Synthesis of saturated benzodioxepinone analogues: Insight into the importance of the aromatic ring binding motif for marine odorants

Article abstract of DOI:10.1002/ejoc.201403142

As part of our research exploring the influence of molecular variations of Calone 1951 on marine fragrance performance, we report the synthesis, crystal structures, and olfactory analysis of the first saturated benzodioxepinone analogues. By su

Full text of DOI:10.1002/ejoc.201403142

Job/Unit: O43142
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Date: 03-12-14 18:34:14
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DOI: 10.1002/ejoc.201403142
Synthesis of Saturated Benzodioxepinone Analogues: Insight into the
Importance of the Aromatic Ring Binding Motif for Marine Odorants
Christopher M. Plummer,[a] Robert Gericke,[b] Philip Kraft,[c] Aaron Raynor,[a]
[d]
[d]
[a]
[a]
ˇ
Jordan Froese, Tomás Hudlický, Trevor J. Rook, Oliver A. H. Jones, and
Helmut M. Hügel*[a]
Keywords: Fused-ring systems / Oxygen heterocycles / Fragrances / Structure–activity relationships / Cyclization
As part of our research exploring the influence of molecular
variations of Calone 1951® on marine fragrance perform- showed that an aromatic ring system is necessary for binding
ance, we report the synthesis, crystal structures, and olfac- to the marine odour receptor(s), and that the addition of an
tory analysis of the first saturated benzodioxepinone ana- alkene or methyl substituent has little effect on the low re-
interactions occurring within the receptor. Our results
logues. By substitution of the aromatic moiety of the benzo-
dioxepinone fragrance molecule with a saturated ring coun-
ceptor affinity. However, a weak marine odour character was
found for the 6-methyl saturated derivatives, which could
terpart, we endeavoured to discover the molecular interac- possibly be explained by superposition analysis of the re-
tions of the aromatic and aliphatic rings with fragrance re-
ceptor sites, and also to shed light on any potential chiral
spective structures, which were derived from X-ray coordi-
nates.
Introduction
The synthetic perfumery ingredient Calone 1951® [7-
methyl-2H-1,5-benzodioxepin-3(4H)-one] offers an interest-
ing molecular framework for research into structure–odour
relationships (SOR). First synthesised in 1966 by Beere-
boom, Cameron, and Stephens of Pfizer, this material is
used to convey the scent of seaside plus sea breeze with
floral overtones, and is typically found in levels below 1%
in fine perfumes (Figure 1).[1] For the compounds claimed
in the original patent the odour threshold grew as the satu-
rated chain was increased in size from methyl (0.031 ng/L
air, Calone 1951®) through to propyl (0.10 ng/L air, Ald-
olone®) and butyl (0.26 ng/L air), but longer chain benzo-
dioxepinone analogues were not explored.[2]
Figure 1. Molecular structures, odour descriptions, and odour
thresholds of Calone 1951® (1) and two experimental analogues 2
and 3.
Kraft et al.[3,4] revealed that more powerful benzodioxep-
inone fragrances than had been previously hypothesised
could be synthesised, and a computational olfactophore
model was generated from the data set of the growing li-
brary of analogues. In a second study, it was found that
odour potency, and therefore receptor-binding strength,
was increased when the 7-alkyl group was replaced with
conjugated olefinic substituents (Figure 1). The modified
olfactophore model consisted of two hydrogen-bond ac-
ceptors that anchor the molecule into the receptor, an aro-
matic and an aliphatic binding site, as well as six excluded
volumes inaccessible to the molecule. The model could bind
both pseudo-twist-boat and pseudo-half-chair conformers
of the heterocyclic ring system.
[a] School of Applied Sciences, RMIT University,
GPO Box 2476, Melbourne, Victoria 3001, Australia
E-mail: helmut.hugel@rmit.edu.au
[b] Institut für Anorganische Chemie, Technische Universität
Bergakademie Freiberg,
A team lead by Gaudin et al.[5] synthesised a library of
benzodioxepinones that included monodeoxygenated and
fully deoxygenated analogues of the original benzodioxep-
inone template. Discrepancies in potency led the researchers
to suspect that any differences between the three sets of an-
alogues could be rationalised by the preferred conformation
of the seven-membered ring. Computational models re-
09596 Freiberg, Germany
[c] Givaudan Schweiz AG, Fragrance Research,
Überlandstrasse 138, 8600 Dübendorf, Switzerland
[d] Department of Chemistry and Centre for Biotechnology,
Brock University,
500 Glenridge Avenue, St. Catharines, Ontario L2S 3A1,
Canada
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201403142.
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H. M. Hügel et al.
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vealed that while the potent benzodioxepinone molecular method to access this new class of compounds. Cyclohexene
template favoured the pseudo-twist-boat conformation with was anti-dihydroxylated to give the racemic compound
the carbonyl moiety coplanar with the aromatic ring, the trans-cyclohexane-1,2-diol (4a) in 39% yield, and syn-di-
much weaker benzocycloheptanone derivatives favoured the hydroxylated to give the meso compound cis-cyclohexane-
pseudo-half-chair conformation that placed the carbonyl 1,2-diol (4b) in 82% yield.[12,13] Attempts were first made
group completely out of plane. This contributed to the to follow the existing method of Williamson etherification
theory that coplanarity between the aromatic ring and the with ethyl bromoacetate, but this led only to complex mix-
ketone group was linked to potent marine fragrance (Fig- tures of polymerised products. Fortunately, it was possible
ure 2).
to etherify the diols in a Lewis-acid-catalysed reaction,
thereby avoiding the use of strongly basic alkoxide interme-
diates.[14] Etherification of diols 4a and 4b with ethyl diazo-
acetate using boron trifluoride diethyl etherate as a catalyst
gave diether compounds 5a and 5b in a 35 and 28% yields,
respectively (Scheme 1). It should be noted that the synthe-
sis of diether 5b from diol 4b required careful monitoring
at 0 °C to prevent polymerisation. This was the first indica-
tion that the erythro saturated benzodioxepinone analogues
were somewhat less stable than their threo counterparts.
Figure 2. Minimum-energy conformation of Calone 1951®, show-
ing a pseudo-twist-boat conformation, generated with the MOE The two diether compounds were then subjected to Dieck-
2013.0801 software package using the Amber 12 force field with
mann condensation conditions by addition to a suspension
of potassium tert-butoxide followed by an acid-catalysed
Extended Hückel Theory (EHT) parameters.[6]
decarboxylation to give target saturated benzodioxepinone
compounds 6a and 6b in 27 and 17% yields, respectively.
An X-ray crystal structure of 6a was obtained from the ra-
cemic mixture. The compound crystallised in a space group
Odour discrimination/perception is a combinatorial phe-
nomenon. In the nose, different odorants are detected by
different combinations of olfactory receptors and various
receptor combinations generate specific odour percep-
containing a glide plane Ϫ the two enantiomers were mir-
rored in the unit cell, and thus a structure could be success-
fully elucidated. The X-ray crystal structure showed that
the cyclohexyl ring existed in a chair conformation, while
the dioxepinone ring existed in a pseudo-twist-boat confor-
mation (Figure 3).
tions.[7] It is well known that the absolute configuration of
molecules is crucially important in determining human per-
ception of odours.[8] It is also recognised that a substance
evokes a sensation of smell provided that its molecular
shape matches a complementary space in a receptor.[9] We
can therefore define the scent of a substance by its molec-
ular shape. As the benzodioxepinone rings are the essential
structural characteristic of marine odorants, we are there-
fore interested in the effect of modulating the molecular
shape by an aliphatic/aromatic ring exchange. The qualita-
tive and quantitative olfactory analysis of our previously
synthesised Calone 1951® analogues clearly indicates that a
chemical modification at any position of the benzodiox-
epinone template has a significant effect on the marine fra-
grance characteristics.[10] Accordingly, we chose to synthe-
sise a library of saturated benzodioxepinone analogues.
Results and Discussion
To construct the target saturated benzodioxepinone
molecules, we decided to build the dioxepinone ring onto
the cyclohexyl ring in a fashion analogous to the pathway
originally described in the 1966 Pfizer patent for Ca-
lone 1951®.[11] This route involves an initial etherification
of various substituted catechols before subjection of the
Scheme 1. Precursor diol compounds 4a–4g were etherified to yield
the corresponding diether intermediates (i.e., 5a–5g), which were
then cyclised and decarboxylated to yield the corresponding satu-
rated benzodioxepinone compounds (i.e., 6a–6g).
An X-ray crystal structure was also acquired for 6b with
products to a base-catalysed 7-exo-trig ring-closing Dieck- considerable difficulty, as the compound had a melting
mann condensation and subsequent decarboxylation. Ef- point below room temperature (Figure 4). The bond lengths
forts were first made to synthesise the two possible unsub- for C-3–C-8, C-7–C-8, O-2–C-3, and O-3–C-8 differ signifi-
stituted fully saturated analogues. These analogues were cantly between the two analogues, with erythro analogue 6b
chosen to give insight into the conformational alignments having longer bond lengths in all cases. The bond angles in
in relation to that of the original benzodioxepinone tem- the region where the cyclohexyl ring joins the dioxepinone
plate, but also to aid in the development of a synthetic ring also differ significantly between the two analogues. The
2
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Synthesis of Saturated Benzodioxepinone Analogues
of green tonality with chemical and acidic aspects upon
drying down.
Using the method developed for the synthesis of the two
unsubstituted saturated benzodioxepinone compounds (i.e.,
6a and 6b) from diol precursors 4a and 4b, seven additional
saturated benzodioxepinone compounds were successfully
synthesised, and their odour descriptions, and thresholds
where sufficiently potent, were determined (Scheme 1).
Two unsaturated benzodioxepinone analogues, com-
pounds 6c and 6d, were synthesised in order to investigate
whether the addition of an alkene/sp2 orbital could aid in
the binding of these molecules to the hypothesised aromatic
binding pocket, and thereby lower the odour thresholds in
comparison with their fully saturated analogues. The path-
Figure 3. Molecular structure of rac-hexahydro-2H-benzo[b][1,4]di-
oxepin-3(4H)-one (6a) showing thermal ellipsoids at the 50% prob-
ability level.[15]
angle for C-7–C-8–O-3 differs by 6.83(9)°, and the C-8–O- way to threo unsaturated analogue 6c involved the anti-di-
3–C-9 angle by 2.84(9)°, with erythro analogue 6b having hydroxylation of cyclohexa-1,4-diene using m-chloroper-
the larger value in each case. This phenomenon is probably oxybenzoic acid (mCPBA), followed by acid-catalysed ep-
due to repulsion between the hydrogen atoms on C-7 and oxide cleavage to give racemic unsaturated diol 4c.[17] The
C-9, with the shortest H–H distance being only 2.07 Å. This synthetic pathway to the erythro analogue 6d involved a
may show that the erythro analogues are the more strained syn-dihydroxylation with osmium tetroxide to give unsatu-
structures, which could explain their instability and the rated diol 4d[18] (Scheme 2). These diols were readily trans-
lower yields for their formation compared to the threo ana- formed into their unsaturated benzodioxepinone analogues
logues.
using the Dieckmann condensation method, although it
should be noted that the cyclisation yield for erythro ana-
logue 6d was problematic due to an innate tendency for this
compound to undergo intermolecular polymerisation rather
than intramolecular cyclisation. Compound 6c was found
to be almost odourless, while erythro analogue 6d was
found to have a high but measurable odour threshold of
297 ng/L air. Compound 6d generated interest due to its
unusual fruity-fatty, slightly animalic odour that recalled
dark olives and became more balsamic, fruity, and cinna-
mate-like in the dry-down.
Figure 4. Molecular structure of meso-hexahydro-2H-benzo[b][1,4]-
dioxepin-3(4H)-one (6b) showing thermal ellipsoids at the 50%
probability level.[16]
On examination of the molecular structures, it can be
seen that both of the stereoisomeric dioxepinone rings are
in pseudo-twist-boat conformations similar to that of the
original benzodioxepinone template. In place of the planar
aromatic ring, the saturated derivatives have six-membered
Scheme 2. The synthesis of diol precursors 4c and 4d from cyclo-
hexa-1,4-diene; NMO = N-methylmorpholine N-oxide.
The synthesis of a 7-methyl saturated analogue was re-
cyclohexyl rings in chair conformations. The two rings exist quired to accurately compare the difference between the
in a relatively coplanar fashion in threo analogue 6a, with aromatic lead compounds and their experimental saturated
the carbonyl group pointing only marginally out of the counterparts. The synthesis of enantiopure threo and
plane of the cyclohexyl ring. In erythro analogue 6b, the erythro 7-methyl analogues was ultimately achieved starting
carbonyl moiety is completely out of the plane of the six- from the naturally occurring chiral terpenoid (R)-(+)-pule-
membered ring.
gone. Pulegone was first stereoselectively reduced by so-
The threo analogue (i.e., 6a) was found to have a medici- dium borohydride to give enantiopure hydroxy compound 7
nal, fruity odour with additional sweet facets, and an odour (Scheme 3). Fortunately, this reaction did not require chiral
threshold of 210 ng/L air. The erythro analogue (i.e., 6b) control agents due to the high stereoselectivity of sodium
was the more potent analogue of the two, having an odour borohydride in the reduction of α,β-unsaturated ketones.[19]
threshold of 141 ng/L air, and a rather different fragrance Ozonolysis of this compound yielded an unstable acyloin
profile which was best described as a fruity, animalic odour intermediate, which was then further reduced without isola-
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tion to give a mixture of two enantiopure diol compounds, a partially reduced analogue of a metabolite from a recom-
4e and 4f (2:1 ratio, respectively). The diastereomers were binant strain of Escherichia coli, produced by the cis-di-
readily separated by flash chromatography due to subtle hydroxylation of toluene by toluene dioxygenase (TDO).[22]
differences in polarity. The configuration of the two dia- This diol was readily transformed into its saturated benzo-
stereomers was most easily confirmed by comparison of dioxepinone analogue using the Dieckmann method to give
1
their H NMR spectra with those of their saturated benzo- compound 6g, which was found to have a weak but green-
dioxepinone analogues. The protons at the positions adja- rosy, vaguely woody-earthy Folrosia [4-(1Ј-methylethyl)-
cent to the carbonyl group show distinct coupling patterns cyclohexan-1-ol] effect. Starting diol 4g was also hydroge-
that are unmistakably different between the threo and nated, and the products were benzoylated to allow separa-
erythro analogues.
tion by flash chromatography. Benzoylated compounds 8
and 9 were separated by flash chromatography, and then
debenzoylated to give two further enantiopure cis-diol com-
pounds, 4h and 4i[23] (Scheme 4).
Scheme 4. Synthesis of saturated enantiopure cis-diol precursors 4h
and 4i from unsaturated cis-diol compound 4g.
Scheme 3. The synthesis of enantiopure 7-methyl diol compounds
4e and 4f from (R)-(+)-pulegone. DMS = dimethyl sulfide.
Owing to the unpredictable yields associated with the
erythro analogues described above, a new synthetic route
was explored. This route involved a parallel method set out
for the synthesis of the benzodioxepinone library produced
by Kraft et al.[3] The first step comprised a Williamson
etherification of the diols with 3-chloro-2-(chloromethyl)-
prop-1-ene, but instead of the typical potassium carbonate
base, the strong base sodium hydride was used to depro-
tonate the weakly acidic hydroxy groups. Analogously to
the aromatic benzodioxepinone synthesis, the isolated
methylene intermediate was then oxidised to the ketone by
ruthenium tetroxide, generated in situ by the action of so-
dium metaperiodate on ruthenium chloride, to give the tar-
get saturated benzodioxepinone (Scheme 5).
The isomerically pure targets, compounds 6e and 6f, were
readily synthesised from the 7-methyl diol precursors. Once
again, the erythro analogue had a less than favourable
cyclisation yield. The threo analogue (i.e., 6e) was described
as weak and slightly woody with very minor marine, watery,
and salty nuances, while the erythro analogue (i.e., 6f) was
described as having an odour reminiscent of fatty alcohols
(i.e., 1-nonanol), and also had a slightly woody-fruity
odour. It was found once again that the erythro compound
was the more potent fragrance analogue. A crystal structure
was obtained for analogue 6e as this compound was the
most similar in structure to lead compound Calone 1951®
(Figure 5). The molecular structure of 6e is practically iden-
tical to that of unsubstituted threo compound 6a except for
a methyl group situated 1.531(5) Å from C-5.
Model reactions were carried out on saturated diol com-
pounds 4a and 4b. This method was found to give clean
reactions, but more importantly, the yields of the threo and
erythro analogues were comparable. Interestingly, the two
Figure 5. Molecular structure of (5aR,7R,9aR)-7-methylhexahydro-
2H-benzo[b][1,4]dioxepin-3(4H)-one (6e) showing thermal ellip-
soids at the 50% probability level.[20]
To further probe the effect of saturation on the benzo-
dioxepinone template, we sought to synthesise several 6-
substituted analogues. To achieve this goal, an enantiopure
unsaturated cis-diol 4g was obtained from the microbial
Scheme 5. Precursor diol compounds 4h and 4i were etherified to
yield the corresponding methylene intermediates (i.e., 5h and 5i),
which were then oxidised to yield the corresponding saturated
oxidation of toluene.[21] This unsaturated diol compound is benzodioxepinone compounds (i.e., 6h and 6i).
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Synthesis of Saturated Benzodioxepinone Analogues
methylene intermediate compounds synthesised from 4a
and 4b also showed fragrance qualities, which were de-
scribed as “agrestic, leathery” and “agrestic, thymol, carva-
crol, leathery, tar”, for the threo and erythro analogues,
respectively. The two enantiopure 6-methyl compounds 6h
and 6i were readily prepared from diols 4h and 4i in good
yields using this alternative method. Compound 6h was de-
scribed as weak, green, and rubbery, with a marine effect,
and was the weakest compound of the series, with an odour
threshold of 297 ng/L air. Compound 6i had an odour
threshold of 177 ng/L air, and was described as weak, green,
with a slightly oily medicinal odour reminiscent of the
medicinal aspects of Calone 1951®, but also with marine
facets of Calone 1951®.
Structure–Odour Correlations and Conclusions
The olfactory properties of saturated benzodioxepinones
6a–6i are summarised in Figure 6. The most potent ana-
logue synthesised in this study was unsubstituted erythro
analogue 6b, which had an odour threshold of 141 ng/L air,
an almost 5000-fold decrease in potency from the lead com-
pound Calone 1951® (threshold 0.031 ng/L air). However,
the saturated analogues showed significantly different
odour profiles compared to their aromatic counterparts,
with the exception of 6h and 6i, which were found to have
marine effects. The olfactory properties of 6a–6g are com-
pletely consistent with the published marine olfactophore
models that require an aromatic binding feature to be pres-
ent in the molecule.[3,4] These compounds are therefore
binding to multiple non-marine olfactory receptors, rather
less specifically and with low affinity. This results in a pot-
Figure 6. The experimental saturated benzodioxepinone library
showing odour descriptions and thresholds.
pourri of different odour impressions ranging from fruity, receptor binding, as only from a C-5 alkyl chain onwards
medicinal, and chemical to fruity-green and fatty. With does a positive receptor affinity result.[3,4]
odour thresholds above 100 ng/L air, they are considered
quite weak odorants.
The most interesting result, though, concerned the 6-
methyl substituent of compounds 6g–6i. A methyl group in
Interestingly, the unsaturation of 6aǞ6c and 6bǞ6d this position appeared to impart a green nuance to com-
had a detrimental effect on odour strength. Unsaturation pounds 6g–6i, but only the fully saturated analogues (i.e.,
of threo analogue 6a caused the odour threshold to rise 6h and 6i) contained the additional marine side notes. This
from 210 ng/L air to a threshold value out of the range of marine odour was more pronounced in 6i, and it somehow
what can be considered useful as a perfumery ingredient. did indeed recall Calone 1951®. With an odour threshold
Unsaturated erythro analogue 6d had a higher odour of 177 ng/L air, this compound was still significantly weaker
threshold than its saturated counterpart 6b by 156 ng/L air. than Calone 1951®. Its antipode 6h had an odour threshold
The fruity-fatty, slightly animalic odour of 6d was, however, of 297 ng/L air, and also contained rubbery facets, while the
interesting in that it distinctly recalled dark olives, which is odour character of 6i was greener, but also more marine,
a rare and unusual odour character. Methyl substitution at despite medicinal and slightly oily facets.
the 7-position as a way to address the hydrophobic binding
The aromatic ring system thus appears to be a prerequi-
site was not effective, and compounds 6e and 6f were rather site for binding to the marine odour receptor(s), and an
weaker by blotter analysis than 6a and 6b. These analogues alkene or methyl substituent has little effect on receptor af-
did address different odour receptors to some extent, as finity. The question remains as to why compounds 6h and
they were slightly woody-fruity in odour, and in the case 6i appear to have residual affinity for the marine odorant
of 6f, more specifically recalling 1-nonanol. The published receptors. Superposition analysis of the molecular struc-
marine olfactophore models require longer alkyl chains to tures of 6a and 6i on the minimum-energy conformer of
address the hydrophobic binding pocket, and this result Calone 1951® might offer some explanation (Figure 7). The
showed that the methyl group of Calone 1951® does not threo-configured 6a (blue) overlays agreeably with Ca-
have much beneficial interaction with the receptor. Longer lone 1951® (black), except that it features no methyl group,
alkyl substituents up to butyl may conformationally hinder is non-planar, and contains no aromatic binding element
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FTIR spectra were obtained with a Perkin–Elmer Spectrum 100
spectrometer. Melting points were recorded with a Stuart SMP10
melting-point apparatus.
for the receptor. The aromatic binding pocket of the marine
receptor appears to refuse the cyclohexyl hydrophobe: a
negative interaction. In erythro compounds 6h and 6i, the
cyclohexyl ring is at an angle to the dioxepinone ring, and
hence is bent away, avoiding such a repulsion. Unsaturated
analogue 6g is at a shallower angle, and is therefore closer
to the aromatic binding feature of the marine receptor,
which could explain the lack of any marine tonality. The
explanation as to why parent erythro compound 6b and
compound 6f do not have marine odour can be deduced
from a positive hydrophobic interaction of the 6-methyl
group with the marine receptor(s). It is known that two
Crystals suitable for single-crystal X-ray diffraction were obtained
by recrystallisation from methanol (compound 6a) or from EtOAc/
hexane (compound 6b and 6e). Using a drop of Nujol (inert oil),
crystals were mounted onto a nylon loop, and then they were trans-
ferred into a stream of cold nitrogen. For the mounting of com-
pound 6b, the crystals had been previously cooled with nitrogen to
prevent their melting. The reflections were collected with a D8
Bruker diffractometer (compounds 6a and 6b) equipped with an
APEX-II area detector and a 1 μS microsource; or with a STOE
IPDS-2(T) diffractometer (compound 6e) equipped with an image
hydrogen-bond acceptors are sufficient for binding, and plate detector and a fine-focus sealed tube source. In all three cases,
a graphite-monochromator and Mo-Kα radiation (λ = 0.71073 Å)
were used. For compounds 6a and 6b, data collection was carried
out in φ- and ω-scan modes using SMART software, SAINT was
used to process the data, and the absorption corrections were done
with SADABS. For compound 6e, data collection was carried out
in ω-scan mode, and the data was processed with X-Area. The
structures were solved with direct methods, and were refined with
full-matrix least-squares methods on F2 using the SHELX-TL
package. Thermal ellipsoid plots were created with ORTEP-3
v2.02.
that therefore a hydrophobic methylene unit is tolerated op-
posite to the remaining ether-oxygen atom.[5] In any case,
the weak character, intensity, and persistence of the satu-
rated analogues is indicative that the planar aromatic ring
structure is an indispensable feature of the marine odorant
family, and that simple modifications such as the addition
of a methyl group or alkene to the basic molecular structure
is not sufficient to aid in receptor binding.
The minimum-energy conformer of Calone 1951® was generated
using the MOE 2013.0801 software package using the Amber 12
force field with Extended Hückel Theory (EHT) parameters.[6]
Olfactory evaluations were performed by expert perfumers with a
10% solution of the sample substance in dipropylene glycol (DPG).
The odour thresholds were determined by GC-Olfactometry: Dif-
ferent dilutions of the sample substance were injected into a gas
chromatograph in descending order of concentration until the pan-
ellist failed to detect the respective substance at the sniffing port.
The panellist smelled in blind and pressed a button on perceiving
an odour. If the recorded time matched the retention time, the sam-
ple was further diluted. The last concentration detected at the cor-
rect retention time was the individual odour threshold. The re-
ported threshold values are the geometrical mean values of the in-
dividual odour thresholds of the different panellists.
Figure 7. Rigid-body superposition of the X-ray structure of 6a
(blue, Figure 3) and the structure of 6i (magenta) derived from X-
ray coordinates of 6b (Figure 4) on the minimum-energy conformer
of Calone 1951® (black, Figure 2) with the Discovery Studio 4.1
software package using a 100% electrostatic field.[24]
Experimental Section
rac-Cyclohexane-1,2-diol (4a):[12] The physical and spectroscopic
data are identical to those previously reported for this compound.
General Remarks: Unless otherwise noted, all materials obtained
from commercial suppliers were used as received. All reactions were
carried out under an atmosphere of nitrogen unless otherwise
noted. Dichloromethane was dried and distilled from CaH2; tetra-
hydrofuran (THF) was dried and distilled from sodium benzo-
phenone ketyl. Ethyl diazoacetate was prepared from ethyl ester
glycine hydrochloride according to the method of Searle et al.[25]
3-Chloro-2-(chloromethyl)-1-propene was prepared from penta-
erythritol according to the method of Lynch and Dailey.[26] Thin-
layer chromatography was carried out on aluminium-backed SiO2
gel TLC plates (60 F254), which were visualised with either KMnO4
dip (KMnO4, K2CO3, NaOH, H2O) or iodine stain. Flash column
chromatography was carried out with Davisil LC35a SiO2 (40–
63 μm). Silica was deactivated by flushing with a triethylamine
solution (5% v/v) before flash chromatography. NMR spectra were
obtained with a Bruker Avance III 300 MHz spectrometer, and the
White solid, 39% yield, m.p. 102–104 °C. IR: ν = (ATR): 3357,
˜
3262, 2932, 1065 cm–1. 1H NMR (300 MHz, CDCl3): δ = 3.40–3.29
(m, 2 H), 3.13 (s, 2 H), 2.02–1.90 (m, 2 H), 1.76–1.63 (m, 2 H),
1.35–1.17 (m, 4 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 75.6,
32.8, 24.3 ppm. HRMS: calcd. for C6H12O2 116.0837; found
116.0826.
meso-Cyclohexane-1,2-diol (4b):[13] The physical and spectroscopic
data are identical to those previously reported for this compound.
White solid, 82% yield, m.p. 95–96 °C. IR (ATR): ν = 3391, 3258,
˜
1
2929, 1073 cm–1. H NMR: (300 MHz, CDCl3): δ = 3.81–3.76 (m,
2 H), 1.92 (s, 2 H), 1.83–1.72 (m, 2 H), 1.69–1.51 (m, 4 H), 1.40–
1.24 (m, 2 H) ppm. 13C NMR: (75 MHz, CDCl3): δ = 70.6, 29.8,
21.4 ppm. HRMS: calcd. for C6H12O2 116.0837; found 116.0826.
rac-Cyclohex-4-ene-1,2-diol (4c):[17] The physical and spectroscopic
data are identical to those previously reported for this compound.
1
residual solvent peaks from the deuterated solvents (CDCl3: H δ
White solid, 34% yield, m.p. 92–94 °C. IR (ATR): ν = 3318. 1053,
˜
1
= 7.27 ppm, 13C δ = 77.0 ppm; [D6]DMSO: H δ = 2.5 ppm, 13C δ
677 cm–1. 1H NMR (300 MHz, [D6]DMSO): δ = 5.49–5.47 (m, 2
= 128 ppm) were used as a reference. EI-HRMS spectra were re-
H), 4.65–4.63 (m, 2 H), 3.46–3.40 (m, 2 H), 2.33–2.23 (m, 2 H),
corded with a Waters GCT Premier (HR-TOFMS) instrument 1.93–1.81 (m, 2 H) ppm. 13C NMR (75 MHz, [D6]DMSO): δ =
equipped with an Agilent 7890 GC. CI-HRMS spectra were re-
124.6, 70.2, 32.9 ppm. HRMS: calcd. for C6H10O2 114.0681; found
corded with a Bruker autoflex speed (MALDI-TOF) instrument. 114.0681.
6
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O43142
/KAP1
Date: 03-12-14 18:34:14
Pages: 11
Synthesis of Saturated Benzodioxepinone Analogues
meso-Cyclohex-4-ene-1,2-diol (4d):[18] The physical and spectro-
scopic data are identical to those previously reported for this com-
H), 0.96 (d, J = 6.6 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ
= 165.8, 132.5, 129.9, 129.2, 127.9, 80.3, 67.1, 32.3, 30.8, 30.5, 18.7,
17.7 ppm.
pound. White solid, 46% yield, m.p. 77–78 °C. IR (ATR): ν = 3244,
˜
1
1057, 894, 754 cm–1. H NMR (300 MHz, CDCl3): δ = 5.64–5.55
(1R,2S,6R)-2-Hydroxy-6-methylcyclohexyl Benzoate (9):[23] The
(m, 2 H), 3.99–3.92 (m, 2 H), 2.44–2.20 (m, 4 H), 2.09 (s, 2 H)
physical and spectroscopic data are identical to those previously
ppm. 13C NMR (75 MHz, CDCl3): δ = 123.6, 68.8, 30.8 ppm.
reported for this compound. White solid. [α]2D3 = –9.7 (c = 0.99,
1
CH Cl ), m.p. 84–85 °C. IR (ATR): ν = 1692, 1293, 713 cm–1. H
(1R,5R)-5-Methyl-2-(propan-2-ylidene)cyclohexan-1-ol (7):[19] The
˜
2
2
NMR (300 MHz, CDCl3): δ = 8.08–8.03 (m, 2 H), 7.61–7.54 (m, 1
H), 7.50–7.42 (m, 2 H), 5.04–4.97 (m, 1 H), 3.99 (q, J = 2.3 Hz, 1
H), 1.95–1.64 (m, 5 H), 1.50–1.35 (m, 3 H), 1.06 (d, J = 6.8 Hz, 3
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 165.6, 132.6, 130.1,
129.3, 128.0, 76.2, 71.3, 35.3, 26.3, 24.3, 23.1, 17.7 ppm.
physical and spectroscopic data are identical to those previously
reported for this compound. White solid, 92% yield, m.p. 28–39 °C.
1
IR (ATR): ν = 3327, 2915, 1455, 1374 cm–1. H NMR (300 MHz,
˜
CDCl3): δ = 4.74–4.69 (m, 1 H), 2.41–2.18 (m, 2 H), 1.85–1.39 (m,
11 H), 1.2 (d, J = 2.8 Hz, 1 H), 1.12 (d, J = 6.9 Hz, 3 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 132.4, 125.3, 67.7, 39.3, 31.7, 26.6,
22.1, 21.1, 20.0, 19.3 ppm. HRMS: calcd. for C10H18O 154.1358;
found 154.1354.
(1S,2R,3S)-3-Methylcyclohexane-1,2-diol (4h):[23] The physical and
spectroscopic data are identical to those previously reported for
this compound. White solid. [α]2D2 = +54.2 (c = 1.06, CHCl3), m.p.
69–70 °C. IR (ATR): ν = 3315, 2943, 1458, 1059 cm–1. 1H NMR
˜
Synthesis of Diols 4e and 4f: A solution of (1R,5R)-5-methyl-2-
(propan-2-ylidene)cyclohexan-1-ol (7; 13.7 g) in CH2Cl2 (400 mL)
was cooled to –78 °C. The cooled solution was then treated with a
continuous steam of ozone. When the reaction was complete (i.e.,
when the starting material had been consumed) the addition of
ozone was stopped, and the reaction mixture was purged with ni-
trogen (1 h) at –78 °C. Dimethyl sulfide (70 mL) was then added,
and the resulting mixture was stirred at 0 °C for 1 h, and then at
room temperature overnight. The mixture was then concentrated
under reduced pressure, followed by extraction with EtOAc (4ϫ
100 mL). The organic extracts were combined, then dried (MgSO4),
and concentrated under reduced pressure.
(300 MHz, CDCl3): δ = 3.99–3.94 (m, 1 H), 3.22–3.15 (m, 1 H),
2.05–1.86 (m, 3 H), 1.83–1.38 (m, 5 H), 1.06–0.92 (m, 1 H), 1.01
(d, J = 6.6 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 77.3,
69.5, 33.0, 32.3, 31.1, 19.1, 18.2 ppm. HRMS: calcd. for C7H14O2
130.0994; found 130.0988.
(1S,2R,3R)-3-Methylcyclohexane-1,2-diol (4i):[23] The physical and
spectroscopic data are identical to those previously reported for
this compound. Yellow oil. [α]2D3 = +1.1 (c = 1.03, CHCl3). IR
1
(ATR): ν = 3375, 2929, 975 cm–1. H NMR (300 MHz, CDCl ): δ
˜
3
= 3.75 (s, 1 H), 3.60–3.50 (m, 1 H), 2.36 (s, 1 H), 2.21 (s, 1 H),
1.75–1.62 (m, 2 H), 1.59–1.44 (m, 2 H), 1.34–1.19 (m, 3 H), 1.02
(d, J = 6.8 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 73.7,
72.6, 35.3, 27.8, 26.6, 23.5, 18.0 ppm. HRMS: calcd. for C7H14O2
130.0994; found 130.1012.
The resulting residue was then taken up in MeOH (150 mL) and
H2O (25 mL), and the mixture was cooled to 0 °C. A solution of
NaBH4 (3 g) in EtOH (150 mL) was added dropwise. Stirring was
then continued for 2 h at room temperature. The reaction mixture
was poured into brine (500 mL), and the resulting mixture was ex-
tracted with hexane (3ϫ 300 mL). The organic extracts were com-
bined, dried (MgSO4), and concentrated under reduced pressure.
The resulting oil was purified by flash chromatography on silica gel
(EtOAc/hexane) to give a mixture of (1R,2R,4R)-4-methylcyclo-
hexane-1,2-diol (4e) and (1S,2R,4R)-4-methylcyclohexane-1,2-diol
(4f) (2:1 ratio; 36% combined yield).
General Method 1. Synthesis of Compounds 5a–5g: BF3·OEt2 (0.5 mL)
was slowly added to an ice-cold solution of diol 4a–4g (40 mmol)
and ethyl diazoacetate (10 g, 88 mmol, 2.2 equiv.) in CH2Cl2
(80 mL). After the addition was complete, the mixture was stirred
at 0 °C for 1 h, then the reaction was quenched by the addition of
a saturated solution of NaHCO3 (100 mL). The mixture was then
extracted with EtOAc (3ϫ 100 mL). The organic extracts were
combined, dried (MgSO4), and concentrated under reduced pres-
sure. The resulting residue was purified by flash chromatography
on silica gel (EtOAc/hexane) to give the corresponding diether (i.e.,
5a–5g).
(1R,2R,4R)-4-Methylcyclohexane-1,2-diol (4e): White solid. [α]2D4
–28.5 (c = 0.36, CH Cl ), m.p. 62–63 °C. IR (ATR): ν = 3300, 1055,
=
˜
2
2
1003 cm–1. H NMR (300 MHz, CDCl3): δ = 3.46–3.30 (m, 2 H),
2.15 (d, J = 3.2 Hz, 1 H), 2.10 (d, J = 3.5 Hz, 1 H), 2.00–1.91 (m,
2 H), 1.73–1.46 (m, 2 H), 1.40–1.24 (m, 1 H), 1.09–0.92 (m, 2 H),
0.94 (d, J = 6.4 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
75.5, 75.0, 41.3, 32.8, 32.1, 31.1, 21.6 ppm. HRMS: calcd. for
C7H14O2 130.0994; found 130.1008.
1
rac-Diethyl 2,2Ј-[Cyclohexane-1,2-diylbis(oxy)]diacetate (5a): Yel-
low oil, 35% yield. IR (ATR): ν = 1750, 1198, 1120 cm–1. 1H NMR
˜
(300 MHz, CDCl3): δ = 4.33–4.16 (m, 8 H), 3.37–3.27 (m, 2 H),
2.12–2.04 (m, 2 H), 1.72–1.65 (m, 2 H), 1.39–1.15 (m, 4 H), 1.28
(t, J = 7.1 Hz, 6 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 170.2,
82.2, 67.2, 59.8, 29.6, 22.9, 13.5 ppm. HRMS: calcd. for C14H24O6
288.1573; found 288.1675.
(1S,2R,4R)-4-Methylcyclohexane-1,2-diol (4f): White solid. [α]2D6
+23.2 (c = 0.36, CH Cl ), m.p. 88–89 °C. IR (ATR): ν = 2296,
=
˜
2
2
2951, 1033 cm–1. H NMR (300 MHz, CDCl3): δ = 3.94 (s, 1 H),
3.66–3.55 (m, 1 H), 2.36–2.30 (m, 1 H), 2.23 (d, J = 5.6 Hz, 1 H),
1.97–1.86 (m, 1 H), 1.69–1.61 (m, 1 H), 1.52–1.12 (m, 5 H), 0.94
(d, J = 6.2 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 71.7,
68.5, 36.9, 30.9, 30.3, 27.3, 22.0 ppm. HRMS: calcd. for C7H14O2
130.0994; found 130.0995.
1
meso-Diethyl 2,2Ј-[Cyclohexane-1,2-diylbis(oxy)]diacetate (5b): Yel-
low oil, 27% yield. IR (ATR): ν = 1750, 1194, 1114, 1026 cm–1. 1H
˜
NMR (300 MHz, CDCl3): δ = 4.29–4.11 (m, 8 H), 3.69–3.64 (m, 2
H), 2.00–1.87 (m, 2 H), 1.74–1.60 (m, 2 H), 1.59–1.47 (m, 2 H),
1.35–1.20 (m, 2 H), 1.28 (t, J = 7.1 Hz, 6 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 170.5, 78.0, 66.1, 60.0, 27.1, 21.5, 13.7 ppm.
HRMS: calcd. for C14H24O6: 288.1573; found 288.1630.
(1R,2S,6S)-2-Hydroxy-6-methylcyclohexyl Benzoate (8):[23] The
physical and spectroscopic data are identical to those previously
reported for this compound. Yellow oil. [α]2D1 = +65.8 (c = 1.06,
rac-Diethyl 2,2Ј-[Cyclohex-4-ene-1,2-diylbis(oxy)]diacetate (5c): Yel-
low oil, 34% yield. IR (ATR): ν = 1750, 1198, 1121 cm–1. 1H NMR
˜
CH Cl ). IR (ATR): ν = 2932, 1698, 1269, 708 cm–1. 1H NMR (300 MHz, CDCl3): δ = 5.55–5.52 (m, 2 H), 4.36 (d, J = 16.6 Hz,
˜
2
2
(300 MHz, CDCl3): δ = 8.08 (d, J = 6.9 Hz, 2 H), 7.62–7.54 (m, 1
H), 7.51–7.41 (m, 2 H), 4.80 (dd, J = 10.3, 2.6 Hz, 1 H), 4.20–4.15
(m, 1 H), 2.29–2.12 (m, 1 H), 1.95–1.43 (m, 5 H), 1.30–1.06 (m, 2
2 H), 4.29 (d, J = 16.4 Hz, 2 H), 4.21 (q, J = 7 Hz, 4 H), 3.69–3.61
(m, 2 H), 2.64–2.53 (m, 2 H), 2.22–2.10 (m, 2 H), 1.29 (t, J =
7.1 Hz, 6 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 170.3, 123.5,
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

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/KAP1
Date: 03-12-14 18:34:14
Pages: 11
H. M. Hügel et al.
79.0, 67.6, 60.1, 30.6, 13.7 ppm. HRMS: calcd. for C14H22O6 (5aR,6R,9aS)-6-Methyl-3-methyleneoctahydro-2H-benzo[b][1,4]di-
FULL PAPER
286.1416; found 286.1338.
oxepine (5i): Yellow oil, 42% yield. [α]2D3 = –92.9 (c = 1.14, CH2Cl2).
IR (ATR): ν = 2929, 1116, 902 cm–1. 1H NMR (300 MHz, CDCl ):
˜
3
meso-Diethyl 2,2Ј-[Cyclohex-4-ene-1,2-diylbis(oxy)]diacetate (5d):
δ = 5.03–5.00 (m, 1 H), 4.96–4.93 (m, 1 H), 4.49–4.34 (m, 2 H),
4.15–4.04 (m, 2 H), 3.69–3.62 (m, 1 H), 3.55–3.52 (m, 1 H), 2.05–
1.88 (m, 1 H), 1.82–1.73 (m, 1 H), 1.59–1.45 (m, 2 H), 1.36–1.17
(m, 3 H), 0.97 (d, J = 6.8 Hz, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 148.4, 111.7, 82.9, 78.7, 73.2, 65.9, 35.6, 27.5, 24.0,
23.9, 17.5 ppm. HRMS: calcd. for C11H18O2 182.1306; found
182.1304.
Yellow oil, 32% yield. IR (ATR): ν = 1749, 1196, 1120 cm–1. 1H
˜
NMR (300 MHz, CDCl3): δ = 5.62–5.53 (m, 2 H), 4.33–4.15 (m, 8
H), 3.90–3.84 (m, 2 H), 2.54–2.25 (m, 4 H), 1.27 (t, J = 7 Hz, 6 H)
ppm. 13C NMR (75 MHz, CDCl3): δ = 170.6, 123.6, 76.3, 66.7,
60.4, 28.8, 13.9 ppm. HRMS: calcd. for C14H22O6Na [M + Na]+
309.1314; found 309.1675.
Diethyl 2,2Ј-{[(1R,2R,4R)-4-Methylcyclohexane-1,2-diyl]bis(oxy)}-
diacetate (5e): Yellow oil, 78% yield. [α]2D4 = –4.2 (c = 1.07,
General Method 3. Synthesis of Compounds 6a–6g: A solution of
ester 5a–5g (20 mmol) in THF (150 mL) was added dropwise to a
stirred solution of KOtBu (4.5 g, 40 mmol, 2 equiv.) in THF
(100 mL) at 0 °C. The mixture was stirred at 0 °C for 2 h, then it
was quenched by the addition of HCl (0.2 m; 800 mL) and ice
(500 g). The resulting solution was then extracted with CH2Cl2 (3ϫ
200 mL). The organic extracts were combined, dried (MgSO4), and
concentrated under reduced pressure.
CH Cl ). IR (ATR): ν = 1751, 1732, 1198, 1121 cm–1. 1H NMR
˜
2
2
(300 MHz, CDCl3): δ = 4.07–3.80 (m, 8 H), 3.06–2.90 (m, 2 H),
1.82–1.72 (m, 2 H), 1.38–1.28 (m, 1 H), 1.20–0.90 (m, 2 H), 0.96
(t, J = 7.1 Hz, 6 H), 0.75–0.53 (m, 2 H), 0.61 (d, J = 6.6 Hz, 3 H)
ppm. 13C NMR (75 MHz, CDCl3): δ = 170.3, 170.2, 83.2, 82.6,
67.4, 67.4, 59.9, 38.9, 32.0, 30.3, 29.7, 21.0, 13.6 ppm. HRMS:
calcd. for C15H26O6 302.1729; found 302.1646.
The residue was taken up in EtOH (100 mL) and HCl (2 m;
500 mL), and the mixture was stirred at reflux for 2 h. The solution
was diluted with H2O (300 mL), and the mixture was extracted
with CH2Cl2 (3ϫ 200 mL). The combined organic extracts were
washed with H2O (200 mL), dried (MgSO4), and concentrated un-
der reduced pressure. The resulting residue was purified by flash
chromatography on silica gel (EtOAc/hexane) to give the corre-
sponding saturated benzodioxepinone compound (i.e., 6a–6g).
Diethyl 2,2Ј-{[(1S,2R,4R)-4-Methylcyclohexane-1,2-diyl]bis(oxy)}-
diacetate (5f): Yellow oil, 23% yield. [α]2D2 = +4.1 (c = 1.09,
CH Cl ). IR (ATR): ν = 1750, 1197, 1117 cm–1. 1H NMR
˜
2
2
(300 MHz, CDCl3): δ = 4.31–4.12 (m, 8 H), 3.94–3.89 (m, 1 H),
3.43–3.36 (m, 1 H), 2.11–2.02 (m, 1 H), 1.79–1.71 (m, 1 H), 1.56–
1.21 (m, 11 H), 0.94 (d, J = 5.8 Hz, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 170.9, 170.5, 80.7, 74.8, 67.2, 65.3, 60.3, 60.2, 33.8,
31.0, 28.4, 27.7, 21.7, 13.9, 13.9 ppm. HRMS: calcd. for C15H26O6
302.1729; found 302.1760.
rac-Hexahydro-2H-benzo[b][1,4]dioxepin-3(4H)-one (6a): White so-
lid, 27 % yield, m.p. 48–50 °C. IR (ATR): ν = 2939, 1721,
˜
Diethyl 2,2Ј-{[(1S,2R)-3-Methylcyclohex-3-ene-1,2-diyl]bis(oxy)}di-
1
1116 cm–1. H NMR (300 MHz, CDCl3): δ = 4.31 (d, J = 16.6 Hz,
acetate (5g): Yellow oil, 34% yield. [α]1D9 = –41.1 (c = 1.05, CH2Cl2).
2 H), 4.25 (d, J = 16.6 Hz, 2 H), 3.34–3.22 (m, 2 H), 2.06–1.97 (m,
2 H), 1.81–1.66 (m, 2 H), 1.44–1.15 (m, 4 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 211.6, 88.4, 77.1, 31.4, 24.0 ppm. HRMS:
calcd. for C9H14O3 170.0943; found 170.0939.
1
IR: ν = 1750, 1198, 1106 cm–1. H NMR (300 MHz, CDCl ): δ =
˜
3
5.53 (s, 1 H), 4.49 (d, J = 16.8 Hz, 1 H), 4.43 (d, J = 16.8 Hz, 1
H), 4.27–4.07 (m, 6 H), 3.94 (d, J = 3 Hz, 1 H), 3.62–3.55 (m, 1
H), 2.27–2.13 (m, 1 H), 2.05–1.89 (m, 2 H), 1.86 (d, J = 1.5 Hz, 3
H), 1.82–1.70 (m, 1 H), 1.32–1.24 (m, 6 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 170.8, 170.4, 132.0, 125.5, 79.8, 77.6, 69.1,
66.0, 60.4, 60.1, 24.4, 21.1, 20.8, 13.9, 13.9 ppm. HRMS: calcd. for
C15H24O6Na [M + Na]+ 323.1471; found 323.1542.
Odour description: Medicinal, fruity odour that is linear in the dry-
down with additional sweet facets in the fond.
Odour threshold: 210 ng/L air (stan. dev. 176 ng/L air)
meso-Hexahydro-2H-benzo[b][1,4]dioxepin-3(4H)-one (6b): Colour-
less oil, 17% yield. IR: ν = (ATR): 2943, 1712, 1119 cm–1. 1H NMR
General Method 2. Synthesis of Compounds 5h and 5i: A solution
of compound 4h or 4i (1.36 g, 10.48 mmol) in DMF (30 mL) was
added dropwise to a solution of sodium hydride (60% dispersion
in mineral oil; 1.05 g, 26.2 mmol) in DMF (60 mL). The resulting
solution was stirred for 1 h. A solution of 3-chloro-2-(chloro-
methyl)-1-propene (1.31 g, 10.48 mmol) in DMF (40 mL) was then
added dropwise over a period of 1 h, and the resulting solution was
stirred for 48 h. The reaction was then quenched by the addition
of a saturated solution of NaHCO3 (100 mL), and the mixture was
extracted with Et2O (4ϫ 100 mL). The organic extracts were com-
bined, washed with H2O (2ϫ 100 mL), dried (MgSO4), and con-
centrated under reduced pressure. The resulting residue was then
purified by flash chromatography on silica gel (EtOAc/hexane) to
give the corresponding methylene compound (i.e., 5h or 5i).
˜
(300 MHz, CDCl3): δ = 4.35 (d, J = 16.8 Hz, 2 H), 4.06 (d, J =
16.8 Hz, 2 H), 3.88–3.82 (m, 2 H), 2.06–1.94 (m, 2 H), 1.71–1.59
(m, 2 H), 1.58–1.47 (m, 2 H), 1.43–1.30 (m, 2 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 212.0, 80.7, 73.6, 27.5, 22.1 ppm. HRMS:
calcd. for C9H14O3 170.0943; found 170.0903.
Odour description: Fruity, animalic odour of green tonality with
chemical aspects and acidic facets in the dry-down.
Odour threshold: 141 ng/L air (stan. dev. 99 ng/L air).
rac-5a,6,9,9a-Tetrahydro-2H-benzo[b][1,4]dioxepin-3(4H)-one (6c):
White solid, 39% yield, m.p. 63–64 °C. IR (ATR): ν = 1722, 1132,
˜
1
774, 678 cm–1. H NMR (300 MHz, CDCl3): δ = 5.57–5.55 (m, 2
H), 4.37 (d, J = 16.4 Hz, 2 H), 4.26 (d, J = 16.4 Hz, 2 H), 3.70–
3.63 (m, 2 H), 2.59–2.48 (m, 2 H), 2.26–2.13 (m, 2 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 211.1, 124.0, 85.0, 76.7, 32.1 ppm.
HRMS: calcd. for C9H12O3 168.0790; found 168.0787.
(5aR,6S,9aS)-6-Methyl-3-methyleneoctahydro-2H-benzo[b][1,4]-
dioxepine (5h): Yellow oil, 65% yield. [α]2D4 = +137.4 (c = 1.09,
CH Cl ). IR (ATR): ν = 2929, 1109, 898 cm–1 1H NMR
.
˜
2
2
(300 MHz, CDCl3): δ = 5.00 (s, 1 H), 4.92 (s, 1 H), 4.49–4.02 (m,
4 H), 3.82–3.77 (m, 1 H), 3.29–3.23 (m, 1 H), 2.26–2.10 (m, 1 H),
1.95–1.84 (m, 1 H), 1.82–1.71 (m, 1 H), 1.65–1.37 (m, 3 H), 1.08–
0.94 (m, 1 H), 0.97 (d, J = 6.6 Hz, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 148.4, 111.0, 83.5, 79.0, 72.1, 65.9, 33.1, 31.2, 29.0,
19.8, 17.9 ppm. HRMS: calcd. for C11H18O2 182.1306; found
182.1303.
Odour description: Very weak to odourless, and uncharacteristic in
smell.
meso-5a,6,9,9a-Tetrahydro-2H-benzo[b][1,4]dioxepin-3(4H)-one
(6d): White solid, 3% yield, m.p. 73–75 °C. IR (ATR): ν = 1720,
˜
1125, 1097, 835, 680 cm–1. 1H NMR (300 MHz, CDCl3): δ = 5.68–
5.58 (m, 2 H), 4.43 (d, J = 16.9 Hz, 2 H), 4.12 (d, J = 16.9 Hz, 2
8
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Synthesis of Saturated Benzodioxepinone Analogues
H), 4.07 (t, J = 6.3 Hz, 2 H), 2.65–2.52 (m, 2 H), 2.39–2.26 (m, 2
(m, 1 H), 1.87–1.77 (m, 1 H), 1.60–1.42 (m, 3 H), 1.15–0.96 (m, 1
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 211.3, 123.2, 78.2, 73.9, H), 0.98 (d, J = 6.4 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ
27.5 ppm. HRMS: calcd. for C9H12O3 168.0786; found 168.0770.
= 212.0, 84.4, 82.7, 76.9, 69.8, 32.9, 31.2, 28.1, 19.8, 17.5 ppm.
HRMS: calcd. for C10H16O3 184.1099; found 184.1105.
Odour description: Fruity-fatty, slightly animalic odour that also
recalls dark olives, and in the dry-down becomes more balsamic,
fruity, and cinnamate-like.
Odour description: Weak, green-rubbery odour with a marine ef-
fect.
Odour threshold: 297 ng/L air (stan. dev. 125 ng/L air).
Odour threshold: 297 ng/L air (stan. dev. 188 ng/L air).
(5aR,7R,9aR)-7-Methylhexahydro-2H-benzo[b][1,4]dioxepin-3(4H)-
one (6e): White solid, 40% yield. [α]2D6 = –278.1 (c = 1.00, CH2Cl2),
(5aR,6R,9aS)-6-Methylhexahydro-2H-benzo[b][1,4]dioxepin-3(4H)-
one (6i): Yellow oil, 66% yield. [α]2D4 = –167.2 (c = 1.03, CH2Cl2).
m.p. 47–49 °C. IR (ATR): ν = 2945, 1722, 1455, 1120 cm–1. 1H
IR (ATR): ν = 2932, 1722, 1123 cm–1. 1H NMR (300 MHz,
˜
˜
NMR (300 MHz, CDCl3): δ = 4.30 (d, J = 16.6 Hz, 2 H), 4.24 (d,
J = 16.2 Hz, 2 H), 3.39–3.25 (m, 2 H), 2.04–1.94 (m, 2 H), 1.76–
1.66 (m, 1 H), 1.62–1.36 (m, 2 H), 1.28–0.93 (m, 2 H), 0.97 (d, J
= 6.6 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 211.6, 88.3,
87.8, 77.2, 77.2, 39.7, 32.6, 30.9, 30.8, 21.5 ppm. HRMS: calcd. for
C10H16O3 184.1099; found 184.1089.
CDCl3): δ = 4.51–3.94 (m, 4 H), 3.88–3.81 (m, 1 H), 3.64–3.61 (m,
1 H), 2.06–1.92 (m, 1 H), 1.90–1.81 (m, 1 H), 1.66–1.52 (m, 2 H),
1.42–1.13 (m, 3 H), 1.01 (d, J = 6.8 Hz, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 212.1, 86.7, 79.3, 77.7, 69.8, 35.6, 27.5, 23.7,
22.9, 17.5 ppm. HRMS: calcd. for C10H16O3 184.1099; found
184.1096.
Odour description: Weak, slightly woody odour that is linear in the
dry-down and shows slightly marine, watery, and salty nuances.
Odour description: Weak, green, slightly oily medicinal odour rem-
iniscent of the medicinal aspects of Calone 1951, but also with ma-
rine facets of Calone 1951.
(5aR,7R,9aS)-7-Methylhexahydro-2H-benzo[b][1,4]dioxepin-3(4H)-
one (6f): Yellow oil, 8% yield. [α]2D2 = +176.6 (c = 1.04, CH2Cl2).
Odour threshold: 177 ng/L air (stan. dev. 72 ng/L air).
IR (ATR): ν = 2927, 1721, 1123 cm–1 1H NMR (300 MHz,
.
˜
Supporting Information (see footnote on the first page of this arti-
CDCl3): δ = 4.43 (d, J = 17 Hz, 1 H), 4.25 (d, J = 16.4 Hz, 1 H),
4.16 (d, J = 16.4 Hz, 1 H), 3.95 (d, J = 17 Hz, 1 H), 3.91–3.80 (m,
2 H), 2.01–1.91 (m, 1 H), 1.72 (q, J = 17.9 Hz, 1 H), 1.60–1.36 (m,
4 H), 1.26–1.07 (m, 1 H), 0.98 (d, J = 6.2 Hz, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 212.0, 81.9, 78.6, 77.2, 69.9, 32.1, 31.4, 30.5,
28.3, 22.1 ppm. HRMS: calcd. for C10H16O3: 184.1099; found
184.1105.
1
cle): H and 13C NMR spectra of compounds 4–9, and crystallo-
graphic data for compounds 6a, 6b, and 6e.
Acknowledgments
Financial support from RMIT University, Melbourne is acknowl-
edged. Thanks are due to Benjamin Alford, Anthony Lingham,
and Scott McMaster for their help and troubleshooting. Thanks
are also due to Alain Alchenberger and Dominique Lelièvre for
the olfactory analysis, and to Katarina Grman and her panelists
for the odour threshold determinations, as well as to Jörg Wagler
for his assistance with crystallography, and to Frank Antolasic and
Paul Morrison for their assistance with mass spectrometry.
Odour description: Odour reminiscent of fatty alcohols, especially
nonanol, with slightly woody and fruity character and green-rub-
bery aspects in the dry-down.
(5aS,9aR)-9-Methyl-5a,6,7,9a-tetrahydro-2H-benzo[b][1,4]dioxepin-
3(4H)-one (6g): White solid, 34% yield. [α]2D2 = –2.8 (c = 1.38,
1
CH Cl ), m.p. 29–31 °C. IR (ATR): ν = 1729, 1122, 847 cm–1. H
˜
2
2
NMR (300 MHz, CDCl3): δ = 5.75–5.70 (m, 1 H), 4.43–3.95 (m, 6
H), 2.34–2.20 (m, 1 H), 2.09–1.93 (m, 2 H), 1.76–1.73 (m, 3 H),
1.72–1.59 (m, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 211.8,
130.8, 128.3, 80.7, 79.6, 73.9, 73.3, 24.2, 22.9, 19.8 ppm. HRMS:
calcd. for C10H14O3 182.0943; found 182.0948.
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General Method 4. Synthesis of Compounds 6h and 6i: Compound
5h or 5i (5 mmol) was dissolved in MeCN (25 mL), H2O (25 mL),
and CCl4 (15 mL), and sodium metaperiodate (1.07 g, 5 mmol) and
ruthenium trichloride (0.1 g, 0.5 mmol) were added. The mixture
was stirred for 24 h, then further sodium metaperiodate (1.07 g,
5 mmol) and ruthenium trichloride (0.1 g, 0.5 mmol) were added.
The solution was stirred for a further 24 h. The reaction mixture
was then poured into H2O (100 mL), and the resulting mixture was
extracted with CHCl3 (3ϫ 100 mL). The combined organic extracts
were washed with a saturated solution of NaHSO3 (100 mL) and
with H2O (100 mL), dried (MgSO4), and concentrated under re-
duced pressure. The resulting residue was purified by flash
chromatography on silica gel (EtOAc/hexane) to give the corre-
sponding saturated benzodioxepinone compound (i.e., 6h or 6i).
(5aR,6S,9aS)-6-Methylhexahydro-2H-benzo[b][1,4]dioxepin-3(4H)-
one (6h): White solid, 58% yield. [α]2D3 = +213.1 (c = 1.08, CH2Cl2),
m.p. 47–49 °C. IR (ATR): ν = 2937, 1722, 1127, 1114 cm–1. 1H
˜
NMR (300 MHz, CDCl3): δ = 4.45–3.91 (m, 4 H), 3.90–3.86 (m, 1
H), 3.44 (dd, J = 10.5, 2.6 Hz, 1 H), 2.30–2.14 (m, 1 H), 2.04–1.93
Eur. J. Org. Chem. 0000, 0–0
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Date: 03-12-14 18:34:14
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H. M. Hügel et al.
FULL PAPER
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Crystal data for 6e: a = 8.1940(8) Å, b = 6.1852(4) Å, c =
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Z = 2, space group P 21. CCDC-1020849 contains the supple-
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1727.4(4) Å3, Z = 8, space group C 2/c. CCDC-968784 con-
tains the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
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Received: August 28, 2014
Published Online: ᭿
10
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Job/Unit: O43142
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Date: 03-12-14 18:34:14
Pages: 11
Synthesis of Saturated Benzodioxepinone Analogues
Odour Compounds
C. M. Plummer, R. Gericke, P. Kraft,
A. Raynor, J. Froese, T. Hudlický,
T. J. Rook, O. A. H. Jones,
H. M. Hügel* ................................. 1–11
As part of our research exploring the influ-
ence of molecular variations of Ca-
lone 1951® on marine fragrance perform-
ance, we report the synthesis, crystal struc-
tures, and olfactory analysis of the first
saturated benzodioxepinone analogues.
Our results showed that an aromatic ring
system is necessary for binding to the mar-
ine odour receptor(s).
Synthesis of Saturated Benzodioxepinone
Analogues: Insight into the Importance of
the Aromatic Ring Binding Motif for Mar-
ine Odorants
Keywords: Fused-ring systems / Oxygen
heterocycles / Fragrances / Structure–ac-
tivity relationships / Cyclization
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