl, Et3N (85%) and
then NaI, 1,2-dimethoxyethane, reflux, 98%; (d) Et3BHLi; (e) Na(Hg),
MeOH, 95%; (f) PdCl2(PhCN)2, CH2Cl2, 2 days, 74% from 36.
95%] then gave conocarpan.40 This material was examined by
chiral HPLC and found to have an ee of 98%; its [a]2D2 was −99.7
(c 1.03, MeOH). The sign of the specific rotation is opposite to that
reported1 for (+)-conocarpan indicating that either the original
configurational assignment was indeed in error, as suggested by the
chiroptical studies,10 or that the Sharpless epoxidation had taken
an abnormal stereochemical course. As described below, these
matters were later settled in favor of configurational revision of
(+)-conocarpan, so that the compound we had made was actually
(−)-conocarpan, with the 2R,3R absolute configuration shown
by structure 1. However, experimental proof was not obtained
until we had completed a second route to the natural product (see
below).
While working on the above synthesis we developed another
route that is shorter and that also provided an opportunity to
compare the cis : trans ratio for two different modes of 5-exo-
trigonal radical cyclization. The key step in this second approach
is the radical cyclization 38 → 39.
Scheme 7 Reagents and conditions: (a) p-NO2C6H4COCl, Et3N, then re-
crystallize product, 70% after first crystallization; in a separate experiment
yield was 62% after three crystallizations; (b) K2CO3, 80% MeOH, 97%; (c)
NaOH, water, 40, 64% or 83% after correction for recovered 23b; (d) MsCl,
Et3N, 100%; (e) NaI, 2-butanone, reflux, 71%; (f) Bu3SnH, AIBN, PhMe,
80 ◦C, 69%; (g) ethylidenetriphenylphosphorane, 69%; (h) PdCl2(PhCN)2,
CH2Cl2, 10 days, 85%; (i) Na(Hg), MeOH, 95%.
and so the amount formed, if any, must have been very small.
The aldehyde group was next converted into a 1-propenyl unit
by Wittig reaction with ethylidenetriphenylphosphorane. This
reaction afforded a 3 : 1 Z : E mixture (43), and equilibration
37
with PdCl2(PhCN)2 for 24 h gave material (37) that was largely
the E-isomer (E : Z = 96.9 : 3.1) in near quantitative yield. When
the equilibration time was prolonged for 10 days, no Z-isomer
could be detected (1H NMR, 400 MHz), but this was achieved at
the expense of a lower yield (85%). Finally, removal of the tosyl
group with Na(Hg) produced (−)-conocarpan (95%); [a]2D2 −46.5
(c 0.28, MeOH).40,45 Our synthetic material had an ee of 88% (i.e.
enantiomeric ratio = 94 : 6) as judged by chiral HPLC. We did
not establish the stage at which the enantiomeric ratio was eroded
from 99 : 1 (for epoxide 23b) to 94 : 6 (for synthetic conocarpan
1), but suspect that the allylic benzylic ether 38 is involved46 as, in
the earlier steps, scrambling at the benzylic position would lead to
diastereoisomers—which were not observed by 1H NMR for any
of the material used in the synthesis.
Our starting point was again epoxide 23, but with this batch
we crystallized the derived p-nitrobenzoate (23 → 23a → 23b) to
raise the ee (measured by chiral HPLC) from ca. 89% to 97.8%
(Scheme 7).
Opening of epoxide 23b under basic conditions (aqueous
NaOH) with the sodium salt of phenol 4041 (2 equiv.) gave diol 41 in
83% yield (after correction for recovered epoxide). Bis-mesylation
(100%) and treatment with NaI42 in refluxing 2-butanone served
to convert the diol into the olefin 3843,44 [65% or 80% after
correction for recovered bis-mesylate (19%)] needed for the radical
cyclization. This was conducted in the usual way by slow addition
of a solution of stannane and AIBN in PhMe to a hot (80 ◦C)
solution of the substrate in the same solvent. The desired trans
disubstituted dihydrobenzofuran 39 was isolated in 69% yield. We
did not observe (1H NMR, 300 MHz) the corresponding cis isomer
Proof of absolute stereochemistry
Since our synthetic conocarpan was levorotatory instead of
dextrorotatory, and our target had been the absolute configuration
shown by 1, which is reported for dextrorotatory material, we
needed to establish that the Sharpless asymmetric epoxidation had
followed the expected course21,47 so that the absolute configuration
of our synthetic compound was indeed that shown in 1. We were
unable to find an example in the literature—with proof of the
stereochemical outcome—of Sharpless asymmetric epoxidation
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of a styrene derivative with a para oxygen substituent.22 The
most straightforward method of obtaining such proof in our case
would have been by X-ray analysis, but attempts to obtain suitable
crystals of a heavy atom derivative of conocarpan or of epoxide
23b were unsuccessful. Accordingly, we sought evidence based on
chemical degradation of epoxide 23b to (S)-1-phenyl-1-propanol,
whose absolute configuration is known from chemical correlation
with S-(−)-mandelic acid.48,49
experiments confirm that the asymmetric epoxidation (22 → 23)
follows the expected course; consequently, natural (+)-conocarpan
must have the absolute stereochemistry shown in 52.
Our enantiomerically enriched epoxide 23b was converted into
mesylate 44 (Scheme 8), from which olefin 45 was smoothly formed
by treatment with NaI in refluxing DME. Normally Zn would be
used to convert the presumed intermediate iodo epoxide into an
olefin; the present method does not seem to have been reported
before, although direct conversion of an iodo epoxide into an
allylic alcohol by reaction with iodide ion has been suggested in
a mechanistic scheme.50 Hydroxyl protection by silylation (45 →
46) and double bond hydrogenation gave 47. The tosyl group was
then removed by the action of Na(Hg). Triflation of the resulting
phenol (48 → 49) allowed us to remove the phenolic oxygen by
hydrogenolysis51 (49 → 50). Finally, (S)-1-phenylpropanol 51 was
released by desilylation. The compound had [a]2D2 −29.3 (c 1.23,
CHCl3) [lit.48 −45.6 (c 1.3, CHCl3)], corresponding to an ee of
64%. Our starting epoxide 23b had an ee of 98% and we did
not identify the stage at which there is erosion of optical purity;
possibly, it occurs during the hydrogenation via migration of the
double bond into conjugation with the benzene ring, followed
by saturation. Stereochemical scrambling at any other stage is
unlikely on mechanistic grounds. The absolute configuration of
levorotatory 51 has been established48,49 and so our degradation
Conclusions
The present work shows that stereochemical revision for (+)-
conocarpan is required, as discussed above. Our first synthesis,
which gives a final product of very high ee, does not proceed via
an ether that is both benzylic and allylic, and there appears to be
no erosion of enantiomeric purity. In the second route, which does
involve such a fragile C–O bond, we started with an epoxide of
high ee and obtained conocarpan of lower ee. The two modes of 5-
exo-trigonal radical closure also afford different levels of cis/trans
selectivity, with closure of an aryl radical onto a pendant vinyl
group, as in the second route, being more selective.
Experimental
General methods
The J values are spacings measured directly from the spectrum.
All experiments were done under an inert atmosphere (N2 or
Ar), unless stated to the contrary. Column sizes are quoted as
diameter × height. [a]D values are given in 10−1 deg cm2 g−1.
First route
Toluene-4-sulfonic acid 4-[(2S,3R)-3-hydroxymethyloxyranyl)]-
˚
phenyl ester (23). Crushed 4 A molecular sieves (0.5 g), activated
at >200 ◦C and 0.3 mmHg for 24 h, were added to a solution of
(−)-diisopropyl tartrate (0.050 mL, 0.23 mmol) in CH2Cl2 (4 mL),
and the flask was lowered into a cold bath (−25 ◦C, CO2–CCl4).
Ti(Oi-Pr)4 (0.10 mL, 0.34 mmol) was then added, followed by
t-BuOOH (3 M in isooctane, 1.6 mL, 4.8 mmol). The mixture
was stirred for 10 min and then 22 (728.4 mg, 2.390 mmol) in
CH2Cl2 (1.2 mL plus 0.8 mL as a rinse) was added dropwise by
syringe. The mixture was stirred for 2 h and then quenched by
addition of aqueous NaOH (30% w/v, 0.38 mL) saturated with
NaCl. Stirring was continued for 10 min and then MgSO4 (ca.
500 mg) and Celite (ca. 1 g) were added. The mixture was swirled
and the solids were filtered off. Evaporation of the filtrate and flash
chromatography of the residue over silica gel (2.5 × 35 cm), using
first 50–60% EtOAc–hexane (step gradient elution) and then 6 :
3 : 1 EtOAc–hex◦ane–MeOH, gave 23 (712.4 mg, 93%) as a white
solid: mp 51–53 C; 1H NMR (CDCl3, 500 MHz) d 1.74 (dd, J =
5.1, 7.7 Hz, 1 H), 2.49 (s, 3 H), 3.18 (ddd, J = 2.3, 2.3, 3.6 Hz,
1 H), 3.83 (ddd, J = 3.6, 7.8, 12.6 Hz, 1 H), 3.93 (d, J = 2.0 Hz,
1 H), 4.06 (ddd, J = 2.5, 4.9, 12.9 Hz, 1 H), 6.99 (apparent d
as part of AAꢀBBꢀ system, J = 8.7 Hz, 2 H), 7.21 (apparent d
as part of AAꢀBBꢀ system, J = 8.5 Hz, 2 H), 7.30 (apparent d
as part of AAꢀBBꢀ system, J = 8.3 Hz, 2 H), 7.71 (apparent d
as part of AAꢀBBꢀ system, J = 8.3 Hz, 2 H); 13C NMR (CDCl3,
Scheme
8 Reagents and conditions: (a) MsCl, Et3N; (b) NaI,
1,2-dimethoxyethane, reflux, 57% over two steps; (c) t-BuMe2SiOSO2CF3,
sym-collidine, 100%; (d) 5% Rh–Al2O3, THF, H2, 99%; (e) Na(Hg), MeOH,
60% and recovered 47 (32%); (f) (CF3SO2)2O, Et3N, 75%; (g) Pd/C, Et3N,
H2, 100%; (h) Bu4NF, 71%.
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brownish oil that was processed promptly: [a]2D2 +13.04 (c 1.38,
CHCl3); H NMR (CDCl3, 400 MHz) d 0.00 (s, 3 H), 0.04 (s,
100 MHz) d 22.0 (t), 55.1 (d), 61.3 (t), 62.8 (d), 122.8 (d), 127.2
(d), 128.7 (d), 130.1 (d), 132.5 (s), 136.1 (s), 145.7 (s), 149.7 (s);
mmax (CHCl3 cast; cm−1) 3419, 3069, 2986, 2926, 2872, 1598, 1505,
1372, 1198, 1176, 1150; exact mass m/z calcd for C16H16NaOS
343.06107, found 343.06134.
Samples of the Mosher esters (from the above opti-
cally active epoxy alcohol and the corresponding racemic
epoxy alcohol) were prepared by adding (R)-a-methoxy-a-
(trifluoromethyl)phenylacetyl chloride to a stirred solution of the
epoxy alcohol and Et3N in CH2Cl2. Analysis of the derived crude
Mosher esters by 1H NMR showed the diastereomeric ratio of the
aboveepoxy alcohol to be 94:6. Analysis ofthe epoxyalcoholfrom
another batch (but prepared under the same conditions) by chiral
HPLC [Chiralpak AD-RH (150 × 4.6 mm), 1 : 1 MeCN–water,
flow 0.5 mL min−1, detection at 232 nm. Baseline separation of a
racemic sample; retention times 11.9 min and 14.3 min] showed
the enantiomeric ratio to be 94.7 : 5.3.
1
3 H), 0.88 (s, 9 H), 2.43 (s, 3 H), 3.79 (dd, J = 4.5, 10.6 Hz, 1 H),
3.99 (dd, J = 8.2, 10.6 Hz, 1 H), 4.21 (ddd, J = 4.3, 4.3, 8.3 Hz,
1 H), 5.05 (d overlapping with br s, J = 4.2 Hz, 2 H), 6.65–6.73
(m, 4 H), 6.96 (apparent d as part of AAꢀBBꢀ system, J = 8.6 Hz,
2 H), 7.27 (apparent d as part of AAꢀBBꢀ system, J = 8.5 Hz,
2 H), 7.29 (apparent d as part of AAꢀBBꢀ system, J = 8.7 Hz,
2 H), 7.65 (apparent d as part of AAꢀBBꢀ system, J = 8.4 Hz,
2 H); 13C NMR (CDCl3, 100 MHz) d −5.5 (q), −5.4 (q), 18.2 (s),
21.7 (q), 25.8 (q), 40.9 (d), 65.7 (t), 77.9 (d), 115.9 (d), 117.5 (d),
122.4 (d), 127.8 (d), 128.5 (d), 129.7 (d), 132.0 (s), 138.8 (s), 145.5
(s), 149.1 (s), 150.2 (s), 151.7 (s); mmax (CHCl3 cast; cm−1) 3489,
2952, 2927, 2856, 1597, 1507, 1373, 1198, 1176, 1092, 837; exact
mass m/z calcd for C28H35INaO6SSi 677.08606, found 677.08627.
(b) Toluene-4-sulfonic acid 4-[(1S,2S)-3-(tert-butyldimethyl-
silanyloxy)-2-iodo-1-(1-methoxy-4-oxocyclohexa-2,5-dienyloxy)-
propyl]phenyl ester (27). PhI(OAc)2 (45.4 mg, 0.141 mmol)
was added in one portion to a stirred and cooled (0 ◦C)
solution of the above toluene-4-sulfonic acid 4-[(1S,2S)-3-(tert-
butyldimethylsilanyloxy)-1-(4-hydroxyphenoxy)-2-iodopropyl]-
phenyl ester (containing ca. 6.5% anti isomer) (81.0 mg,
0.124 mmol) in MeOH (1.3 mL). Stirring was continued for 30 min
and then EtOAc (10 mL) was added. The mixture was washed
with saturated aqueous NaHCO3 and brine, dried (MgSO4) and
evaporated. Flash chromatography of the residue over silica gel
(1.5 × 30 cm), using 0–20% EtOAc–hexane containing Et3N (ca.
3 drops per 100 mL) (gradient elution), gave 27 (77.3 mg, 91%)
as a light orange oil, which appeared to be a single isomer (1H
NMR, 13C NMR): [a]D22 +39.38 (c 1.49, CH2Cl2); 1H NMR (CDCl3,
400 MHz) d 0.00 (s, 3 H), 0.04 (s, 3 H), 0.88 (s, 9 H), 2.41 (s, 3 H),
3.33 (s, 3 H), 3.52 (dd, J = 4.2, 11.0 Hz, 1 H), 3.79 (dd, J = 6.9,
11.0 Hz, 1 H), 3.99 (ddd, J = 4.3, 5.1, 6.8 Hz, 1 H), 4.72 (d, J =
5.2 Hz, 1 H), 5.95 (dd, J = 2.1, 10.3 Hz, 1 H), 6.08 (dd, J = 2.1,
10.5 Hz, 1 H), 6.48 (dd, J = 3.2, 10.3 Hz, 1 H), 6.64 (dd, J =
3.2, 10.4 Hz, 1 H), 6.90 (apparent d as part of AAꢀBBꢀ system,
J = 8.7 Hz, 2 H), 7.18 (apparent d as part of AAꢀBBꢀ system,
J = 8.6 Hz, 2 H), 7.27 (apparent d as part of AAꢀBBꢀ system,
J = 8.5 Hz, 2 H), 7.64 (apparent d as part of AAꢀBBꢀ system,
J = 8.4 Hz, 2 H); 13C NMR (CDCl3, 100 MHz) d −5.4 (q), −5.2
(q), 18.2 (s), 21.7 (q), 25.8 (q), 41.3 (d), 51.5 (q), 65.5 (t), 73.1 (d),
93.6 (s), 122.3 (d), 128.2 (d), 128.5 (d), 129.0 (d), 129.7 (d), 129.8
(d), 132.2 (s), 139.7 (s), 143.5 (d), 144.2 (d), 145.5 (s), 149.3 (s),
184.8 (s); mmax (CH2Cl2 cast; cm−1) 3055, 2953, 2930, 2896, 2857,
1688, 1674, 1639, 1599, 1501, 1471, 1378, 1199, 1177, 1094, 867,
839; exact mass m/z calcd for C29H37INaO7SSi 707.09663, found
707.09677. Anal. calcd for C29H37IO7SSi: C 50.87; H 5.45; S 4.68.
Found: C 50.78; H 5.55; S 4.87%.
Toluene-4-sulfonic acid 4-[(1S,2R)-1-(4-Allyloxyphenoxy)-2,3-
dihydroxypropyl]phenyl ester (25). Epoxy alcohol 23 (>88% ee,
10.94 g, 34.15 mmol) was added in one portion to a stirred
and heated (70 ◦C) solution of O-allylhydroquinone (12.32 g,
82.04 mmol) and aqueous NaOH (1 M, 34 mL, 34 mmol) in water
(66 mL), and stirring was continued for 2.5 h. The mixture was
allowed to cool, poured into aqueous NaOH (1 M, 100 mL), and
extracted three times with Et2O. The combined organic extracts
were washed with brine, dried (Na2SO4) and evaporated. Flash
chromatography of the residue over silica gel (5 × 35 cm), using
50–80% EtOAc–hexane containing Et3N (ca. 3 drops per 100 mL)
(gradient elution), gave 25 (12.26 g, 76%) as a yellowish oil, and
recovered 23 (1.09 g, 10%). Diol 25 had: [a]2D2 +46.77 (c 1.94,
1
CH2Cl2); H NMR (CDCl3, 400 MHz) d 2.16 (br s, 1 H), 2.46
(overlapping s and br s, 4 H), 3.79 (m, 2 H), 3.93 (dd, J = 5.4,
9.8 Hz, 1 H), 4.45 (ddd, J = 1.5, 1.5, 5.3 Hz, 2 H), 5.08 (d, J =
6.1 Hz, 1 H), 5.27 (dddd, J = 1.4, 1.4, 1.4, 10.5 Hz, 1 H), 5.38
(dddd, J = 1.6, 1.6, 1.6, 17.3 Hz, 1 H), 6.02 (dddd, J = 5.3, 5.3,
10.6, 17.3 Hz, 1 H), 6.71–6.77 (m, 4 H), 7.00 (apparent d as part
of AAꢀBBꢀ system, J = 8.6 Hz, 2 H), 7.30 (apparent d as part
of AAꢀBBꢀ system, J = 8.1 Hz, 2 H), 7.33 (apparent d as part
of AAꢀBBꢀ system, J = 8.6 Hz, 2 H), 7.69 (apparent d as part of
AAꢀBBꢀ system, J = 8.3 Hz, 2 H); 13C NMR (CDCl3, 100 MHz)
d 21.7 (q), 62.8 (t), 69.4 (t), 74.5 (d), 81.1 (d), 115.6 (d), 117.1 (d),
117.6 (s), 122.6 (d), 128.3 (d), 128.4 (d), 129.7 (d), 132.4 (s), 133.4
(d), 137.1 (s), 145.4 (s), 149.3 (s), 151.4 (s), 153.4 (s); mmax (CDCl3
cast; cm−1) 3400, 3069, 2924, 1597, 1505, 1373, 1212, 1199; exact
mass m/z calcd for C25H26NaO7S 493.12915, found 493.12900.
Toluene-4-sulfonic acid 4-[(1S,2S)-3-(tert-butyldimethylsilany-
loxy)-2-iodo-1-(1-methoxy-4-oxocyclohexa-2,5-dienyloxy)propyl]-
phenyl ester (27).
(a) Toluene-4-sulfonic acid 4-[(1S,2S)-3-(tert-butyldimethyl-
Toluene-4-sulfonic acid 4-[(2R,3S,3aS,7aS)-3-(tert-butyldi-
methylsilanyloxymethyl) - 2,3,3a,4,5,7a - hexahydro - 7a - methoxy -
5-oxobenzofuran-2-yl]phenyl ester (29) and Toluene-4-sulfonic
acid 4-[(2R,3S,3aR,7aR)-3-(tert-butyldimethylsilanyloxymethyl)-
2,3,3a,4,5,7a-hexahydro-7a-methoxy-5-oxobenzofuran-2-yl]phenyl
ester (28). A solution of Bu3SnH (0.04 mL, 0.15 mmol) and
AIBN (6.0 mg, 0.037 mmol) in PhMe (3 mL) was added over
4 h to a stirred and heated (80 ◦C) solution of 27 (65.4 mg,
0.0955 mmol) in PhMe (1 mL) (N2 atmosphere). After the
addition, heating was continued for 1 h, and the mixture was
silanyloxy)-1-(4-hydroxyphenoxy)-2-iodopropyl]phenyl
ester.
(Ph3P)4Pd (269.3 mg, 0.2330 mmol) was added to a stirred
solution of 26 (2.5371 g, 3.652 mmol) and dimedone (1.1353 g,
8.099 mmol) in THF (13 mL), and stirring was continued for
1 h. Evaporation of the solvent and flash chromatography
of the residue over silica gel (3 × 45 cm), using 10–20%
EtOAc–hexane (gradient elution), gave toluene-4-sulfonic acid 4-
[(1S,2S)-3-(tert-butyldimethylsilanyloxy)-1-(4-hydroxyphenoxy)-
2-iodopropyl]phenyl ester (2.3587 g, 99%) as an unstable,
1836 | Org. Biomol. Chem., 2008, 6, 1831–1842
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then allowed to cool to room temperature. Evaporation of the
solvent and flash chromatography of the residue over silica gel
(1.5 × 30 cm), using 8–20% EtOAc–hexane containing Et3N (ca.
3 drops per 100 mL), gave three fractions, each as a yellowish
oil. The fastest eluting fraction was one isomer (28) (14.0 mg,
26.3%), the middle eluting fraction was a mixture of unwanted
diastereomers [i.e. cis disubstitution on the oxygen heterocycle
(see below)] (5.6 mg, 10.5%), and the slowest eluting fraction was
another diastereoisomer (29) (23.6 mg, 45.3%). The total yield of
desired product amounted to 72%.
the filtrate and flash chromatography of the residue over silica gel
(1.5 × 35 cm), using 8% EtOAc–hexane, gave 34 (1.3980 g, 95%) as
a colorless oil (containing ca. 3% of the Z isomer) with 1H NMR
data identical to those reported for 33.
Toluene-4-sulfonic acid 4-[(2R,3S)-2,3-dihydro-3-iodomethyl-5-
(1E)-1-propenylbenzofuran-2-yl]phenyl ester (36).
(a)
Toluene-4-sulfonic
acid
4-[(2R,3S)-2,3-dihydro-3-
(methanesulfonyloxy)methyl-5-(1E)-1-propenylbenzofuran-2-yl]-
phenyl ester. MeSO2Cl (0.025 mL, 0.32 mmol) was added
dropwise by syringe to a stirred and cooled (0 ◦C) solution of
35 (120.0 mg, 0.2750 mmol) and Et3N (0.04 mL, 0.29 mmol)
in CH2Cl2 (3 mL). The cooling bath was removed and stirring
was continued for 15 min. The mixture was washed with water
and dried (MgSO4). Evaporation of the solvent and flash
chromatography of the residue over silica gel (1.5 × 30 cm), using
20% EtOAc–hexane, gave toluene-4-sulfonic acid 4-[(2R,3S)-2,3-
dihydro-3-(methanesulfonyloxy)methyl-5-(1E)-1-propenylben-
zofuran-2-yl]phenyl ester (120.1 mg, 85%) as a white solid, which
The relative configurations were established by NOE measure-
ments shown in Fig. 1.
The fast eluting isomer 28 had: [a]2D2 −56.66 (c 2.49, CHCl3); 1H
NMR (C6D6, 400 MHz) d 0.00 (s, 6 H), 0.97 (s, 9 H), 1.80 (dddd,
J = 4.3, 4.3, 8.8, 8.8 Hz, 1 H), 1.87 (s, 3 H), 2.48 (dd, J = 4.8,
16.6 Hz, 1 H), 2.60 (dd, J = 6.4, 16.6 Hz, 1 H), 2.93 (dddd, J = 1.4,
4.9, 6.2, 9.7 Hz, 1 H), 3.28 (s, 3 H), 3.30 (dd, J = 4.2, 10.9 Hz, 1 H),
3.41 (dd, J = 4.6, 10.8 Hz, 1 H), 5.05 (d, J = 8.9 Hz, 1 H), 5.95 (d,
J = 10.4 Hz, 1 H), 6.56 (dd, J = 1.4, 10.4 Hz, 1 H), 6.70 (apparent
dd as part of AAꢀBBꢀ system, J = 0.6, 8.5 Hz, 2 H), 7.12 (apparent
d as part of AAꢀBBꢀ system, J = 8.7 Hz, 2 H), 7.22 (apparent d
as part of AAꢀBBꢀ system, J = 8.8 Hz, 2 H), 7.77 (apparent dd as
part of AAꢀBBꢀ system, J = 0.3, 8.5 Hz, 2 H); 13C NMR (C6D6,
100 MHz) (two signals overlap in the aromatic region) d −5.6 (q),
18.3 (s), 21.1 (q), 25.9 (overlapping q and d), 37.9 (t), 44.1 (d), 49.4
(q), 55.1 (d), 60.0 (t), 81.8 (d), 103.5 (s), 122.9 (d), 128.8 (d), 129.7
(d), 133.5 (s), 140.1 (s), 143.0 (d), 144.8 (s), 149.9 (s), 196.0 (s);
mmax (CHCl3 cast; cm−1) 2953, 2929, 2857, 1689, 1597, 1502, 1376,
1198, 1176, 1155, 866, 837.
◦
contained 4% of the Z isomer (1H NMR): mp 40–42 C; [a]2D2
−49.71 (c 6.59, CHCl3); 1H NMR (CDCl3, 400 MHz) d 1.86 (dd,
J = 1.7, 6.6 Hz, 3 H), 2.45 (s, 3 H), 2.98 (s, 3 H), 3.71 (ddd, J =
5.1, 5.1, 8.9 Hz, 1 H), 4.39 (dd, J = 8.4, 10.3 Hz, 1 H), 4.50 (dd,
J = 5.0, 10.3 Hz, 1 H), 5.58 (d, J = 5.2 Hz, 1 H), 6.08 (dq, J = 6.6,
15.6 Hz, 1 H), 6.33 (dd, J = 1.6, 15.7 Hz, 1 H), 6.84 (d, 8.2 Hz,
1 H), 6.97 (apparent d as part of AAꢀBBꢀ system, J = 8.7 Hz,
2 H), 7.18 (s, 1 H), 7.20 (dd, J = 1.7, 8.3 Hz, 1 H), 7.29 (apparent
d as part of AAꢀBBꢀ system, J = 8.8 Hz, 2 H), 7.31 (apparent dd
as part of AAꢀBBꢀ system, J = 0.5, 8.1 Hz, 2 H), 7.70 (apparent d
as part of AAꢀBBꢀ system, J = 8.4 Hz, 2 H); 13C NMR (CDCl3,
100 MHz) d 18.3 (q), 21.6 (q), 37.5 (q), 50.7 (d), 70.0 (t), 85.7 (d),
109.8 (d), 121.9 (d), 122.6 (d), 124.0 (d), 124.1 (s), 126.7 (d), 127.8
(d), 128.4 (d), 129.7 (d), 130.0 (d), 131.9 (s), 132.2 (s), 139.7 (s),
145.4 (s), 149.3 (s), 158.5 (s); mmax (CHCl3 cast; cm−1) 3024, 2937,
1503, 1490, 1360, 1198, 1176, 1154, 960, 867, 816; exact mass m/z
calcd for C26H26NaO7S2 537.10122, found 537.10121.
The slow eluting isomer 29 had: [a]2D2 −20.65 (c 5.88, CHCl3);
1H NMR (C6D6, 400 MHz) 0.00 (s, 3 H), 0.01 (s, 3 H), 0.95 (s,
9 H), 1.92 (s, 3 H), 2.46 (dd, J = 11.7, 15.9 Hz, 1 H), 2.63 (dd,
J = 4.9, 15.9 Hz, 1 H), 2.92–3.00 (m, 2 H, found to be Ha and
Hb by 2D experiments), 3.13 (s, 3 H), 3.45 (d, J = 5.9 Hz, 2 H),
4.90 (d, J = 9.0 Hz, 1 H), 6.04 (dd, J = 0.7, 10.5 Hz, 1 H),
6.58 (d, J = 10.3 Hz, 1 H), 6.76 (apparent d as part of AAꢀBBꢀ
system, J = 8.1 Hz, 2 H), 7.18 (apparent d as part of AAꢀBBꢀ
system, J = 8.6 Hz, 2 H), 7.33 (apparent d as part of AAꢀBBꢀ
system, J = 8.6 Hz, 2 H), 7.80 (apparent d as part of AAꢀBBꢀ
system, J = 8.3 Hz, 2 H); 13C NMR (C6D6, 125 MHz) d −5.7 (q),
−5.6 (q), 18.1 (s), 21.1 (q), 25.8 (q), 36.3 (t), 46.6 (d), 49.3 (q),
50.9 (d), 59.8 (t), 83.8 (d), 103.8 (s), 122.8 (d), 128.3 (d), 128.8
(d), 129.65 (d), 129.71 (d), 133.6 (s), 140.7 (d), 140.9 (s), 144.8 (s),
150.0 (s), 196.6 (s); mmax (CHCl3 cast; cm−1) 2953, 2929, 2886, 2857,
1720, 1691, 1502, 1376, 1198, 1178, 1154, 1093, 867, 838; exact
mass m/z calcd for C29H38NaO7SSi 581.19997, found 581.19977.
The fact that some cis disubstitution product was formed
was established by aromatizing that material (by treatment with
TsOH·H2O) and showing that the aromatic product was isomeric
with the product of aromatization of the desired trans disubstitu-
tion product.
(b)
Toluene-4-sulfonic
acid
4-[(2R,3S)-2,3-dihydro-3-
iodomethyl-5-(1E)-1-propenylbenzofuran-2-yl]phenyl ester (36).
NaI (177.8 mg, 1.186 mmol) was added to a stirred suspension
of Zn powder (0.1681 g, 2.571 mmol) and toluene-4-sulfonic
acid
4-[(2R,3S)-2,3-dihydro-3-(methanesulfonyloxy)methyl-5-
(1E)-1-propenylbenzofuran-2-yl]phenyl ester (containing 4% of Z
isomer) (120.1 mg, 0.2334 mmol) in glyme (0.26 mL). The mixture
was refluxed overnight, allowed to cool, and then filtered through
a pad of Celite (3 × 1.5 cm). Evaporation of the solvent and flash
chromatography of the residue over silica gel (1.5 × 30 cm), using
5–8% EtOAc-hexane, gave iodide 36.
Evidently the iodide is inert to reduction in refluxing glyme
when treated with Zn powder. This crude material was therefore
reduced using Bu3SnH (see later).
In another experiment, specifically designed to prepare the
iodide, NaI (566.0 mg, 3.776 mmol) was added in one portion to a
stirred solution of toluene-4-sulfonic acid 4-[(2R,3S)-2,3-dihydro-
3-(methanesulfonyloxy)methyl-5-(1E)-1-propenylbenzofuran-2-
yl]phenyl ester (a batch containing 6% of Z isomer) (403.5 mg,
0.7841 mmol) in glyme (3 mL). The mixture was refluxed for 1.5 h,
allowed to cool and diluted with EtOAc (10 mL). The mixture
was washed with water (1 × 5 mL), saturated aqueous Na2S2O3
Toluene-4-sulfonic acid 4-[(2R,3S)-3-(tert-butyldimethylsilanyl-
oxymethyl)-2,3-dihydro-5-(1E)-1-propenylbenzofuran-2-yl]phenyl
ester (34). PdCl2(PhCN)2 (84.6 mg, 0.221 mmol) was added in
one portion to a stirred solution of 33 (E : Z = 1.8 : 1, 1.4696 g,
2.6680 mmol) in CH2Cl2 (10 mL) and the mixture was stirred for
3.5 days (N2 atmosphere), diluted with Et2O (10 mL) and filtered
through a pad of Florisil (3 × 3 cm), using Et2O. Evaporation of
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solution (1 × 5 mL), and brine (1 × 5 mL), dried (MgSO4) and
evaporated. Flash chromatography of the residue over silica gel
(2 × 30 cm), using 13% EtOAc–hexane, gave 36 (421.1 mg, 98%)
as a colorless oil, which contained 6% of the Z isomer (1H NMR):
[a]2D2 −80.22 (c 5.97, CHCl3); 1H NMR (CDCl3, 400 MHz) d 1.88
(dd, J = 1.4, 6.6 Hz, 3 H), 2.47 (s, 3 H), 3.34 (dd, J = 9.7, 9.7 Hz,
1 H), 3.53 (dd, J = 4.0, 10.2 Hz, 1 H), 3.54 (ddd, J = 4.0, 4.0,
8.9 Hz, 1 H), 5.49 (d, J = 4.3 Hz, 1 H), 6.10 (dq, J = 6.6, 15.6 Hz,
1 H), 6.36 (dd, J = 1.2, 15.8 Hz, 1 H), 6.85 (d, J = 8.2 Hz, 1 H),
6.98 (apparent d as part of AAꢀBBꢀ system, J = 8.7 Hz, 2 H),
7.21 (s, 1 H), 7.24 (d, J = 8.3 Hz, 1 H), 7.32–7.36 (m, 4 H), 7.73
(apparent d as part of AAꢀBBꢀ system, J = 8.2 Hz, 2 H); 13C
NMR (CDCl3, 100 MHz) d 9.7 (t), 18.6 (q), 22.0 (q), 53.4 (d), 89.3
(d), 110.2 (d), 122.1 (d), 122.8 (d), 124.2 (d), 127.0 (d), 128.0 (d),
128.4 (s), 128.8 (d), 130.1 (d), 130.5 (d), 132.2 (s), 132.7 (s), 140.3
(s), 145.6 (s), 149.6 (s), 158.6 (s); mmax (CDCl3 cast; cm−1) 3021,
2913, 2851, 1597, 1502, 1489, 1374, 1245, 1198, 1177, 1154, 1093,
966, 862, 551; exact mass m/z calcd for C25H23INaO4S 569.02540,
found 569.02546.
122.6 (d), 123.3 (d), 126.4 (d), 127.2 (d), 128.5 (d), 129.8 (d), 130.6
(d), 131.6 (s), 131.8 (s), 132.4 (s), 140.0 (s), 145.4 (s), 149.3 (s),
158.1 (s); mmax (CH2Cl2 cast; cm−1) 3021, 2962, 2928, 1598, 1503,
1486, 1375, 1243, 1199, 1177, 1154, 1094, 968, 868; exact mass
m/z calcd for C25H24NaO4S 443.12875, found 443.12864.
This material was then exposed to the action of PdCl2(PhCN)2
as follows:
PdCl2(PhCN)2 (21 mg, 0.55 mmol) was added in one portion to
a stirred solution of 37 (0.281 mg, 0.667 mmol) in CH2Cl2 (3 mL)
and the mixture was stirred for 48 h (N2 atmosphere), diluted with
Et2O (10 mL) and filtered through a pad of Florisil (3 × 3 cm),
using Et2O. Evaporation of the filtrate and flash chromatography
of the residue over silica gel (1.5 × 35 cm), using 8% EtOAc–
hexane, gave 37 (0.2072 mg, 74% from the iodide) as a colorless
oil free of the Z isomer (1H NMR 400 MHz).
Toluene-4-sulfonic acid 4-[(2R,3S)-2,3-dihydro-3-iodomethyl-
5-(1E)-1-propenylbenzofuran-2-yl]phenyl ester (36). Imidazole
(20.6 mg, 0.303 mmol), followed by Ph3P (42.6 mg, 0.162 mmol)
and then I2 (46.9 mg, 0.185 mmol), was added to a stirred solution
of 35 (74.0 mg, 0.170 mmol) in PhMe (3 mL). The mixture was
heated at 100 ◦C for 1.5 h and then allowed to cool. EtOAc (10 mL)
was added and the mixture was washed with saturated aqueous
Na2S2O3 solution (2 × 5 mL) and dried (MgSO4). Evaporation of
the solvent and flash chromatography of the residue over silica gel
(1.5 × 30 cm), using 13% EtOAc–hexane, gave 36 (75.9 mg, 82%)
as a colorless oil with spectral data identical to those reported
above.
Toluene-4-sulfonic acid 4-[(2R,3S)-2,3-dihydro-3-methyl-5-(1E)-
1-propenylbenzofuran-2-yl]phenyl ester (37). AIBN (7.9 mg,
0.048 mmol) was added to a stirred solution of crude iodide 36
[from mesylate (0.1201 g) and assumed to be 0.233 mmol] and
Bu3SnH (0.09 mL, 0.3 mmol) in PhMe (3.6 mL). The reaction
vessel was flushed thoroughly with N2 and then heated in an oil
bath set at 80 ◦C. Heating was continued for 1 h and then the
mixture was allowed to cool. Evaporation of the solvent and flash
chromatography of the residue over 10% KF–silica gel52 (1.5 ×
30 cm), using 5–8% EtOAc–hexane (gradient elution), gave an
inseparable 7 : 3 mixture of starting iodide and 37. This mixture
was re-subjected to the above conditions, using Bu3SnH (0.08 mL)
in PhMe (3.6 mL). Chromatography of the crude material under
the same conditions as above gave 37 (67.0 mg, 68% over 2 steps
from the mesylate).
In an improved reduction procedure, Et3BHLi (1 M in THF,
3.4 mL, 3.4 mmol) was added dropwise by syringe to a stirred
and cooled (0 ◦C) solution of 36 obtained via the procedure below
(923.4 mg, 1.690 mmol) in THF (10 mL). The ice bath was left
in place but not recharged and stirring was continued for 3.5 h.
Water (0.5 mL) was added, followed by aqueous NaOH (1 M,
4 mL) and finally H2O2 (1.5 mL, 30%). The mixture was stirred for
an additional 20 min and then partitioned between water (10 mL)
and Et2O (20 mL). The organic phase was washed with water (1 ×
10 mL) and brine (1 × 10 mL), dried (MgSO4) and evaporated.
Flash chromatography of the residue over silica gel (2 × 35 cm),
using hexane and then 13% EtOAc–hexane, gave 37 (697.9 mg,
98%) as a colorless oil which contained 3% of the Z isomer (1H
NMR): [a]2D2 −59.93 (c 2.24, CH2Cl2); 1H NMR (CDCl3, 400 MHz)
d 1.42 (d, J = 6.9 Hz, 3 H), 1.86 (dd, J = 1.7, 6.6 Hz, 3 H), 2.45 (s,
3 H), 3.34 (m, 1 H), 5.12 (d, J = 8.4 Hz, 1 H), 6.09 (dq, J = 6.7,
15.7 Hz, 1 H), 6.36 (dd, J = 1.7, 15.7 Hz, 1 H), 6.77 (d, J = 8.8 Hz,
1 H), 6.99 (apparent d as part of AAꢀBBꢀ system, J = 8.7 Hz,
2 H), 7.12 (s, 1 H), 7.12–7.13 (m, 1 H), 7.32 (apparent dd as part
of AAꢀBBꢀ system, J = 0.7, 7.9 Hz, 2 H), 7.33 (apparent d as part
of AAꢀBBꢀ system, J = 8.4 Hz, 2 H), 7.72 (apparent d as part of
AAꢀBBꢀ system, J = 8.4 Hz, 2 H); 13C NMR (CDCl3, 100 MHz) d
18.3 (q), 18.4 (q), 21.7 (q), 45.6 (d), 91.7 (d), 109.3 (d), 120.8 (d),
4-[(2R,3R)-2,3-Dihydro-3-methyl-5-(1E)-1-propenylbenzofuran-
2-yl]phenol [(+)-conocarpan] (1). Na(Hg) (Aldrich, 10% Na,
868.9 mg, 3.779 mmol Na) was added in one portion to a stirred
solution of isomerically pure 37 (197.0 mg, 0.4685 mmol) in
80% MeOH (8 mL), and stirring was continued overnight. The
solution was then decanted from the Hg, and diluted with water
(10 mL). The mixture was extracted with Et2O (3 × 10 mL), by
which stage the aqueous layer was free of product (TLC control,
silica, 30% EtOAc–hexane). The combined organic extracts were
washed with brine and dried (MgSO4). Evaporation of the solvent
and flash chromatography of the residue over silica gel (1.5 ×
25 cm), using 0–15% EtOAc–hexane, gave 1 (119.0 mg, ◦95%) as
◦
a white, c◦rystalline solid: mp 120–123 C [lit.4a 133–135 C; lit.4g
124–126 C]; [a]D22 −99.7 (c 1.03, MeOH), lit.4a [a]2D1 +122 (for
dextrorotary conocarpan) (c 1.03, MeOH); 1H NMR (CDCl3,
500 MHz) d 1.40 (d, J = 6.8 Hz, 3 H), 1.86 (dd, J = 1.6, 6.6 Hz,
3 H), 3.37–3.43 (m, 1 H), 5.00 (s, 1 H), 5.08 (d, J = 8.9 Hz, 1 H),
6.09 (dq, J = 6.6, 15.6 Hz, 1 H), 6.37 (d, J = 15.6 Hz, 1 H), 6.76
(d, J = 8.1 Hz, 1 H), 6.83 (apparent d as part of AAꢀBBꢀ system,
J = 8.5 Hz, 2 H), 7.12–7.14 (m, 2 H), 7.30 (apparent d as part of
AAꢀBBꢀ system, J = 8.5 Hz, 2 H); 13C NMR (CDCl3, 125 MHz)
d 17.9 (q), 18.4 (q), 45.3 (d), 92.7 (d), 109.3 (d), 115.5 (d), 120.8
(d), 123.1 (d), 126.3 (d), 127.9 (d), 130.8 (d), 131.3 (s), 132.4 (s),
132.9 (s), 155.7 (s), 158.3 (s); mmax (CH2Cl2 cast, microscope; cm−1)
3395, 3022, 2962, 2928, 2882, 1614, 1517, 1487, 1240, 1202,
1171, 964, 831; exact mass m/z calcd for C18H18O2 266.13068,
found 266.13042. HPLC analysis [Chiralcel OD column (0.46 ×
15.0 cm); 95:5 heptane–isopropanol; flow rate 1 mL min−1; 40 ◦C;
detection at 207 nm.; retention times 7.4 min and 10.9 min]
showed that the compound had an ee of 98%.
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Second route
When the experiment was repeated on a larger scale with the
dimesylate (2.1255 g, 2.94 mmol), the yield was 65% [or 80% based
on recovered 38 (398.1 mg, 19%)].
Toluene-4-sulfonic acid 4-[(1S,2R)-1-(4-formyl-2,3-dihydroxy-2-
iodophenoxy)propyl]phenyl ester (41). Epoxy alcohol 23b (er =
98.9 : 1.1) (1.8694 g, 5.8350 mmol) was added in one portion to
a stirred and heated (sand bath, 70 ◦C) solution of 4-hydroxy-
3-iodobenzaldehyde41 (2.6359 g, 10.628 mmol) in a mixture of
aqueous NaOH (1 M, 5.8 mL, 5.8 mmol) and water (6 mL).
Stirring at 70 ◦C was continued for 2.5 h. The mixture was allowed
to cool and was then poured into aqueous NaOH (1 M, 10 mL).
The aqueous phase was extracted with Et2O and the combined
organic extracts were washed with brine and dried (MgSO4).
Evaporation of the solvent and flash chromatography of the
residue over silica gel (2.5 × 35 cm), using 50–80% EtOAc–hexane
containing Et3N (ca. 3 drops per 100 mL) (gradient elution), gave
41 [2.1124 g, 64%, or 83% based on recovered 23b (436.8 mg,
Toluene-4-sulfonic acid 4-[(2S,3R)-2,3-dihydro-5-formyl-3-
methylbenzofuran-2-yl]phenyl ester (39). A solution of Bu3SnH
(0.62 mL, 2.3 mmol) and AIBN (48.1 mg, 0.293 mmol) in PhMe
(18 mL) was added over 4 h (syringe pump) to a stirred and heated
(80 ◦C) solution of 38 (910.4 mg, 1.704 mmol) in PhMe (18 mL)
(N2 atmosphere). After the addition the mixture was heated for a
further 2 h and then allowed to cool. Evaporation of the solvent
and flash chromatography of the residue over KF–silica gel (10%
w/w, 2.5 × 30 cm), using 25% EtOAc–hexane, gave 39 (482.6 mg,
69%) as a light yellowish oil: [a]2D2 −50.54 (c 0.77, CHCl3);
1H NMR (CDCl3, 400 MHz) d 1.40 (d, J = 6.9 Hz, 3 H), 2.38
(s, 3 H), 3.31–3.38 (m, 1 H), 5.19 (d, J = 8.4 Hz, 1 H), 6.88 (d,
J = 8.1 Hz, 1 H), 6.96 (apparent d as part of AAꢀBBꢀ system,
J = 8.7 Hz, 2 H), 7.24–7.27 (m, 4 H), 7.64–7.67 (m, 4 H), 9.80 (s,
1 H); 13C NMR (CDCl3, 100 MHz) (the spectrum shows minor
aromatic impurities) d 18.3 (q), 21.7 (q), 44.8 (d), 92.7 (d), 109.8
(d), 122.8 (d), 124.7 (d), 127.1 (d) 128.5 (d), 129.8 (d), 131.0 (s),
132.4 (s), 133.1 (s), 133.4 (d), 138.9 (s), 145.5 (s), 149.6 (s), 164.3
(s), 190.5 (d); mmax (CHCl3 cast; cm−1) 2964, 2928, 1690, 1605,
1504, 1483, 1373, 1247, 1198, 1177, 1154, 1093, 867; exact mass
m/z calcd for C23H20NaO5S 431.09237, found 431.09242.
◦
23%)] as a white, crystalline solid: mp 55–58 C; [a]2D2 −39.52
(c 5.69, CHCl3); 1H NMR (CDCl3, 400 MHz) d 2.33 (br s, 1 H),
2.45 (s, 3 H), 2.75 (br s, 1 H), 3.82 (dd, J = 3.7, 11.5 Hz, 1 H),
3.94 (dd, J = 5.2, 11.5 Hz, 1 H), 4.03–4.06 (m, 1 H), 5.40 (d, J =
5.8 Hz, 1 H), 6.64 (d, J = 8.6 Hz, 1 H), 7.03 (apparent d as part
of AAꢀBBꢀ system, J = 8.7 Hz, 2 H), 7.30 (apparent dd as part of
AAꢀBBꢀ system, J = 0.6, 8.6 Hz, 2 H), 7.33 (apparent d as part of
AAꢀBBꢀ system, J = 8.6 Hz, 2 H), 7.60 (dd, J = 2.0, 8.6 Hz, 1 H),
7.69 (apparent d as part of AAꢀBBꢀ system, J = 8.4 Hz, 2 H), 8.27
(d, J = 2.0 Hz, 1 H), 9.76 (s, 1 H); 13C NMR (CDCl3, 100 MHz)
d 21.7 (q), 62.3 (t), 74.4 (d) 81.4 (d), 87.4 (s), 113.3 (d), 122.9 (d),
128.2 (d), 128.3 (d), 129.8 (d), 131.7 (d), 131.8 (s), 132.3 (s), 135.2
(s), 140.9 (d), 145.6 (s), 149.6 (s), 160.1 (s), 189.2 (d); mmax (CDCl3
cast; cm−1) 3417, 3067, 2927, 2883, 2731, 1694, 1587, 1502, 1480,
1371, 1255, 1198, 1177, 1155, 1093, 1038, 869; exact mass m/z
calcd for C23H21INaO7S 590.99450, found 590.99454.
Toluene-4-sulfonic acid 4-[(2R,3S)-2,3-dihydro-(3-methyl-5-
(1E)-1-propenylbenzofuran-2-yl)phenyl ester (E-43) and toluene-4-
sulfonic acid 4-[(2R,3S)-2,3-dihydro-3-methyl-5-(1Z)-1-propenyl-
benzofuran-2-yl]phenyl ester (Z-43).
(a) Use of t-BuOK. t-BuOK (33.0 mg, 0.294 mmol) was added
to a stirred suspension of Ph3PEt+I− (129.6 mg, 0.3098 mmol) in
Et2O (2 mL), and the mixture was stirred for 0.5 h. A solution of
39 (54.2 mg, 0.133 mmol) in Et2O (1 mL) was added by syringe.
The mixture was stirred for 15 min and then Et2O (5 mL) was
added, and the mixture was washed twice with water and once
with brine and dried (MgSO4). Evaporation of the solvent and
flash chromatography of the residue over silica gel (1.5 × 30 cm),
using 5–10% EtOAc–hexane (gradient elution), gave 43 (33.9 mg,
62%) as a yellowish oil. Integration of the allylic methyl peaks
Toluene-4-sulfonic acid 4-[(R)-1-(4-formyl-2-iodophenoxy)allyl]-
phenyl ester (38). NaI (91.7 mg, 0.612 mmol) was added to
a stirred solution of 42 (29.5 mg, 0.0408 mmol) in 2-butanone
(2 mL), and the mixture was refluxed for 4 h, and then allowed to
cool. The solvent was evaporated and the residue was partitioned
between EtOAc and saturated aqueous Na2S2O3. The combined
organic extracts were washed with brine, dried (MgSO4) and
evaporated. Flash chromatography of the residue over silica gel
(0.5 × 20 cm), using 30% EtOAc–hexane, gave 38 (15.7 mg, 71%)
as an amber oil: [a]D22 −8.88 (c 13.43, CH2Cl2); 1H NMR (CDCl3,
500 MHz) d 2.48 (s, 3 H), 5.36 (dd, J = 0.8, 10.4 Hz, 1 H), 5.50 (dd,
J = 0.8, 17.1 Hz, 1 H), 5.83 (d, J = 5.9 Hz, 1 H), 6.05 (ddd, J =
5.9, 10.4, 17.0 Hz, 1 H), 6.88 (d, J = 8.5 Hz, 1 H), 7.06 (apparent
d as part of AAꢀBBꢀ system, J = 8.6 Hz, 2 H), 7.33 (apparent d
as part of AAꢀBBꢀ system, J = 8.5 Hz, 2 H), 7.45 (apparent d as
part of AAꢀBBꢀ system, J = 8.8 Hz, 2 H), 7.73 (apparent d as part
of AAꢀBBꢀ system, J = 8.3 Hz, 2 H), 7.76 (dd, J = 2.0, 8.5 Hz,
1 H), 8.34 (d, J = 1.9 Hz, 1 H), 9.83 (s, 1 H); 13C NMR (CDCl3,
125 MHz) d 21.7 (q), 81.4 (d), 87.8 (s), 113.6 (d), 117.8 (t), 122.8
(d), 127.8 (d), 128.4 (d), 129.8 (d), 131.5 (d), 131.6 (s), 132.4 (s),
136.2 (d), 137.6 (s), 141.2 (d), 145.5 (s), 149.3 (s), 160.6 (s), 189.2
(d); mmax (CH2Cl2 cast; cm−1) 3065, 2922, 2834, 2727, 1695, 1587,
1501, 1479, 1371, 1252, 1197, 1177, 1154, 1093, 866; exact mass
m/z calcd for C23H19INaO5S 556.98902, found 556.98890. Anal.
calcd for C23H19IO5S: C 51.69; H 3.58; S 6.00. Found: C 51.41;
H 3.65; S 5.92%.
1
in the H NMR spectrum showed the E : Z ratio to be 1 : 3;
apart from this ratio difference, all spectral data corresponded to
those reported above for 37 (i.e. the 97 : 3 mixture of the same
compounds).
(b) Use of BuLi. BuLi (1.6 M in hexanes, 0.06 mL, 0.096 mmol)
was added to a stirred and cooled (0 ◦C) suspension of Ph3PEt+I−
(39.5 mg, 0.0944 mmol) in THF (2 mL). Stirring was continued
for 15 min and 39 (35.7 mg, 0.0796 mmol) in THF (1.3 mL plus
0.3 mL as a rinse) was added dropwise by syringe. Stirring was
continued for 2 h and the mixture was then quenched by addition
of saturated aqueous NaHCO3 (0.5 mL), and partitioned between
water (5 mL) and Et2O (10 mL). The organic extract was dried
(MgSO4) and evaporated. Flash chromatography of the residue
over silica gel (0.5 × 30 cm), using 20% EtOAc–hexane containing
ca. 1% Et3N, gave 43 (23.2 mg, 69%) as a yellowish oil, which was
a mixture of Z and E isomers.
Toluene-4-sulfonic acid 4-[(2R,3S)-2,3-dihydro-3-methyl-5-(1E)-
1-propenylbenzofuran-2-yl]phenyl ester (37). PdCl2(PhCN)2
(9.4 mg, 0.025 mmol) was added to a stirred solution of 43
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(102.3 mg, 0.2433 mmol) in CH2Cl2 (2 mL), and stirring was
continued for 23 h. Et2O (3 mL) was added and the solution
was filtered through a pad of Florisil (3 × 2 cm) using Et2O
(25 mL). Evaporation of the solvent and flash chromatography of
the residue over silica gel (1 × 30 cm) using 8% EtOAc–hexane
containing Et3N (ca. 3 drops per 100 mL), gave 37 (100.9 mg,
99%) as a colorless oil: [a]D22 −54.15 (c 5.94, CH2Cl2). The material
contained 3.1% of the Z isomer (1H NMR).
Toluene-4-sulfonic acid 4-[(S)-1-(tert-butyldimethylsilanyloxy)-
propyl]phenyl ester (47). Rh–Al2O3 (5% w/w, 9.7 mg,
0.0047 mmol) was added to a solution of 46 (30.3 mg,
0.0724 mmol) in THF (1.8 mL). The mixture was stirred and
degassed by sequentially evacuating the flask (house vacuum) and
then admitting H2, this sequence being repeated twice more. The
mixture was stirred overnight under H2 (balloon) and then filtered
through a short pad (0.5 × 1 cm) of silica gel, using CH2Cl2 as
a rinse. Evaporation of the filtrate gave 47 (30.3 mg, 99%) as a
colorless oil: [a]2D2 −26.43 (c 3.03, CHCl3); 1H NMR (CDCl3, 400
MHz) d 0.00 (s, 3 H), 0.18 (s, 3 H), 1.00 (t, J = 7.2 Hz, 3 H),
1.03 (s, 9 H), 1.72–1.88 (m, 2 H), 2.61 (s, 3 H), 4.70 (apparent
t, J = 5.5 Hz, 1 H), 7.08 (apparent d as part of AAꢀBBꢀ system,
J = 8.6 Hz, 2 H), 7.36 (apparent d as part of AAꢀBBꢀ system,
J = 8.7 Hz, 2 H), 7.45 (apparent d as part of AAꢀBBꢀ system,
J = 8.6 Hz, 2 H), 7.84 (apparent d as part of AAꢀBBꢀ system, J =
8.3 Hz, 2 H); 13C NMR (CDCl3, 100 MHz) d −5.0 (q), −4.7 (q),
9.8 (q), 18.2 (s), 21.7 (q), 25.8 (q), 33.5 (t), 75.5 (d), 121.9 (d), 127.0
(d), 128.5 (d), 129.6 (d), 132.3 (s), 144.7 (s), 145.2 (s), 148.3 (s);
mmax (CHCl3 cast; cm−1) 3034, 2957, 2929, 2857, 1598, 1501, 1472,
1463, 1378, 1257, 1198, 1175, 1155, 1094, 1060, 1014; exact mass
m/z calcd for C22H32NaO4SSi 443.16828, found 443.16826.
Isomerization with 10-day reaction time. PdCl2(PhCN)2
(5.3 mg, 0.0138 mmol) was added to a stirred solution of 43
(36.0 mg, 0.0856 mmol) in CH2Cl2 (2 mL), and stirring was
continued for 10 days. The solution was filtered through a pad
of Florisil (1 × 1 cm), using CH2Cl2 as a rinse. Evaporation of
the solvent and flash chromatography of the residue over silica
gel (0.5 × 30 cm), using 13% EtOAc–hexane containing Et3N (ca.
3 drops per 100 mL), gave 37 (30.5 mg, 85%) as a colorless oil with
spectral data identical to those reported above for the first route,
1
except that the Z isomer could not be detected in the H NMR
spectrum (400 MHz).
4-[(2R,3R)-2,3-dihydro-3-methyl-5-(1E)-1-propenylbenzofuran-
2-yl]phenol [(+)-conocarpan] (1). Desulfonylation was done by
the same method as described for the first route: [a]D −46.5 (c 0.28,
MeOH). HPLC analysis of the synthetic conocarpan [Chiralcel
OD column (0.46 × 15.0 cm); 90 : 10 heptane–isopropanol; flow
4-[(S)-1-(tert-Butyldimethylsilanyloxy)propyl]phenol (48). Na-
(Hg) (815.0 mg, 10% Na, 3.543 mmol) was added to a stirred,
cloudy solution of 47 (316.4 mg, 0.7444 mmol) in 80% MeOH
(5.4 mL). The flask was flushed with Ar and stirring was continued
for 45 min to give a clear, colorless solution. The mixture was then
decanted from the remaining amalgam into a separatory funnel
containing phosphate buffer solution (KH2PO4–NaOH, pH 7,
8 mL) and Et2O (8 mL). Saturated aqueous oxalic acid (2 mL) was
then added and the biphasic mixture was shaken and separated.
The aqueous layer was extracted with Et2O (2 × 6 mL) and the
combined organic extracts were washed with brine, dried (MgSO4)
and evaporated. Flash chromatography of the residue over silica
gel (1.5 × 25 cm), using 0–20% EtOAc–hexanes (gradient elution),
gave 48 as a colorless oil (119.3 mg, 60%) and recovered 47
(102.3 mg, 32%). Phenol 48 had: [a]2D2 −19.32 (c 1.41, CHCl3);
1H NMR (C6D6, 400 MHz) (phenolic OH not observed) d −0.09
(s, 3 H), 0.05 (s, 3 H), 0.87 (t, J = 6.7 Hz, 3 H), 1.06 (s, 9 H),
1.66–1.88 (m, 2 H), 4.54 (dd, J = 5.5, 7.1 Hz, 1 H), 6.62 (apparent
d as part of AAꢀBBꢀ system, J = 8.8 Hz, 2 H), 7.19 (apparent
dd as part of AAꢀBBꢀ system, J = 0.6, 8.6 Hz, 2 H); 13C NMR
(C6D6, 100 MHz) d −4.8 (q), −4.4 (q), 10.3 (q), 18.4 (s), 26.1
(q), 34.1 (t), 76.5 (d), 115.1 (d), 127.4 (d), 137.7 (s), 155.4 (s);
mmax (CHCl3 cast; cm−1) 3349, 3024, 2958, 2930, 2858, 1614, 1600,
1514, 1472, 1463, 1361, 1252, 1059, 836; exact mass m/z calcd for
C15H26NaO2Si 289.15943, found 289.15935.
◦
rate 0.6 mL min−1; 40 C; detection at 210 nm.; retention times
10.69 min and 12.60 min] showed that the compound had an ee of
88%.
Proof of absolute configuration
Toluene-4-sulfonic acid 4-[(S)-1-hydroxyallyl]phenyl ester (45).
NaI (2.42 g, 16.1 mmol) was added to a stirred solution of 44 (total
product from previous experiment, ca. 1.6 mmol) in glyme (8 mL).
The vessel was flushed with Ar and the mixture was refluxed for
12 h, and then allowed to cool. The mixture was diluted with
EtOAc (10 mL), washed with saturated aqueous Na2S2O3 (8 mL),
water (8 mL) and brine (5 mL), dried (MgSO4) and evaporated.
Flash chromatography of the residue over silica gel (1.5 × 30 cm),
using 27% EtOAc–hexanes containing a trace (0.4–1% v/v) of
Et3N, gave 45 (279.8 mg, 57% over 2 steps from the hydroxy
1
epoxide) as a colorless oil: [a]2D2 +4.63 (c 0.57, CHCl3); H NMR
(C6D6, 300 MHz) d 1.10 (d, J = 3.7 Hz, 1 H), 1.74 (s, 3 H), 4.62–
4.65 (m, 1 H), 4.86 (dt, J = 1.5, 10.3 Hz, 1 H), 5.03 (dt, J =
1.5, 17.1 Hz, 1 H), 5.64 (ddd, J = 5.9, 10.3, 17.1 Hz, 1 H), 6.57
(apparent d as part of AAꢀBBꢀ system, J = 8.3 Hz, 2 H), 6.92–6.98
(m, 4 H), 7.63 (apparent d as part of AAꢀBBꢀ system, J = 8.3 Hz,
2 H); 13C NMR (C6D6, 100 MHz) (two signals coincident) d 21.2
(q), 74.4 (d), 114.7 (t), 122.6 (d), 128.7 (d), 129.8 (d), 133.4 (s),
140.5 (d), 142.3 (s), 144.9 (s), 149.5 (s); mmax (CHCl3 cast; cm−1)
3533, 3400, 3068, 2981, 2924, 2872, 1597, 1500, 1402, 1371, 1197,
1175, 1154, 1093, 867; exact mass m/z calcd for C16H16NaO4S
327.06615, found 327.06657.
Attempts to prepare the Mosher ester by a literature method53
gave material that had clearly undergone extensive epimerization
during the derivatization, as the ratio of diastereoisomers was 2.3 :
0.95 (1H NMR), while the parent epoxide had an er of 98.9 : 1.1.
We were unable to separate the corresponding racemic alcohol by
chiral HPLC.
Trifluoromethanesulfonic acid 4-[(S)-1-(tert-butyldimethyl-
silanyloxy)propyl]phenyl ester (49). (CF3SO2)2O (0.07 mL,
0.4 mmol) was added dropwise by syringe to a stirred and
cooled (−78 ◦C) solution of 48 (99.9 mg, 0.375 mmol) and
Et3N (0.09 mL, 0.6 mmol) in CH2Cl2 (1.8 mL) (Ar atmosphere).
Stirring was continued for 10 min and then saturated aqueous
NaHCO3 (0.5 mL) was added. The cooling bath was removed
and the mixture was poured into a separatory funnel containing
water (5 mL) and CH2Cl2 (5 mL). The mixture was shaken and
the organic phase was dried (MgSO4) and evaporated. Flash
chromatography of the residue over silica gel (1.5 × 20 cm), using
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13% EtOAc–hexanes containing a trace (0.5–1% v/v) of Et3N,
gave 49 (111.6 mg, 75%) as a colorless oil: [a]2D2 −21.08 (c 0.48,
CHCl3); 1H NMR (C6D6, 400 MHz) d 0.00 (s, 3 H), 0.18 (s 3 H),
0.95 (t, J = 7.4 Hz, 3 H), 1.12 (s, 9 H), 1.57–1.77 (m, 2 H), 4.54
(dd, J = 5.1, 6.9 Hz, 1 H), 7.04 (apparent d as part of AAꢀBBꢀ
system, J = 8.7 Hz, 2 H), 7.18 (apparent dd as part of AAꢀBBꢀ
system, J = 0.5, 8.9 Hz, 2 H); 13C NMR (C6D6, 100 MHz) d
−5.0 (q), −4.7 (q), 9.7 (q), 18.3 (s), 25.9 (q), 33.6 (t), 75.4 (d),
119.3 (s, CF3 quartet, J = 318.6 Hz), 121.0 (d), 127.7 (d), 146.1
(s), 148.6 (s); mmax (CHCl3 cast; cm−1) 2959, 2932, 2859, 1500,
1427, 1251, 1214, 1143, 890, 861, 837; exact mass m/z calcd for
C16H25F3NaO4SSi 421.10872, found 421.10906.
5 (a) Levorotatory conocarpan: B. Freixa, R. Vila, E. A. Ferro, T. Adzet
and S. Can˜igueral, Planta Medica, 2001, 67, 873–875; (b) M. R. G. Vega,
M. G. de Carvalho, J. R. Velandia and R. Braz-Filho, Rev. Latinoam.
Qu´ım., 2001, 29, 63–72.
6 Conocarpan isolated from the leaves of Piper regnelli (reference 3),
the roots of Krameria cystisoides (reference 4a), Krameria tomentosa
(reference 4l) and Krameria triandra (reference 4c), and the stems of
Anogeissus acuminata (reference 4e) is reported to be dextrorotatory;
our own synthetic material, of proven absolute configuration 1, is
levorotatory and the CD curve of its acetate has negative De at 260 nm.
The acetate of conocarpan isolated from timber (reference 1) is reported
to have positive De at 260 nm and so the parent conocarpan must be
dextrorotatory. Consequently all these plant sources afford material
of the same absolute configuration. With the following exception,
other references to conocarpan that we have examined do not give
the specific rotation. Conocarpan isolated from the leaves of Piper
fulvescens C. DC, (reference 5a) is reported to have [a]2D1 = −108.26
(c 0.025,solvent not reported).
(S)-tert-Butyldimethyl(1-phenylpropoxy)silane
(50). Pd/C
(10% w/w, 60.8 mg, 0.0571 mmol) was added to a solution of
49 (99.0 mg, 0.248 mmol) and Et3N (0.11 mL, 0.79 mmol) in
EtOAc (5 mL). The stirred mixture was degassed by sequentially
evacuating the flask (house vacuum) and then admitting H2, the
procedure being repeated twice more. A hydrogen-filled balloon
was then connected to the flask and stirring was continued for
3 h. The heterogeneous mixture was filtered through a short pad
(0.5 × 1.0 cm) of silica gel, using EtOAc as a rinse. Evaporation of
the solvent gave 50 (62.6 mg, 100%) as a yellowish oil: [a]2D2 −32.21
7 The relevance of this property to malaria control has not been
established. For a review on malaria control, see: R. P. Tripathi, R. C.
Mishra, N. Dwivedi, N. Tewari and S. S. Verma, Current Med. Chem.,
2005, 12, 2643–2659, and references therein.
8 (a) Antitrypanosomal activity: P. S. Luize, T. Ueda-Nakamura, B. P. D.
Filho, D. A. G. Cortez and C. V. Nakamura, Biol. Pharm. Bull., 2006,
29, 2126–2130; (b) antibacterial activity: G. L. Pessini, B. P. D. Filho,
C. V. Nakamura and D. A. G. Cortez, Mem. Inst. Oswaldo Cruz, 2003,
98, 1115–1120; (c) antifungal activity: M. P. De Campos, V. C. Filho,
R. Z. Da Silva, R. A. Yunes, S. Zacchino, S. Juarez, R. C. Bella Cruz and
A. Bella Cruz, Biol. Pharm. Bull., 2005, 28, 1527–1530; (d) G. L. Pessini,
B. P. D. Philo, C. V. Nakamura and D. A. G. Cortez, J. Braz. Chem.
Soc., 2005, 16, 1130–1133; (e) photoprotective activity: M. Carini, G.
Aldini, M. Orioli and R. M. Facino, Planta Medica, 2002, 68, 193–197.
9 S. Apers, A. Vlietinck and L. Pieters, Phytochem. Rev., 2003, 2, 201–217.
10 T. Kurta´n, E. Baitz-Ga´cs, Z. Majer and S. Antus, J. Chem. Soc., Perkin
Trans. 1, 2000, 453–461.
1
(c 0.66, CHCl3); H NMR (C6D6, 400 MHz) d −0.10 (s, 3 H),
0.04 (s, 3 H), 0.87 (t, J = 7.3 Hz, 3 H), 0.97 (s, 9 H), 1.58–1.79 (m,
2 H), 4.51 (dd, J = 5.2, 7.0 Hz, 1 H), 7.07 (tt, J = 1.3, 6.7 Hz,
1 H), 7.16–7.19 (m, 2 H), 7.26–7.28 (m, 2 H); 13C NMR (C6D6,
100 MHz) d −4.8 (q), −4.5 (q), 10.2 (q), 18.4 (s), 26.1 (q), 34.0
(t), 76.7 (d), 126.2 (d), 127.2 (d), 128.3 (d), 145.8 (s); mmax (CHCl3
cast; cm−1) 3065, 3028, 2958, 2930, 2858, 1493, 1472, 1463, 1453,
1361, 1257, 1104, 1086, 1058, 1013, 860, 837, 775, 699; exact mass
m/z calcd for C15H26NaOSi 273.16451, found 273.16448.
11 For a recent application of the chiroptical rules, see: S. Garc´ıa-
´
Mun˜oz, M. Alvarez-Corral, L. Jime´nez-Gonza´lez, C. Lo´pez-Sa´nchez,
A. Rosales, M. Mun˜oz-Dorado and I. Rodr´ıguez-Garc´ıa, Tetrahedron,
2006, 62, 12182–12190.
12 (a) G. Snatzke and P. C. Ho, Tetrahedron, 1971, 27, 3645–3653;
(b) G. Snatzke, F. Znatzke, A. L. To¨ke´s, M. Ra´kosi and R. Bognar,
Tetrahedron, 1973, 29, 909–912.
13 H. Achenbach, W. Utz, A. Usubillaga and H. A. Rodriguez, Phyto-
chemistry, 1991, 30, 3753–3757.
14 For synthetic routes to neolignans, see: M. Sefkow, Synthesis, 2003,
2595–2625.
15 For a different approach to neolignan synthesis, see: M. Okazaki and
Y. Shuto, Biosci. Biotechnol. Biochem., 2001, 65, 1134–1140.
16 Preliminary communication: D. L. J. Clive and E. J. L. Stoffman, Chem.
Commun., 2007, 2151–2153.
Acknowledgements
We thank the Natural Sciences and Engineering Research Council
of Canada for financial support.
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reported in references 4g, 4l and 4c extremely closely, but showed some
differences from the values reported in reference 4a.
1842 | Org. Biomol. Chem., 2008, 6, 1831–1842
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The Royal Society of Chemistry 2008
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