Efficient syntheses of pterulone, pterulone B and related analogues.

Article abstract of DOI:10.1039/b306356a

An efficient synthesis of the three halogenated naturally occurring products, pterulone (2), pterulone B (3) and alcohol 5, and of a wide range of related unnatural analogues has been achieved starting from the two readily available 1-benzoxepine sulfonyl

Full text of DOI:10.1039/b306356a

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Efficient syntheses of pterulone, pterulone B and related
analogues†
Philippe Lemaire,a Geneviève Balme,*a Philippe Desbordesb and Jean-Pierre Vorsb
a Laboratoire de Chimie Organique 1, CNRS UMR 5622, Université Claude Bernard, Lyon I,
CPE. 43, Bd du 11 Novembre 1918, 69622 Villeurbanne, France.
E-mail: balme@univ-lyon1.fr; Fax: 04 72 43 12 14; Tel: 04 72 44 14 16
b Bayer CropScience, 14-20 Rue Pierre Baizet, 69009 Lyon, France
Received 9th June 2003, Accepted 24th September 2003
First published as an Advance Article on the web 23rd October 2003
An efficient synthesis of the three halogenated naturally occurring products, pterulone (2), pterulone B (3) and
alcohol 5, and of a wide range of related unnatural analogues has been achieved starting from the two readily
available 1-benzoxepine sulfonyl-containing intermediates 6a and 6b. The biological activities of pterulone and
some of the synthesized analogues were tested against a wide spectrum of phytopathogenic fungi.
pterulone (2) and alcohol 4 as well as of some of their
Introduction
unnatural analogues. The synthetic strategies employed in the
sythesis of these compounds were based on ring-closing
metathesis (RCM)5 and an intramolecular Wittig reaction.6 A
reaction sequence similar to this last strategy was simul-
taneously developed by our group in an approach toward
pterulone (2) and a great number of unsaturated analogues.7
Our main goal has therefore been to find a new method of
preparation of the 2,3-dihydro-1-benzoxepine skeleton that is
sufficiently flexible to be applied to the synthesis of several nat-
ural products and a wide range of related unnatural analogues
in order to study their biological properties and the structure–
activity relationships.
Pterulinic acid ((E/Z)-1), pterulone ((E)-2)1 and pterulone B
((E)-3),2 three novel halogenated antibiotics having a 2,3-di-
hydro-1-benzoxepine skeleton as a key structural element
were isolated in 1997 from fermentations of the Pterula species
(Fig. 1). These compounds are effective inhibitors of the
eukaryotic respiratory chain at the NADH site of the ubi-
quinone oxidoreductase (complex I). Among them, pterulone
has been shown to possess the most potent antifungal activity
and to be only weakly cytotoxic in vitro.3 More recently, two
additional metabolites possessing the same chlorinated 2,3-
dihydro-1-benzoxepine skeleton (E/Z)-4 and (E)-5, have been
isolated from the latex of the fungus Mycena galopus.4 The
limited availability of these products from the natural source,
their significant biological activities as well as their unusual
structures make them interesting synthetic targets.
Considering the great utility of the sulfonyl group8 in organic
synthesis, we have envisioned a cycloannulation reaction involv-
ing a 2-hydroxybenzyl phenyl sulfone as a 1,4-dinucleophilic
reactant and a 3-halo-2-halomethyl-1-propene as a 1,3-di-
electrophilic reactant (Scheme 1). This synthetic sequence
would provide ready access to the 1-benzoxepine intermediate 6
bearing a sulfone group which could then be subjected to a
number of further transformations. For example, it could be
used as a stabilizing carbanion in an alkylation reaction step
and as a leaving group in nucleophilic displacements. Thus,
for a given Y group, by varying the sulfone alkylation or/and
sulfinate displacement, this procedure appeared to be suitable
To date, few approaches have been developed for the
synthesis of two of these natural chlorinated products, namely
Fig. 1 Natural products recently isolated.
† Electronic supplementary information (ESI) available: further
experimental details: synthesis and characterisation of compounds 6a,
9a–12a, 14, 19, 20, 22a,b, 23a,b, 25b, 27a,b, 28a,b, 29a,b, 30–33. See
http://www.rsc.org/suppdata/ob/b3/b3/b306356a
Scheme 1 Plan of the intended chemistry.
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 3
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 2 0 9 – 4 2 1 9
4209

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Table 1 Ring-closure studies
Entry
X
Y
Base, number equiv. Solvent
Dilution/mol LϪ1 Temperature
Additive Yield of 6 (%)
Yield of 12 (%)
1
2
3
4
5
6
7
8
9
I
I
COCH3
COCH3
t-BuOK, 1.3
LDA, 2
NaH, 2
NaH, 2
LHMDS, 2
LHMDS, 2
THF
THF
THF
DMF
THF
THF
THF
THF
THF
THF
THF
0.05
0.05
0.05
0.05
0.05
0.013
0.05
0.05
0.05
0.01
0.015
Ϫ78 then Ϫ20 ЊC n-Bu4NI
No traces
37a
62%a
Traces
rt
rt
0
Cl COCH3
Cl COCH3
Cl COCH3
Cl COCH3
No reaction
60b
40b
d
rt
rt
63
LiBr
78a
Traces
73a
I
CO2CH3 t-BuOK, 1.3
Ϫ78 then Ϫ20 ЊC n-Bu4NI
Ϫ78 then Ϫ20 ЊC n-Bu4NI
No traces
No traces
60a
Cl CO2CH3 t-BuOK, 1.3
Cl CO2CH3 LHMDS, 1
Cl CO2CH3 LHMDS, 1
Cl CO2CH3 LHMDS, 1
42c
d
rt
rt
rt
d
10
11
60a
LiBr
72a
Traces
a Isolated yield. b NMR ratios. c 13% of the starting material was also recovered. d Unisolated.
Scheme 2 Phenol alkylation.
for the construction of a great variety of pterulone structures
including more substituted analogues.
high dilution. Under these conditions, the chlorinated com-
pound 9a was isolated in 53% yield together with small
amounts of the dimer easily separated by filtration. In a similar
manner, 7b was converted to 9b in 49% isolated yield.
Results and discussion
The intramolecular C-alkylation studies were then conducted
on chlorides 9a and 9b and on the corresponding iodides 11a
and 11b which are expected to be more reactive substrates for
this seven-membered ring formation. The latter were prepared
by halogen exchange of chlorides 9a and 9b with sodium iodide
in refluxing acetone. One problem generally encountered with
the cyclisation to medium-size rings is the formation of dimeric
products due to entropic factors.14 We have examined the cyclis-
ation of these four sulfones and found the role of the counter-
ion to be crucial. Table 1 summarizes some significant results
under varied conditions. Thus, when a THF solution of
t-BuOK was added dropwise to a THF solution of 11a in the
presence of n-Bu4NI15 at Ϫ78 ЊC, the exclusive formation of the
dimeric product 12a was observed. (entry 1). The reaction was
also found to proceed in absence of n-Bu4NI but at lower rate.
The reaction of 11a with sodium hydride did not proceed in
THF (entry 3), whereas it afforded a 60 : 40 mixture of the
mono and dimeric products in a polar solvent such as DMF
(entry 4). In marked contrast, when the reaction was performed
on 9a in the presence of 2 equiv. of LDA, the expected annul-
ation product 6a was isolated in 37% yield (entry 2). A better
result was obtained when the alkylation was conducted on 9a,
in THF, at room temperature in the presence of 2 equiv. of
LHMDS (entry 5). It was possible to increase the yield of this
seven-membered ring from 63% to 78% by carrying out the
reaction in more dilute conditions (0.013 M) and in the pres-
ence of 1 equiv. of LiBr16 (entry 6). Cyclisation of the corre-
sponding sulfone ester 9b under these optimized conditions
The starting point for the synthesis of these various heterocyclic
substrates was the sulfones 7a and 7b readily obtained from
commercially available 4-hydroxyacetophenone and methyl
4-hydroxybenzoate using a slight modification of the procedure
reported by Kaiser et al.9 The challenging annulation of
these dinucleophiles via O-alkylation with 3-halo-2-halo-
methyl-1-propene and subsequent intramolecular displacement
of the allylic halide by the sulfone to provide the required seven-
membered ring was then undertaken. The preparation of vari-
ous nitrogen containing heterocycles Such related annulation
reactions had been previously reported10 but to our knowledge,
the synthesis of oxygen heterocycles from bisalkylation of an
hydroxysulfone is without precedent.
We began our studies by examining the alkylation of the
phenol group of 7a with the commercially available dichloride 8
(Scheme 2). Various reaction conditions have been reported for
the O-alkylation of phenols with this dielectrophile. Our initial
attempts using standard conditions11 (K2CO3 in refluxing ace-
tone) were complicated by formation of the diether 10a along
with the desired 2-(chloromethyl)-2-propenyl ether 9a. This was
not a surprise, since, as reported in the literature, the formation
of this side product is known to be strongly influenced by the
substituents on the benzene moiety.12 A variety of conditions
were tried in order to minimize the formation of this byproduct.
The best results were obtained by treating 7a with an excess of
dichloride 8 (2.5 equiv.) in the presence of K2CO3 (2.5 equiv.)
and n-Bu4NI (0.8 equiv.) in DMF at room temperature,13 in
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 2 0 9 – 4 2 1 9
4210

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Scheme 3 Synthesis of pterulone (2) and alcohol 5.
only needed 1 equiv. of base to provide the monomeric product
Our strategy to prepare pterulone B (3) involved the intro-
6b in 72% yield (entry 11).
duction of the (E)-olefin on the aryl moiety by Wittig olefin-
ation of the aldehyde 15 obtained by oxidation of alcohol 5
(Scheme 4). We anticipated that this approach would require
another olefin isomerisation step.21 In order to minimize the
number of steps of this synthesis, we decided to examine the
feasibility of the simultaneous isomerisation of the chloroolefin
and the side chain double bond. Thus, the synthesis of 3 started
from ester 14 (Z : E, 85 : 15) which was reduced with DIBAL-H.
The resulting hydroxy group was oxidized using the procedure
developed by Ley and Griffith22 (catalytic TPAP, stoichiometric
NMO) to give the corresponding aldehyde 15 in 76% yield.
The Wittig reaction of 15 with the ylide derived from known
phosphonium 1623 afforded the adduct 17 as an inseparable
diastereomeric mixture of geometric isomers. Several attempts
under classical conditions using iodine20 or thermal thio-
phenol-AIBN system24 failed to promote a clean isomerisation
of both olefins in one step.25 Consequently, we decided to
develop a two-step procedure for these olefin isomerisations.
The first step began with isomerisation of the side-chain olefin
to give the pure (E)-olefin. We found that treatment of 17 under
the mild conditions developed by Spencer and co-workers26
(0.1 equiv. (MeCN)2PdCl2, CH2Cl2, rt, 4 h) produced the pure
(E)-olefin with concomitant partial removal of the ketal pro-
tected group. Subsequent in situ acidic treatment of the crude
product with pyridinium p-toluenesulfonate in aqueous acetone
gave the ketone 18 in an 85 : 15 Z–E olefinic mixture with
regard to the chlorinated double bond. The homogeneity of the
This two-reaction sequence, in which the previous chlorine–
iodine exchange is not needed, allows a rapid entry into the
1-benzoxepine skeleton.
With the requisite intermediate 6a in hand, we developed a
synthetic approach to pterulone (2) as shown in Scheme 3. The
key step to introduce the enone was accomplished in a single
operation by oxidative cleavage of the exocyclic double bond
followed by base-induced elimination of sulfinic acid.17 Thus,
ozonolysis of 6a was performed at Ϫ78 ЊC, in CH2Cl2 and fol-
lowed by reduction of the ozonide with dimethyl sulfide. In situ
addition of DBU upon warming to room temperature cleanly
effected the elimination of sulfinic acid to quantitatively give
the expected unsaturated ketone 13a.
The remaining step to complete the synthesis of pterulone (2)
was to introduce the vinyl chloride moiety. To this end, we
envisioned a direct Wittig reaction of 13a with the ylide derived
from the commercially available chloromethyltriphenyl-
phosphonium chloride. Indeed, despite the presence of two
carbonyl groups on intermediate 13a, it was anticipated that the
seven-membered ring ketone could be the more reactive one.
We were delighted to see that the Wittig olefination of the
seven-membered ring ketone proceeded, as expected. The
chemoselectivity was excellent even when using an excess
(1.3 equiv.) of the ylide prepared by treatment of chloro-
methyltriphenylphosphonium chloride (1.4 equiv.) with BuLi
(1.3 equiv.) in THF.18 The adduct 2, isolated in 82% yield was a
87 : 13 Z–E olefinic mixture, a result consistent with related
Wittig reaction products obtained from other pterulone inter-
mediates.5 Exposure of this chlorovinylated compound to UV
irradiation (254 nm) in benzene or hexane19 for 1.5 h led to an
enrichment of the desired (E) isomer to give pterulone (2) as a
35 : 65 Z–E olefinic mixture.
1
(E)-isomer in the branched chain was confirmed by H NMR
analysis (JHC᎐CH = 12 Hz). Treatment of the chlorovinylated
product with᎐ I2 in heptane at 100 ЊC for 50 min led to an
enrichment of the desired (E)-isomer to give pterulone B as a
30 : 70 Z–E olefinic mixture.
The next phase of this programme was to prepare various
analogues from the two common synthetic substrates 6a,b
(Scheme 5). These versatile compounds may allow us to access
saturated oxepanes by reductive removal of the sulfone group
before oxidative cleavage of the exocyclic double bond. In addi-
tion, this functional group is also suitable for the introduction
of diversity. As we were interested in examining the possibility
of introducing alkyl groups at C5 in order to prepare more
substituted analogues, we began this study by investigating
the synthesis of these compounds. To this end, 6b was treated
with 1 equiv. of LHMDS at room temperature in THF, in the
We then turned our attention to the synthesis of two other
naturally occurring 2,3-dihydro-1-benzoxepines, the alcohol 5
and pterulone B (3), from the same ester intermediate 6b. The
vinyl chloride 14 was readily synthesized in nearly quantitative
yield (97%) by a sequence of two reactions similar to that pre-
viously discussed (Scheme 3). Isomerisation of the chlorinated
double bond was here performed with I2 in heptane20 and
reduction of the ester moiety with DIBAL-H afforded the
expected natural product 5 in 87% yield over the last two steps
as a 30 : 70 Z–E olefinic mixture. (natural product 25 : 75).
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 2 0 9 – 4 2 1 9
4211

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Scheme 4 Synthesis of pterulone B (3).
presence of 1 equiv. of DMPU. The resulting anion was
quenched with ethyl bromide, allyl bromide or benzyl bromide
to afford the corresponding alkylated products 19, 20 and 21b
respectively in 58, 67 and 83% yield.27 Under these conditions,
the sulfone α-alkylation of the ketone analogue 6a with benzyl
bromide led to the formation of a complex mixture of products.
Addition of a further equivalent of base to promote the
dilithiation of the ketosulfone followed by addition of 2 equiv.
of DMPU and of 1 equiv. of alkylating agent gave a single
product 21a isolated in 97% yield. Addition of more than 1
equiv. of alkylating agent afforded a mixture of products that
resulted from C-alkylation at both the α position of the sulfone
and of the ketone.
It is noteworthy that the synthesis of these alkylated products
could be achieved by a one-pot, two-step procedure. Intermedi-
ate 9b was first converted to 6b by reaction with 1 equiv. of
LHMDS in THF at room temperature followed by an addi-
tional equivalent of LHMDS and 1 equiv. of DMPU. Then
addition of benzyl bromide to the resulting anion led to the
formation of the expected compound 21b in 61% isolated yield.
This methodology was successfully applied to analogue 9a but
needed at least a twofold excess of base at the start of the
reaction to provide 21a in 53% yield.
Ozonolysis of these two alkylated sulfones 21a (resp. 21b)
followed by subsequent in situ base-induced elimination of
sulfinic acid under the previously described conditions afforded
the corresponding enone 22a (resp. 22b) in quantitative yield.
Wittig reaction of 22a (resp. 22b) with chloromethylene-
triphenylphosphorane occurred regioselectively at the seven-
membered ring carbonyl group to give an 85 : 15 mixture of
the (E/Z)-chlorovinyl derivatives 23a (resp. 23b) in 53% yield
(resp. 60% yield).
The preparation of saturated analogues was then investigated
(Scheme 5). To this end, the sulfone group of 6b was submitted
to reductive cleavage with excess sodium amalgam in MeOH
(15 equiv. 5% Na–Hg, Na2HPO4, rt, 2 h). These conditions
resulted in the cleavage of the sulfone group and in the reduc-
tive opening of the seven-membered ring by cleavage of the
allylic C–C bond. This unanticipated problem was solved by
using only 3 equiv. of sodium amalgam. Using these conditions,
the expected seven-membered saturated oxacycle 24b was iso-
lated in quantitative yield. Ozonolytic cleavage of the double
bond led to the ketone 26b which was subjected to the pre-
viously described Wittig olefination and the expected chloro-
vinylated product 28b was obtained in 76% yield over the three
steps (85% yield based on recovered starting material). A simi-
lar reaction sequence starting from 21b afforded 29b in 53%
overall yield.
Reductive desulfonylation of the corresponding ketosulfone
6a with sodium amalgam (6 equiv. 5% Na–Hg, Na2HPO4, rt,
2 h) caused concomitant over-reduction of the keto group lead-
ing to a mixture of alcohol 30 and dimeric product 31.28 How-
ever, to our delight, when this mixture was treated under the
conditions developed by Sharpless and co-workers29 (RuCl3,
NaIO4), oxidative cleavage of both the glycol and the double
bond as well as oxidation of the secondary alcohol occurred
simultaneously leading to the desired diketone 26a in 55% iso-
lated yield. The above two-step reaction was applied to sulfone
21a and the saturated ketone 27a was obtained in 45% overall
yield. Finally, Wittig reaction of 26a and 27a with chloro-
methylenetriphenylphosphorane under conditions similar to
those described for compound 22a led to the saturated chlorin-
ated analogues 28a and 29a in good yields.
Pterulone (2) and related analogues were tested against a
wide spectrum of phytopathogenic fungi: Botrytis cinerea,
Septoria nodorum, Monilia fructigena, Magnaporthe grisea,
Rhizoctonia solani and Septoria tritici. Table 2 summarizes their
biological activities expressed as a percentage of control of the
fungi.
Pterulone (2) showed excellent control of all tested fungi at
50 ppm. Its activity was found to be slightly better for the Z
enriched mixture than for the 35 : 65 mixture of the (Z/E)-
isomer. Pterulone B (3) also showed good control, although
weaker than for pterulone (2), of the different fungi. The
natural alcohol 5 described as being strongly active against
yeast cultures5 was surprisingly found to be only moderately
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 2 0 9 – 4 2 1 9
4212

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Scheme 5 Synthesis of various analogues starting from 9a and 9b.
active against phytopathogenic fungi. The unnatural ethyl ester
poor activities demonstrating the importance of this functional
analogue 14 showed an activity almost as excellent as pterulone
(2). In contrast, the aldehyde analogue 15 and the various
analogues of pterulone (2) or its ethyl ester 14 (compounds 23a,
23b, 28a, 28b, 29a and 29b) were found to be poorly or moder-
ately active against the various fungi, S. nodorum and M. grisae
being the more sensitive fungi. All other compounds lacking the
chlorovinyl moiety showed, with very few exceptions, no or
group for fungicidal activity.
Conclusion
In summary, we have established that the coupling of
2-hydroxybenzyl phenyl sulfone 7a and 7b with the com-
mercially available 3-chloro-2-chloromethyl-1-propene may
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 2 0 9 – 4 2 1 9
4213

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Table 2 Fungicidal activities of pterulone and related analogues
Compound Z : E ratio Concentration/µg mLϪ1 B. cinereaa S. nodorumb M. fructigenaa M. griseaa M. griseab R. solania S. triticia
Untreated
2
0
20
100
0
0
0
0
0
0
0
10
0
0
0
0
0
0
10
0
0
0
100
100
80
80
0
10
90
80
20
50
40
10
50
90
70
80
70
20
0
0
n.d.c
100
80
0
n.d.
100
100
30
0
20
100
n.d.
n.d.
0
10
100
40
0
100
100
100
100
0
0
100
0
0
0
0
0
0
10
0
0
0
0
0
0
0
0
90
100
20
0
35 : 65
87 : 13
30 : 70
85 : 15
—
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
2
3
5
6a
6b
20
n.d.
n.d.
90
n.d.
n.d.
100
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
0
n.d.
0
n.d.
0
n.d.
40
n.d.
0
—
20
100
30
0
0
10
0
0
30
0
0
0
14
85 : 15
85 : 15
—
—
—
—
—
—
—
80 : 20
50 : 50
—
—
—
—
—
65 : 35
65 : 35
60 : 40
60 : 40
15
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
20
n.d.
0
n.d.
20
n.d.
20
n.d.
19
0
13a
13b
21b
21b
22a
22b
23a
23b
24b
26a
26b
27a
27b
28a
28b
29a
29b
10
10
0
10
70
100
100
100
10
n.d.
10
n.d.
10
n.d.
30
10
0
10
0
0
0
0
0
10
0
0
20
0
0
0
0
0
0
0
0
20
50
0
80
30
30
n.d.
10
0
0
a Crushed mycelium. b Spore suspension. c n.d : not determined.
allow the rapid construction of the 1-benzoxepine skeleton (6a
and b) that is present in several naturally occurring products.
We have thus achieved the total synthesis of natural products
such as pterulone, pterulone B and of a great variety of
analogues.
acidic solution to increase DMF solubility in the aqueous
phase). The organic layer was dried over magnesium sulfate,
concentrated under reduced pressure and the residue was puri-
fied by flash column chromatography (ethyl acetate–petroleum
ether 35 : 65) to give the title compound 9b (1.63 g, 50%) as a
white solid, Rf 0.41 (ethyl acetate–petroleum ether, 2 : 3); mp:
92 ЊC (Found: C, 57.73; H, 5.00. C19H19ClO5S requires C, 57.79;
H, 4.85%); νmax(KBr)/cmϪ1 3090, 2910, 1725, 1600, 1425, 1310,
1270, and 1140; δH(300 MHz; CDCl3; Me4Si) 3.80 (3H, s,
OCH3), 4.08 (s, 2H, CH2Cl), 4.37 (2H, s, CH2SO2Ph), 4.47 (2H,
Experimental
Synthesis
Commercially available starting materials were used without
further purification. Solvents were dried according to standard
procedures. All reactions were carried out under a nitrogen
atmosphere. Melting points were determined on a Büchi appar-
atus and are uncorrected. NMR spectra were recorded on a
Bruker ALS 300 using the solvent indicated. Chemical shifts
δ are reported in ppm relative to the internal reference. High
resolution mass spectra were obtained on a Thermofinnigan
LCQ-advantage or on a Thermofinnigan MAT95XL. Flash
chromatography was conducted using Merck silica gel 60
(40–63 µm). Thin layer chromatography was carried out on
Merck silica 60/F-254 aluminium backed plates. The petroleum
ether used was the fraction bp 40–60 ЊC. IR spectra were
measured on a Perkin Elmer 681 spectrometer.
s, OCH ), 5.22 (1H, s, one of C᎐CH ), 5.36 (1H, s, one of
᎐
2
2
C᎐CH ), 6.8 (1H, d, J = 8.67 Hz, C(5)–H), 7.41 (2H, m, SO Ph),
᎐
2
2
7.6 (3H, m, SO2Ph), 7.89 (1H, s, C(2)–H), 7.98 (dd, J = 8.67, 2.2
Hz, C(6)–H); δC(75 MHz; CDCl3; Me4Si) 44.9, 52.05, 56.35,
68.3, 111.3, 117.2, 118.0, 123.05, 128.6, 128.8, 132.45, 133.65,
134.1, 138.45, 139.5, 160.0, 166.1.
Di-ether 10b, yellow–white solid (934 mg, 29%), Rf 0.46
(ethyl acetate–petroleum ether, 3 : 2); mp: 114–116 ЊC;
νmax(KBr)/cmϪ1 3080, 2990, 2940, 1720, 1605, 1500, 1420, 1310,
1270, and 1140; δH(300 MHz; CDCl3; Me4Si) 3.85 (3H, s,
OCH3), 4.45 (2H, s, CH2SO2Ph), 4.47 (2H, s, OCH2), 5.34 (2H,
s, C᎐CH ), 6.88 (1H, d, J = 8.64 Hz, C(5)–H), 7.42 (2H, m,
᎐
2
SO2Ph), 7.6 (3H, m, SO2Ph), 7.74 (1H, d, J = 2.07 Hz, C(2)–H),
7.98 (dd, J = 8.64, 2.2 Hz, C(6)–H); δC(75 MHz; CDCl3; Me4Si)
52.05, 56.9, 69.25, 111.8, 116.95, 117.4, 123.3, 128.95, 129.3,
132.9, 134.1, 134.4, 138.7, 138.8, 160.6, 166.45.
3-Benzenesulfonyl-4-(2-chloromethylallyloxy)benzoic acid
methyl ester 9b and di-ether 10b
To a solution of 3-benzenesulfonylmethyl-4-hydroxybenzoic
acid methyl ester (2.5 g, 8.16 mmol) in N,N-dimethylformamide
(150 mL) was added tetrabutylammonium iodide (3.0 g, 8.16
mmol), potassium carbonate (2.90 g, 20.4 mmol) and 3-chloro-
2-chloromethyl-1-propene (2.36 mL, 20.4 mmol). The mixture
was stirred for 20 h at room temperature, and was then cooled
to 0 ЊC. The reaction mixture was diluted with diethyl ether
(100 mL) and 1 M hydrochloric acid was added until pH = 2.
The di-ether 10b came out of solution and was filtered off and
washed with diethyl ether. The combined filtrates were extrac-
ted with diethyl ether (4 × 50 mL). The combined extracts were
washed four times in acidic solution (1 M HCl, pH = 2) and
twice with brine (extraction and washing were carried out in
3-Benzenesulfonyl-4-(2-iodomethylallyloxy)benzoic acid methyl
ester 11b
To a solution of 9b (667 mg, 1.69 mmol) in acetone (17 mL) was
added sodium iodide (380 mg, 2.53 mmol). The mixture was
stirred for 14 h under reflux and was then cooled to room tem-
perature and quenched with water. After extraction with di-
chloromethane, the combined organic layers were first washed
with saturated sodium thiosulfate, and then with brine, dried
over magnesium sulfate and concentrated under reduced pres-
sure. Compound 11b (808 mg, 98%) was obtained as a white
solid, Rf 0.5 (ethyl acetate–petroleum ether, 1 : 1); νmax(KBr)/
cmϪ1 3080, 3000, 2920, 1705, 1605, 1500, 1430, 1360, 1300,
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 2 0 9 – 4 2 1 9
4214

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1260, and 1140; δH(300 MHz; CDCl3; Me4Si) 3.82 (3H, s,
with brine, dried over magnesium sulfate and concentrated
OCH3), 3.89 (s, 2H, CH2I), 4.39 (2H, s, CH2SO2Ph), 4.45 (2H,
under reduced pressure to give the title compound 13a (35 mg,
98%) as a white solid, Rf 0.61 (ethyl acetate–petroleum ether,
1 : 1); mp: 92–93 ЊC (Found: C, 71.33; H, 5.11. C12H10O3
requires C, 71.28; H, 4.98%); νmax(KBr)/cmϪ1 3090, 2990, 1740,
1680, 1600 1360 and 1225; δH(300 MHz; CDCl3; Me4Si) 2.62
(3H, s, COCH3), 4.60 (2H, s, C(2)–H), 6.44 (1H, d, J = 12.0 Hz,
C(4)–H), 7.25 (2H, m, C(5)–H and C(9)–H), 8.0 (1H, dd,
J = 8.49, 2.07 Hz, C(8)–H), 8.1 (1H, d, J = 2.07 Hz, C(6)–H);
δC(75 MHz; CDCl3; Me4Si) 26.9, 77.9, 121.5, 127.4, 130.4,
132.6, 133.8, 134.5, 141.8, 162.7, 195.5, 195.9.
s, OCH ), 5.13 (1H, s, one of C᎐CH ), 5.41 (1H, s, one of
᎐
2
2
C᎐CH ), 6.79 (1H, d, J = 8.82 Hz, C(5)–H), 7.38 (2H, m,
᎐
2
SO2Ph), 7.58 (3H, m, SO2Ph), 7.89 (1H, d, J = 2.2 Hz, C(2)–H),
7.98 (dd, J = 8.67, 1.83 Hz, C(6)–H); δC(75 MHz; CDCl3;
Me4Si) 4.95, 52.06, 56.37, 68.99, 111.28, 116.78, 117.16, 123.04,
128.61, 128.86, 132.44, 133.72, 134.12, 138.45, 140.86, 160.0,
166.11.
5-Benzenesulfonyl-3-methylene-2,3,4,5-tetrahydrobenzo[b]-
oxepine-7-carboxylic acid methyl ester 6b and dimeric product
12b
1-(3-Chloromethylene-2,3-dihydrobenzo[b]oxepin-7-yl)ethanone
2
To a solution of 9b (100 mg, 0.253 mmol) in dry THF (17 mL)
and lithium bromide (28.5 mg, 0.303 mmol), a 1.06 M solution
of lithium bis(trimethylsilyl)amide (LHMDS) in THF (303 µL,
0.303 mmol) was added dropwise. The reaction mixture was
stirred for 5 min, and the reaction was quenched by addition of
water and acidified with dilute hydrochloric acid. After extrac-
tion with dichloromethane, the combined organic layers were
washed with brine, dried over magnesium sulfate and concen-
trated under reduced pressure. The residue was purified by flash
column chromatography (ethyl acetate–petroleum ether, 35 : 65)
to give the title compound 6b (65 mg, 75%) as a white solid, Rf
0.41 (ethyl acetate–petroleum ether, 2 : 3); mp: 84–86 ЊC;
νmax(KBr)/cmϪ1 3080, 2980, 2890, 1725, 1610, 1580, 1500, 1450,
1310, 1250, and 1140; δH(300 MHz; CDCl3; Me4Si) 2.98 (1H,
dd, J = 13.9, 7.1 Hz, C(4)–Ha), 3.21 (1H, dd, J = 13.9, 7.1 Hz,
C(4)–Hb), 3.86 (s, 3H, OCH3), 4.21 (1H, d, J = 13.4 Hz, C(2)–
Ha), 4.46 (1H, t, J = 7.35 Hz, C(5)–H), 4.73 (1H, d, J = 13.4 Hz,
To
a suspension of (chloromethyl)triphenylphosphonium
chloride (139.5 mg, 0.401 mmol) in dry THF (2.7 mL) at 0 ЊC
was added a solution of 2 M n-BuLi in hexane (186 µl,
0.373 mmol). After 1 h of stirring at 0 ЊC, the resulting red
solution, was added dropwise to a solution of 13a (58 mg, 0.287
mmol) in THF (3.9 mL) at 0 ЊC. Stirring was continued for
30 min, and the reaction mixture was quenched by addition of
water and acidified with dilute hydrochloric acid. The aqueous
mixture was extracted three times with dichloromethane. The
combined organic layers were washed with brine, dried over
magnesium sulfate and concentrated under reduced pressure.
The residue was purified by column chromatography on silica
(ethyl acetate–petroleum ether, 1 : 9) to give the title compound
2 as a 87 : 13 Z–E mixture (55 mg, 82%). White–yellow solid, Rf
0.4 (ethyl acetate–petroleum ether, 1 : 4); mp: 85–90 ЊC;
νmax(KBr)/cmϪ1 3060, 2990, 2920, 2840, 1670, 1590, 1490, 1360,
1260 and 1230; δH(300 MHz; CDCl3; Me4Si) Z isomer 2.57 (3H,
s, COCH3), 4.89 (2H, s, C(2)–H), 6.39 (3H, s, C(4)–H and C(5)–
C(2)–Hb), 4.99 (1H, s, one of C᎐CH ), 5.09 (1H, s, one of
᎐
2
C᎐CH ), 6.98 (1H, d, J = 8.28 Hz, C(9)–H), 7.43 (2H, m,
᎐
2
SO2Ph), 7.62 (3H, m, SO2Ph), 7.76 (1H, d, J = 2.07 Hz, C(6)–
H), 7.94 (1H, dd, J = 8.46, 2.0 Hz, C(8)–H); δC(75 MHz; CDCl3;
Me4Si) 32.2, 52.5, 69.7, 77.4, 116.6, 123.35, 124.3, 126.25, 129.2,
129.85, 132.5, 134.30, 136.1, 137.05, 141.25, 162.85, 166.35; m/z
(CI) 217 (MH Ϫ PhSO2Hϩ, 100%), 359 (MHϩ, 90). found MHϩ
359.09545. C19H19O5S requires 359.08749.
H and C᎐CHCl), 7.08 (1H, d, J = 8.46 Hz, C(9)–H), 7.76 (1H,
dd, J = 8.3, 2.25 Hz, C(8)–H), 7.86 (d, J = 2.25 Hz, 1H, C(6)–
H); δH(300 MHz; CDCl3; Me4Si) E isomer 2.57 (3H, s, COCH3),
᎐
4.59 (2H, s, C(2)–H), 6.17 (1H, s, C᎐CHCl), 6.87 (1H, d,
᎐
J = 11.88 Hz, C(4)–H), 7.02 (1H, d, J = 11.88 Hz, C(5)–H), 7.08
(1H, d, J = 8.46 Hz, C(9)–H), 7.76 (1H, dd, J = 8.49, 2.25 Hz,
C(8)–H), 7.90 (1H, d, J = 2.25 Hz, C(6)–H); δC(75 MHz; CDCl3;
Me4Si) Z isomer 26.9, 68.5, 120.9, 121.8, 127.8, 128.1, 129.1,
129.6, 133.0, 133.7, 138.0, 163.2, 197.0.
Compound 12b. Rf 0.32 (ethyl acetate–petroleum ether, 1 : 1);
mp: 190 ЊC (decomp.); νmax(KBr)/cmϪ1 3060, 2980, 2950, 2860,
1725, 1650, 1610, 1580, 1500, 1440, 1300, 1250, and 1140;
δH(300 MHz; CDCl3; Me4Si) 3.0 (1H, dd, J = 13.74, 10.35 Hz,
PhSO2CH–CH2a), 3.39 (1H, dd, J = 13.74, 5.28 Hz, PhSO2CH–
CH2b), 3.56 (1H, d, J = 10.56 Hz, O–CH2a), 3.84 (4H, m, OCH3
Spectroscopic data were identical to those reported in
literature.
A solution of the 87 : 13 Z–E mixture (42 mg, 0.179 mmol)
was exposed to UV irradiation at 254 nm in benzene for 1.5 h.
After purification by flash column chromatography (ether–
petroleum ether, 2 : 3) compound 2 was obtained as a 35 : 65
Z–E mixture (26 mg, 63%).
and O–CH b), 4.98 (1H, s, one of C᎐CH ), 5.13 (1H, s, one of
᎐
2
2
C᎐CH ), 5.28 (1H, dd, J = 10.17, 5.46 Hz, CH-SO Ph), 6.13
᎐
2
2
(1H, d, J = 8.85 Hz, C(9)–H), 7.24 (2H, m, SO2Ph), 7.45 (1H, m,
SO2Ph), 7.59 (2H, m, SO2Ph), 7.62 (1H, dd, J = 8.85, 2.07 Hz,
C(8)–H), 7.94 (1H, d, J = 2.07 Hz, C(6)–H); δC(75 MHz; CDCl3;
Me4Si) 32.4, 52.2, 60.55, 73.5, 110.2, 121.15, 122.7, 123.2,
128.35, 129.5, 131.05, 131.7, 133.3, 137.8, 138.0, 159.8, 166.3;
m/z (CI) 217 (MH/2 Ϫ PhSO2Hϩ, 100%), 359 (MHϩ/2, 75), 717
(5). Found MHϩ 717.18320. C38H37O10S2 requires 717.17499.
(3-Chloromethylene-2,3-dihydrobenzo[b]oxepin-7-yl)methanol 5
To a solution of compound 14 (Z : E = 85 : 15, 115 mg, 0.459
mmol) in dichloromethane (3.4 mL) at Ϫ78 ЊC, was added
a 1 M solution of diisobutylaluminium hydride (1.1 mL,
1.10 mmol) in hexane. After stirring the reaction mixture for
1 h 15 min at this temperature were added methanol (1 mL) and
a 0.7 M solution of potassium and sodium tartrate (5 mL). The
reaction mixture was allowed to reach room temperature and
was stirred for 14 h then water and dichloromethane were
added. After extraction with dichloromethane, the combined
organic layers were washed with brine, dried over magnesium
sulfate and concentrated under reduced pressure. The title
compound 5 was obtained with no further purification as a
85 : 15 Z–E mixture. White–yellow solid (100 mg, 98%), Rf 0.22
(ethyl acetate–petroleum ether, 3 : 7); mp: 64–69 ЊC (Found:
C, 64.50; H, 5.26. C12H11ClO2 requires C, 64.73; H, 4.98%);
νmax(KBr)/cmϪ1 3600, 3050, 2900, 1500, 1225 and 1000; δH(300
MHz; CDCl3; Me4Si) Z isomer 4.65 (2H, s, CH2OH), 4.88 (2H,
7-Acetylbenzo[b]oxepine-3-one 13a
Ozone was bubbled through a solution of 6a (50 mg, 0.175
mmol) in dichloromethane (20 mL) at Ϫ78 ЊC until a blue color
persisted. Oxygen gas was then passed through the reaction
mixture to remove excess O3 until the solution became colorless.
The ozonide was reduced by addition of 2 mL of dimethyl
sulfide. The solution was allowed to warm up to room temper-
ature and stirred for 14 h, then 1,8-diazabicyclo[5.4.0]undec-7-
ene (DBU) (28 µL, 0.183 mmol) was added. The reaction
mixture was stirred for 5 min, and was quenched by addition of
water and acidified with 1 M hydrochloric acid to increase
dimethyl sulfoxide solubility in water. After extraction with
dichloromethane, the combined organic layers were washed
twice in acidic solution to remove dimethyl sulfoxide and then
s, C(2)–H), 6.35 (3H, s, C(4)–H and C(5)–H and C᎐CHCl), 7.04
᎐
(1H, m, C(9)–H), 7.19 (2H, m, C(6)–H and C(8)–H); δH(300
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 2 0 9 – 4 2 1 9
4215

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MHz; CDCl3; Me4Si) E isomer 2.34 (1H, br s, OH), 4.56 (2H, s,
J = 11.6 Hz, C(4)–H), 6.79 (1H, d, J = 11.6 Hz, C(5)–H), 6.96
(1H, m, C(9)–H), 7.0 (2H, m, C(6)–H and C(8)–H); δH(300
MHz; CDCl3; Me4Si) E–E isomer 1.35 (3H, s, CH3), 1.81 (2H,
C(2)–H), 4.65 (2H, s, CH OH), 6.13 (1H, s, C᎐CHCl), 6.55 (1H,
᎐
2
d, J = 11.88 Hz, C(4)–H), 6.85 (1H, d, J = 11.88 Hz, C(5)–H),
7.04 (1H, m, C(9)–H), 7.19 (2H, m, C(6)–H and C(8)–H);
δC(75 MHz; CDCl3; Me4Si) Z isomer 64.9, 68.7, 120.7, 120.8,
128.1, 128.4, 128.5, 128.2, 131.5, 136.3, 138.9, 159.0; δC(75
MHz; CDCl3; Me4Si) E isomer 64.9, 73.0, 119.6, 120.6, 128.1,
128.4, 128.5, 127.4, 131.5, 135.9, 138.9, 159.2.
Following the same procedure, compound 14 (Z : E = 30 : 70,
15 mg, 0.059 mmol), diisobutylaluminium hydride (125 µL,
0.125 mmol) and dichloromethane (0.4 mL) gave the title com-
pound 5 as a 30 : 70 Z–E mixture. White–yellow solid (13.1 mg,
98%).
m, C–CH ), 2.35 (2H, m, H C–CH᎐CH), 3.9 (4H, m, OCH -
᎐
2
2
2
CH O), 4.53 (2H, s, C(2)–H), 6.10 (2H, m, H C–CH᎐CH and
᎐
2
2
C᎐CHCl), 6.32 (1H, m, Ar–CH᎐CH), 6.52 (1H, d, J = 11.6 Hz,
᎐
᎐
C(4)–H), 6.79 (1H, d, J = 11.6 Hz, C(5)–H), 6.96 (1H, m, C(9)–
H), 7.0 (2H, m, C(6)–H and C(8)–H); δC(75 MHz; CDCl3;
Me4Si) Z–Z isomer 23.77, 24.31, 39.43, 65.10, 65.12, 68.69,
110.18, 120.45, 126.63, 127.88, 128.19, 128.22, 128.76, 129.01,
130.23, 133.11, 133.56, 138.94, 158.12.
85 : 15 and 0 : 100 Z–E 6-(3-chloromethylene-2,3-dihydro-
benzo[b]oxepin-7-yl)hex-5-en-2-one 18
3-Chloromethylene-2,3-dihydrobenzo[b]oxepine-7-carbaldehyde
15
To a solution of compound 17 (79 mg, 0.237 mmol) in di-
chloromethane (1.5 mL) was added bis(acetonitrile)-
palladium() (6 mg, 0.023 mmol) and the reaction mixture was
stirred for 4 h at room temperature. Acetone (0.5 mL) and
p-toluenesulfonic acid monohydrate (cat.) were then added to
completely remove the ketal protected group. After being
stirred for 15 min, the reaction mixture was filtered through a
short pad of silica gel, and eluted with ethyl acetate. The solvent
was removed under reduced pressure and the residue purified
by flash column chromatography (ethyl acetate–petroleum
ether, 1 : 9) to give the title compound 18 as an 85 : 15 and
0 : 100 mixture of (Z)- and (E)-isomers. Colorless oil (55 mg,
80%), Rf 0.33 (ethyl acetate–petroleum ether, 1 : 4).
To a suspension of compound 5 (92 mg, 0.413 mmol), 4-meth-
ylmorpholine N-oxide monohydrate (NMO) (84 mg, 0.620
mmol) and 4 Å molecular sieves (207 mg) in dichloromethane
(1 mL) at 0 ЊC was added tetrapropylammonium peruthenate
(14.6 mg, 0.041 mmol). The mixture was stirred for 1 h and was
then filtered trough a silica pad and purified by flash column
chromatography on silica (ethyl acetate–petroleum ether, 3 : 7)
to give the title compound 15 as a 85 : 15 Z–E mixture. White
solid (70 mg, 76%), Rf 0.58 (ethyl acetate–petroleum ether,
3 : 7); mp: 95–98 ЊC (Found: C, 65.60; H, 4.25. C12H9ClO2
requires C, 65.35; H, 4.11%); νmax(KBr)/cmϪ1 3090, 2900, 1690,
1600, 1225 and 1000; δH(300 MHz; CDCl3; Me4Si) Z isomer
4.90 (2H, s, C(2)–H), 6.41 (3H, m, C(4)–H, C(5)–H and
30 : 70 and 0 : 100 Z–E 6-(3-chloromethylene-2,3-dihydro-
benzo[b]oxepin-7-yl)hex-5-en-2-one 3
C᎐CHCl), 7.14 (1H, d, J = 8.3 Hz, C(9)–H), 7.70 (1H, dd,
᎐
J = 8.3, 2 Hz, C(8)–H), 7.75 (1H, d, J = 2.07 Hz, C(6)–H), 9.91
(1H, s, HCO); δH(300 MHz; CDCl3; Me4Si) E isomer 4.6 (2H, s,
To a solution of compound 18 (55 mg, 0.190 mmol) in a mix-
ture of heptane and dichloromethane (7 : 1) was added a crystal
of iodine. The reaction mixture was warmed for 50 min at
100 ЊC after witch it was cooled to room temperature and
hydrolysed by addition of saturated aqueous sodium thiosul-
fate and then extracted with dichloromethane. The combined
organic layers were dried over magnesium sulfate and evapor-
ated under reduced pressure. The residue was purified by flash
column chromatography (ethyl acetate–petroleum ether, 1 : 9)
to give the title compound 3 as a 30 : 70 and 0 : 100 mixture of
Z and E isomers. Colorless oil (50 mg, 92%), Rf 0.33 (ethyl
acetate–petroleum ether, 1 : 4); νmax(film)/cmϪ1 3090, 2910,
1725, 1600, 1500, 1225 and 960; δH(300 MHz; CDCl3; Me4Si)
C(2)–H), 6.2 (1H, s, C᎐CHCl), 6.9 (1H, d, J = 11.9 Hz, C(4)–H),
᎐
7.0 (1H, d, J = 11.9 Hz, C(5)–H), 7.14 (1H, d, J = 8.3 Hz, C(9)–
H), 7.70 (1H, dd, J = 8.3, 2 Hz, C(8)–H), 7.75 (1H, d, J = 2.07
Hz, C(6)–H), 9.91 (1H, s, HCO); δC(75 MHz; CDCl3; Me4Si) Z
isomer 68.5, 121.6, 122.2, 127.7, 129.5, 130.5, 128.4, 132.4,
135.2, 137.85, 162.2, 191.1.
3-Chloromethylene-7-[4-(2-methyl-1,3-dioxolan-2-yl)but-1-
enyl]-2,3-dihydrobenzo[b]oxepine 17
To a suspension of phosphonium salt 16 (196 mg, 0.413 mmol)
in dry THF (3.2 mL) at 0 ЊC was added a 2 M solution of
n-BuLi in hexane (217 µl, 0.435 mmol). After being stirred for
1 h at 0 ЊC, this mixture was added dropwise to a solution of 15
(48 mg, 0.217 mmol) in THF (3.6 mL) at 0 ЊC. The reaction
mixture was stirred for 25 min, and was quenched by the addi-
tion of water and acidified with dilute hydrochloric acid. After
extraction with dichloromethane, the combined organic layers
were washed with brine, dried over magnesium sulfate and con-
centrated under reduced pressure. The residue was purified by
flash column chromatography (ethyl acetate–petroleum ether,
1 : 9) to give the title compound 17 as a 85 : 15 and 60 : 40
mixture of four (Z)- and (E)-isomers. Colorless oil (47 mg,
71%), Rf 0.3 (ethyl acetate–petroleum ether, 1 : 9); δH(300 MHz;
CDCl3; Me4Si) Z–Z isomer 1.32 (3H, s, CH3), 1.81 (2H, m,
E-E isomer 2.15 (3H, s, CH ), 2.47 (2H, m, H C–CH᎐CH), 2.59
᎐
3
2
(2H, m, COCH ), 4.52 (2H, s, C(2)–H), 6.0 (2H, m, H C–CH᎐
᎐
2
2
CH, C᎐CHCl), 6.33 (1H, m, Ar–CH᎐CH), 6.50 (1H, d,
᎐
᎐
J = 11.6, C(4)–H), 6.79 (1H, d, J = 11.6 Hz, C(5)–H), 6.90 (1H,
m, C(9)–H) 7.17 (2H, m, C(6)–H and C(8)–H); δH(300 MHz;
CDCl3; Me4Si) E-Z isomer 2.18 (3H, s, CH3), 2.47 (2H, m,
H C–CH᎐CH), 2.59 (2H, m, COCH ), 4.83 (2H, s, C(2)–H), 6.0
᎐
2
2
(1H, m, H C–CH᎐CH), 6.33 (4H, m, Ar–CH᎐CH, C᎐CHCl,
᎐
᎐
᎐
2
C(4)–H, C(5)–H), 6.90 (1H, m, C(9)–H), 7.17 (2H, m, C(6)–H
and C(8)–H); δC(75 MHz; CDCl3; Me4Si) E-E isomer 27.46,
30.45, 43.58, 73.02, 119.54, 120.54, 124.29, 127.05, 127.26,
128.54, 129.91, 131.31, 131.62, 132.92, 136.81, 158.84, 208.51;
m/z (CI) 289 (MHϩ, 93%), 279 (100), 291 (20); found MHϩ
289.0995. C17H18ClO2 requires 289.0917
C–CH ), 2.44 (2H, m, H C–CH᎐CH), 3.9 (4H, m, OCH -
᎐
2
2
2
CH O), 4.86 (2H, s, C(2)–H), 5.63 (1H, m, H C–CH᎐CH), 6.32
᎐
2
2
5-Benzenesulfonyl-5-benzyl-3-methylene-2,3,4,5-tetrahydro-
benzo[b]oxepine-7-carboxylic acid methyl ester 21b
(4H, m, Ar–CH᎐CH, C᎐CHCl, C(4)–H and C(5)–H), 6.96 (1H,
᎐
᎐
m, C(9)–H), 7.0 (2H, m, C(6)–H and C(8)–H); δH(300 MHz;
CDCl3; Me4Si) E–Z isomer 1.32 (3H, s, CH3), 1.81 (2H, m,
From compound 6b. To a solution of 6b (195 mg, 0.543 mmol)
in dry THF was added 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H )-
pyrimidinone (DMPU) (0.072 mL, 0.605 mmol). This was fol-
lowed by the dropwise addition of a 1.06 M solution of lithium
bis(trimethylsilyl)amide in THF (0.6 mL, 0.605 mmol). After
stirring for 15 min at room temperature benzyl bromide (73 µL,
0.605 mmol) was added and the reaction mixture was stirred for
another 5 min. The reaction mixture was then hydrolysed with
water. 1 M hydrochloric acid was added to neutralise the
C–CH ), 2.35 (2H, m, H C–CH᎐CH), 3.9 (4H, m, OCH -
᎐
2
2
2
CH O), 4.84 (2H, s, C(2)–H), 6.10 (1H, m, H C–CH᎐CH), 6.32
᎐
2
2
(4H, m, Ar–CH᎐CH, C᎐CHCl, C(4)–H, C(5)–H), 6.96 (1H, m,
᎐
᎐
C(9)–H), 7.0 (2H, m, C(6)–H and C(8)–H); δH(300 MHz;
CDCl3; Me4Si) Z–E isomer 1.35 (3H, s, CH3), 1.81 (2H, m,
C–CH ), 2.44 (2H, m, H C–CH᎐CH), 3.9 (4H, m, OCH -
᎐
2
2
2
CH O), 4.55 (2H, s, C(2)–H), 5.63 (1H, m, H C–CH᎐CH), 6.10
᎐
2
2
(1H, m, C᎐CHCl), 6.32 (1H, m, Ar–CH᎐CH), 6.52 (1H, d,
᎐
᎐
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 2 0 9 – 4 2 1 9
4216

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mixture. After extraction with dichloromethane, the combined
organic layers were washed with brine, dried over magnesium
sulfate and concentrated under reduced pressure. The resi-
due was purified by flash column chromatography (dichloro-
methane–ethyl acetate–petroleum ether, 1 : 2 : 7) to give
compound 21b (211 mg, 86%) as a white solid.
ether, 2 : 3); mp: 131–132 ЊC (Found: C, 71.59; H, 5.70.
C26H24O4S requires C, 72.20; H, 5.70%); νmax(KBr)/cmϪ1 3060,
2920, 2840, 1680, 1600, 1490, 1440, 1360, 1300, 1250, and 1140;
δH(300 MHz; CDCl3; Me4Si) 2.6 (3H, s, COCH3), 3.0 (1H, d,
J = 14.8 Hz, C(4)–Ha), 3.1 (1H, d, J = 14.8 Hz, C(4)–Hb), 3.5
(1H, d, J = 13.7 Hz, C(2)–Ha), 4.0 (1H, d, J = 13.7 Hz, C(4)–
Hb), 4.3 (1H, d, J = 14.7 Hz, PhCH2a), 4.4 (1H, d, J = 14.7 Hz,
PhCH b), 4.74 (2H, s, C᎐CH ), 6.9 (3H, m, C(9)–H and
᎐
From compound 9b. To a solution of 9b (200 mg, 0.507 mmol)
in dry THF (33 mL) was added dropwise a 1.06 M solu-
tion of LHMDS in tetrahydrofuran (1.15 mL, 1.11 mmol).
After stirring for 5 min 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H )-
pyrimidinone (DMPU) (134 µL, 1.11 mmol) was added. The
solution was stirred for 15 min when benzyl bromide (67 µL,
0.557 mmol) was added. The reaction mixture was stirred for
another 5 min then quenched by addition of water and acidi-
fied with dilute hydrochloric acid. After extraction with di-
chloromethane, the combined organic layers were washed with
brine, dried over magnesium sulfate and concentrated under
reduced pressure. The residue was purified by column chrom-
atography on silica (dichloromethane–ethyl acetate–petroleum
ether, 1 : 2 : 7) to give the title compound 21b (139 mg, 61%)
as a white solid, Rf 0.33 (ethyl acetate–petroleum ether, 1 : 3);
mp: 164–165 ЊC; νmax(KBr)/cmϪ1 3080, 2980, 2950, 2920, 1720,
1605, 1500, 1440, 1400, 1300, 1260, 1140 and 1120; δH(300
MHz; CDCl3; Me4Si) 3.0 (1H, d, J = 14.8 Hz, C(4)–Ha),
3.1 (1H, d, J = 14.8 Hz, C(4)–Hb), 3.5 (1H, d, J = 13.7 Hz,
C(2)–Ha), 3.93 (3H, s, OCH3), 4.0 (1H, d, J = 13.7 Hz, C(2)–
2
2
CH2Ph), 7.12 (3H, m, CH2Ph), 7.42 (2H, m, SO2Ph), 7.60 (3H,
m, SO2Ph), 7.9 (1H, dd, J = 8.4, 2.2 Hz, C(8)–H), 8.44 (1H, d,
J = 2.1 Hz, C(6)–H); δC(75 MHz; CDCl3; Me4Si) 27.0, 38.5,
43.3, 52.7, 73.7, 76.8, 113.5, 123.8, 125.7, 127.8, 128.6, 128.9,
130.7, 131.3, 131.4, 132.7, 134.4, 134.6, 134.8, 136.3, 142.8,
165.7, 196.9.
1-(5-Benzyl-3-chloromethylene-2,3-dihydrobenzo[b]oxepin-7-yl)-
ethanone 23a
Compound 23 was prepared following the same procedure as
described for the preparation of pterulone (2), using (chloro-
methyl)triphenylphosphonium chloride (85.5 mg, 0.246 mmol),
n-BuLi (0.226 mmol), compound 22a (60 mg, 0.205 mmol).
Purification (ethyl acetate–petroleum ether, 5 : 95) gave
compound 23a as an 80 : 20 Z–E mixture. Yellow–white solid
(45 mg, 68%), Rf 0.53 (ethyl acetate–petroleum ether, 1 : 4); mp:
89–94 ЊC (Found: C, 73.52; H, 5.74. C20H17ClO2 requires C,
73.96; H, 5.28%); νmax(KBr)/cmϪ1 3080, 3020, 2920, 2850, 1670,
1600, 1490, 1450, 1380 and 1270; δH(300 MHz; CDCl3; Me4Si)
Z isomer 2.42 (3H, s, COCH3), 3.95 (2H, s, PhCH2), 4.91 (2H, s,
Hb), 4.3 (2H, s, PhCH ), 4.7 (2H, 2 × s, C᎐CH ), 6.87 (3H, m,
᎐
2
2
PhCH2), 7.12 (3H, m, C(9)–H and CH2Ph), 7.41 (2H, m,
SO2Ph), 7.60 (3H, m, SO2Ph), 7.97 (1H, dd, J = 8.3, 1.9 Hz,
C(8)–H), 8.55 (1H, d, J = 1.86 Hz, C(6)–H); δC(75 MHz; CDCl3;
Me4Si) 38.3, 43.1, 52.7, 73.7, 76.8, 113.5, 123.8, 125.7, 126.1,
127.8, 128.6, 128.8, 131.3, 131.5, 132.2, 134.3, 134.8, 135.1,
136.3, 142.7, 165.3, 166.6; m/z (CI) 307 (MH Ϫ PhSO2Hϩ,
100%), 449 (MHϩ, 20). Found MHϩ 449.14237. C26H24O5S
requires 449.13444.
C(2)–H), 6.26 (1H, s, C᎐CHCl), 6.42 (1H, s, C(4)–H), 7.09 (1H,
᎐
d, J = 8.46 Hz, C(9)–H), 7.3 (5H, m, Ph), 7.7 (1H, dd, J = 8.4,
2.07 Hz, C(8)–H), 8.06 (1H, d, J = 2.07 Hz, C(6)–H); δH(300
MHz; CDCl3; Me4Si) E isomer 2.39 (3H, s, COCH3), 4.10 (2H,
s, PhCH2), 4.59 (2H, s, C(2)–H), 6.12 (1H, s, C᎐CHCl), 7.0 (1H,
᎐
s, C(4)–H), 7.09 (1H, d, J = 8.46 Hz, C(9)–H), 7.3 (5H, m, Ph),
7.7 (1H, dd, J = 8.4, 2.07 Hz, C(8)–H), 8.15 (1H, d, J = 2.07 Hz,
C(6)–H); δC(75 MHz; CDCl3; Me4Si) Z isomer 26.4, 44.75, 70.4,
119.6, 121.4, 126.6, 128.26, 128.44, 128.7, 128.9, 130.3, 130.35,
132.85, 133.75, 138.5, 139.2, 163.6, 196.7.
1-(5-Benzenesulfonyl-5-benzyl-3-methylene-2,3,4,5-tetrahydro-
benzo[b]oxepin-7-yl)ethanone 21a
From compound 6a. To a solution of 6a (200 mg, 0.584 mmol)
in dry THF, was added 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H )-
pyrimidinone (DMPU) (0.152 mL, 1.27 mmol). This was fol-
lowed by the dropwise addition of a 1.06 M solution of
LHMDS in THF (1.28 mL, 1.27 mmol). After stirring for 15
min at room temperature benzyl bromide (70 µL, 0.584 mmol)
was added and the reaction mixture was immediately quenched
by addition of water and acidified with dilute hydrochloric acid.
After extraction with dichloromethane, the combined organic
layers were washed with brine, dried over magnesium sulfate
and concentrated under reduced pressure. The residue was
purified by flash column chromatography (dichloromethane–
ethyl acetate–petroleum ether, 1 : 2 : 7) to give the title
compound 21a (366 mg, 53%) as a white solid.
3-Methylene-2,3,4,5-tetrahydrobenzo[b]oxepine-7-carboxylic
acid methyl ester 24b
To a suspension of compound 6b (175 mg, 0.488 mmol) and
sodium phosphate dibasic (NaH2PO4) (277 mg, 1.95 mmol) in a
1 : 1 mixture of THF and methanol (10 mL) was added at 0 ЊC a
5% sodium amalgam (1.01 g, 2.2 mmol). The reaction mixture
was stirred at room temperature until the reduction was com-
plete (TLC). The reaction mixture was then hydrolysed with
water and mercury was removed by filtration. After extraction
with dichloromethane, the organic layer was dried over mag-
nesium sulfate and evaporated under reduced pressure. Com-
pound 24b was obtained (108 mg, quantitative) as a colorless
oil, Rf 0.73 (ethyl acetate–petroleum ether, 3 : 7); νmax(film)/cmϪ1
3090, 2980, 1725, 1610, 1500, 1430, 1280 and 1250; δH(300
MHz; CDCl3; Me4Si) 2.53 (2H, m, C(4)–H), 2.93 (2H, m, C(5)–
From compound 9a. To a solution of 9a (600 mg, 1.58 mmol)
in dry THF (50 mL) was added dropwise a 1.06 M solution of
LHMDS in THF (3.17 mL, 3.17 mmol). After 5 min was added
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H )-pyrimidinone (DMPU)
(134 µL, 3.17 mmol) and a 1.06 M solution of lithium bis-
(trimethylsilyl)amide in THF (1.58 mL, 1.58 mmol). After stir-
ring for 15 min, benzyl bromide (188 µL, 1.58 mmol) was added
and the reaction was immediately hydrolysed by addition of
water and acidified with dilute hydrochloric acid. After extrac-
tion with dichloromethane, the combined organic layers were
washed with brine, dried over magnesium sulfate and concen-
trated under reduced pressure. The residue was purified by
flash column chromatography (dichloromethane–ethyl acetate–
petroleum ether, 1 : 2 : 7) to give the title compound 21a
(366 mg, 53%) as a white solid, Rf 0.5 (ethyl acetate–petroleum
H), 3.89 (3H, s, OCH ), 4.49 (2H, s, C(2)–H), 5.0 (2H, 2 × s, C᎐
᎐
3
CH2), 7.0 (1H, d, J = 8.1 Hz, C(9)–H), 7.86 (2H, m, C(6)–H and
C(8)–H). δC(75 MHz; CDCl3; Me4Si) 33.0, 34.4, 52.4, 77.3,
114.8, 121.4, 125.3, 129.8, 132.8, 133.8, 146.4, 164.0, 167.3; m/z
(EI) 218 (Mϩ, 55%), 159 (70), 61 (80), 43 (100). Found Mϩ.
218.09429. C13H14O3 requires 218.0943.
3-Oxo-2,3,4,5-tetrahydrobenzo[b]oxepine-7-carboxylic acid
methyl ester 26b
Ozone was bubbled through a solution of 24b (62 mg, 0.284
mmol) in dichloromethane (20 mL) at Ϫ78 ЊC until a blue color
persisted. The solution was purged of excess ozone by bubbling
oxygen through it until the solution became colorless, and
the ozonide was reduced by the addition of 2 mL of dimethyl
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 2 0 9 – 4 2 1 9
4217

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(1)
sulfide. The solution was allowed to warm up to room temper-
ature and stirred for 14 h when it was hydrolysed with water.
1 M hydrochloric acid was added to increase dimethyl sulfoxide
solubility in water. After extraction with dichloromethane, the
organic layers were combined, washed twice in acidic solution
(pH = 2) to remove dimethyl sulfoxide and then with brine,
dried over magnesium sulfate and evaporated under reduced
pressure to give the title compound 26b (63 mg, 100%), Rf 0.38
(ethyl acetate–petroleum ether, 35 : 65); νmax(film)/cmϪ1 2970,
1725, 1610, 1580, 1490, 1430, and 1250; δH(300 MHz; CDCl3;
Me4Si) 3.0 (2H, m, C(4)–H), 3.14 (2H, m, C(5)–H), 3.9 (3H, s,
OCH3), 4.55 (2H, s, C(2)–H), 7.0 (1H, d, J = 8.3 Hz, C(9)–H),
7.86 (2H, m, C(6)–H and C(8)–H); δC(75 MHz; CDCl3; Me4Si)
27.85, 40.2, 52.5, 78.3, 121.9, 126.3, 129.9, 130.0, 133.21, 162.0,
166.8, 210.0; m/z (EI) 220 (Mϩ, 100%), 161 (65), 147 (65).
Found Mϩ. 220.07355. C12H12O4 requires 220.0736.
M. fructigena, 0.1 for M. grisae, 0.1 for R. solani and 0.5 for
S. tritici.
The final OD was measured at the beginning of the levelling-
off phase of the growth at 405 nm for S. tritici and at 620 nm
for the other pathogens. The initial OD was estimated at 0.2 for
S. tritici and at 0.08 for the other pathogens. The fungicidal
activity of each compound was calculated according to the
Abbott formula (eqn. (1)).
Acknowledgements
We are grateful to Dr Adeline Mousques and Ms Christine
Martinez from Bayer CropScience (Lyon) for the design of the
biological assay and the test of the various compounds.
References
7-Acetyl-4,5-dihydrobenzo[b]oxepin-3(2H)-one 26a
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To a well stirred solution of 30 and 31 (188 mg, 0.921 mmol
calculated based on the molecular weight of 30) in acetonitrile
(1.9 mL), carbon tetrachloride (1.9 mL), and water (2.9 mL)
was added sodium periodate (NaIO4) (1.28 mg, 5.99 mmol).
The resulting mixture was allowed to stir for 10 min at 0 ЊC
when ruthenium chloride (4.7 mg, 0.023 mmol) was added. The
mixture turned black and thick. The mixture was stirred for
14 h and then it was hydrolysed with a saturated sodium thio-
sulfate solution. 1 M hydrocloric acid was added to avoid emul-
sion. After extraction with dichloromethane, the combined
organic layers were washed with brine, dried over magnesium
sulfate and evaporated under reduced pressure. The residue was
purified by column chromatography on silica (ethyl acetate–
petroleum ether, 3 : 7) to give compound 26a (104 mg, 55%) as a
white solid, Rf 0.33 (ethyl acetate–petroleum ether, 35 : 65); mp:
80–82 ЊC (Found: C, 70.5; H, 5.95. C12H12O3 requires C, 70.6;
H, 5.92%); νmax(KBr)/cmϪ1 3040, 2980, 2920, 1720, 1670, 1590,
1490, 1420, 1360, 1310 and 1250; δH(300 MHz; CDCl3; Me4Si)
2.57 (3H, s, COCH3), 3.02 (2H, m, C(5)–H), 3.13 (2H, m, C(4)–
H), 4.55 (2H, s, C(2)–H), 7.05 (1H, d, J = 8.3 Hz, C(9)–H), 7.8
(2H, m, C(6)–H and C(8)–H); δC(75 MHz; CDCl3; Me4Si) 26.9,
28.0, 40.2, 78.2, 121.9, 129.0, 130.0, 132.0, 133.5, 162.2, 197.2,
209.9.
Biological tests
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Each compound was dissolved in acetonitrile at a concentration
of 7 mg mLϪ1 (7000 ppm). The solution was further diluted
with methanol to 1/50th in order to give a final concentration for
the test of 50 ppm. 50 µL of the resulting solution was dis-
pensed in a 96-well microtiter plate and the solvent was evapor-
ated at room temperature.
Compounds were tested against the phytopathogenic fungi
Botrytis cinerea, Monilia fructigena, Magnaporthe grisae,
Rhizoctonia solani and Septoria tritici as crushed mycelium,
and Septoria nodorum and Magnaporthe grisae as spore
suspensions.
S. tritici was grown on a medium containing 14.6 g of -
glucose, 7.1 g of bacteriological peptone (OXOID), 1.4 g of
yeast extract (Merck) in demineralized water (1 L) and adjusted
to pH 5.5. Other pathogens were grown on a medium contain-
ing 14.6 g of -glucose, 7.1 g of mycological peptone (OXOID),
1.4 g of yeast extract (Merck) in demineralized water (1 L) and
adjusted to pH 5.0.
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8132.
S. nodorum (500 sp mLϪ1) and M. grisae (5000 sp mLϪ1) were
inoculated as spore suspensions. Other pathogens were inocu-
lated as crushed mycelium (1/10th of the final volume). The
optical density (OD) was adjusted to 0.1 for B. cinerea, 0.5 for
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 2 0 9 – 4 2 1 9
4218

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yields of the expected product.
26 J. Yu, M. J. Gaunt and J. B. Spencer, J. Org. Chem., 2002, 67, 4627–
4629.
27 This alkylation reaction did not proceed in the absence of DBU.
28 When the reductive desulfonylation was carried out in the presence
of less than 6 equimolar amounts of sodium amalgam, a significant
amount of the starting material was recovered along with a mixture
of 30 and 31.
29 P. H. J. Carlsen, T. Katsuki, V. S. Martin and K. B. Sharpless, J. Org.
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23 G. Carr, C. Dean and D. Whittaker, J. Chem. Soc., Perkin Trans. 2,
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4219