DOI: 10.1002/ejoc.

201501338

Full Paper

Fragrances

Synthesis and Olfactory Properties of Silicon-Containing

Analogs of Rosamusk, Romandolide, and Applelide: Insights
into the Structural Parameters of Linear Alicyclic Musks
Junhui Liu,*[a] Yue Zou,[b] Wu Fan,[a] Jian Mao,[a] Guobi Chai,[a] Peng Li,[a] Zhan Qu,[a]
Yongli Zong,[a] Jianxun Zhang,*[a] and Philip Kraft*[c]

Abstract: A series of silicon-containing derivatives of linear alicyclic musks comprising sila-Rosamusk (3b), sila-Romandolide
(5b), sila-Applelide (11b), and the corresponding dehydro derivatives was synthesized from sila-analogs of Artemone and Herbac, respectively, by means of sodium borohydride reduction
and subsequent esterification with the corresponding acid
chlorides in the presence of triethylamine. The olfactory properties of the new sila-odorants 3b13b are reported in compari-

son with their carba-analogs 3a13a, and quantitative

threshold data allowed the generation of an improved musk
olfactophore model featuring a correlation of 80.5 % with a
null-cost distance of 244. This olfactophore model shows that
it is likely that linear and macrocyclic musks address the same
odorant receptors, and it should facilitate the design of new
musks.

Introduction

of 54 %.[2a] In this paper, we report the synthesis of sila-analogs

of Rosamusk (3a), Romandolide (5a), and Applelide (11a), and
use their olfactory properties for the generation of an improved

Musk odorants are indispensable classic perfumery ingredients

that impart volume, diffusivity, and sensuality to a fragrance.[1]
Five main classes of musk odorants are known at present: nitro
musks, polycyclic aromatic musks (PCM), macrocyclic musks, linear musks, and dienone musks. The last of these has, however,
not yet found its way to the market. Due to the phototoxicity
of nitro musks, and the limited biodegradability of polycyclic
musks in standard tests, the most interesting musk families today are those of macrocyclic and linear musks. The commercially important linear musks, the so-called fourth generation of
musks, include Rosamusk (3a), Helvetolide, Romandolide (5a),
Serenolide, Applelide (11a), and Sylkolide (Figure 1). Their musk
odors have been rationalized with a conformational space rich
in horseshoe-shaped molecules that could thus mimic macrocyclic musks in binding to the respective odorant receptors.[1,2]
This hypothesis was substantiated by a common olfactophore
model of macrocyclic and linear musks that gave a correlation

[a] Key Laboratory of Tobacco Flavor Basic Research, Zhengzhou Tobacco

Research Institute of CNTC,
No. 2 Fengyang Street High-Tech Zone, Zhengzhou 450001, China
E-mail: ljhpku@outlook.com
jxzh258@sina.com
[b] Givaudan Fragrances (Shanghai) Ltd,
298 Li Shi Zhen Road, Shanghai 201203, China
[c] Givaudan Schweiz AG,Fragrance Research,
berlandstrasse 138, 8600 Dbendorf, Switzerland
E-mail: philip.kraft@givaudan.com
https://www.givaudan.com
Supporting information and ORCID(s) from the author(s) for this article
are available on the WWW under http://dx.doi.org/10.1002/
ejoc.201501338.
Eur. J. Org. Chem. 0000, 00

Figure 1. The building blocks Cyclademol (1a) and its 2-analog 2a, as well
as the most important linear alicyclic musk odorants derived from 1a, and
Sylkolide, which can be seen as a seco derivative of 2-Cyclademol (2a).

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Results and Discussion

olfactophore model that makes it even more plausible that

these two families of musk odorants address the same olfactory
receptors.

Six-membered silacyclic compounds have recently been synthesized for the probe and imaging applications.[11,12] The ringexpansion of four-membered silacycles with activated alkynes
mediated by transition-metal catalysts is an efficient approach
to these systems,[13] and has been used to synthesize the silaanalogs of Artemone and Herbac in good yields (Scheme 1).[13h]
These two compounds are the oxidation products of Cyclademol (1a) and its 2-analog 2a. Cyclademol (1a) has a camphoraceous, borneol- and terpineol-type odor without much
interest for perfumery. Its main importance is as building block
for the synthesis of linear musks. The sila-analogs of Cyclademol
(1a)[1a] and its dehydro derivative 2a (Figure 1) should be accessible by simple hydride reduction of sila-Artemone and silaHerbac. This would then give access to sila-Rosamusk (3b), silaRomandolide (5b), and sila-Applelide (11b), and also to their
corresponding dehydro derivatives (Figure 2).

Rosamusk (3a) is prepared by the reaction of 3,7-dimethylocta-1,6-diene with acetic acid using sulfuric acid as catalyst.[1a]
It displays an unusual combination of floral rosy-geranium character with musky, fruity pear, and violet aspects.[3] It was recently used as a nuanceur by Nicolas Beaulieu in Aromatics in
White (Clinique, 2014), but it is commercially less important.[1]
Helvetolide (odor threshold, th = 1.1 ng/L air, activ = 3.87 pM),
discovered in 1990 by Giersch and Schulte-Elte,[4a] was the first
commercially successful member of the family of linear musks.
It has a modern musk note with a fruity, pear aspect situated
olfactorily in between Ambrettolide and ethylene brassylate.[4b]
In combination with Habanolide [(12E)-oxacyclohexadec-12-en2-one], it has become eponymous for white musk accords since
the time it was used at 8.8 % in Emporio White Her (Armani,
2001) by Alberto Morillas. Romandolide[4c] (5a; th = 0.4 ng/L air,
activ = 1.48 pM) was discovered by Alvin Williams by substituting the gem-dimethyl moiety of Helvetolide with a carbonyl
group to create a more easily synthesizable molecule. It has a
fruity musk odor of agrestic tonality, and is somewhat less fruity
than Helvetolide. Romandolide (5a) was recently featured by
Daphne Bugey and Fabrice Pellegrin in Valentina Pink (Valention, 2015), in which it was set against a fruity strawberryblackberry accord. Applelide (11a; th = 1.5 ng/L air) is even easier to
synthesize, and has a powdery fruity musk odor with a distinct
fruity green apple note, which somewhat restricts its use. In
certain contexts, however, this green apple note of Applelide
(11a) brings a desirable signature, as for instance in the spicy
oriental Spicebomb Extreme (Viktor & Rolf, 2015), where it
goes well with the cinnamic tones on top. Sylkolide[4d] is so
far the only commercial linear musk that does not derive from
Cyclademol (1a), but rather can be seen as a seco derivative of
its 2-analog 2a. It has a radiant musk note with red fruits
aspects that, due to the volatility of the compound, unveils already from the top notes. And yet Sylkolide also enhances
woody facets, as was recently nicely demonstrated by Aurelien
Guichard with a hinoki wood accord in Ever Bloom (Shiseido,
2015).

Scheme 1. Ring-expansion reactions to give sila-Artemone and sila-Herbac.[13h]

Silicon is the second most abundant element, and the most

similar to carbon. The SiC bond is, however, about 20 % longer
than the analogous CC bond, which significantly increases the
molecular volume upon sila-substitution. This makes sila-analogs interesting test probes for olfactophore and pharmacophore models. Upon sila-substitution, the molecular weight increases by 16 atomic mass units, and together with the polarization of the SiC bond, this leads to a decreased vapor pressure, and an increased substantivity of sila-odorants in functional applications.[510]

Figure 2. Odor descriptions, detection thresholds in ng L1 air, activity in pM

air, and calculated activity in pM air of the sila-analog of Rosamusk (3a), Romandolide (5a), and Applelide (11a) according to the generated olfactophore
model in Figure 3. For the threshold data and the measured and calculated
activities of the other musk odorants in the data set, see the Supporting
Information.

Although a variety of methods have been developed to prepare open-chain organosilanes, the incorporation of silicon atoms into ring systems remains relatively unexplored.[9,10] With
the aim of improving the olfactophore model of musk odorants
by structureodor correlations and threshold data, we report in
this paper the synthesis and olfactory properties of new siliconcontaining linear alicyclic musks.
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As shown in Scheme 2, treatment of sila-Herbac with an excess of NaBH4 at room temperature in MeOH gave, after a reaction time of 1 h, sila-Cyclademol (1b) in 95 % isolated yield. The
corresponding dehydro derivative (i.e., 2b) was also prepared
in 98 % isolated yield by the same procedure (Scheme 2).
2

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Scheme 2. Preparation of sila-Rosamusk (3b) and its dehydro derivative 4b

from sila-Herbac and sila-Artemone by carbonyl reduction and esterification.

With 1b and 2b in hand, our first synthetic targets were the

sila-analog of Rosamusk (3a) and its dehydro derivative (i.e.,
3b), by acylation. As shown in Scheme 2, sila-Rosamusk (3b)
was prepared in 85 % isolated yield by the reaction of 1b with
acetyl chloride in the presence of an excess of Et3N. The reaction of 2b with acetyl chloride also proceeded smoothly to give
4b in excellent yield. Surprisingly, the dominant odor characters
of 3b and 4b were woody and herbal, with no musk, floral, or
rosy tonalities being present.
Next, we tackled the synthesis of linear silacyclic musks 5b
10b. Sila-Romandolide (5b) was prepared as shown in
Scheme 3. Acylation of hydroxyacetic acid with propionyl chloride gave 2-(propionyloxy)acetic acid (14) (R = Et). Without purification, this compound was then transformed into 2-chloro-2oxoethyl propionate (15) (R = Et) by treatment with SOCl2 at
reflux. Subsequent reaction of 15 with 1b in the presence of
Et3N then gave sila-Romandolide (5b) in 74 % isolated yield
after flash chromatography. Compounds 6b10b were also synthesized in high yields following the same procedure
(Scheme 3).

Scheme 4. Preparation of sila-Applelide (11b), its 2-dehydro derivative 12b,

and 2,2-gem-dimethyl analog 13b.

Generally, the presence of a dimethyl carbinol moiety on the

Cyclademol (1a) building block destabilizes horseshoe-shaped
conformations, and for silacyclic musk 13b, the first nonhorseshoe conformation appears already at 0.4 kcal mol1 above the
global energy minimum; and yet its conformational space is
still largely in a horseshoe shape. The Grignard reaction of silaArtemone with methylmagnesium bromide provided the corresponding dimethyl carbinol (i.e., 16) in 86 % yield. This was then
subjected to esterification with 2-chloro-2-oxoethyl propionate
to give target structure 13b in 57 % yield. Due to steric hindrance in the esterification, the reaction of the homologous
dialkyl carbinol failed completely, however (Scheme 4).

StructureOdor Correlation and a Refined Musk

Olfactophore Model
The odor descriptions, odor thresholds, and activity values of
the sila-analogs of Rosamusk (3a), Romandolide (5a), and
Applelide (11a) are compiled in Figure 2. In comparison with
Romandolide (5a, th = 0.4 ng/L air, activ = 1.48 pM), silaRomandolide (5b, th = 2.21 ng/L air, activ = 7.71 pM) is noticeably weaker, especially on blotter, where the lower vapor pressure comes into full effect. The odor character of 5b is also less
musky and more woody, although the fruity aspects of Romandolide (5b) are clearly discernible. In the corresponding cyclopropanoate (i.e., 7b), the musk character is clearly more prominent, so as a result it is closer to Romandolide (5a). The odor
thresholds of 5b and 7b were, however, both determined to be
2.21 ng L1 air. Interestingly, 2-unsaturated sila-Romandolide
(6b) is, with an odor threshold of 4.41 ng L1 air, twice as weak
as 5b and 7b, while its cyclopropanoate 8b is, with an odor
threshold of 0.28 ng L1 air, eight times as strong as silaRomandolide (5b) or its cyclopropanoate 7b. Thus, 2-[1-(1,1dimethyl-1,4,5,6-tetrahydrosilin-3-yl)ethoxy]-2-oxoethyl
cyclopropanoate (8b) is the most potent odorant of the series

Scheme 3. Preparation of linear silacyclic musks 5b10b.

All attempts to synthesize the sila-analogs of Helvetolide and

Serenolide were unsuccessful due to the decomposition of 1b
and 2b in the presence of the required Lewis acids, such as
BF3, AlCl3, and MeAlCl2.[2b] However, sila-Applelide (11b) and its
dehydro derivative 12b were easily prepared in good yields by
the condensation of 1b and 2b, respectively, with 3-ethoxy-3oxopropanoic acid in the presence of N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (EDC) and DMAP (4dimethylaminopyridine) (Scheme 4).
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investigated, and it is also the most musky, with a pleasant
powdery tonality and some green side aspects.
Not surprisingly, saturated 9b and unsaturated 10b cyclopentanoates are both much weaker than 8b, especially the saturated compound (i.e., 9b), for which we measured an odor
threshold of 12.5 ng L1 air. Due to its high molecular weight of
Mr = 326.51, 9b appears even weaker on blotter, and it is mainly
woody and fruity in smell, with only a slight hint of musk. The
unsaturated analog (i.e., 10b), however, is a genuine musk odorant, with the typical fruity aspects of linear musks, and a distinct
animalic facet. With an odor threshold of 1.13 ng L1 air and a
molecular weight of Mr = 324.49 (C17H28O4Si), it is on a par with
the cyclopentanoate of Helvetolide (C20H36O3, Mr = 324.50),
which is the highest molecular weight odorant known to
date.[1a,1c] With an odor threshold of 17.7 ng L1 air, the silaanalog of Applelide (11a) is the weakest odorant of the series,
and has a mainly fruity, woody odor, though a musk inflection
is clearly perceivable. This musk character becomes more pronounced in 2-unsaturated derivative 12b, which is, with an
odor threshold value of 3.13 ng L1 air, over five times stronger
than the parent saturated compound (i.e., 11b). The introduction of a second 2-methyl group into 6b to give 2,2-gemdimethyl-substituted analog 13b has no influence on the odor
threshold, but it does shift the odor more towards a woody and
waxy side. And yet 2-2-methyl-sila-Romandolide 13b still has
to be considered a musk odorant, with an odor threshold of
3.13 ng L1 air.

Figure 3. The refined musk olfactophore model with Romandolide (5a; black,
activ = 1.48 pM, calcd. 2.95 pM), sila-Romandolide (5b; silver, activ = 7.71 pM,
calcd. 5.29), and Serenolide (gold activ = 0.714 pM, calcd. 4.99 pM) bound to
it. Due to the lack of threshold data for compounds with absolute configuration, the model contains no stereoinformation, and arbitrary enantiomers of
the compounds are depicted. The reported threshold values represent the
racemates, so medians of the individual enantiomers.

hydrophobe in front of the HBA; yet, for Romandolide (5a;

black) it is the propionate tail. For sila-Romandolide (5b; silver),
it is also the nonpolar propionate tail that docks to this aliphatic
hydrophobe. For sila-Romandolide (5b), the second aliphatic
hydrophobe is addressed by the 1,1-dimethylsilinanyl ring,
while in the case of Romandolide (5a), the methyl group of the
ethoxy moiety is bound. This accounts for the lower calculated
activity of 2.95 pM for 5a (activ = 1.48 pM) in comparison with
sila-Romandolide (5b; calcd. 5.29 pM, activ = 7.71 pM). Thus, the
model differentiates the activities of the parent compound and
its sila-analog quite well. However, Serenolide is, at 0.714 pM,
almost twice as potent as Romandolide, yet its calculated activity is, at 4.99 pM, around 70 % less than the calculated activity
for Romandolide (5a; 2.95 pM). In line with the significant difference in threshold between 8b and 6b, and the opposite variation of intensities for 6b compared with 5b, vs. 8b in comparison with 7b, the model features no additional double-bondspecific electronic binding site(s), and attempts to explain these
effects by conformational preferences alone. Yet, as can be seen
from the comparison between measured and calculated activities in Figure 2, this constitutes an oversimplification that is not
fully supported by the experimental data.
Still the correlation improved from 54 % for the previous
model[2a] to 80.5 % for the refined model, and since the linear
musks are arranged alongside the perimeter of a macrocyclic
ring (Figure 3), with a convincing null-cost distance of 244, it
makes it even more likely that linear alicyclic and macrocyclic
musks address the same odorant receptor(s).
To account for the different activities of the linear musk investigated and macrocyclic musks of the training set (see Supporting Information), four excluded volumes were placed by
the Discovery Studio 4.1 software. These form an irregular tetrahedron with edges of 10.21, 8.79, 7.92, 7.85, 7.72, and 4.35

It does appear at first sight that the 2 double bond has a

significant influence on the musk character, and though it is
positioned in same relative spatial geometry as the 3 double
bond in Sylkolide (Figure 1), the significant difference in the
odor threshold between 8b (th = 0.28 ng L1 air) and 6b (th =
4.41 ng L1 air) clearly indicates that this is due to conformational rather than electronic effects. Thus, we were very interested in using the quantitative threshold data in Figure 2 for
the refinement of our musk olfactophore model.[2a] Combining
these data with the published threshold values of linear and
macrocyclic musks,[2a] the olfactophore model shown in Figure 3 was generated using the Discovery Studio 4.1 software
package[14] with a conformational space of 10 kcal mol1. While
the odor thresholds were used as such in ng L1 air for the
previous model,[2a] this time the activity (activ) was specified in
picomoles per liter of air (pM). In this way, the molecular weight
is taken into consideration, and so the number of molecules
interacting on the receptor level is reflected.
As detailed in the Supporting Information, the olfactophore
model consists of two hydrogen-bond acceptors (HBA) at a distance of 6.96 from one another; this explains why CPD ketone
(1-oxacyclohexadecane-2,13-dione, ketodecanolide) also binds
and smells musky. Two aliphatic hydrophobes are situated at a
distance of 7.51 from one another, and one of these is right
in front of one of the hydrogen-bond acceptors at a distance
of only 0.91 . As one of the features can be omitted in the
docking to the refined musk olfactophore, both a polar hydrogen-bond acceptor and an aliphatic hydrophobe bind equally
well in that region. For Serenolide (gold, Figure 3), the gemdimethyl group on the cyclohexyl ring binds in this aliphatic
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39.50 ppm), or external tetramethylsilane (29Si, = 0.00 ppm). HRMS
was carried out with a VG-ZAB-HS instrument. The sensory properties of all odorants were determined by six expert perfumers using
solutions of the respective compounds (10 % in ethanol) applied to
the smelling blotters. The odor thresholds were determined by GColfactometry: different dilutions of the sample substances were injected into a gas chromatograph in descending order until three
panelists evaluating in blind, failed to detect the odor impression
at the correct retention time.

that slices through the plane defined by the imaginary macrocyclic perimeter in Figure 3.
Interestingly, the cyclopropyl analog (i.e., 7b) of sila-Romandolide (5b) binds to the refined musk olfactophore model with
the opposite orientation compared to both Romandolide (5a)
and sila-Romandolide (5b), with the gem-dimethyl group in the
aliphatic hydrophobe in front of the HBA. This explains its
somewhat better activity, but while the tendency is correct, the
calculated value of 2.92 pM is far better than the 5.29 pM for
5b, and both are lower than the experimental values of 7.40
and 7.71 pM, respectively. The dimethyl tetrahydrosiline ring of
6b binds less well and in a different conformation compared to
the isolated aliphatic hydrophobe, and this explains the calculated and observed lessening of its activity on the musk receptor(s). In 8b, with the cyclopropyl moiety being bound to the
aliphatic hydrophobe in front of the HBA, the fit of the dimethyl
tetrahydrosiline unit into the other aliphatic hydrophobe is,
however, quite good. This explains the better calculated activity
of 3.24 pM (Figure 2), which is, however, not as good as the
experimental value of 0.93 pM. In 9b and 10b, the binding of
the cyclopentyl ring to the hydrophobe in front of the HBA
displaces the fit of the sila-substituted six-membered ring to
the other aliphatic hydrophobe. But in this case it also becomes
clear that the double bond of 10b must have some additional
influence not predicted by the refined olfactophore model.
Similarly to cyclopropanoate 7b, sila-Applelide (11b) binds
in the opposite orientation, with the 1,1-dimethylsilinanyl substituent outside both of the hydrophobes, and this is also true
for its 2-unsaturated counterpart 12b. Instead, in both cases
the methyl group in the position to the ring is bound to the
hydrophobe in front of the HBA, leading to overly low predictions for their activity of 4.06 and 4.21 pM, respectively, and
little differentiation due to the double bond. Finally, 2,2-gemdimethyl-substituted analog 13b is again bound to the improved musk olfactophore in the conventional way, with a very
good prediction of its activity (9.64 pM) compared to the measured value (10.5 pM).

Carbonyl Reduction of Sila-Herbac and Sila-Artemone: NaBH4

(152 mg, 4.0 mmol) was added to a solution of sila-Herbac or silaArtemone (4.0 mmol) in MeOH (5 mL) at 0 C. The mixture was
warmed to room temp., and stirred for 1 h. The reaction was then
quenched with water (10 mL), and the mixture was extracted with
EtOAc (3 20 mL). The combined organic phase was washed with
brine, and dried with Na2SO4. The solvent was removed under reduced pressure, and the resulting residue was purified by flash column chromatography (petroleum ether/EtOAc, 10:1) to give the desired compound (i.e., 1b/2b).
1b: Colorless oil (653 mg, 95 %). 1H NMR (CDCl3): = 0.010 (s, 3 H),
0.033 (s, 3 H), 0.170.28 (m, 1 H), 0.340.44 (m, 1 H), 0.640.75 (m,
2 H), 0.840.98 (m, 1 H), 1.12 (d, J = 8.0 Hz, 3 H), 1.351.50 (m, 2 H),
1.60 (br., 1 H), 1.671.85 (m, 1 H), 1.982.06 (m, 1 H), 3.503.60 (m,
1 H) ppm. 13C NMR (CDCl3): = 4.11, 4.10, 1.56, 13.85, 15.03,
15.33, 19.32, 19.35, 23.62, 23.66, 31.68, 31.70, 43.28, 43.42, 73.62,
73.76 ppm. HRMS: calcd. for C9H20OSi [M]+ 172.1283; found
172.1287. C9H20OSi (172.34): calcd. C 62.72, H 11.70; found C 62.70,
H 11.74.
2b: Colorless oil (666 mg, 98 %). 1H NMR ([D6]DMSO): = 0.016 (s,
3 H), 0.021 (s, 3 H), 0.60 (t, J = 8.0 Hz, 2 H), 1.08 (d, J = 8.0 Hz, 3 H),
1.641.76 (m, 2 H), 1.891.99 (m, 1 H), 2.012.11 (m, 1 H), 3.873.96
(m, 1 H), 4.70 (d, J = 8.0 Hz, 1 H), 5.57 (s, 1 H) ppm. 13C NMR
([D6]DMSO): = 1.36, 11.76, 21.34, 22.38, 29.25, 71.73, 115.93,
164.43 ppm. HRMS: calcd. for C9H18OSi [M]+ 170.1127; found
170.1130. C9H18OSi (170.32): calcd. C 63.47, H 10.65; found C 63.45,
H 10.69.
Acetylation of 1b/2b: A solution of acetyl chloride (3.0 mmol) in
CH2Cl2 (2 mL) was added to a solution of 1b/2b (3.0 mmol) in
CH2Cl2 (10 mL) and Et3N (1 mL). The reaction mixture was stirred
at 20 C for 18 h, and then the solvent was removed under reduced
pressure. CH2Cl2 (30 mL) and water (30 mL) were added to the
resulting residue. The organic layer was separated, washed with
brine (10 mL), and dried with Na2SO4. The solvent was removed in
vacuo. The resulting residue was further purified by silica gel column chromatography (petroleum ether/EtOAc, 10:1) to give the desired compound (i.e., 3b/4b).

Conclusions
The refined musk olfactophore model is certainly not the last
word on the subject, but it still represents a major advancement
that should inspire further work in the areas of linear and macrocyclic musks. Sila-substitution has proved to be an interesting
way to gain additional insight and refine the quantitative structureodor correlations to improve olfactophore models.

3b: Colorless oil (546 mg, 85 %). 1H NMR (CDCl3): = 0.01 (s, 3 H),
0.04 (s, 3 H), 0.200.29 (m, 1 H), 0.340.44 (m, 1 H), 0.650.75 (m, 2
H), 0.790.97 (m, 1 H), 1.131.16 (m, 3 H), 1.301.44 (m, 1 H), 1.56
1.66 (m, 1 H), 1.671.77 (m, 1 H), 1.952.05 (m, 4 H), 4.644.75 (m,
1 H) ppm. 13C NMR (CDCl3): = 4.11, 1.58, 1.55, 9.29, 9.30, 13.82,
15.75, 15.81, 16.00, 23.50, 23.54, 28.01, 31.42, 40.97, 41.00, 75.94,
75.97, 174.16, 174.18 ppm. HRMS: calcd. for C11H22O2Si [M]+
214.1389; found 214.1386.

Experimental Section
General Remarks: Sila-Artemone and sila-Herbac were prepared
according to the published procedure.[13h] Unless otherwise stated,
all other chemicals were commercially available, and were used
without further purification. Column chromatography was carried
out with silica gel (100200 mesh, J & K Scientific). 1H (300 or
400 MHz) and 13C (75.5 or 100 MHz) NMR spectra were recorded
using CDCl3 or [D6]DMSO as the solvent. Chemical shifts (ppm) were
calibrated using internal CHCl3/CDCl3 (1H, = 7.26 ppm; 13C, =
77.00 ppm), internal [D5]/[D6]DMSO (1H, = 2.50 ppm; 13C, =
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4b: Colorless oil (522 mg, 82 %). 1H NMR (CDCl3): = 0.03 (s, 3 H),
0.04 (s, 3 H), 0.600.65 (m, 2 H), 1.28 (d, J = 8.0 Hz, 3 H), 1.731.81
(m, 2 H), 2.012.06 (m, 5 H), 5.15 (q, J = 6.7 Hz, 1 H), 5.60 (s, 1 H)
ppm. 13C NMR (CDCl3): = 1.73, 1.70, 11.74, 19.28, 21.33, 21.51,
30.02, 75.25, 120.05, 158.22, 170.23 ppm. HRMS: calcd. for
C11H20O2Si [M]+ 212.1233; found 212.1232.
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Typical Procedure for the Synthesis of Linear Silacyclic Musks
5b10b: A mixture of propionyl chloride (2.10 g, 22.7 mmol) and
hydroxyacetic acid (610 mg, 8.0 mmol) was heated at 40 C until the
hydroxyacetic acid was completely dissolved. The excess propionyl
chloride was then distilled off to give crude compound 14 as a
colorless oil, which was used immediately without purification.

(m, 2 H), 1.701.82 (m, 4 H), 1.871.94 (m, 4 H), 2.012.06 (m, 2 H),
2.802.90 (m, 1 H), 4.611 (s, 1 H), 4.615 (s, 1 H), 5.24 (q, J = 6.7 Hz,
1 H), 5.62 (s, 1 H) ppm. 13C NMR (CDCl3): = 1.80, 1.78, 11.66,
19.13, 21.45, 25.82, 29.85, 29.88, 29.90, 43.31, 60.71, 76.52, 121.06,
157.28, 167.25, 176.01 ppm. HRMS: calcd. for C17H28O4Si [M]+
324.1757; found 324.1755.

A mixture of 14 (310 mg, 2.3 mmol) and SOCl2 (3 mL) was heated
under reflux for 3 h. The excess SOCl2 was then removed under
vacuum to give 15 as a pale yellow oil.

Synthesis of 11b/12b: 3-Ethoxy-3-oxopropanoic acid (264 mg,

2.0 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCHCl; 384 mg, 2.0 mmol), and DMAP (306 mg,
2.5 mmol) were added to a solution of 1b/2b (2.0 mmol) in CH2Cl2
(5 mL) at 0 C. The reaction mixture was warmed to room temp.,
and stirred for 1 h. Then the mixture was diluted with CH2Cl2
(20 mL), and subsequently washed with water and brine. The organic phase was dried over Na2SO4, and the solvent was removed
under reduced pressure. The resulting residue was purified by flash
column chromatography (petroleum ether/EtOAc, 30:1) to give the
desired compound (i.e., 11b/12b, respectively).

Compound 15 was dissolved in CH2Cl2 (2 mL), and the solution was

added to a solution of 1b/2b (2.0 mmol) in CH2Cl2 (10 mL) and
Et3N (1 mL). The mixture was stirred at 20 C for 18 h. After this
time, the solvent was removed under reduced pressure, and CH2Cl2
(30 mL) and water (30 mL) were added to the resulting residue. The
organic layer was separated, washed with brine (10 mL), and dried
with Na2SO4. The solvent was removed in vacuo. The resulting residue was purified by silica gel column chromatography (petroleum
ether/EtOAc, 10:1) to give the desired compound (i.e., 5b10b).

11b: Colorless oil (331 mg, 58 %). 1H NMR (CDCl3): = 0.010.04

(m, 6 H), 0.190.30 (m, 1 H), 0.320.45 (m, 1 H), 0.640.78 (m, 2 H),
0.800.99 (m, 1 H), 1.151.21 (m, 3 H), 1.251.32 (m, 3 H), 1.321.46
(m, 1 H), 1.601.80 (m, 2 H), 1.942.07 (m, 1 H), 3.333.37 (m, 2 H),
4.144.26 (m, 2 H), 4.60 (s, 1 H), 4.704.83 (m, 1 H) ppm. 13C NMR
(CDCl3): = 4.14, 1.59, 13.70, 13.77, 14.08, 15.67, 15.74, 15.82,
16.29, 23.42, 23.47, 31.32, 31.62, 40.82, 40.88, 42.11, 61.41, 61.50,
166.25, 166.75 ppm. HRMS: calcd. for C14H26O4Si [M]+ 286.1600;
found 286.1601.

5b: Colorless oil (423 mg, 74 %). 1H NMR (CDCl3): = 0.010.04 (m,
6 H), 0.210.29 (m, 1 H), 0.340.43 (m, 1 H), 0.650.72 (m, 2 H), 0.79
0.97 (m, 1 H), 1.171.21 (m, 6 H), 1.311.43 (m, 1 H), 1.601.74 (m,
2 H), 1.962.06 (m, 1 H), 2.44 (q, J = 8.0 Hz, 2 H), 4.59 (s, 1 H), 4.60
(s, 1 H), 4.754.85 (m, 1 H) ppm. 13C NMR (CDCl3): = 4.17, 4.15,
1.63, 1.61, 8.96, 13.67, 13.73, 15.65, 15.83, 16.25, 23.41, 23.43,
27.16, 31.29, 31.62, 40.83, 40.89, 60.82, 77.71, 77.75, 167.59, 167.64,
173.76 ppm. HRMS: calcd. for C14H26O4Si [M]+ 286.1600; found
286.1604.

12b: Colorless oil (392 mg, 69 %). 1H NMR (CDCl3): = 0.02 (s, 3 H),
0.03 (s, 3 H), 0.61 (t, J = 8.0 Hz, 2 H), 1.26 (t, J = 8.0 Hz, 3 H), 1.29
(d, J = 8.0 Hz, 3 H), 1.701.82 (m, 2 H), 1.992.05 (m, 2 H), 3.35 (s, 2
H), 4.144.22 (m, 2 H), 5.19 (q, J = 6.7 Hz, 1 H), 5.61 (s, 1 H) ppm.
13
C NMR (CDCl3): = 1.84, 1.81, 11.63, 14.01, 19.01, 21.42, 29.80,
41.93, 61.35, 76.55, 120.79, 157.39, 165.68, 166.50 ppm. HRMS: calcd.
for C14H24O4Si [M]+ 284.1444; found 284.1449.

6b: Colorless oil (471 mg, 83 %). 1H NMR (CD3OD): = 0.04 (s, 3 H),
0.05 (s, 3 H), 0.630.69 (m, 2 H), 1.15 (t, J = 8.0 Hz, 2 H), 1.31 (d, J =
6.4 Hz, 3 H), 1.751.86 (m, 2 H), 2.052.11 (m, 2 H), 2.43 (q, J =
8.0 Hz, 2 H), 4.63 (s, 2 H), 5.18 (q, J = 6.7 Hz, 2 H), 5.64 (s, 1 H) ppm.
13
C NMR (CDCl3): = 1.81, 1.78, 8.95, 11.66, 19.14, 21.45, 27.14,
29.82, 60.76, 76.61, 121.07, 157.30, 167.15, 173.71 ppm. HRMS: calcd.
for C14H24O4Si [M]+ 284.1444; found 284.1440.

Synthesis of 16 by Grignard Reaction: At 20 C under a nitrogen

atmosphere, MeMgBr (1.0 M in THF; 3 mL, 3.0 mmol) was added to
a solution of sila-Artemone (504 mg, 3.0 mmol) in THF (10 mL). The
mixture was stirred for 1 h, and then it was poured into satd. NH4Cl
(30 mL) at 20 C. At ambient temp., the reaction mixture was extracted with diethyl ether (30 mL). The organic layer was separated,
washed with water (30 mL) and brine (10 mL), and dried with
Na2SO4. The solvent was removed under reduced pressure. The resulting residue was purified by flash column chromatography (petroleum ether/EtOAc, 1:1) to give the desired compound (i.e., 16).

7b: Colorless oil (470 mg, 79 %). 1H NMR (CDCl3): = 0.01 (s, 3 H),
0.03 (s, 3 H), 0.190.31 (m, 1 H), 0.320.45 (m, 1 H), 0.630.75 (m, 2
H), 0.880.99 (m, 3 H), 1.041.11 (m, 2 H), 1.141.20 (m, 3 H), 1.31
1.40 (m, 1 H), 1.601.78 (m 3 H), 1.942.06 (m, 1 H), 4.590 (s, 1 H),
4.599 (s, 1 H), 4.734.86 (m, 1 H) ppm. 13C NMR (CDCl3): = 4.16,
4.14, 1.62, 1.60, 8.82, 12.59, 13.68, 13.74, 15.60, 15.65, 15.82,
16.26, 23.42, 23.44, 31.30, 31.59, 40.82, 40.88, 60.91, 77.70, 77.74,
167.62, 167.66, 174.20 ppm. HRMS: calcd. for C15H26O4Si [M]+
298.1600; found 298.1597.

16: Colorless oil (475 mg, 86 %). 1H NMR (CDCl3): = 0.05 (s, 6 H),
0.610.64 (m, 2 H), 1.31 (s, 6 H), 1.50 (br., 1 H), 1.751.79 (m, 2 H),
2.102.14 (m, 2 H), 5.69 (s, 1 H) ppm. 13C NMR (CDCl3): = 1.50,
11.79, 22.34, 28.67, 29.72, 74.42, 115.80, 165.67 ppm. HRMS: calcd.
for C10H20OSi [M]+ 184.1283; found 184.1279.

8b: Colorless oil (515 mg, 87 %). 1H NMR (CDCl3): = 0.04 (s, 3 H),
0.05 (s, 3 H), 0.600.66 (m, 2 H), 0.900.96 (m, 2 H), 1.051.10 (m, 2
H), 1.32 (d, J = 8.0 Hz, 3 H), 1.701.82 (m 3 H), 2.012.07 (m 2 H),
4.616 (s, 1 H), 4.621 (s, 1 H), 5.23 (q, J = 6.7 Hz, 1 H), 5.62 (s, 1 H)
ppm. 13C NMR (CDCl3): = 1.82, 1.80, 8.78, 11.63, 12.55, 19.12,
21.42, 29.78, 60.80, 76.56, 121.01, 157.29, 167.12, 174.11 ppm.
HRMS: calcd. for C15H24O4Si [M]+ 296.1444; found 296.1442.
9b: Colorless oil (528 mg, 81 %). 1H NMR (CDCl3): = 0.000.04 (m,
6 H), 0.200.29 (m, 1 H), 0.340.44 (m, 1 H), 0.640.74 (m, 2 H), 0.78
0.96 (m, 1 H), 1.151.17 (m, 3 H), 1.201.40 (m, 1 H), 1.561.75 (m,
6 H), 1.842.04 (m, 5 H), 2.792.87 (m, 1 H), 4.58 (s, 1 H), 4.59 (s, 1
H), 4.754.85 (m, 1 H) ppm. 13C NMR (CDCl3): = 4.19, 4.17, 1.65,
1.64, 13.65, 13.71, 15.60, 15.66, 15.80, 16.25, 23.39, 23.40, 25.81,
29.84, 29.85, 29.88, 29.90, 31.25, 31.63, 40.80, 40.86, 43.28, 43.31,
60.73, 77.61, 77.67, 167.67, 167.71, 175.99 ppm. HRMS: calcd. for
C17H30O4Si [M]+ 326.1913; found 326.1918.

Synthesis of 13b: 2-Chloro-2-oxoethyl propionate was prepared according to the procedure used for the synthesis of 15. A solution
of 2-chloro-2-oxoethyl propionate (300 mg, 2.0 mmol) in CH2Cl2
(2 mL) was added to a solution of 16 (2.0 mmol) in CH2Cl2 (10 mL)
and Et3N (1 mL). The resulting mixture was stirred at 20 C for 18 h.
The solvent was then removed under reduced pressure, and CH2Cl2
(30 mL) and water (30 mL) were added. The organic layer was separated, washed with brine (10 mL), and dried with Na2SO4. The solvent was removed under reduced pressure. The resulting residue
was purified by silica gel column chromatography (petroleum
ether/EtOAc, 10:1) to give the desired compound (i.e., 13b).

10b: Colorless oil (544 mg, 84 %). 1H NMR (CDCl3): = 0.04 (s, 3 H),
0.05 (s, 3 H), 0.610.65 (m, 2 H), 1.32 (d, J = 8.0 Hz, 3 H), 1.561.62

13b: Colorless oil (340 mg, 57 %). 1H NMR (CDCl3): = 0.04 (s, 6 H),
0.600.64 (m, 2 H), 1.18 (t, J = 8.0 Hz, 3 H), 1.52 (s, 6 H), 1.721.79

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Full Paper
(m, 2 H), 2.022.06 (m, 2 H), 2.44 (q, J = 8.0 Hz, 2 H), 4.53 (s, 2 H),
5.58 (s, 1 H) ppm. 13C NMR (CDCl3): = 1.62, 8.94, 11.65, 22.17,
26.25, 27.14, 28.78, 60.92, 86.01, 118.74, 160.95, 166.35, 173.69 ppm.
HRMS: calcd. for C15H26O4Si [M]+ 298.1600; found 298.1598.

Acknowledgments
The authors thank Joos Kiener for help with the data acquisition
for the generation of the refined musk olfactophore model, and
Dr. Lijun Zhou for the odor-threshold determination. The National Natural Science Foundation of China (NSFC) (grant numbers 21102178 and 21402239) is acknowledged for funding.

[9]

Keywords: Fragrances Silicon Silanes Molecular

modeling Structureactivity relationships
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Received: October 19, 2015

Published Online:

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Full Paper
Fragrances

Sila-Rosamusk, sila-Romandolide, silaApplelide, and their dehydro derivatives were synthesized from sila-analogs
of Artemone and Herbac by
hydride reduction and subsequent esterification. The olfactory properties of
these compounds allowed a refined
musk olfactophore model to be developed. The model shows that it is likely
that linear and macrocyclic musks address the same odorant receptors.

J. Liu,* Y. Zou, W. Fan, J. Mao,

G. Chai, P. Li, Z. Qu, Y. Zong,
J. Zhang,* P. Kraft* ............................ 18
Synthesis and Olfactory Properties
of Silicon-Containing Analogs of
Rosamusk, Romandolide, and Applelide: Insights into the Structural
Parameters of Linear Alicyclic Musks

DOI: 10.1002/ejoc.201501338

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Eur. J. Org. Chem. 2016 ISSN 10990682

SUPPORTING INFORMATION
DOI: 10.1002/ejoc.201501338
Title: Synthesis and Olfactory Properties of Silicon-Containing Analogs of Rosamusk, Romandolide, and Applelide:
Insights into the Structural Parameters of Linear Alicyclic Musks
Author(s): Junhui Liu,* Yue Zou, Wu Fan, Jian Mao, Guobi Chai, Peng Li, Zhan Qu, Yongli Zong, Jianxun
Zhang,* Philip Kraft*

Table of Contents

1.

Olfactophore Model

2.

NMR Spectra of New Compounds

1. Olfactophore Model
Definition: HBA (hydrogen bond acceptor) HBA HYDROPHOBIC HYDROPHOBIC 4 EXCLUDED VOLUMES
Weights: 3.31204; 3.31204; 3.31204; 3.31204; 3.31204.
Spacing: 50. Variable Weight: No. Variable Tolerance: No. Olfactophore Space: 9215.84
Fixed Cost: 245.412. Null Cost: 644.308. Null Cost Distance: 243.55.

Geometric features:

Figure S1. Geometric features of the refined musk olfactophore model.

Figure S2. Graphical representation of the correlation of the model in logarithmic scale.

Figure S3. Odor thresholds and comparative calculation of activities for the musk odorants features the Supporting Information of
ref.[2a]
using the refined musk olfactophore model depicted in Figure 3.

Figure S3, contd. Odor thresholds and comparative calculation of activities for the musk odorants features the Supporting Information
of ref.[2a] using the refined musk olfactophore model depicted in Figure 3.

2. NMR Spectra of New Compounds

1

H NMR-1b

13

C NMR-1b

H NMR-2b

13

C NMR-2b

H NMR-3b

13

C NMR-3b

10

H NMR-4b

11

13

C NMR-4b

12

H NMR-5b

13

13

C NMR-5b

14

H NMR-6b

15

13

C NMR-6b

16

H NMR-7b

17

13

C NMR-7b

18

H NMR-8b

19

13

C NMR-8b

20

H NMR-9b

21

13

C NMR-9b

22

H NMR-10b

23

13

C NMR-10b

24

H NMR-11b

25

13

C NMR-11b

26

H NMR-12b

27

13

C NMR-12b

28

H NMR-13b

29

13

C NMR-13b

30

H NMR-16

31

13

C NMR-16

32