Chemomicrobial synthesis of (R)- and (S)-lavandulol

Article abstract of DOI:10.1016/j.tetlet.2011.06.072

(R)- and (S)-Lavandulol are important compounds in the cosmetics industry and in pheromone research. We have developed syntheses of (R)- and (S)-lavandulol from (S)- and (R)-limonene, respectively, by microbial Baeyer-Villiger oxidation of the intermediate unsaturated hydroxy ketone. It has been found that the same strain of Acremonium roseum can be successfully used in the key step of the synthesis of both enantiomers of lavandulol.

Full text of DOI:10.1016/j.tetlet.2011.06.072

Tetrahedron Letters 52 (2011) 4461–4463
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Tetrahedron Letters
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Chemomicrobial synthesis of (R)- and (S)-lavandulol
b
a
a,
⇑
b
a
´
´
Anna Gliszczynska , Radosław Bonikowski , Józef Kula , Czesław Wawrzenczyk , Kornelia Ciołak
a Institute of General Food Chemistry, Technical University of Lodz, Stefanowskiego 4/10, 90-924 Lodz, Poland
b Department of Chemistry, Wroclaw University of Environmental and Life Sciences, C.K. Norwida 25/27, 50-375 Wrocław, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
(R)- and (S)-Lavandulol are important compounds in the cosmetics industry and in pheromone research.
We have developed syntheses of (R)- and (S)-lavandulol from (S)- and (R)-limonene, respectively, by
microbial Baeyer–Villiger oxidation of the intermediate unsaturated hydroxy ketone. It has been found
that the same strain of Acremonium roseum can be successfully used in the key step of the synthesis of
both enantiomers of lavandulol.
Received 12 May 2011
Revised 9 June 2011
Accepted 17 June 2011
Available online 25 June 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Lavandulol
Limonene
Baeyer–Villiger oxidation
Acremonium roseum
Terpenes
(R)-Lavandulol (6-R) and its acetate (5-R) are valuable compo-
nents of French lavender oil, but their content in it amounts to only
about 1–3%.1 According to recent findings, a richer source of these
compounds is the essential oil obtained from Tanacetum sp. (23–
35%, of unknown configuration).2 (R)-Lavandulol and its esters
have been identified in the pheromones of some global insect
pests.3
The (S)-enantiomer (6-S), like the senecioate and isovalerate
esters, has been identified in the female sex pheromones of the
vine mealybug.4 For several years, it has been known that it is only
the (R)-enantiomer which has the fresh odor reminiscent of herbs
and lemon, while its antipode is almost odorless.5 So, easy access to
the two lavandulol enantiomers is of importance both in perfum-
ery and in control of insect populations. Lavandulol is an acyclic
monoterpene alcohol inconsistent with the isoprene rule, and thus
its carbon skeleton may not be obtained by ordinary isomeri-
zation (rearrangement) of popular terpene hydrocarbons such as
pinene, myrcene, or limonene, which are commonly used for the
production of regular terpene alcohols (linalool, citronellol,
enantiomers, limonene represents an ideal starting material for a
practical synthesis of lavandulol (Scheme 1).
Both enantiomeric ketoaldehydes 1 are easily obtainable from
limonenes.8 In our study, 1-S {97% pure, GC; (½a 2D2
ꢁ12.3 (c 2.3,
ꢀ
CHCl3)} was obtained by ozonolysis of (S)-limonene, and 1-R {98%
pure, GC; (½a 2D1
ꢀ
+15.2 (c 1.6, CHCl3)} by ozonolysis of (R)-limo-
nene.8g Our strategy of a two-step reconstruction of the carbon
skeleton of lavandulol relies on the addition of two carbon atoms
in a Grignard reaction and a subsequent loss of two carbon atoms
in a Baeyer–Villiger reaction. Our initial attempts to shorten the
chain in ketone
3 through a Baeyer–Villiger oxidation with
m-chloroperbenzoic acid or with bis-trimethylsilyl peroxide, which
is supposed to provide selective oxidation in the presence of C@C9
bonds, were completely unsuccessful. On the other hand, the enzy-
matic Baeyer–Villiger oxidation is known to tolerate unsaturation
in substrates10 and the microbial B.V. oxidation is known on a
kilogram scale.11 Therefore, with a view to the synthesis of a
sensory-active (R)-lavandulol (6-R), we attempted to conduct a bio-
transformation of hydroxy ketone 3-S ([
organisms.
a]
ꢁ4.83) using micro-
D
menthol,
a-terpineol). Even though a number of papers have been
published concerning the synthesis of both lavandulol enantiomers
6 and enzymatic separation of their racemate,5–7 the only commer-
cially available substances are racemic lavandulol and its acetate.
This work presents an efficient method for the synthesis of (R)-
and (S)-lavandulol (6-R and 6-S) from (S)- and (R)-limonene,
respectively. In view of its low cost and ready availability of both
On the basis of published results concerning the catalytic activ-
ity of the strains Rhodotorula rubra AM4, Rhodotorula marina AM77
and Acremonium roseum AM346 in Baeyer–Villiger oxidation
reactions, we chose these microorganisms for the screening
procedure.12 In the biotransformation of hydroxy ketone 3-S whole
enzymatic systems that have wild strains of R. rubra AM4,
R. marina AM77 and A. roseum AM346 were used. The screening
procedure led to the selection of A. roseum AM346 for the prepara-
tive transformation. This strain converted hydroxy ketone 3-S in
high yield into diol 4-R through Baeyer–Villiger oxidation followed
⇑
Corresponding author. Tel.: +48 42 631 34 18; fax: +48 42 636 28 60.
E-mail address: jozef.kula@p.lodz.pl (J. Kula).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.06.072

´
A. Gliszczynska et al. / Tetrahedron Letters 52 (2011) 4461–4463
4462
O
OH
OH
OH
O
OH
O
a
c
d
b
OH
R1
4-R
4-S
R1
R2
R2
R1 R2
3-R
3-S
R1
2-R
2-S
R2
1-R; R1=isopropenyl, R2=H
1-S; R1=H, R2=isopropenyl
OH
OAc
R2 R1
e
f
OAc
OAc
R1
f
OH
OH
+
R2
R2
5-R
5-S
R1
R2 R1
6-R
6-S
R2 R1
6a-R
6a-S
5a-R
5a-S
Scheme 1. Reagents and conditions: (a) MeMgCl, THF, 30 °C, 87%; (b) PCC, CH2Cl2, 72%; (c) Acremonium roseum, 11–18 days, 81–92%; (d) Ac2O, py, 8 °C, 16 h, 94% (crude
material); (e) SOCl2, Et3N, rt, 60% (crude material); (f) NaOH, MeOH, H2O, 89% (crude material).
oxidation. The time course of diol formation was measured by
TLC and GC (Fig. 2).
To isolate the product, a large-scale incubation of hydroxy ke-
tone 3-R by A. roseum AM346 was carried out for 18 days. After
the biotransformation, the culture was extracted as described in
the Experimental Section in the Supplementary data, and the met-
abolic product (4-S) was isolated in an 81% yield (266 mg from
380 mg of substrate) as the pure S-enantiomer (100% ee by chi-
ral-GC, [a]D +6.14). It seems that one of the reasons for such a high
yield from the biotransformations and for the product purity is the
relatively good solubility of the hydroxy ketone 3 in the aqueous
microbiological medium. After selective acetylation, diol 4-R was
dehydrated by thionyl chloride in triethylamine, yielding a mixture
of lavandulyl acetate (5-R) and isolavandulyl acetate (5a-R) in a
ratio of 1:1. Alkaline hydrolysis of the acetates resulted in the for-
mation of a mixture of alcohols 6-R and 6a-R which were then sep-
arated on a silica gel column impregnated by silver nitrate to
deliver pure (R)-lavandulol (6-R; 80% ee, chiral-GC) and (R)-isolav-
andulol (6a-R; 95% pure, GC).
Figure 1. Time course (according to GC) in the biotransformation of 3-S by A.
roseum AM346.
In summary, we have developed a novel chemomicrobial
procedure to synthesize optically active lavandulol from natural
limonene. The methodology developed is suitable for the prepa-
ration of both enantiomers of lavandulol, the optical purity of
which is dependent on the ee of the limonene used. This
sequence represents the first application of limonene and the
first application of microbial Baeyer–Villiger oxidation for the
synthesis of a natural monoterpene alcohol inconsistent with
the isoprene rule.
Figure 2. Time course (according to GC) in the biotransformation of 3-R by A.
roseum AM346.
by hydrolysis. The transformation process was monitored by
means of TLC and GC analysis. After 3 days of incubation in a cul-
ture of A. roseum AM346, the amount of 3-S gradually started to
decrease whereas the amount of diol 4-R increased in proportion
(Fig. 1).
Supplementary data
Supplementary data (experimental procedures and character-
ization data for all new compounds along with copies of 1H, 13C
NMR spectra) associated with this article can be found, in the on-
line version, at doi:10.1016/j.tetlet.2011.06.072.
This product was isolated after 11 days in
(191 mg from 240 mg of substrate) with 82% ee by chiral-GC
([
a 92% yield
a
]
ꢁ4.92). In the light of the above result, it was important
D
to find out whether this key step in lavandulol synthesis could
also be conducted with the other enantiomeric hydroxy ketone
References and notes
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mation of hydroxy ketone 3-R in
AM346 gave diol 4-S as the only product of the Baeyer–Villiger
a] +6.00) using the same microorganism. The biotransfor-
D
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a
culture of A. roseum

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