Synthesis of (?)-elemoxide, a commercially important fragrance compound

Article abstract of DOI:10.1016/j.tetlet.2018.08.003

(?)-Elemoxide, a fragrant compound was synthesised using commercially available elemol in four steps with overall yield of 32%. The cyclic ether skeleton was constructed via intramolecular hydroalkoxylation using I₂ and PhSiH₃ catalytic system. Also, intramolecular oxymercuration-demercuration was employed as an alternate approach for cyclization. The various regioselective strategies involving epoxidation of alkene, reduction of epoxide and intramolecular cyclization were the highlights of the work. The key intermediate diol serves as a versatile intermediate for the synthesis of elemoxide and elemene.

Full text of DOI:10.1016/j.tetlet.2018.08.003

Accepted Manuscript
Synthesis of (-)-Elemoxide, a commercially important fragrance compound
Lima Rodrigues, Mahesh S. Majik, Santosh G. Tilve, Solima Wahidullah
PII:
S0040-4039(18)30972-9
https://doi.org/10.1016/j.tetlet.2018.08.003
TETL 50178
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Accepted Date:
9 July 2018
1 August 2018
Please cite this article as: Rodrigues, L., Majik, M.S., Tilve, S.G., Wahidullah, S., Synthesis of (-)-Elemoxide, a
commercially important fragrance compound, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.
2018.08.003
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Graphical Abstract
Synthesis of (-)-Elemoxide, a commercially
important fragrance compound
Leave this area blank for abstract info.
Lima Rodrigues,a Mahesh S. Majik,*a Santosh G. Tilve, a Solima Wahidullah, b

1
Tetrahedron Letters
Synthesis of (-)-Elemoxide, a commercially important fragrance compound
Lima Rodriguesa , Mahesh S. Majika, , Santosh G. Tilvea and Solima Wahidullah b
a Department of Chemistry, Goa University, Taleigao Plateau Goa
b Bio-organic Chemistry Laboratory, CSIR-National Institute of Oceanography, Dona Paula Goa 403 004, India
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
(-)-Elemoxide, a fragrant compound was synthesised using commercially available elemol in
four steps with overall yield of 32%. The cyclic ether skeleton was constructed via
intramolecular hydroalkoxylation using I2 and PhSiH3 catalytic system. Also, intramolecular
oxymercuration-demercuration was employed as an alternate approach for cyclization. The
various regioselective strategies involving epoxidation of alkene, reduction of epoxide and
intramolecular cyclization were the highlights of the work. The key intermediate diol serves as a
versatile intermediate for the synthesis of elemoxide and elemene
Available online
Keywords:
Regioselective reaction
Iodine-silane catalyses
Oxymercuration -demercuration
Elemoxide
2009 Elsevier Ltd. All rights reserved.
Natural product
research to explore the potentials of this compound for further
study. Realising the importance of this compound for food and
Introduction
fragrance industry, we report here the facile synthetic approach
for the building of elemoxide using 4 steps from (-)-elemol.
Fragrance or aroma compounds, traditionally used as
perfumery, are volatile organic compounds of low molecular
weight containing either aliphatic or aromatic structure found in
flowers, plants, trees. Presently 90% of commercial fragrance
compounds are synthetic chemicals.1 In 2000, Karft et al. have
published a review article on the chemistry, properties and SARs
of many classes of perfumery agents.2 These odorant molecules
are having direct application as flavouring and perfumery agents
in food and cosmetic industries such as spray perfumes, body
care, home care, soaps & detergents and incense.3 As a
Results and discussion
Scheme 1 illustrates the retrosynthetic analysis of (-)-
elemoxide (5) from (-)-elemol (1). It was envisaged that
elemoxide could be synthesised from alcohol 4 via dehydration-
isomerization reaction. Alcohol 4 in turn could be derived from
regioselective cyclization of diol 3. The ring opening of epoxide
2 via regioselective manner could lead to diol 3. Epoxide 2 could
be synthesised from commercially available elemol (1) via
regioselective oxidation of double bond.
consequence, there is huge demand to explore fragrance
chemistry through design and synthesis of new odorants.
Sesquiterpenes are volatile compounds found in many natural
sources, which are widely used as sources of many aroma
industries.4 Elemoxide is a multiordorant sesquiterpene oxide
being combination of rhubarb, laurel, thyme and florex and is
known to be a good flavoring agent. In 2004, the U.S. patent
describes an article on elemoxide as a minor product of
dehydration of naturally occurring elemol. The patent claims that
this compound is a stronger and a better odorant in the class of
sesquiterpenes.5 Later, in 2006 Wahidullah et al. reported the
study on dehydration and rearrangement of elemol under acidic
condition and characterized few pharmacologically important
products.6 However, they succeeded in isolating trace amount (8
%) of sesquiterpene oxide i.e. elemoxide during their column
chromatographic purification step. Although, elemoxide is
having commercial importance, but due to its scarcity from
natural source and lack of synthetic methods, has hampered the
Scheme 1. Retrosynthesis of (-)-elemoxide a fragrant compound
First, the common intermediate diol 3, which was identified as
advance intermediate 3 was synthesised for further conversion to
elemoxide. Our synthetic approach for the synthesis of diol 3 is
depicted in Scheme 2. One strategy to access this class of
———
 Corresponding author. Tel.: +0-8669609175; fax: +0-000-000-0000; e-mail: majik@unigoa.ac.in

2
Tetrahedron
intermediates involves direct monoepoxidation of the
olefin shall provide us the required product. Hence, olefin was
subjected to oxymercuration reaction under anhydrous condition
wherein mercurial intermediate was generated insitu, which on
reduction using standard conditions13 (NaBH4 in the presence of
aq. sodium hydroxide in THF) afforded the desired cyclized
product 4 along with unreacted starting material. Low conversion
yields were obtained using standard mercuration condition. The
reason attributed to this low conversion could be the less
nucleophilicity of hydroxyl group of alcohol. In next attempt, the
yield of intramolecular cyclization was improved by employing
modified condition using stoichiometric amount of Cs2CO3
during oxymercuration step.
corresponding diene. It has been well precedent in the literature
that the regioselectivity of diene epoxidation is controlled by
electronic factors, as with peracid oxidants,7 or by a directing
group, as with Sharpless epoxidation.8 In the synthesis of
liphagal, A. Manzaneda et al. clearly demonstrated the
chemoselectivity of m-CPBA to oxidize the more hindered but
also the more electron-rich alkene, regardless of the steric
hindrance.9 Pleasingly, oxidation of elemol (1) with m-CPBA at 0
°C in CH2Cl2 was found to be chemoselective producing requisite
epoxide. The stereochemistry of epoxy ring of 2 was not of
consequence in the further manipulation and was assumed to be
trans (with respect to angular methyl group) based on 1H NMR
shift.
Furthermore, to increase the efficiency for constructing the
cyclic ether skeleton of elemoxide, various reagents such as
PdCl2(PPh3)2/CuCl,14,15 RuCl2(p-cymene)2/CuOAc16,17 and
KOtBu/n-BuLi18,19 were attempted without any success. In 2015,
M. Shibuya and co-workers demonstrated the
applicability of
Silane−Iodine catalytic system for the intramolecular
hydroalkoxylation of unactivated alkenes.20 Using the same
strategy, we treated olefin 3 with I2 and PhSiH3 to deliver
expected cyclic ether in 70% yield. With the sufficient amount of
cyclic ether 4 in hand, we subjected it to dehydration and
isomerization using acetic acid/perchloric acid condition to give
(-)-elemoxide (5) in 70% yield (Scheme 4). This completed the
efficient synthesis of (-)-elemoxide a fragrant compound in 4
steps.
Scheme 2. Synthesis of Diol 3 via regioselective epoxidation
Reagents and conditions: a) m-CPBA(1.2 equiv), CH2Cl2, 0 °C (2 h)
then rt (1 h); 80% (b) compd 2 (0.84 mmol), LiAlH4 (1.5 equiv),
anhyd THF (20 mL), 0 °C-rt, 82%; (c) compd 2 (4.20 mmol), LiAlH4
(1.5 equiv), anhyd THF (7 mL), 0 °C-rt; 83%
The reductive ring opening of epoxides, especially in
enantiopure form, to the corresponding alcohols is a powerful
tool in synthetic organic chemistry.10 Reductive cleavage of
oxiranes can be performed in the presence of various dissolving
metals, metal hydrides.11 LiAlH4 is commonly used in epoxide
reductive ring opening.12 The reaction and regioselectivity of the
product depends highly on the substitution of the epoxide ring
carbons. Generally the opening of the epoxy ring occurs at the
less substituted carbon; however when the reaction of epoxide
was carried out using LiAlH4 and THF (20 mL) under diluted
condition, gave reverse selectivity i.e. primary alcohol 3a as
major product. Repetition of the reaction by changing
temperature of reaction gave similar results. Interestingly, we
found that the solvent volume used for the reaction could lead to
expected regioselectivity. Subsequently, the expected alcohol 3
was obtained as the major product under LiAlH4 reductive
condition employing less amount of THF (7 mL) as solvent.
Scheme 4. Synthesis of (-)-Elemoxide
In 2006, Wahidulla, S. et al. had carried out dehydration of
(+)-elemol (1) with glacial acetic acid and perchloric acid to give
complex mixture of compounds wherein elemoxide was found in
8% yield.6 We thought to overcome these drawbacks of complex
mixture by making the particular intermediate which gets
exclusively converted into elemoxide rather than other related
products. The previously proposed mechanism claims that, the
diol is one of the intermediate product in the formation of
elemoxide. Hence our second synthetic attempt was the reaction
of diol with glacial acetic acid and perchloric acid using
After synthesis of alcohol containing an olefinic moiety, our
efforts were focused on the construction of a bicyclic skeleton of
elemoxide through intramolecular cyclization methods. After a
brief survey of reaction conditions, we found that the
Wahidulla’s procedure. Herein, we obtained elemoxide in 26 %
yield along with other natural product α-elemene (6)6 (47%).
Hence, our experiment gives the experimental proof for the
previously proposed mechanism for the formation of elemoxide.
intramolecular oxymercuration followed by demercuration on
Conclusion
In conclusion, we have accomplished a new concise synthesis
of (-)-elemoxide a fragrant compound in four steps involving
32% overall yield via regioselective epoxidation, regioselective
ring opening and regioselective intramolecular cyclization as key
steps. Out of 4 steps, 3 steps involves regioselectivity in
formation of products, which is the highlight of this synthetic
endeavour. α-Elemene was also synthesized in good yield
starting from elemol. We believe that all chemistry employed in
this study can be applied to the synthesis of elemoxide in gram
Scheme 3. Regioselective intramolecular cyclization

3
scale with the potential of commercialization for perfumery or
food industry.
Acknowledgments
The author thanks DST-SERB (New Delhi, India) (project no.
YSS/2014/000776) for Young Scientist Research grant and
funding. L.R. is thankful to DST-SERB for the fellowship.
Supplementary data
Highlight of Present Work
Supplementary data (experimental procedures and spectral
data) associated with this article can be found, in the online
version, at
1) For the synthesis of the target elemoxide,
Iodine catalysed cyclization, which is an
emerging and vast growing area in the
synthesis of organic molecules due to its
atom economy and greener method was
utilized as one of key steps. Using this
strategy, we developed a cyclic ether
skeleton for the synthesis of sesquiterpene
oxide. It is novel in that there are only very
few examples of the hydroalkoxylation in
sesquiterpene chemistry. In this study, we
found that the regular method of
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3) We believe that our results related to the
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could be of interest to the vast readers of Tet
Lett. and hope that editorial board and
reviewers will find interest on our findings.