A short and efficient synthesis of (±)-trans-sabinene hydrate

Article abstract of DOI:10.1016/S0040-4039(01)01081-4

A short synthesis of sabinene hydrate is reported. It uses cheap starting materials and affordable reagents. The main product of the synthesis is trans-sabinene hydrate.

Full text of DOI:10.1016/S0040-4039(01)01081-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 5589–5591
A short and efficient synthesis of ( )-trans-sabinene hydrate
Christophe C. Galopin
Givaudan Flavors Corp., Research and Development Department, Organic Chemistry Section, 1199 Edison Drive, Cincinnati,
OH 45216, USA
Received 24 May 2001; revised 13 June 2001; accepted 19 June 2001
Abstract—A short synthesis of sabinene hydrate is reported. It uses cheap starting materials and affordable reagents. The main
product of the synthesis is trans-sabinene hydrate. © 2001 Elsevier Science Ltd. All rights reserved.
trans-Sabinene hydrate 1 is an important flavor chemi-
cal found in a variety of essential oils from mint1 and
herbs.2 Its flavor has been described as cooling, minty,
eucalyptol and green with a sweet spicy terpineol-like
character. Although trans-sabinene hydrate is commer-
cially available from a few flavor ingredient suppliers,
its current market price ($1200–1800/kg) limits its use
in flavors.
Our initial objective was to build this structure by using
the Nazarov cyclization of 6-methyl-1,4-heptadien-3-
one 2 (Scheme 1).9 However, like many mono-substi-
tuted dienones of this kind, this compound failed to
cyclize under a variety of conditions. A variation10 of
the Nazarov cyclization, treating isopentyl acrylate 4
with polyphosphoric acid (PPA), gave a cyclized
product, but not the desired cyclopentenone 3. Instead,
we obtained an isomer to which structure 5 was tenta-
tively assigned.11
HO
These experiments convinced us that the best way of
making cyclopentenone 3 might be the intramolecular
aldol condensation of dione 8 as described by Fanta
and Erman.5 In order to avoid ozonolysis of a-ter-
pinene or oxidative hydroboration of 6-methyl-5-hep-
ten-2-one,5 we thought of making the dione 8 by using
the Stetter addition of isovaleraldehyde 7 to methyl-
vinylketone 6 (Scheme 2).12 We first repeated the origi-
nal procedure from Stetter using 10 mol% catalyst to
give the desired product in 64% yield. We found out
1
Several syntheses of trans-sabinene hydrate have been
published. However partial syntheses start with expen-
sive materials such as 3-thujone3 or sabinene,4 while
total syntheses either use impractical reactions such as
ozonolysis5 or diazoalkane coupling,6 or require too
many steps.7 There is a need for a simple, straightfor-
ward total synthesis of sabinene hydrate that can be
upscaled for large production. We wish to present a
practical synthesis of sabinene hydrate that is short,
efficient and cost effective.
O
O
H+
2
3
The challenge in the synthesis of sabinene hydrate is
building the 5+3 bicyclic skeleton. It appeared to us8
that the best way of building this skeleton was to use
3-isopropyl-2-cyclopentenone 3 as an intermediate since
it has a double bond that can be functionalized into a
cyclopropane ring, and a ketone that could be trans-
formed into the tertiary alcohol of sabinene hydrate 1.
O
O
O
PPA
4
5
Fax: (513)948-3582; e-mail: christophe.galopin@givaudan.com
Scheme 1. Attempts at a one-step synthesis of 3.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01081-4

5590
C. C. Galopin / Tetrahedron Letters 42 (2001) 5589–5591
O
second attack was directed by the steric hindrance of
the isopropyl group on the b-carbon.
S
Cl-
O
H
O
N
Ph
OH
+
O
Et3N, EtOH
This is in contradiction with the attack of MeLi on
sabina ketone 10, which was shown5 to be directed by
the steric hindrance of the cyclopropane group and
yield the cis-sabinene hydrate 12 as the major product.
6
7
8
NaOH
EtOH, H2O
This difference may be explained by the size of the
nucleophile. The small MeLi may only interact unfa-
vorably with substituents at the a-carbon whereas the
bigger CH2ꢀS(ꢀO)Me2 can interact with substituents
both a- and b- to the ketone. Therefore MeLi will
attack on the less hindered face of the a-carbon (which
is anti to the cyclopropane ring) whereas the sulfoxide
will attack on the less hindered face of the b-carbon
(which is syn to the cyclopropane).
o
O
O
O
O
s
1.1eq
9
3
10
11
3
o
2.2eq
s
In conclusion, we have developed a short and efficient
(28% overall yield) synthesis of trans-sabinene hydrate
by using common reagents. There are only two expen-
sive reagents in this route: Stetter’s thiazolium ion and
the Corey–Chaykovsky reagent precursor, trimethylsul-
foxonium iodide. However, the former is only used in
catalytic amounts while the latter can easily be made in
the laboratory.15
9
OH
O
HO
HO
LiAlH4
+
( )-1
12
13
11
--
Scheme 2. Total synthesis of ( )-1.
Acknowledgements
that decreasing the amount of catalyst to 5 or even 1
mol% increased the yield of the reaction up to 82% but
reaction times of up to 2 days had to be used. Cycliza-
tion was done in 70% as described by Fanta and
Erman.5 Attempts at changing the reaction conditions
of the cyclization only returned lower yields.
I wish to thank Dr. Philip Christenson, Givaudan
Flavors, for helpful discussions and the officers of
Givaudan for permission to publish this work.
References
The cyclopentenone was then cyclopropanated using
the Corey–Chaykovsky reagent 9 made by deprotona-
tion of trimethylsulfoxonium iodide with sodium
hydride.13 To our surprise this reaction resulted in a
mixture of starting material 3, desired product (sabina
ketone, 10) and overreacted product (epoxysabinene,
11) in a 4:3:1 ratio (Scheme 2). Modification of reaction
temperature and mode of addition resulted in the same
type of mixture suggesting that the attack on the very
electrophilic cyclopentanone 10 is faster than the attack
on the unreactive, polysubstituted enone 3.
1. (a) Karasawa, D.; Shimizu, S. Agric. Biol. Chem. 1978, 42
(2), 433–437; (b) Lawrence, B. M. Perf. Flav. 1993,
18(July/August), 67.
2. (a) Libbey, L. M.; Sturtz, G. J. Ess. Oil Res. 1990,
2(July/August), 193–195; (b) Oberdieck, R. Z. Natur-
forsch. 1981, 36, 23–29.
&
3. BaeckStro¨m, P.; Koutek, B.; Saman, D.; Vrkoc, J.
Bioorg. Med. Chem. 1996, 4 (3), 419–421 and references
cited therein.
4. Patent JP 55051081, 1978 for Lion Corp.
5. Fanta, W. I.; Erman, W. F. J. Org. Chem. 1968, 33 (4),
1656–1658.
Since the reduction of epoxysabinene 11 to sabinene
hydrate is known,4 cyclopentenone 3 was reacted with
2.2 equiv. of Corey–Chaykovsky reagent at room tem-
perature in DMSO overnight to be converted com-
pletely to epoxysabinene 11 in 71% yield (Scheme 2).
The epoxide was reduced with LiAlH4 to give a mixture
of ( )-trans-sabinene hydrate ( )-1, ( )-cis-sabinene
hydrate 12 and ( )-sabinane alcohol 13 in a surprising
10:1.6:2.8 ratio.14
6. Marx M. Ph.D. Thesis, Columbia University, 1966, 86–
92
7. Cheng, D.; Knox, K. R.; Cohen, T. J. Am. Chem. Soc.
2000, 122, 412–413.
8. Attempts at building both cycles at the same time either
by ring contraction of a cyclohexadiene, (such as the one
used in the synthesis of Vitamin D3: (a) Gill, Harpal, S.
Gill; Londowski, J. M.; Corradino, R. A.; Zinsmeister,
A. R.; Kumar, R. J. Med. Chem. 1990, 33, 480–490; (b)
Paaren, H. E.; DeLuca, H. F.; Schnoes, H. K. J. Org.
Chem. 1980, 45, 3253–3258) or by addition of isovaleral-
doxime to divinylketone (by extrapolating the cyclo-
propanation method described in Ono, N.; Yanai, T.;
The high trans/cis ratio shows that both attacks of the
Corey–Chaykovsky reagent have taken place on the
same side of the molecule. This would suggest that the

C. C. Galopin / Tetrahedron Letters 42 (2001) 5589–5591
5591
Hamamoto, I.; Kamimura, A.; Kaji, A. J. Org. Chem.
1985, 50, 2807–2809) were unsuccessful.
13. Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1965, 87,
1353.
9. For a review on Nazarov cyclizations see: Santelli-Rouvier,
14. Assignment of trans and cis isomers was done by matching
of GC-MS spectra to the Givaudan library and com-
parison of 1H NMR data with the 1H NMR spectrum
described by Fanta and Erman.5 NMR data for ( )-1 were
C.; Santelli, M. Synthesis 1983, 429–442.
10. Conia, J.-M.; Leriverend, M.-L. Tetrahedron Lett. 1968,
17, 2101–2104.
1
11. The mass-spectrum of the obtained compound showed a
very good match (95% confidence) to that of 3,4-dimethyl-
cyclohex-2-enone from the Givaudan library. 1H NMR
however suggested that no ethylenic proton were present
and that methyl groups were attached to quaternary
carbons. Structure 5 agrees well with our observations but
other structures, such as 2,3-dimethylcyclohex-
2-enone, cannot be ruled out.
as follows: H 300 MHz in CDCl3 (l in ppm): 1.92–1.81
(m, 1H); 1.65–1.4 (m, 4H); 1.31 (s, 3H); 1.27–1.14 (m, 1H);
1.07(ddd, J=8.4, 3.6, 1.2 Hz, 1H), 0.98 (d, J=6.9 Hz, 3H);
0.91 (d, J=6.9 Hz, 3H); 0.41 (ddd, J=8.1, 5.4, 1 Hz, 1H);
0.23(dd, J=5.4, 3.6 Hz, 1H); 13C 75 MHz in CDCl3 (l
in ppm): 80.8, 36.8, 34.6, 32.4, 26.1, 25.2, 20.3, 20.2,
13.6.
15. (a) Kuhn, R.; Trischmann, H. Ann. 1958, 611, 117–121; (b)
Forrester, J.; Jones, R. V. H.; Preston, P. N.; Simpson, E.
S. C. J. Chem. Soc., Perkin Trans. 1 1995, 2289–2291.
12. Stetter, H.; Kuhlmann, H. Chem. Ber. 1976, 109, 2890–
2896.
.