The Smelling Principle of Vetiver Oil, Unveiled by Chemical Synthesis

Article abstract of DOI:10.1002/anie.202014609

Vetiver oil, produced on a multiton-scale from the roots of vetiver grass, is one of the finest and most popular perfumery materials, appearing in over a third of all fragrances. It is a complex mixture of hundreds of molecules and the specific odorant, responsible for its characteristic suave and sweet transparent, woody-ambery smell, has remained a mystery until today. Herein, we prove by an eleven-step chemical synthesis, employing a novel asymmetric organocatalytic Mukaiyama–Michael addition, that (+)-2-epi-ziza-6(13)en-3-one is the active smelling principle of vetiver oil. Its olfactory evaluation reveals a remarkable odor threshold of 29 picograms per liter air, responsible for the special sensuous aura it lends to perfumes and the quasi-pheromone-like effect it has on perfumers and consumers alike.

Full text of DOI:10.1002/anie.202014609

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
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Accepted Article
Title: The Odorous Principle of Vetiver Oil, Unveiled by Chemical
Synthesis
Authors: Benjamin List, Jie Ouyang, Hanyong Bae, Samuel Jordi,
Quang Minh Dao, Sandro Dossenbach, Stefanie Dehn, Juilia
Beatrice Lingnau, Chandra Kanta De, and Philip Kraft
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202014609
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10.1002/anie.202014609
Angewandte Chemie International Edition
COMMUNICATION
The Odorous Principle of Vetiver Oil, Unveiled by
Chemical Synthesis
Jie Ouyang, Hanyong Bae, Samuel Jordi, Quang Minh Dao, Sandro Dossenbach, Stefanie Dehn, Julia B. Lingnau,
Chandra Kanta De, Philip Kraft* and Benjamin List*
[a]
[b]
[c]
Dr. Jie Ouyang, Quang Minh Dao, Stefanie Dehn, Julia B. Lingnau, Dr. Chandra Kanta De, Prof. Dr. Benjamin List
Max-Planck-Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 1, 45470 Mülheim an der Ruhr (Germany).
Email: list@kofo.mpg.de
Samuel Jordi, Sandro Dossenbach, Dr. Philip Kraft.
Givaudan Schweiz AG, Fragrances S&T, Ingredients Research, Kemptpark 50, 8310 Kemptthal (Switzerland).
Email: philip.kraft@givaudan.com
Prof. Dr. Hanyong Bae
Department of Chemistry, Sungkyunkwan University 2066, Seobu-ro, Jangan-gu, Suwon, 16419 (Republic of Korea).
vetiver character.[7] An exhaustive analysis by Weyerstahl et al. in 2000
seemed to corroborate that finding, since all other vetiver odorants such as
eremophiladienal (7), 1,7-cyclogerma-1(10)-4-dienal (8), as well as ziza-
6(13)-enone (9) and 2-epi-ziza-6(13)-enone (10), were described by them as
khusimone-like but weaker.[8] However, with a relatively high threshold of
4.7 ng/L air, khusimone (6) cannot be the odorous principle of vetiver oil.
Vetiver oil, produced on a multitone-scale from the roots of vetiver grass, is
one of the finest and most popular perfumery materials, appearing in over a
third of all fragrances.[1] It is a complex mixture of hundreds of molecules
and the specific odorant, responsible for its characteristic suave and sweet
transparent, woody-ambery smell, has remained a mystery until today.
Herein, we prove by an eleven-step chemical synthesis, employing a novel
asymmetric organocatalytic Mukaiyama–Michael addition, that (+)-2-epi-
ziza-6(13)en-3-one is the active smelling principle of vetiver oil. Its olfactory
evaluation reveals a remarkable odor threshold of 29 picograms per liter air,
responsible for the special sensuous aura it lends to perfumes and the quasi
pheromone-like effect it has on perfumers and consumers alike.
This was also what Belhassen et al. concluded in a recent study despite the
fact that khusimone (6) does indeed display the typical woody-ambery
vetiver profile.[9] Using a combination of GC × GC/MS and GC–
olfactometry, they discussed ziza-6(13)en-3-one (9) and 2-epi-ziza-6(13)en-
3-one (10) as potentially important odor vectors since they displayed higher
flavor dilution factors than khusimone (6). They also attributed a typical
vetiver note to ziza-6(13)-en-3-ol (11),[10] the corresponding (R,R)-
configured alcohol of compound 9, but found it weaker. Different to
patchouli (Clearwood) or sandalwood oil (Dreamwood),[5] an industrially
viable biotechnological process does not exist for vetiver oil, and would first
require knowledge about its smelling principles. To make matters worse,
there were even speculations about root bacteria being involved in the
biogenesis of the components.[11] So, independently from Belhassen et al., the
smelling principle of vetiver oil was intensely hounded for in the fragrance
industry. A large-scale distillation (800 g) of vetiver oil Haiti (Fig. 2) with a
50-cm Sulzer column and then Spaltrohr system followed by separation of
the aldehydes and ketones in the best smelling fraction with the Girard P
reagent and subsequent flash chromatographic fractionation indeed
suggested the ketone 10 to be the most likely candidate for the principal
odorant. However, due to the enormous complexity of the essential oil (Fig.
2), of which only 155 components have been identified,[8, 6a] falsifications by
high-impact trace impurities could never be excluded. In addition, easier
accessible synthetic substructures did not smell of vetiver[12], and casted
some doubt again on substances 9–11 being indeed the key vetiver odorants.
Since the presence of an extremely intense odoriferous minor constituent is
always possible and can be overlooked even by state-of-the-art analytical
techniques (Fig. 2), the pure substances are required to reach a definitive
conclusion about their olfactory importance. As for GC–olfactometry, any
effort to physically isolate the key odorant from the complex matrix even by
preparative GC is prone to contaminations.
From ‘Chanel N°5’ (1921) by Ernest Beaux and ‘Vetiver de Guerlain’ (1959)
by Jean-Paul Guerlain to the extreme dose of 90% in the rebellious ‘Turtle
Vetiver’ (LesNez, 2019) by Isabelle Doyen, vetiver oil is omnipresent in
perfumery.[2] No other fragrance material appears more often in the name of
a perfume: fragrantica.com currently lists 2267 masculine, 1976 feminine,
and 2302 unisex perfumes centered on this, in the truest sense, essential oil.
It is a chameleon in applications and can, for instance, be used to make a
classic cologne more masculine or to ground lush feminine florals with a
touch of earthiness.[3] This versatility is due to a characteristic suave and
sweet woody-ambery transparency, an aura-like effect as generally displayed
by odorants of extremely low threshold, such as Paradisone [(+)-(1R,2S,Z)-
methyl dihydrojasmonate][4] and rotundone[5]. The essential oil of vetiver is
obtained in 0.2–0.3% yield by hydrodistillation of the dried roots of the tufted
perennial grass Chrysopogon zizanioides (L.) Roberty. Despite a price of
350–500 $/kg, its worldwide consumption is estimated at 300–400 t/year, of
which 60% comes from the Les Cayes commune of Haiti.[6] As one of the
most complex essential oils, it contains several hundred sesquiterpene
derivatives with a broad structural diversity, many of which are not yet
identified. It is this complexity that has made the analysis of vetiver oil
immensely challenging, despite the significant advances of modern analytic
methods. No satisfactory reconstitution of this key perfumery material is
available to the perfumer, and no single molecule conveys the typical vetiver
character.[5] In the odor profile of vetiver, a fresh hesperidic, citrusy
grapefruit top connects with a dark and distinct suave and sweet transparent
woody-ambery base to form a universal skeleton, a perfume within a perfume
that can be interpreted in an almost infinite variety. While the citrusy
grapefruit character is well understood and originates from -vetivone (1),
-vetivone (2), and nootkatone (3), earthy aspects are due to (–)-geosmine
(4), with a little help by nor-acorenone, and the creamy santal character
mainly results from (E)-isovalencenol (5). However, the typical transparent
woody-ambery character of vetiver is still not understood, and its odorous
principle remains enigmatic. Khusimone (6), present in about 2% in the
essential oil and first proposed as a smelling principle in 1980 by Maurer, is
the only component the literature agrees upon to possess this highly desired
In light of these considerations, it became apparent that only a stereoselective
chemical total synthesis could provide clarity. We, therefore, embarked upon
the development of an enantioselective and diastereoselective route toward
2-epi-ziza-6(13)en-3-one (10). In our synthesis design, the emphasis was
placed on developing a route that would early establish the correct (R)-
stereochemistry at C-8, which is common to all the zizaenone natural
products. The synthesis should be more flexible concerning the additional
stereogenic centers, potentially enabling access to different zizaenone
diastereomers for olfactory evaluation.
1
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Figure. 1. The important olfactory contributions to vetiver oil. -Vetivone (1), -vetivone (2) and nootkatone (3) are responsible for the grapefruit-rhubarb top note,
while (–)-geosmin (4) provides earthy aspects and (E)-isovalencenol a creamy, cedar- and sandalwood-type background. The highly desired transparent woody-
amber note has remained a mystery. Previously suggested but not unambiguously confirmed substances include eremophiladienal (7) and 1,7-cyclogerma-1(10),4-
dien-15-al (8), khusimone (6), ziza-6(13)-en-3-ol (11), ziza-6(13)-enone (9), and 2-epi-ziza-6(13)-enone (10).
As delineated in Fig. 3, for the key step in the construction of the unique
carbon skeleton of 2-epi-ziza-6(13)en-3-one (10), we designed an
intramolecular Pauson–Khand cyclization of 1-ethylidene-3-(2-methyl-3-
methylenepent-4-yn-2-yl)cyclopentane (20), which should afford the
tricyclic ziza-6(13)-en-3-one 21. Seeking to realize this synthetic blueprint,
an enantioselective Mukaiyama–Michael reaction of 2-cyclopentenone 12
with the readily accessible and commercially available silyl ketene acetal
(SKA) of methyl isobutyrate appeared to be ideally suited to assemble
enantiopure cyclopentane 15,[13] which in turn appeared to be a convenient
precursor of the Pauson–Khand substrate 20. Surprisingly, however, despite
intense recent research on asymmetric, catalytic Mukaiyama–Michael type
addition reactions, examples with 2-cyclopentenone as electrophile are
extremely rare, and the suggested substrate combination has even been
entirely unprecedented.[14]
2
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Figure 2. GC–Olfactometry of vetiver oil from Haiti. The overview GC trace (FID, upper part) demonstrates the enormous complexity of this natural essential oil,
being overloaded with hundreds of individual peaks. In this jungle of peaks, the blue signal indicates when the typical transparent vetiver character is recognizable
at the sniffing port. As was later verified by co-injection, these indeed correspond to ziza-6(13)-enone (9) and 2-epi-ziza-6(13)-enone (10).
Based on the concept of asymmetric counteranion-directed silylium Lewis
acid catalysis (Si-ACDC), previously developed in our laboratory,[15] we
suspected that our imidodiphosphorimidate (IDPi) catalyst class could enable
the desired transformation.[16] Indeed, after some design and experimentation,
which will be published separately, we could establish a method to access
the desired substituted cyclopentenone 15. Thus, upon treating 0.1 mol% of
imidodiphosphorimidate (IDPi) catalyst 14 with 2-cyclopentenone and silyl
ketene acetal 13, the desired (R)-configured silyl enol ether 15 was obtained
on a multigram scale in 95% yield with an excellent enantiomeric ratio of
98:2. Protodesilylation with trifluoroacetic acid and Wittig reaction with
ethyltriphenylphosphonium bromide provided the olefin 17 in 83% yield,
with an E/Z ratio of 1:1.7.[17] This material was directly converted into the
corresponding methyl ketone 18 in 83% yield on a multigram scale by adding
trimethylsilyl methyllithium, followed by protodesilylation.[18] Subsequent
addition of ethynyl magnesium bromide under conditions established by
Knochel et al. to counteract steric hindrance and reactivity issues, led to the
corresponding alcohol in 81% isolated yield.[19] The dehydration of this
intermediate turned out to be more challenging than expected and could only
be realized by utilizing the mild and efficient Burgess reagent,[20] providing
the desired product 20, the precursor of the central Pauson–Khand reaction
in 70% yield. As expected, the sterically highly demanding intramolecular
Pauson–Khand [2+2+1] cycloaddition became a critical bottleneck of our
synthetic sequence. Several well-established Pauson–Khand protocols failed
to furnish even traces of the desired product 21.[21] After surveying various
despite our best efforts, the powerful Pauson–Khand cyclization established
the entire carbon skeleton of the natural product, inducing all three rings, and
the critical quaternary stereogenic center in its correct configuration.
With enone 21 in hand, we felt in a very good position to accomplish the last
challenge of our synthesis, consisting of the selective reduction of the
cyclopentenone double bond. Even though this transformation seemed
simplistic at first sight, it turned out to be the most difficult one of the entire
sequence. Under various reduction conditions (e.g. Stryker's Reagent,[22]
SmI2,[23] Hantzsch ester,[24] Wilkinson's reagent,[25] etc., see Supp. Info.),
rather than the desired 1,4-reduction product, only products from the
corresponding 1,6-reduction of the exocyclic double bond were obtained.
Accordingly, an indirect method had to be developed. Indeed, by first
epoxidizing the much more reactive exocyclic olefin with freshly prepared
dimethyldioxirane (DMDO), epoxide 22 was smoothly obtained in 75%
yield (dr 9:1 at C-6).[26] The constitution and stereochemistry of this product
were confirmed by X-ray crystallography. Subsequent hydrogenation of the
enone double bond in the presence of Pd/C proceeded readily, along with a
hydrogenative ring-opening of the epoxide to provide alcohol 23 in 64%
yield (dr, 2:1, at C-5). We attributed the moderate diastereofacial
differentiation of this conjugate reduction to the negligible steric effect of the
equatorial methylene group of the epoxide at C-13. The subsequent
dehydration of primary alcohol 23 was realized via a Grieco elimination,[27]
resulting in three diastereoisomers in 65% total yield with a diastereomeric
ratio of 2.9:1:0.1 in favor of target 10. The obtained traces of product 25
presumably result from the isomerization of the minor isomer 24 under the
basic elimination conditions.
options,
a stepwise strategy was chosen, in which an 18-electron
dicobaltatetrahedrane complex was first prepared and isolated by reacting
alkyne 20 with dicobalt octacarbonyl. Its subsequent cyclization was
promoted by tert-butyl(methyl)sulfide in refluxing benzene to afford the
desired product 21 and its separable C2-epimer 27 (cf. Supp. Info.) in 25%
yield. While the overall yield of this transformation remained unsatisfactory,
3
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10.1002/anie.202014609
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Figure 3. Enantioselective total synthesis of 2-epi-ziza-6(13)-en-3-one 10. Reagents and conditions as follow. a) Cyclopentenone 12 (1 eq.), SKA 13 (1.05 eq.),
catalyst 14 (0.1 mol% loading), –78 °C, toluene, 95%, er 98:2. b) 15 (1 eq.), TFA (1.05 eq.), DCM, 23 °C, 10 min, 99%. c) ethyltriphenylphosphonium bromide (1.2
eq.), potassium tert-butoxide (1.2 eq.), THF, –60 °C, 1 h, then desilylated ketone (1 eq.), –60 °C to 23 °C, 83%, E:Z = 1:1.7. d) 17 (1.0 eq), (trimethylsilyl)methyl
lithium (2.5 eq), pentane, 0 °C, then MeOH, 2 h, 83%. e) LaCl3·2LiCl (1.06 eq), THF, 0 °C, then ethynylmagnesium chloride (1.7 eq), 81%. f) Burgess reagent (2.3
eq.), hexane:toluene (9:1), 60 °C, 19 h, 70%. g) Dicobalt octacarbonyl (1.3 eq.), diethyl ether, 23 °C. h) tert-butyl (methyl)sulfane (3.5 eq., based on 20), benzene,
90 °C, 19 h, 25% over 2 steps, diastereoisomers (dr 1.7:1 at C-2) were separated by preparative HPLC. i) DMDO (excess), DCM, 0 °C, 75%, with dr 9:1 at C-6 in
favor of 22. j) Palladium on activated charcoal (3 eq.), H2, ethyl acetate, 23 °C, 64%, dr 2:1 at C-5. k) 23 (1 eq.), 1-nitro-2-selenocyanatobenzene (1.28 eq.),
tributylphosphine (2.5 eq.), THF, 23 °C, 1 h, NaHCO3 (30 eq.), H2O2 (30% aq, 30 eq.), 23 °C, 4 h, 65%, dr (10:24: 5) = 2.9:1:0.1, diastereoisomers were separated
by preparative HPLC. SKA, silyl ketene acetal; TFA, trifluoroacetic acid; DCM, dichloromethane; THF, tetrahydrofuran; Burgess reagent, methyl N-
(triethylammoniumsulfonyl)carbamate; DMDO, dimethyldioxirane; er, enantiomeric ratios were measured by HPLC on a chiral stationary phase; dr, diastereomeric
ratios were determined either by NMR or GC.
Figure 4. Olfactory properties of the (1R)-configured ziza-6(13)-en-3-one stereoisomers 9, 10, 24, and 25; the enantiomeric antipodes ent-9, ent-10, ent-24, and
ent-25 are all odorless. Also shown is arborone (26), the smelling principle of the commercial perfumery ingredient Iso E Super, a superposition (75% electronic,
25% steric) of 2-epi-ziza-6(13)-en-3-one (10) on it explaining its the transparent woody-ambery odor profile in comparison to the odorless enantiomer ent-10, and
the setup for the determination of the odor thresholds by GC–olfactometry.
4
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COMMUNICATION
The olfactory properties and odor thresholds[28] of the four (1R)-configured
ziza-6(13)-en-3-one stereoisomers are summarized in Fig. 4. While the ziza-
6(13)-en-3-one (9) possesses a clean, fresh, transparent woody-ambery
vetiver character with an odor threshold of 0.13 ng/L air, 2-epi-ziza-6(13)-
en-3-one (10) featured a much more pronounced and typical vetiver character
along with an accentuated dry and distinctly transparent woody-ambery note.
This odor character recalls the popular perfumery material Iso E Super with
a related transparent woody-ambery note, in which arborone (26)[29] is
claimed to cause a quasi-pheromone-like attraction.[30] This odor association
was explained by a superposition analysis (75% steric, 25% electronic,
Discovery Studio[31]), a method preferentially used to evaluate the most
substantial common three-dimensional substructure of a set of molecules that
bind to the same receptor during drug or odorant discovery.[32] As is depicted
in the overlay analysis in Fig. 4, 2-epi-ziza-6(13)-en-3-one (10) does
superimpose surprisingly well on arborone (26, overlay similarity/26 = 0.87),
implying the substantial similarity of the smelling principles of vetiver oil
and Iso E Super. As also evident from Fig. 4, the odorless antipode ent-10
does not superimpose that well, especially concerning the crucial hydrophic
gem-dimethyl group of 26.
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[3]
[4]
[5]
[6]
[7]
[8]
[9]
[10]
[11]
Besides, comparing the naturally occurring ziza-6(13)-en-3-one (9) and 2-
epi-ziza-6(13)-en-3-one (10), the synthetic diastereomers 2,5-di-epi-ziza-
6(13)-en-3-one (24) and 5-epi-ziza-6(13)-en-3-one (25) also possess woody-
ambery odors. However, neither 24 with more pronounced hesperidic
rhubarb facets and a 1.3 ng/L threshold, nor 25 with a more cedarwood
character and a 0.23 ng/L threshold in air are stronger or more characteristic
than the natural vetiver odor vector 10, and besides, are also not detectable
in vetiver oil.
[12]
[13]
[14]
[15]
In conclusion, the described enantioselective total synthesis of 2-epi-ziza-
6(13)-en-3-one (10) represents a successful departure from the traditional
separation strategy to disclose an odorous principle. The eleven-step
synthesis lays the foundation for unprecedented enantioselective access to
zizaenes. Threshold evaluation reveals the enantiopure ketone 10 to be the
key contributor to the typical transparent woody-ambery vetiver note, being
over 150 times more potent in odor threshold than khusimone (6), previously
deemed the smelling principle of vetiver. Moreover, the excellent
stereochemical superposition of 2-epi-ziza-6(13)-en-3-one (10) on arborone
(26) could well explain the almost magic attraction that vetiver oil exerts on
humans, and why this surprisingly resembles the irresistible pull of Iso E
Super—an effect still not well-understood physiologically but now tangible
on the molecular level.
[16]
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Acknowledgements
K. H. Altmann, G. Bold, G. Caravatti, D. Denni, A. Flörsheimer, A.
Schmidt, G. Rihs, M. Wartmann, Helv. Chim. Acta 2002, 85, 4086–4110.
The detection odor threshold is defined as the smallest concentration
pereptible by a statistically significant number of panelist and is generally
calculated as the geometrical mean of the individual threshold values of the
different panelists. Here they are measured by GC–olfactometry: Solutions
of the respective compound are injected into a GC instrument at decreasing
concentrations until the panelist fails to detect the substance at the sniffing
port. The panelist smells blind and presses a button upon perceiving an
odor. If the recorded time matched the retention time, the concentration are
halved. The last concentration detected at the correct retention time is the
individual odor threshold
S. Hong, E. J. Corey, J. Am. Chem. Soc. 2006, 128, 1346–1352.
The claim of the quasi-pheromone-like attraction of Iso E Super goes back
to unpublished data of Hanns Hatt and co-workers who found activation of
the vomeronasal recepctor VN1R1 by Iso
communication of B.L. with H.H. from April 28, 2020.
[28]
We thank Robin Clery (Givaudan) for his analytical investigations on vetiver
oil, which independently from Belhassen et al. suggested the 2-epi-ziza-
6(13)en-3-one (10) to be the smelling principle of vetiver oil, and Dominique
Lelievre (Givaudan) for the olfactory evaluation of the compounds. Excellent
service provided by the technicians and the NMR, GC, and HPLC groups of
the MPI für Kohlenforschung is gratefully acknowledged. Funding:
Generous support from the Max Planck Society, the Deutsche
Forschungsgemeinschaft (Leibniz Award to BL), and the European Research
Council (Advanced Grant “C−H Acids for Organic Synthesis, CHAOS”) is
gratefully acknowledged.
[29]
[30]
E Super. Personal
[31]
[32]
Discovery Studio, v. 20.1.0.19295, Dassault Systèmes Biovia Corp., San
Diego, CA 92121 USA, 2019. For more information, see
https://www.3ds.com/products-services/biovia/products/molecular-
modeling-simulation/biovia-discovery-studio/.
S. Handschuh, M. Wagener, J. Gasteiger, J. Chem. Inf. Comput. Sci. 1998,
38, 220–232.
Competing interests
The authors declare the following competing financial interest(s): A patent,
WO2017037141 (A1), has been filed by the MPI fꢀr Kohlenforschung
covering the IDPi catalyst class and their applications in asymmetric
synthesis. SJ, SD and PK are employees of Givaudan S.A., a commercial
producer of perfumes and fragrance ingredients.
Keywords: odorous principle • vetiver oil • enantioselective
synthesis • asymmetric Mukaiyama-Michael addition • 2-epi-ziza-
6(13)en-3-one
5
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10.1002/anie.202014609
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
Fragrance Chemistry
A Most Mysterious Molecule
That Seduces the Senses.
Despite the advance of modern
analytic techniques, the odorous
principle of vetiver oil is still
unknown due to its extremely
complex matrix of over 150
Jie Ouyang, Hanyong Bae, Samuel Jordi,
Quang Minh Dao, Sandro Dossenbach,
Stefanie Dehn, Julia B. Lingnau, Chandra
Kanta De, Philip Kraft* and Benjamin
List*
compounds.
A
concise
Page No. – Page No.
stereoselective total synthesis
proves (+)-2-epi-ziza-6(13)en-3-
one to be the key to the quasi-
pheromone-like aura of vetiver
that magically resembles the
effect of Iso E Super.
The Odorous Principle of Vetiver Oil,
Unveiled by Chemical Synthesis
6
This article is protected by copyright. All rights reserved.