Stereochemistry of terpene derivatives. Part 6: Chemoenzymatic synthesis of chiral bicyclo[3.1.0]hexane derivatives with olfactory properties

Article abstract of DOI:10.1016/j.tetasy.2010.04.052

Starting from (+)-3-carene 1, several chiral fragrant compounds with the bicyclo[3.1.0]hexane system were synthesized. These compounds were used as substrates for the biotransformation with lipases as biocatalysts. Pure diastereoisomers were obtained and

Full text of DOI:10.1016/j.tetasy.2010.04.052

Tetrahedron: Asymmetry 21 (2010) 805–809
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Stereochemistry of terpene derivatives. Part 6: Chemoenzymatic synthesis
q
of chiral bicyclo[3.1.0]hexane derivatives with olfactory properties
a
a
b
a,c,*
Renata Kuriata , Kamila Gajcy , Ilona Turowska-Tyrk , Stanisław Lochy n´ ski
a
Department of Bioorganic Chemistry, Faculty of Chemistry, Wrocław University of Technology, Wybrze z_ e Wyspia n´ skiego 27, 50-370 Wrocław, Poland
Institute of Physical and Theoretical Chemistry, Faculty of Chemistry, Wrocław University of Technology, Wybrze z_ e Wyspia n´ skiego 27, 50-370 Wrocław, Poland
Department of Cosmetology, Wrocław College of Physiotherapy, Ko ´s ciuszki 4, 50-038 Wrocław, Poland
b
c
a r t i c l e i n f o
a b s t r a c t
Article history:
Starting from (+)-3-carene 1, several chiral fragrant compounds with the bicyclo[3.1.0]hexane system
were synthesized. These compounds were used as substrates for the biotransformation with lipases as
biocatalysts. Pure diastereoisomers were obtained and their absolute configuration was confirmed by
X-ray crystallography. The olfactory properties of new compounds were determined.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 10 March 2010
Accepted 13 April 2010
Available online 2 June 2010
1
. Introduction
transformation is a method highly preferred in the preparation of
enantiomerically pure compounds.
1
0
Biocatalysis is an effective tool for the structural modification of
Herein, we report lipase-catalysed kinetic resolution as an
efficient method for gaining the fragrant diastereoisomers of
gem-dimethylbicyclo[3.1.0]hexane derivatives with high enantio-
meric purity. Our goal was to obtain pure diastereoisomers of the
secondary allylic alcohol (+)-1-[(1S,5R)-6,6-dimethylbicyclo-
[3.1.0]hex-2-en-2-yl)]ethanol and their esters and to determinate
absolute configuration of newly formed stereogenic center. These
results enabled us to evaluate and compare the odor characteristics
of pure diastereoisomers with their mixtures.
bioactive, natural, and synthetic compounds. Enzymes, especially
lipases (EC 3.1.1.3), are very useful in the preparation of a broad
range of compounds in their optically active forms. These enzymes
possess wide substrate specificity, generally high chemo-, regio-,
and stereoselectivity, and in many cases perform under mild con-
2
ditions. Moreover, lipases remain enzymatically active in organic
solvents, which makes them the ideal tools in organic synthesis.
Their ability to catalyze hydrolysis as well as transesterifications
is well recognized and has been described in a number of papers
3
on lipases.
2
. Results and discussion
The optically active monoterpene (+)-3-carene 1, a major com-
ponent of Polish turpentine obtained from Pinus sylvestris (L.), is a
natural, inexpensive, and widely available raw material. Easily ob-
tained derivatives of this monoterpene have been used as chiral
auxiliaries in enantioselective transformations.4 Therefore, this
natural product is a convenient substrate in the synthesis of chiral
derivatives with the bicyclo[3.1.0]hexane moiety, displaying inter-
The key compound, secondary allylic alcohol (+)-1-[(1S,5R)-6,6-
dimethylbicyclo[3.1.0]hex-2-en-2-yl)]ethanol (RS,1S,5R)-4, was
synthesized in a three-step procedure from the monoterpene
hydrocarbon (+)-3-carene 1. Ozonolysis of 1 followed by intramo-
lecular aldol condensation of ketoaldehyde 2 afforded bicyclic
1
1
enone 3, which was reduced with lithium aluminum hydride to
5
12
esting olfactory properties. Moreover, (+)-3-carene 1 was used as
alcohol (RS,1S,5R)-4. The authors of this procedure did not
observe that the reduction of enone 3 proceeded with asymmetric
induction, leading to the formation of a diastereoisomeric mixture
in an 85:15 ratio (CGC) (Scheme 1).
a starting material in the synthesis of chiral, biologically active
6
7
products such as b-amino acids and sulfides.
Since 1961, when Ohloff published the results of his research on
the enantioselective perception of chiral odorants, it is well known
The excess of one diastereoisomer can be explained by the pres-
ence of a gem-dimethylcyclopropane moiety as a steric hindrance.
Acetate (RS,1S,5R)-5 was obtained from a mixture of alcohol
RS,1S,5R)-4 in one step reaction in pyridine medium with the
addition of acetyl chloride (Scheme 1).
8
that stereochemistry plays an important role in odor properties.
Enantiomers of one compound can both differ in intensity and eli-
9
cit different odor sensations. Thus, there is a strong emphasis on
(
receiving products in a single stereoisomer form. Nowadays, bio-
Secondary allylic alcohol (RS,1S,5R)-4 was a substrate for enzy-
matic transesterifications in anhydrous conditions. In these reac-
tions lipases from Burkholderia cepacia, Pseudomonas fluorescence,
and Candida rugosa were used in the presence of vinyl acetate as
q
Part 5 see Ref. 1.
*
Corresponding author. Tel.: +48 71 320 24 00; fax: +48 71 328 40 64.
E-mail address: stanislaw.lochynski@pwr.wroc.pl (S. Lochy n´ ski).
1
3
an acyl donor (Scheme 2).
0
957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.04.052

8
06
R. Kuriata et al. / Tetrahedron: Asymmetry 21 (2010) 805–809
O
c
HO
d
O
a
O
b
O
CHO
1
2
3
(R,S)-4
(R,S)-5
Scheme 1. Reagents: (a) (1) O
3
; (2) Zn/AcOH; (b) 5% NaOH; (c) LiAlH
4
; (d) AcCl, Py.
The influence of temperature and reaction time was also inves-
tigated (Table 1). The best results for biotransformations were ob-
tained for Amano PS lipase from B. cepacia at 37 °C for 24 h. Under
these conditions the enzyme was able to convert only one form of
alcohol 4. It led us to obtain a pure diastereoisomer of acetate
HO
1
4
(R,1S,5R)-5 and a mixture of alcohol (S,1S,5R)-4 (which was not
a
a
a substrate for this enzyme) with unreacted alcohol (R,1S,5R)-4
in an 89:11 ratio.
(RS,1S,5R)-4
Diastereopure acetate (R,1S,5R)-5, obtained by enzymatic
transesterification in anhydrous conditions, was reduced with lith-
ium aluminum hydride to the secondary alcohol (R,1S,5R)-4,15
which was transformed to the crystalline p-nitrobenzoate deriva-
tive (R,1S,5R)-6 (Scheme 3).
O
O
O
O
The newly formed stereogenic center in the side chain at C-9 was
determined by X-ray crystallography as having an (R)-configuration
and was assigned on the basis of the known absolute configuration
at the C-1 and C-5 carbon atoms in the gem-dimethylbicyclo
(
S,1S,5R)-5
(R,1S,5R)-5
+
+
[
3.1.0]hex-2-ene system (Fig. 1).
The second strategy for obtaining pure diastereoisomeric com-
HO
HO
pounds was the enzymatic hydrolysis of (+)-1-[(1S,5R)-6,6-dim-
ethylbicyclo[3.1.0]hex-2-en-2-yl)]ethyl acetate (RS,1S,5R)-5. The
biotransformations were carried out at room temperature with
shaking (150 rpm) in a biphasic system consisting of 0.05 M phos-
phate buffer, pH 7, and a mixture of diisopropyl ether and hexane
with one of the lipases from B. cepacia, P. fluorescence, and C. rugosa
(
R,1S,5R)-4
(S,1S,5R)-4
Scheme 2. Reagents: (a) lipase, AcOC H , i-Pr O, powdered molecular sieves 3 Å.
2 3 2
1
6
(
Scheme 4). All enzymes tested gave no acceptable results; bio-
catalysts did not show stereospecificity when hydrolyzing acetate
RS,1S,5R)-5, giving a mixture of (R)- and (S)-isomers of alcohol 4
(
Table 1
with an unreacted mixture of acetate (RS,1S,5R)-5.
Results of enzymatic transesterification of (+)-1-[(1S,5R)-6,6-dimethylbicy-
clo[3.1.0]hex-2-en-2-yl)]ethanol (RS,1S,5R)-4
All of the obtained compounds, pure diastereoisomeric forms
and their mixtures, exhibited various interesting fragrances.17
The comparative analysis of the odoriferous properties of alcohols
(RS,1S,5R)-4, (R,1S,5R)-4, (S,1S,5R)-4 and esters (RS,1S,5R)-5,
Lipase
Time (h)
ee of acetate (%)
3
7 °C
45 °C
(
R,1S,5R)-5 showed that all diastereoisomers are medium intensive
Amano PS from Burkholderia cepacia
3
7
4
8
62.9
68.4
85.6
86.8
59.1
71.7
84.8
85.2
with fruity or herbal-balsamic note. Odor characteristics of the
newly obtained pure diastereoisomers in comparison with diaste-
reoisomeric mixture (RS,1S,5R)-4 and (RS,1S,5R)-5 are given in
Table 2.
The search for the effective odor vector with chiral fragrance is
very challenging. All of the possible stereoisomers of a certain chi-
ral odorants have to be prepared in a diastereopure form and the
odoriferous properties have to be evaluated. Herein, we have
shown that biocatalysis is an easy way to obtain chiral fragrant
compounds and it is a good alternative to a chemical synthesis.
2
4
AK from Pseudomonas fluorescence
AYS from C. rugosa
3
7
4
8
42.7
76.2
82.1
83.4
51.8
74.9
83.2
84.1
2
4
3
7
4
8
7.6
7.5
12.3
15.7
7.1
9.4
19.3
24.6
9
2
4
O
O
O
a
HO
b
O
O2N
(
R,1S,5R)-4
(R,1S,5R)-6
(R,1S,5R)-5
Scheme 3. Reagents: (a) LiAlH
4
; (b) p-NBCl, Py.

R. Kuriata et al. / Tetrahedron: Asymmetry 21 (2010) 805–809
807
(
Amano). All materials were obtained from commercial suppliers:
Sigma, Aldrich, Fluka, POCh, Serva, and used without purification.
The course of all the reactions, composition of products, and their
purities were checked by thin-layer chromatography (TLC) and gas
chromatography (GC). The enantiomeric excess was determined by
chiral gas chromatography (CGC). TLC was carried out on Silica Gel
6
0 F254 0.2 mm (Merck). Plates were developed in a mixture of hex-
ane, diethyl ether, ethyl acetate, and acetone in various ratios and
visualized with 20% ethanolic H SO , containing 0.1% of anisalde-
2
4
hyde. Preparative column chromatography was carried out on sil-
ica gel (230–400 mesh, Merck) with a mixture of hexane, diethyl
ether, ethyl acetate, and acetone (various ratios) as an eluent. Ana-
lytical GC was performed on Hewlett Packard 5890 (series II)
instrument using capillary column HP-5 (length 25 m, temperature
1
20–180 °C). Melting points were determined on a Boetius appara-
tus. IR spectra were taken from liquid films or in KBr on Perkin–El-
1
13
mer 621 spectrometer. H and C NMR spectra were recorded in
CDCl with TMS as an internal standard on a Bruker Avance™
DRX 300 or Bruker Avance™ DRX 600 instrument. Chemical shifts
d) are reported in ppm and coupling constants (J) are given in
3
(
1
3
1
hertz. C– H substitution was determined with DEPT-135 experi-
ments. The names of the compounds are compatible with IUPAC
nomenclature. Numbering of carbon atoms in all the compounds
1
13
was changed to simplify interpretation of H and C NMR spectra.
Optical rotation measurements were obtained on a PolAAr-31
automatic polarimeter (Optical Activity Ltd). X-ray data were col-
lected at ambient temperature using a KM4CCD
j-axis diffractom-
eter with graphite-monochromated Mo K radiation. The data
a
were corrected for Lorentz and polarization effects. Data collection,
reduction, and analysis were carried out with CRYSALIS CCD and CRYSALIS
1
8
RED programs. The structure was solved by direct methods and
2
refined by the full matrix least-squares method on all F data using
1
9
SHELXS97 and SHELXL97 programs.
Non-hydrogen atoms were
refined with anisotropic displacement parameters. Methyl hydro-
gen atoms were located in F maps and refined as part of rigid rid-
Figure 1. Crystal structure of (R,1S,5R)-6.
D
ing and rotating groups; the remaining hydrogen atoms were
positioned geometrically and treated as riding. Crystallographic
data (excluding structure factors) for the structure in this paper
have been deposited to the Cambridge Crystallographic Data Cen-
tre as supplementary publication number CCDC 766355.
The examples described herein demonstrate the usefulness of the
lipase-mediated reaction in the synthesis of single stereoisomers.
The only limitation is finding a well-fitting biocatalyst for a given
compound.
3
. Experimental
3
.1. (+)-1-[(1S,5R)-6,6-Dimethylbicyclo[3.1.0]hex-2-en-2-yl)]-
2
D
5
ethanol (RS,1S,5R)-4
(
+)-3-Carene was purchased from Acros Organics (½
aꢀ
¼ þ15:3
2
6
3
(
neat); n ¼ 1:4697, d = 0.864 g/cm , bp = 170–171 °C, ee = 100%).
D
Bicyclic enon 3 (4.00 g, 26.6 mmol) in anhydrous diethyl ether
The sources of lipases were Amano PS from B. cepacia (Aldrich),
lipases AK from P. fluorescence (Amano), lipases AYS from C. rugosa
(
4
80 ml) was dropped to the solution of LiAlH (1.40 g, 36.9 mmol)
O
O
O
a
O
a
O
HO
HO
O
+
+
(
R,1S,5R)-4
(S,1S,5R)-5
(RS,1S,5R)-5
(R,1S,5R)-5
(S,1S,5R)-4
2
Scheme 4. Reagents: (a) lipase, i-Pr O/hexane, phosphate buffer pH 7.
Table 2
Odor characteristics of pure isomers and their mixture
Compound
Odor characteristics
(
(
(
(
(
RS,1S,5R)-4
RS,1S,5R)-5
R,1S,5R)-4, ee = 100%
S,1S,5R)-4, ee = 78%
R,1S,5R)-5, ee = 100%
Medium intensive, fruity with peppermint note
Medium intensive, sweet with resinous note
Medium intensive, floral-woody with gerbera and apple note
Medium intensive, fruity with chemical-camphor note
Medium intensive, woody-balsamic with honey note

8
08
R. Kuriata et al. / Tetrahedron: Asymmetry 21 (2010) 805–809
in anhydrous diethyl ether (80 ml). The mixture was stirred at
10 °C until TLC monitoring showed the absence of substrate 3
about 1 h). Then, distilled water was dropped carefully until white
precipitate was observed. Next, the solution was decanted and
dried over anhydrous MgSO . After removing the solvent, the crude
3.3. Enzymatic hydrolysis of (+)-1-[(1S,5R)-6,6-dimethylbicyclo-
[3.1.0]hex-2-en-2-yl)]ethyl acetate (RS,1S,5R)-5
ꢁ
(
Enzymatic hydrolysis of (+)-1-[(1S,5R)-6,6-dimethylbicyclo-
[3.1.0]hex-2-en-2-yl)]ethyl acetate 5 was carried out in a biphasic
system (3.8 ml) consisting of 0.05 M phosphate buffer, pH 7
(3.0 ml), and a mixture of diisopropyl ether (0.2 ml) with n-hexane
(0.6 ml). After the addition of the substrate (0.60 g, 3.1 mmol) and
100 mg of suitable lipase the reactions were carried out at room
temperature with shaking (150 rpm). The reactions were stopped
after certain periods of time, and the product was extracted twice
with 15 ml of ethyl acetate and the organic phase was dried over
4
product 4 was purified by column chromatography (eluent: hex-
ane–ethyl acetate 7:1) to give mixture of alcohol (RS,1S,5R)-4
(
3.0 g, 19.7 mmol, 74% yield). Chiral gas chromatography showed
two diastereoisomers of alcohol (RS,1S,5R)-4 in a ratio of 85 to
2
D
8
28
ꢁ1
1
3
1
5. ½a
ꢀ
¼ þ87:0 (c 1.0, CHCl
3
); nD ¼ 1:4783; IR (film, cm ):
354 (vs); 3019 (s); 2867 (s); 1638 (w); 1449 (s); 1373 (vs);
065 (vs); 802 (vs); H NMR (CDCl , 300 MHz): 0.68 (s, 3H at C-7
1
3
or at C-8, S-isomer); 0.70 (s, 3H at C-7 or at C-8, R-isomer); 0.93
s, 3H at C-7 or at C-8, S-isomer); 0.95 (s, 3H at C-7 or at C-8, R-iso-
mer); 1.16 (d, J = 6.5 Hz, 3H at C-10); 1.23 (t, J = 7.1 Hz, 1H at C-5);
4
anhydrous MgSO . After filtration, the solvent was removed by
evaporation and the obtained products were purified by column
chromatography and analyzed by GC and CGC.
(
1
3
.53 (dd, J = 6.5, 3.0 Hz, 1H at C-1, R-isomer); 1.63 (dd, J = 6.6,
.0 Hz, 1H at C-1, S-isomer); 1.97 (d, J = 16.0 Hz, 1H at C-4); 2.32
3.4. Enzymatic transesterification of (+)-1-[(1S,5R)-6,6-di-methyl
bicyclo[3.1.0]hex-2-en-2-yl)]ethanol (RS,1S,5R)-4; (+)-(1S)-1-[(1S,
5R)-6,6-dimethylbicyclo[3.1.0]hex-2-en-2-yl)]ethanol (S,1S,5R)-4;
(+)-(1R)-1-[(1S,5R)-6,6-dimethylbicyclo[3.1.0]hex-2-en-2-yl)]
ethyl acetate (R,1S,5R)-5
(
4
dd, J = 18.1, 8.2 Hz, 1H at C-4, R-isomer); 2.51–2.52 (m, 1H at C-
, S-isomer); 4.11 (q, J = 6.5 Hz, 1H at C-9, S-isomer); 4.26 (q,
13
J = 6.3 Hz, 1H at C-9, R-isomer); 5.24 (s, 1H at C-3); C NMR (CDCl
5 MHz): 13.10 (C-7 or C-8, S-isomer); 13.18 (C-7 or C-8, R-iso-
mer); 19.40 (C-6); 21.54 (C-10, S-isomer); 21.96 (C-10, R-isomer);
3
,
7
2
3
6.33 (C-7 or C-8); 29.22 (C-5, R-isomer); 29.82 (C-5, S-isomer);
1.06 (C-4, S-isomer); 31.71 (C-4, R-isomer); 36.73 (C-1); 66.85
Enzymatic transesterification of (+)-1-[(1S,5R)-6,6-dimethyl-
bicyclo[3.1.0]hex-2-en-2-yl)]ethanol (RS,1S,5R)-4 was carried out
in diisopropyl ether (6 ml) with the addition of 40 mg of powdered
molecular sieves (3 Å mesh). 2.00 g (13.1 mmol) of the substrate;
1600 mg of suitable lipase and vinyl acetate (3.60 ml, 39.1 mmol)
were added. The reactions were carried out at 37 °C in a shaker
(150 rpm). The reaction was stopped after certain periods of time
by filtration followed by evaporation of the organic layer. The
resulting product was purified by column chromatography (eluent:
hexane–acetone from 40:1 to 10:1) to give alcohol 4 and acetate 5.
(
C-9, S-isomer); 67.30 (C-9, R-isomer); 124.42 (C-3, R-isomer);
1
7
26.62 (C-3, S-isomer); 148.32 (C-2). Anal. Calcd for C10H16O: C,
8.90; H, 10.59. Found: C, 78.69; H, 10.67.
3
.2. (+)-1-[(1S,5R)-6,6-Dimethylbicyclo[3.1.0]hex-2-en-2-yl)]-
ethyl acetate (RS,1S,5R)-5
The mixture of alcohol (RS,1S,5R)-4 (0.80 g, 5.2 mmol) in
2
9
anhydrous diethyl ether (60 ml) and anhydrous pyridine
Alcohol (S,1S,5R)-4: ee = 78%; ½
a
ꢀ
¼ þ12:0 (c 1.0, CHCl
3
);
D
3
0
ꢁ1
(
0.64 ml, 7.9 mmol) was intensively stirred at an ice bath tem-
perature. Next, the solution of fresh distilled acetyl chloride
0.56 ml, 7.9 mmol) in anhydrous diethyl ether (60 ml) was
n
¼ 1:4717; IR (film, cm ): 3354 (vs); 3019 (s); 2867 (s); 1638
D
1
3
(w); 1449 (s); 1373 (vs); 1065 (vs); 802 (vs); H NMR (CDCl ,
(
300 MHz): 0.68 (s, 3H at C-7 or at C-8); 0.93 (s, 3H at C-7 or at
C-8); 1.16 (d, J = 6.5 Hz, 3H at C-10); 1.23 (t, J = 7.1 Hz, 1H at C-
5); 1.63 (dd, J = 6.6, 3.0 Hz, 1H at C-1); 1.97 (d, J = 16.0 Hz, 1H at
C-4); 2.51–2.52 (m, 1H at C-4); 4.11 (q, J = 6.5 Hz, 1H at C-9);
added carefully. The reaction was carried out at room tempera-
ture and stopped when TLC analysis showed the absence of sub-
strate 4, and then the reaction mixture was diluted with diethyl
ether (120 ml). To the obtained slightly acidic environment a
solution of dilute HCl was added. The aqueous phase was ex-
tracted three times with diethyl ether. All ether phases were
1
3
3
5.24 (s, 1H at C-3); C NMR (CDCl , 75 MHz): 13.10 (C-7 or C-8);
19.40 (C-6); 21.54 (C-10); 26.33 (C-7 or C-8); 29.82 (C-5); 31.06
(C-4); 36.73 (C-1); 66.85 (C-9); 126.62 (C-3); 148.32 (C-2). Anal.
washed with 2% H
rated NaCl solution. The organic phase was dried over MgSO
and after removing the solvent, the crude product (RS,1S,5R)-5
was obtained (0.88 g, 4.5 mmol, 86% yield). Chiral gas chroma-
tography showed two diasteroisomers of acetate (RS,1S,5R)-5 in
2
SO
4
solution, 10% NaHCO
3
solution, and satu-
Calcd for C10
H16O: C, 78.90; H, 10.59. Found: C, 78.64; H, 10.74.
2
6
28
4
Acetate (R,1S,5R)-5: ½
aꢀ
D
3
¼ þ180:0 (c 1.0, CHCl ); nD ¼ 1:4597;
ꢁ1
IR (film, cm ): 3021 (w); 2940 (m); 1737 (s); 1641 (w); 1448 (m);
1
3
1371 (m); 1242 (vs); 1048 (m); H NMR (CDCl , 600 MHz): 0.77 (s,
3H at C-7 or at C-8); 1.05 (s, 3H at C-7 or at C-8); 1.32 (d, J = 6.4 Hz,
3H at C-10); 1.33 (t, J = 7.4 Hz, 1H at C-5); 1.66 (dd, J = 7.1, 3.2 Hz,
1H at C-1); 2.05 (s, 3H at C-12); 2.07 (d, J = 18.1 Hz, 1H at C-4); 2.43
(dd, J = 18.1, 7.7 Hz, 1H at C-4); 5.38 (s, 1H at C-3); 5.43 (q,
2
D
8
26
a ratio of 85 to 15. ½
a
ꢀ
¼ þ225:0 (c 1.0, CHCl
3
), nD ¼ 1:4578;
ꢁ1
IR (film, cm ): 2868 (s); 1736 (vs); 1448 (m); 1371 (m); 1242
(
3
vs); 1062 (m); 800 (w); 1H NMR (CDCl
H at C-7 or at C-8, R-isomer); 0.71 (s, 3H at C-7 or at C-8, S-iso-
3
, 300 MHz): 0.69 (s,
1
3
3
J = 6,5 Hz, 1H at C-9); C NMR (CDCl , 75 MHz): 14.95 (C-7 or C-
mer); 0.96 (s, 3H at C-7 or at C-8, S-isomer); 0.98 (s, 3H at C-7 or
at C-8, R-isomer); 1.24 (d, J = 6.6 Hz, 3H at C-10); 1.25 (t,
J = 7.9 Hz, 1H at C-5); 1.58 (dd, J = 6.5, 3.1 Hz, 1H at C-1, R-iso-
mer); 1.61 (dd, J = 7.0, 3.4 Hz, 1H at C-1, S-isomer); 1.97 (s, 3H
at C-12); 2.02 (d, J = 16.1 Hz, 1H at C-4); 2.36 (dd, J = 18.3,
8); 18.70 (C-10); 19.13 (C-6); 21.41 (C-7 or C-8); 27.94 (C-5);
28.88 (C-4); 29.98 (C-1); 46.73 (C-12); 75.15 (C-9); 108.31 (C-3);
18 2
148.53 (C-2); 170.86 (C-11). Anal. Calcd for C12H O : C, 74.19;
H, 9.34. Found: C, 74.11; H, 9.46.
7
5
(
.8 Hz, 1H at C-4, R-isomer); 2.51–2.53 (m, 1H at C-4, S-isomer);
3.5. (+)-(1R)-1-[(1S,5R)-6,6-Dimethylbicyclo[3.1.0]hex-2-en-2-
yl)]ethanol (R,1S,5R)-4
.22 (q, J = 6,4 Hz, 1H at C-9, S-isomer); 5.30 (s, 1H at C-3); 5.36
q, J = 6,1 Hz, 1H at C-9, R-isomer);1 C NMR (CDCl
3
3
, 75 MHz):
1
3.07 (C-7 or C-8); 19.43 (C-6); 21.30 (C-10, R-isomer); 21.70
Acetate (obtained by enzymatic transesterification in anhy-
(
C-10, S-isomer); 26.32 (C-7 or C-8); 29.11 (C-5); 30.40 (C-4, S-
isomer); 31.78 (C-4, R-isomer); 35.93 (C-1, S-isomer); 36.69 (C-
, R-isomer); 43.73 (C-12); 66.83 (C-9, S-isomer); 69.33 (C-9, R-
isomer); 124.40 (C-3, S-isomer); 125.34 (C-3, R-isomer); 143.61
C-2); 170.35 (C-11). Anal. Calcd for C12 : C, 74.19; H,
.34. Found: C, 74.11; H, 9.46.
drous conditions) (R,1S,5R)-5 (1.20 g, 6.17 mmol) in anhydrous
diethyl ether (60 ml) was dropped to a solution of LiAlH
4
1
(0.480 g, 12.6 mmol) in anhydrous diethyl ether (80 ml). The mix-
ture was stirred at room temperature until TLC monitoring showed
the absence of substrate 5 (about 1 h). Then, distilled water was
dropped carefully until a white precipitate was observed. Next,
(
9
18 2
H O

R. Kuriata et al. / Tetrahedron: Asymmetry 21 (2010) 805–809
19NO
809
the solution was decanted and dried over MgSO
4
. After removing
Calcd for C17
H
4
: C, 67.76; H, 6.36; N, 4.65. Found: C, 67.63;
the solvent, the crude product was purified by column chromatog-
raphy (eluent: hexane–ethyl acetate 7:1) to give pure alcohol
H, 6.48; N, 4.76. Crystal data: C17
H
19NO
4
, M
r
= 301.33, T = 299 K,
1
, a = 10.2474(19) Å,
Mo K radiation, monoclinic, space group P2
a
29
3
(
R,1S,5R)-4 (0.61 g, 4.0 mmol, 65% yield): ½
a
ꢀ
¼ þ69:0 (c 1.0,
b = 7.4649(9) Å, c = 11.480(2) Å, b = 114.12(2)°, V = 801.5(2) Å ,
D
2
8
ꢁ1
ꢁ3
CHCl
3
); n ¼ 1:4828; IR (film, cm ): 3360 (s); 3078 (m); 2972
Z = 2, D
c
= 1.249 Mg m , R = 0.0475, wR = 0.1077 (for 1524 all
D
(
vs); 2932 (s); 1645 (m); 1451 (s); 1372 (m); 1085 (s); 1069 (s);
data). CCDC 766355.
1
3
H NMR (CDCl , 600 MHz): 0.81 (s, 3H at C-7 or at C-8); 1.06 (s,
3
H at C-7 or at C-8); 1.28 (d, J = 6,5 Hz, 3H at C-10); 1.34 (t,
Acknowledgments
J = 7.1 Hz, 1H at C-5); 1.65 (dd, J = 6.4, 3.0 Hz, 1H at C-1); 2.08 (d,
J = 18.1 Hz, 1H at C-4); 2.43 (dd, J = 18.2, 7.6 Hz, 1H at C-4); 4.38
q, J = 6.3 Hz, 1H at C-9); 5.35 (s, 1H at C-3); 13C NMR (CDCl
The authors would like to thank the Polish Ministry of Science
and Higher Education for supporting this work (Grant no. N
N204 136538), Professor Józef Kula from Technical University of
Łód z´ for evaluation of odor characteristics, and Paweł Szatkowski
from Wrocław University of Technology for assistance.
(
3
,
1
51 MHz): 13.18 (C-7 or C-8); 19.41 (C-6); 21.98 (C-10); 26.33
(
C-7 or C-8); 29.23 (C-5); 31.71 (C-4); 36.69 (C-1); 67.27 (C-9);
1
1
22.87 (C-3); 148.33 (C-2). Anal. Calcd for C10
0.59. Found: C, 78.82; H, 10.68.
H16O: C, 78.90; H,
3
.6. (+)-(1R)-1-[(1S,5R)-6,6-Dimethylbicyclo[3.1.0]hex-2-en-2-
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ꢀ
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D
ꢁ
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1
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1
1
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C-7 or C-8); 29.12 (C-5); 31.84 (C-4); 36.49 (C-1); 71.28 (C-9);
(
1
(
1
1
3
,
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1
1
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