Ring-closing olefin metathesis reactions; Synthesis of iso-β-bisabolol

Article abstract of DOI:10.1016/j.tetlet.2003.12.004

A ring-closing olefin metathesis is the key step in a synthesis of the rare iso-β-bisabolol found in sandalwood oils.

Full text of DOI:10.1016/j.tetlet.2003.12.004

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 1171–1172
Ring-closing olefin metathesis reactions; synthesis of iso-b-bisabolol
*
€
Jutta M. Morgenthaler and Dietrich Spitzner
Institut f€ur Chemie, Abt. Bioorganische Chemie, Universit€at Hohenheim, Garbenstraße 30, D-70599 Stuttgart, Germany
Received 27 October 2003; revised 25 November 2003; accepted 2 December 2003
Abstract—A ring-closing olefin metathesis is the key step in a synthesis of the rare iso-b-bisabolol found in sandalwood oils.
Ó 2003 Elsevier Ltd. All rights reserved.
The bisabolols were isolated from Santalum spp. Besides
the odourless major bisabolols 2 and 3, trace constitu-
ents possessing the isomeric structures 1 and 4 have been
found very recently and synthesized and evaluated for
their odour impact. 1 is an interesting odour active
compound with a strong floral scent.1 Herein we report
a straightforward synthesis of a mixture of the four
stereoisomers of bisabolol 1 using a ring-closing olefin
metathesis (RCM) reaction as the key step.2
dized with PCC to ketone 7. The tertiary alcohol 5 was
obtained from ketone 7 by the addition of in situ gen-
erated allyllithium 6 (from allyltriphenyltin and phenyl-
lithium).8;9 Selective ring-closing olefin metathesis was
achieved using Grubbs second generation catalyst 11 to
yield iso-b-bisabolol 1 as a mixture of all four stereo-
isomers. This mixture had been separated previously by
the DRAGOCO group.1 The number of stereoisomers
of 1 can be reduced by using enantiomerically pure 10.7
This synthetic scheme will be applied to the synthesis of
OH
OH
OH
OH
Iso-β-bisabolol 1
β-Bisabolol 2
α-Bisabolol 3
Iso-α-bisabolol 4
2 starting from aldehyde 10a.10;11 Frater and Muller had
previously prepared bisabolol 2 by a different route.12
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A retrosynthetic analysis (Scheme 1) leads to tri-olefin 5,
which should be regioselectively cyclized by an olefin
metathesis reaction.
The required tri-olefin 5 was prepared by the sequence
described in Scheme 2.3 Conjugate addition4 of the
Grignard reagent 8 to methyl methacrylate in the pres-
ence of CuBr–Me2S complex and TMSCl yielded an
ester, which was reduced to the known alcohol 9.5;6
Oxidation of 9 with PCC gave the unstable aldehyde
10,7 which was reacted with the Grignard reagent 8 to
give an intermediate secondary alcohol, which was oxi-
OH
OH
O
RCM
1
5
7
+
M
Keywords: Metathesis; Monocyclic sesquiterpenes; Bisabolols.
* Corresponding author. Tel.: +49-711-459-2812; fax: +49-711-459-
3703; e-mail: spitzner@uni-hohenheim.de
6, M = Li
Scheme 1.
0040-4039/$ - see front matter Ó 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.12.004

1172
J. M. M€orgenthaler, D. Spitzner / Tetrahedron Letters 45 (2004) 1171–1172
g
MeOOC
f
d,e
a,b
c
OH
O
+
7
5
1
BrMg
Me
Me
9
8
10
N
N
Me
Me
2
Me
Me
RuCl
O
2
Ph
P(C H
)
11 3
6
11
10a
Scheme 2. Reagents and conditions: (a) CuBr–Me2S, LiI, TMSCl, Ar, )78 °C, 4 h, 53%; (b) LAH, ether, 2 h, 91%; (c) PCC, CH2Cl2, rt, 2 h, 89%; (d)
8, THF, reflux, 20 min, 55%; (e) PCC, CH2Cl2, rt, 2 h, 86%; (f) 6, ether, reflux, Ar, 80%; (g) 11, benzene, 80 °C, Ar, 4 h, 93%.
4. Lipshutz, B. H.; Wilhelm, R. S.; Kozlowski, J.
A. Tetrahedron 1984, 40, 5005–5038.
Acknowledgements
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864.
We thank the firm DRAGOCO Gerberding & Co., KG,
Holzminden, Germany,13 for generous support of this
work.
8. Seyfert, D.; Weiner, M. A. Org. Synth. Coll. Vol. V 1973,
452–455.
References and notes
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€
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13. New name: Symrise GmbH & Co., KG.
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