A New Family of Rigid Dienone Musks Challenges the Perceptive Range of the Human Olfactory Receptor OR5AN1

Article abstract of DOI:10.1055/s-0040-1708009

A new family of dienone musks was discovered by alkylation of different aldehydes with but-3-en-1-yn-1-yllithium and subsequent domino reaction of a Saucy-Marbet transfer vinylation-Claisen rearrangement with an intramolecular Diels-Alder reaction, and concluding Lewis acid catalyzed double-bond isomerization. The newly synthesized dienone structures possess pleasant musk odors displaying fatty, slightly fruity and green facets. Although the dienone musks were predicted in silico to bind to the OR5AN1 receptor based on QM/MM calculations, they were found to be inactive in the in vitro assay. The latter results suggest that the OR5AN1 receptor is not the prime musk receptor but primarily responsible for the animalic character of certain macrocyclic ketones and nitro musks.

Full text of DOI:10.1055/s-0040-1708009

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
2020, 31, A–E
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J. Liu et al.
Letter
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A New Family of Rigid Dienone Musks Challenges the Perceptive
Range of the Human Olfactory Receptor OR5AN1
Jie Liua,d
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Vera Hürlimannb
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Roger Emterb
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Stephanie M. Linkerc
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Yue Zoud
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Lijun Zhoud
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Quanrui Wang*a
Sereina Riniker*c
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Philip Kraft*b
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a Department of Chemistry, Fudan University, 2205 Songhu
Road, Shanghai, 200438, P. R. of China
qrwang@fudan.edu.cn
b Givaudan Fragrances S&T, Ingredients Research,
Kemptpark 50, 8310 Kemptthal, Switzerland
philip.kraft@givaudan.com
c Department of Chemistry and Applied Biosciences, ETH
Zürich, Vladimir-Prelog-Weg 2, 8093 Zürich, Switzerland
sriniker@ethz.ch
d Givaudan Fragrances (Shanghai) Ltd, 298 Li Shi Zhen Road,
Shanghai, 201203, P. R. of China
Dedicated to the memory of Professor Georg Fráter
(* 27 September 1941; † 25 June 2019)
Received: 13.02.2020
Accepted after revision: 08.03.2020
Published online: 24.03.2020
Like no other perfumery material, musks embody se-
ductive sensuality, irresistible attraction and erogenous
magnetism, attributes that define a perfume: Musks make
us dream.1 Abstracted from the complex odor of Tonquin
musk (Moschus moschiferus L.) tincture with its principle
odorant (R)-(–)-muscone (1, Figure 1), musks come in many
different molecular shapes and fragrant tonalities.2 Howev-
er, in terms of odor, there are two main subfamilies: the an-
imalic-powdery type with the nitro arene musk ketone (2)
and (R)-(–)-muscone (1) being most representative, and the
musky-floral type with the macrolide Thibetolide/Exal-
tolide (3) as well as the polycyclic aromatic musk (PCM)
Galaxolide (4) as major representatives. The more recent
fourth class of linear alicyclic musks, with Sylkolide (5)3 as
example, also belongs to the musky-floral family. In princi-
ple, this is also true for the latest class of musk odorants
that derived from 6 as principal lead structure discovered
during derivatization of carotol.4 This fifth class features a
dienone motif with the terminal (E)-double bonds substi-
tuted by two bulky moieties, as exemplified in compounds
7–10.5,6 The steric bulk on the -carbon atom is most im-
portant for the muskiness, as demonstrated in 7,5 but the
sila-derivative 11 in comparison with 7 indicated that the
size of the TMS group already slightly exceeds the optimal
dimensions of the binding pocket, as indicated by the in-
DOI: 10.1055/s-0040-1708009; Art ID: st-2020-b0088-l
Abstract A new family of dienone musks was discovered by alkylation
of different aldehydes with but-3-en-1-yn-1-yllithium and subsequent
domino reaction of a Saucy–Marbet transfer vinylation–Claisen rear-
rangement with an intramolecular Diels–Alder reaction, and concluding
Lewis acid catalyzed double-bond isomerization. The newly synthesized
dienone structures possess pleasant musk odors displaying fatty, slight-
ly fruity and green facets. Although the dienone musks were predicted
in silico to bind to the OR5AN1 receptor based on QM/MM calculations,
they were found to be inactive in the in vitro assay. The latter results
suggest that the OR5AN1 receptor is not the prime musk receptor but
primarily responsible for the animalic character of certain macrocyclic
ketones and nitro musks.
Key words fragrances, musk odorants, odorant receptors, olfactory
properties, structure–activity relationships
A window open onto an Italian cliff.
Liguria, cluster pines, summertime. […]
It is like some imaginary musk,
a fairy tale, something more real than reality.
Daniela Andrier, Joy – The Brightness of Life1
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–E
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
J. Liu et al.
Letter
Synlett
creased odor perception threshold (th).7 The ,-double
bond outweighs the contribution of the ,-double bond,8
but both are indispensable for a musk odor sensation.
Whereas linear alicyclic musks display fruity side notes in
the direction of raspberry as in the case of Sylkolide (5) or
pear for Helvetolide, the dienone musks tend towards green
aspects as in 10 and 11 or earthy facets as manifest in the
beetroot character of 9.
lides,11 was reacted with but-3-en-1-yn-1-yl lithium to pro-
vide the dienyne alcohol 15 in 96% yield. In the presence of
trace amounts of p-toluenesulfonic acid monohydrate,
Saucy–Marbet reaction12 of 15 with isopropenyl methyl
ether (16) then furnished in an efficient domino reaction
consisting of [3,3]-sigmatropic rearrangement of 17 and
subsequent IMDA of the allenylic intermediate 18, the
2,6,7,7a-tetrahydro-1H-inden-4-yl ketone 19 in 85% yield.
This unconjugated dienone 19 was devoid of any musk
character and possessed a woody-green odor with carrot-
like earthy aspects instead. We were however much de-
lighted to find the sought-after musk note upon isomeriza-
tion of the dienone system of 19 with aluminum trichlo-
ride, which afforded in 51% yield the new conjugated dien-
one musk 12 with tetrasubstituted ,-double bond and an
encouraging threshold of 2.9 ng/L air.
O
15
16
O2N
NO2
O
O
O
1
2
3
(R)-(–)-muscone
musky, animalic,
powdery
musk ketone
musky, animalic,
powdery
Thibetolide/
Exaltolide
musky, floral
1.4 ng/L air
0.59 ng/L air
0.1 ng/L air
16
OMe
14
BuLi
pTsOH
MePh
O
OH
O
O
O
O
13
15
O
4
5
6
dry,
musky
Galaxolide
musky, floral
th 0.9 ng/L air
Sylkolide
musky, floral-fruity
th 0.60 ng/L air
[3,3]
th 1.0 ng/L air
O
O
17
18
O
O
O
AlCl3
CH2Cl2
DA
O
O
8
7
9
sweet, violet,
musky-woody,
musky, beetroot,
musky
ionone
dried fruits
th 0.54 ng/L air
th 0.66 ng/L air
th 0.26 ng/L air
19
12
woody, green, carrot
musky, sl. fatty, sl. green
th 500 ng/L air
th 2.9 ng/L air
O
O
O
Scheme 1 Synthetic route to the bicyclic dienone musk 12
Si
Although slightly weaker than the representatives 6–10,
this new musk 12 is with C16H24O (232.37 u) both heavier
and more rigid in structure than these leads. Since the se-
quence delineated in Scheme 1 allowed for easy variation of
the substitution patterns, we investigated the structure–
odor correlation of this new family with the derivatives
summarized in Figure 2.
10
11
12
musky, green-
floral, muguet
th 0.90 ng/L air
floral-fatty musk,
rose, sl. green
th 10.6 ng/L air
musky, sl. fatty,
sl. green
th 2.9 ng/L air
Figure 1 The five different classes of musk odorants: Macrocyclic ke-
tones 1, nitro musks 2, macrocyclic lactones 3, polycyclic musks (PCM)
4, linear alicyclic musks 5, and the most recently discovered dienone
musks 6–12
While the gem-dimethyl cyclopentyl substituent of 9 is
at a different position in 12, it is essential nonetheless: The
nor structure 20 is greener and weaker (th 21 ng/L air) but
still musky, and so is the ethyl derivative 21 (th 40 ng/L air),
though it is less green. Interestingly, the isopropyl deriva-
tive 22 (th 25 ng/L air) is somewhat stronger again than the
ethyl derivative 21, and this goes together with a pro-
nounced green tonality. In contrast, the spiro[cyclohexane-
1,2′-inden] system 23 definitely exceeds the boundaries of
the musk receptor and thus, 23 is devoid of any musk char-
Since tandem sigmatropic rearrangements of vinyl
propargyl systems with allenylic intramolecular Diels–
Alder (IMDA) reactions offer facile access to tetrahydro-
indenes,9 we had the idea to construct novel conformationally
confined bicyclic dienone musks by developing a new dom-
ino reaction that combines a propargyl Claisen rearrange-
ment10 with an allenylic IMDA. As outlined in Scheme 1,
2,2,5-trimethyl-4-hexenal (13), easily available for instance
by enolate alkylation of isobutyraldehyde with prenyl ha-
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–E

C
J. Liu et al.
Letter
Synlett
the published protocol with open-source tools, and validat-
ed it using the homology model and ten compounds from
the original reference14 (for details see the Supporting In-
formation). Our results reproduced the correlation between
the QM/MM binding energies and the experimental EC50
values as observed previously14 (cf. the Supporting Infor-
mation). Subsequently, we calculated the QM/MM binding
energy of novel compounds 9, 12, 20–23, 26–27 by using
the same protocol (Table 1). For all compounds, the import-
ant hydrogen bond with Tyr260 and the hydrophobic inter-
actions with the surrounding Phe residues as described pre-
viously14 were established, and the resulting QM/MM bind-
ing energies were found to be in a similar range as reported
for the known musk odorants.14 As an example, the top pos-
es of the lead compound 9 and the new musk 12 are shown
in Figure 3. Interestingly, although the two odorants display
the same key interactions, the dienone moieties do not su-
perimpose. This observation can be explained by the rela-
tively large binding pocket, which allows for different bind-
ing modes to form a hydrogen bond with Tyr260 with only
small differences in binding energy.
O
O
O
20
21
musky,
fatty, weak
th 40 ng/L air
22
green, musky,
fatty, sl. fruity,
th 21 ng/L air
green, musky,
powdery, fruity,
th 25 ng/L air
O
O
O
23
24
odorless
25
weak, woody,
fruity-floral
th 310 ng/L air
green, aromatic,
fruity, clary sage
th 94 ng/L air
O
O
O
26
27
28
odorless
green, fatty,
musky
th 30 ng/L air
musky, fatty,
sl. fruity, green
th 0.4 ng/L air
Figure 2 Olfactory properties of the new dienone musks 20–28
acter. Its gem-diethyl seco-structure 24 is completely odor-
less even. Similarly, the additional methyl substituent on
the cyclohexyl ring in 25 eradicated the muskiness of 12,
and the compound smelled green, aromatic, and fruity in
the direction of clary sage. Incorporating one cyclopentenyl
methyl group as methylene unit into the ring enlarges the
system to the 3,4,5,6,7,8-hexahydronaphthalen-1(2H)-
ylidene 26, which is musky-green and comparable with 20–
22 in terms of intensity. Adding another methyl group at C-
7′, however, culminated in the most intense dienone musk
27 of this new series, possessing a pleasant musk odor with
fatty, slightly fruity and again green facets. With an odor
threshold of 0.4 ng/L air it is almost as intense as the most
potent dienone musk 9 (0.26 ng/L air) reported so far. Com-
pound 28 finally demonstrates that the bulky substructures
on the - and - carbon atom of the dienone backbone
should be trans-configured, since it is, with its two adjacent
gem-dimethyl groups in the ,-annulating cyclopentenyl
ring, completely odorless.
Since this new family of dienone musks 12 (2.9 ng/L air)
and 20–27 is structurally rather rigid and conformationally
confined, it should be ideally suited to characterize the
spectrum of activity of the OR5AN1 receptor, which was
considered to be the prime human musk receptor.13 Ahmed
et al.14 had reported a positive correlation between EC50
values and calculated QM/MM binding energies of a series
of musk odorants to OR5AN1. These binding energies were
obtained from docking into a homology model of OR5AN1
followed by QM/MM optimization. We first reconstructed
Figure 3 Top binding poses (QM/MM geometry optimized) of com-
pounds 9 (cyan) and 12 (yellow) with the homology model of OR5AN1.
Key residues in the binding pocket (Tyr260, Phe105, Phe194, Phe207,
Phe252) are shown in color. In addition, the hydrogen bond between
the carbonyl group of the ligands and Tyr260 is indicated.
Based on the calculations, all dienone musks 9, 12, 20–
23 and 26–27 were predicted to bind to the OR5AN1 musk
receptor with QM/MM binding energies Ebind comparable to
those of the reference musks reported previously.14 To test
this prediction, the OR5AN1 receptor was expressed in
HEK293 cells along with RTP1S and a luciferase reporter
gene according to ref.14 While the results from the literature
were confirmed, including the weak activation by Thibet-
olide/Exaltolide (3), no activation of OR5AN1 by the dien-
one musks 9, 12, 20–23, 26–27 (Table 1) was observed (only
compounds >10% relative efficacy were considered activa-
tors). Since, however, the dienones do smell musky, other
receptors must be involved. Recently, the OR5A2 receptor
was reported to be activated by a diverse range of musk
odorants,15 indicating that OR5A2 might be the prime musk
receptor. However, when we transfected OR5A2 along with
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J. Liu et al.
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Table 1 Comparison of Calculated QM/MM Binding Energy Ebind [kcal/mol] Profiles, Measured EC50 [M], and Relative Efficacy [%] for the Human
OR5AN1 Musk Receptor
Compound
E
bind [kcal/mol]
EC50
Relative efficacy [%]
(OR5AN1)b
(OR5AN1)
(OR5AN1)a
3 (Thibetolide/Exaltolide)
4 (Galaxolide)
–53.1
–45.5
–45.4
–45.9
–48.1
–55.9
–45.3
–49.0
–41.8
–41.7
–45.7
–53.4
–50.9
–48.5
7.4
n.i.
9.4
6.4
1.0
0.88
n.i.
n.i.
n.i.
n.i.
n.i.
n.i.
n.i.
n.i.
16
6
Cyclohexadecanone
52
48
73
100
8
Cyclohexadec-5-en-1-one (Velvione)
1-(tert-Butyl)-3,5-dimethyl-2,4,6-trinitrobenzene (musk xylene)
1-(tert-Butyl)-3,4,5-trimethyl-2,6-dinitrobenzene (musk tibetene)
Dienone musk 9
Dienone musk 12
7
Dienone musk 20
6
Dienone musk 21
7
Dienone musk 22
7
Dienone musk 23
6
Dienone musk 26
7
Dienone musk 27
7
a n.i. = no induction.
b Relative activation to musk tibetene (= 100%).
RTP1S and RTP2 into HEK293 cells, no activation of OR5A2
by ambrettolide, musk ketone, or muscone was observed,
suggesting that OR5A2 is not functionally expressed in our
cell system.
In summary, we have discovered a new family of dien-
one musks16–18 that does not activate the OR5AN1 receptor
in vitro, although computational models predicted it would.
Since only animalic-powdery musks such as ketones 1 and
2 activate OR5AN1 with significant efficacy, we believe this
odorant receptor to be responsible for the animalic rather
than the musk character. The prime musk receptor is then
yet to be discovered and characterized, but the newly syn-
thesized rigid dienone musks will help to shed light on
which receptor that is.
The QM/MM binding energies predicted that the dien-
one musks 9, 12, 20–23, 26–27 bind to OR5AN1 whereas
the in vitro experiments showed no activation of this re-
ceptor with these compounds (Table 1). To elucidate the
reasons behind this discrepancy, we calculated the binding
energy of five additional odorants, which were reported
previously to not activate OR5AN1.14 For all these inactive
compounds, including Galaxolide (4; Table 1), the calculat-
ed energy values were again in a similar range to those of
the active compounds; i.e., they would be predicted to be
active (cf. Supporting Information). These results taken to-
gether indicate that the published computational work-
flow,14 which was validated only against active compounds,
is not able to discriminate between odorants that activate
OR5AN1 and those that do not. A discussion on the possible
causes of this result and on the limitations of the computa-
tional workflow is included in the Supporting Information.
Briefly, we conclude that to distinguish between active and
inactive compounds, it may be necessary to include entro-
pic effects in the computational workflow, for example by
characterizing the dynamics of the system both in the pres-
ence and in the absence of the odorants. This hypothesis is
supported by molecular dynamics simulations of the
OR5AN1–ligand complexes reported previously,14 in which
substantial conformational fluctuations of the binding site
were observed.
Funding Information
The financial support from the National Natural Science Foundation
of China (NNSFC; Grant 21971042) is as well acknowledged with grat-
itude.
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Acknowledgment
We thank Victor Batista and co-workers for providing the homology
model of OR5AN1, exemplary input files for Gaussian09 and helpful
discussions on the computational workflow. We are also grateful to
Cornelia Wartmann for NMR experiments, to Yumiko Weiner-Sekiya
for HRMS measurements, to Sandro Dossenbach, his team and their
panelists for the determination of odor thresholds, and to Dominique
Lelievre for the olfactory evaluation. For the background picture of
the Ligurian coastal forest with its unique musky sun-struck resin
scent that we used in the graphical abstract, we are indebted to
Roman Kaiser.
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–E

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J. Liu et al.
Letter
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Supporting Information
g, 56.0 mmol), p-toluenesulfonic acid monohydrate (2 mg) and
toluene (40 mL). The reaction mixture was heated to 150 °C for
24 h, prior to removal of the solvent and purification by flash
chromatography (PE/MTBE = 95:5, Rf 0.44) and bulb-to-bulb
distillation, which furnished the tetrahydroindenyl ketone 19
(2.8 g, 85%, b.p. 152 °C/0.18 mbar) as a colorless odoriferous
liquid.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0040-1708009.
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References and Notes
(17) Isomerization of 19 to the Dienone Musk 12: At 0 °C, AlCl3
(0.1 equiv, 58 mg, 0.43 mmol) was added to a solution of ketone
19 (1.0 g, 4.3 mmol) in dichloromethane (20 mL). The resulting
mixture was stirred for 2 h at this temperature, and then
allowed to warm to room temp. After stirring overnight,
quenching with 1M aq. HCl, extraction with dichloromethane
(3 × 30 mL), and purification by flash chromatography
(PE/MTBE = 95:5, Rf 0.43) with subsequent bulb-to-bulb distil-
lation provided the (E)-configured dienone musk 12 (510 mg,
51%, b.p. 140 °C/0.14 mbar) as pale-yellow liquid. 1H NMR (400
MHz, CDCl3):  = 5.82 (s, 1 H, 3-H), 2.98 (td, J = 6.5, 2.0 Hz, 2 H,
5′-H2), 2.30 (s, 2 H, 3′-H2), 2.27–2.25 (m, 2 H, 1′-H2), 2.19 (s, 3 H,
1-H3), 1.55 (t, J = 6.5 Hz, 2 H, 6′-H2), 1.09 (s, 6 H, Me2C-2′), 1.02
(s, 6 H, Me2C-7′) ppm. 1H,1H NOESY (500 MHz, CDCl3): 1-H3 × 5′-
H2, 3-H × 3′-H2. 13C NMR (100 MHz, CDCl3):  = 199.2 (s, C-2),
159.8 (s, C-7a′), 151.7 (s, C-4′), 132.9 (s, C-3a′), 118.1 (d, C-3),
48.0 (t, C-1′), 46.7 (t, C-3′), 37.6 (t, C-6′), 36.9 (s, C-2′), 32.7 (s, C-
7′), 32.0 (q, C-1), 29.7 (2q, Me2C-2′), 26.3 (2q, Me2C-7′), 24.4 (t,
C-5′) ppm. Odor description: musky, slightly fatty, slightly
green. Odor threshold (th): 2.9 ng/L air.
(1) Andrier, D. In Joy: The Brightness of Life, In Bulgari: The Perfume
of Gems; Marchettti, S., Ed.; Rizzoli: New York, 2018.
(2) Kraft, P. In Chemistry and Technology of Flavors and Fragrances;
Rowe, D. J., Ed.; Blackwell Publishing: Oxford, 2005, 143.
(3) Kraft, P.; Eichenberger, W. Eur. J. Org. Chem. 2004, 354.
(4) Kula, J.; Bonikowski, R.; Staniszewska, M.; Krakowiak, A.;
Wieczorek, M. W.; Majzner, W. R.; Bujacz, G. D. Eur. J. Org. Chem.
2002, 1826.
(5) Kraft, P.; Popaj, K. Tetrahedron 2006, 62, 12211.
(6) Kraft, P.; Popaj, K. Eur. J. Org. Chem. 2008, 4806.
(7) Geyer, M.; Bauer, J.; Burschka, C.; Kraft, P.; Tacke, R. Eur. J. Inorg.
Chem. 2011, 2769.
(8) Kraft, P.; Jordi, S.; Denizot, N.; Felker, I. Eur. J. Org. Chem. 2014,
554.
(9) For selected examples, see: (a) Gibbs, R. A.; Bartels, K.; Lee, R. W.
K.; Okamura, W. H. J. Am. Chem. Soc. 1989, 111, 3717. (b) Curtin,
M. L.; Okamura, W. H. J. Org. Chem. 1990, 55, 5278. (c) Gidlöf, R.;
Johansson, M.; Sterner, O. Org. Lett. 2010, 12, 5100. (d) Zhao, Y.;
Jin, J.; Boyle, J. W.; Lee, B. R.; Day, D. P.; Susanti, D.; Clarkson, G.
J.; Chan, P. W. H. J. Org. Chem. 2017, 82, 2826.
(18) In vitro OR5AN1 Assay: HEK293T cells were grown in DMEM
medium containing FBS (9%). The cells were seeded in 96-well
plates (10,000 cells/well). After 24 h, the cells were transfected
with plasmids for the expression of human OR5AN1, a human
RTP1S variant (V227I), and a cAMP-responsive element lucifer-
ase reporter using Lipofectamine 2000 according to the manu-
facturer’s instructions. For each plate pcDNA3.1(+)-Lucy-FLAG-
rho-OR5AN1 (0.625 g), pcDNA3.1(+)-RTP1S-V227I (1 g) and
pGL4.29 (1 g) were transfected. The cells were stimulated with
the musks (dissolved in growth medium) 18 h post transfection.
After 4 h, the cells were lysed, and the luciferase activity was
measured. Efficacy was determined as maximal activation over
the full dose-response curve. EC50 values (conc. for 50% efficacy)
were determined by the Graph pad prism program v 6.09 with
four-parameter curve fit. Relative efficacy was calculated in
relation to the most active compound (musk tibetene = 100%).
Compounds with maximal efficacy <10% were considered inac-
tive.
(10) For a general review on propargyl Claisen rearrangements see:
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(11) Mayr, H.; Heilmann, W.; Bäuml, E.; Vorbrüggen, H. Chem. Ber.
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(12) Saucy, G.; Marbet, R. Helv. Chim. Acta 1967, 50, 1158.
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Niimura, Y.; Ihara, S.; Shirasu, M.; Touhara, K. J. Neurosci. 2016,
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(16) Saucy–Marbet/IMDA Reaction to Ketone 19: A 100-mL auto-
clave was charged with a mixture of vinyl propargyl alcohol 15
(2.69 g, 14.0 mmol), isopropenyl methyl ether (16, 4 equiv, 4.04
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–E