Stereochemistry of terpene derivatives. Part 4: Fragrant terpenoid derivatives with an unsaturated gem-dimethylbicyclo[3.1.0]hexane system

Article abstract of DOI:10.1016/j.tetasy.2005.09.004

Starting from (+)-3-carene 1 several chiral fragrant compounds with the bicyclo[3.1.0]hexane system 4-6 and 10-20 were synthesized. These compounds are structural analogues of naturally occurring fragrant compounds, such as ionones and damascones, and possess either an endo- or an exo-cyclic double bond in the bicyclo[3.1.0]hexane moiety. The absolute configuration of selected products was confirmed by X-ray crystallography and circular dichroism analysis.

Full text of DOI:10.1016/j.tetasy.2005.09.004

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 3352–3360
Stereochemistry of terpene derivatives. Part 4:q Fragrant
terpenoid derivatives with an unsaturated
gem-dimethylbicyclo[3.1.0]hexane system
a
b
a
c
_
´
Bozena Fra˛ckowiak, Teresa Olejniczak, Rafał Latajka, Agata Białonska,
c
a,
*
´
Zbigniew Ciunik and Stanisław Lochynski
aDepartment of Bioorganic Chemistry, Faculty of Chemistry, Wrocław University of Technology, Wybrzez_e Wyspian´skiego 27,
50-370 Wrocław, Poland
bDepartment of Chemistry, Agricultural University, Norwida 25, 50-375 Wrocław, Poland
cFaculty of Chemistry, University of Wrocław, F. Joliot-Curie 14, 50-383 Wrocław, Poland
Received 15 June 2005; revised 31 August 2005; accepted 1 September 2005
Available online 20 October 2005
Abstract—Starting from (+)-3-carene 1 several chiral fragrant compounds with the bicyclo[3.1.0]hexane system 4–6 and 10–20 were
synthesized. These compounds are structural analogues of naturally occurring fragrant compounds, such as ionones and dama-
scones, and possess either an endo- or an exo-cyclic double bond in the bicyclo[3.1.0]hexane moiety. The absolute configuration
of selected products was confirmed by X-ray crystallography and circular dichroism analysis.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
pounds in the Horner–Wadsworth–Emmons (HWE)
reaction catalyzed by sodium hydride.12 Herein, we
report syntheses of fragrant derivatives, in which the
bicyclic fragment was preserved with an endo- or exo-
cyclic double bond.
The optically active monoterpene (+)-3-carene 1 is a
convenient substrate in the syntheses of chiral deriva-
tives displaying interesting fragrant properties, in which
the bicyclo[4.1.0]heptane system is preserved.2,3 The
chemical properties of this monoterpene allowed the for-
mation of compounds with the bicyclo[3.1.0]hexane sys-
tem possessing an endo-cyclic double bond.4–6 Recently,
derivatives obtained from (+)-3-carene with the
bicyclo[3.1.0]hexane moiety have been investigated as
chiral auxiliaries in a variety of reactions.7–10
2. Results and discussion
The key compound, a,b-unsaturated aldehyde 3, was
synthesized in a two-step procedure from the monoter-
pene hydrocarbon (+)-3-carene 1 via condensation of
the ketoaldehyde 2.5
Compounds with the bicyclo[3.1.0]hexane system pos-
sess a valuable sandalwood odour in the perfume indus-
try.2 In our previous studies, we obtained a series of
derivatives with a saturated 6,6-dimethylbicyclo[3.1.0]-
hexane moiety substituted at the C-3 position possessing
various groups: hydroxyl, carbonyl or ester (especially
acetates).11 The double bond present in this system
makes it unstable and in some cases drives its conversion
to other systems, for example, to monocyclic com-
This reaction was carried out in acetic acid–morpholine
(1:1) with azeotropic removal of water and led to the
desired product (1R,5S)-(ꢀ)-3,6,6-trimethylbicyclo[3.1.0]-
hex-2-en-2-carboaldehyde 3 (Scheme 1).
O
a
b
CHO
CHO
q See Ref. 1.
1
2
3
*
Corresponding author. Tel.: +48 71 320 2400; fax: +48 71 347
7175; e-mail: stanislaw.lochynski@pwr.wroc.pl
Scheme 1. Reagents: (a) (1) O3, (2) Zn; (b) AcOH.
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.09.004

B. Fra˛ckowiak et al. / Tetrahedron: Asymmetry 16 (2005) 3352–3360
3353
OH
R
OH
R
CHO
a
+
3
(S)-4
(S)-5
(S)-6
R=Al lyl
R=Pr
R=iPr
(R)-4
(R)-5
(R)-6
b
b
NO2
NO2
O
O
O
O
R
R
(S)-7
(S)-8
(S)-9
R=Al lyl
R=Pr
R=iPr
(R)-7
(R)-8
(R)-9
Scheme 2. Reagents: (a) RI or RBr, Mg, Et2O; (b) p-NO2PhCOCl, Py.
Aldehyde 3 was subjected to a Grignard reaction with
three–carbon units of alkylmagnesium halides: allyl-
magnesium bromide, n-propylmagnesium bromide and
isopropylmagnesium iodide, to give the appropriate
unsaturated secondary alcohols (RS)-4–(RS)-6ꢀ as a
mixture of diastereoisomers (Scheme 2). Only the reac-
tion with allylmagnesium bromide afforded a mixture
of diastereoisomeric alcohols (R)-4 and (S)-4 in a 1:1
ratio. In the case of alcohols obtained from n-propyl-
magnesium bromide, diastereoisomer (S)-5, which
possesses a higher Rf value in a TLC analysis, was pre-
dominant in the mixture (68%). The same effect was
observed in the reaction with isopropylmagnesium
iodide [73% of isomer (S)-6].
The separation of these diastereoisomeric mixtures of
alcohols by preparative column chromatography affor-
ded pure diastereoisomers of (R)-4–(R)-6 and (S)-4–
(R)-6. The enantiopure (R)-7–(R)-9 and (S)-7–(S)-9 were
obtained in their crystalline forms. The crystal structure
of (S)-9 was determined and its (S)-configuration at the
stereogenic centre in the side chain was assigned on the
basis of the known absolute configuration at the C-1
and C-5 atoms (Fig. 1). In the CD spectra obtained
for methanolic solutions of the p-nitrobenzoates for iso-
mers (S)-7–(S)-9, the Cotton effect was positive, whereas
for diastereoisomers (R)-7–(R)-9 the effect was negative
(Fig. 2).
Figure 1. Crystal structure of (S)-9.
pounds.13 Many of their analogues have already been
synthesized.14 We obtained three more analogues by
the oxidation of alcohols (RS)-6 with the Dess–Martin
periodinane15 to the appropriate ketones 10–12 (Scheme
3). Earlier reactions with oxidizing agents, such as PCC,
PDC or MnO2, gave mixtures of products, from which
we could not separate the desired ketones 10–12 in high
yields. The crude ketone 10 was converted to compound
13 with a double bond conjugated to the carbonyl group
in the side chain—a close analogue of b-damascone
(Scheme 3).
With the crystal structure of (S)-9, the observed Cotton
effects for (R)-7–(R)-9 and (S)-7–(S)-9 and the analysis
1
of H NMR spectra of alcohols (R)-4–(R)-6 and (S)-4–
(S)-6, we assigned the absolute configurations in their
side chains.
We also synthesized the structural analogue 14 of
another important fragrance compound—the ionone13
from the aldehyde 3 in a Horner–Wadsworth–Emmons
(HWE) reaction with the barium-hydroxide-promoted
modification16 (Scheme 4). This modification of the
HWE reaction provided only one product 14 from sub-
strate 3. Earlier attempts to obtain compound 14 in the
The a- and b-damascone and damascenone, known as
ꢁrose ketonesꢂ, belong to the most famous fragrant com-
ꢀ In compounds: (R)-4–(R)-9 and (S)-4–(S)-9 the letters: (R)- and (S)-
apply to absolute configurations of the carbon atom C-10 in the said
chain in each of them.

3354
B. Fra˛ckowiak et al. / Tetrahedron: Asymmetry 16 (2005) 3352–3360
20
0
OH
R
O
a
R
R=Allyl
R=Pr
R=iPr
(R,S)-4
(R,S)-5
(R,S)-6
10
11
12
O
O
-50
b
10
13
Scheme 3. Reagents: (a) Dess–Martin periodinane, CH2Cl2; (b) DBU,
CH2Cl2.
-100
209
250
300
350
400
(A)
Wavelength [nm]
40
0
O
CHO
a
3
14
Scheme 4. Reagents: (a) CH3COCH2PO(OC2H5)2, Ba(OH)2Æ0.8H2O,
THF–H2O (40:1).
-50
alcohol 15 provided only one diastereoisomer of the
ester 18. Reduction of 18 with LAH gave the primary
alcohol 19, which after esterification with acetyl chloride
was converted into acetate 20. The acetyl derivative 17,
with an endo-cyclic double bond, was obtained in the
same manner from 15 (Scheme 5).
-100
-120
215
250
300
350
400
(B)
Wavelength [nm]
20
0
Some of the obtained optically active compounds exhib-
ited various interesting odours.18 The comparative anal-
ysis of the fragrant properties of alcohols (R)-4–(R)-6
and (S)-4–(S)-9 showed that diastereoisomers S were
more intense than the alcohols with the opposite R abso-
lute configuration in the side chain. The diastereoisomer
(R)-4 also displayed odour different from (S)-4. The
scents of compounds 11–14 are also distinct from
damascone and ionone, their structural analogues.
Odour characteristics for all fragrant compounds are
given in Table 1.
-20
-40
-60
-70
207
250
300
350
400
(C)
Wavelength [nm]
3. Experimental
3.1. General
Figure 2. CD spectra of the purified diastereoisomeric benzoates: A—
(S)-7 (green line) and (R)-7 (blue line); B—(S)-8 (green line) and (R)-8
(blue line); C—(S)-9 (green line) and (R)-9 (blue line).
(+)-3-Carene was purchased from Sigma–Aldrich. The
course of all reactions, composition of products and
their purities were checked by thin-layer chromatogra-
phy (TLC) and gas chromatography (GC). TLC was
carried out on silica gel DC-Alufolien Kieselgel 60
(Merck). Plates were developed in a mixture of hexane,
diethyl ether and acetone in various ratios and visual-
ized with 20% ethanolic H2SO4, containing 0.1% of anis-
aldehyde. Preparative column chromatography was
carried out on silica gel (230–400 mesh, Merck) with a
mixture of hexane, diethyl ether and acetone (various
ratios) as eluent. Analytical GC was performed on a
Hewlett Packard 5890 (seria II) instrument using the
capillary column HP-1 (length 25 m, temperature 120–
180 ꢁC). Melting points (uncorrected) were determined
on a Boetius apparatus. IR spectra were taken from
Wittig–Horner reaction with triphenylphosphineacet-
ylmethylene failed.
The next fragrant compounds 17–20 were obtained from
alcohol 15. The a,b-unsaturated aldehyde 3 was reduced
with LAH to give allyl alcohol 15, which was purified by
crystallization of the p-nitrobenzenoate 16 and then
hydrolyzed under alkaline conditions to furnish alcohol
15 (98% purity by GC). Compound 15 was the key
substrate for the syntheses of the derivatives with the
bicyclo[3.1.0]hexane system which possess an exo-cyclic
double bond. The Claisen rearrangement (ortho-acetate
modification)17 of 15 afforded the enantiomerically pure
c,d-unsaturated ester 18. The steric hindrance created by
the gem-dimethylcyclopropyl group in the molecule of

B. Fra˛ckowiak et al. / Tetrahedron: Asymmetry 16 (2005) 3352–3360
3355
c
O
CHO
b
a
OH
O
OAc
e
NO2
15
17
3
16
d
CO2Et
OH
OAc
a
c
18
19
20
Scheme 5. Reagents: (a) LAH, Et2O; (b) p-NO2PhCOCl, C5H5N; (c) AcCl, Py; (d) CH3C(OC2H5)3, C2H5CO2H; (e) KOH, C2H5OH.
Table 1.
Compound
Odour characteristic
(S)-4
(R)-4
(S)-5
(R)-5
(S)-6
(R)-6
11
Medium intensive, agreeable, floral with tansy (Tanacetum vulgare) note
Medium intensive, agreeable, floral-fruity, with dried apple and weak mushroom note
Medium intensive, agreeable, fresh, floral-woody, more intensive then (R)-5
Medium intensive, agreeable, fresh, floral-woody
Intensive, resinous resembling bornyl acetate, camphen with fir oil note, more intensive than (R)-6
Medium intensive, fresh, floral with fir oil note
Intensive, woody-balsamic
13
14
Medium intensive, woody-balsamic
Medium intensive, floral-woody
15
17
Medium intensive, fruity-herbal with fresh note
Intensive, penetrating, sweet, fruity with woody and dry mandarinꢂs skin note
Intensive, woody with spice note
Medium intensive, floral, linalol and citronellol-like
Balsamic, medium turpentine with fruity note
18
19
20
liquid films or in KBr on a Perkin–Elmer 621 spectrom-
ture, over the range 200–400 nm in a 1 mm path length
cell. Compounds were dissolved in methanol at concen-
trations 0.15–0.25 mg/ml.
1
eter. H and 13C NMR spectra were recorded in CDCl3
with TMSas an internal standard on a Bruker Avance
DRX 300 instrument. Chemical shifts (d) are reported
in parts per million and coupling constants (J) are given
in Hertz. 13C–H substitution was determined with a
DEPT-135 experiments. Optical rotation measurements
were obtained on an Autopol IV automatic polarimeter
(Rudolph). X-ray data were collected at 100 K using an
Oxford Cryosystem device on a Kuma KM4CCD j-axis
diffractometer with graphite-monochromated MoKa
radiation. The data were corrected for Lorentz and
polarization effects. No absorption correction was
applied. Data reduction and analysis were carried out
with the Diffraction (Wrocław) programs.19 The structure
was solved by direct methods and refined by the full-
matrix least-squares method on all F2 data using
programs.20 Non-hydrogen atoms were refined with
anisotropic thermal parameters; hydrogen atoms were
included from the Dq maps and refined with isotropic
thermal parameters. Crystallographic data for structures
reported herein have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publica-
tion number CCDC 273888. CD spectra were recorded
on a Jasco J-715 spectropolarimeter at room tempera-
3.1.1. (1R,5S)-(ꢀ)-3,6,6-Trimethylbicyclo[3.1.0]hex-2-en-
2-carboaldehyde 3. Aldehyde 3 was synthesized accord-
ing to a known procedure.5 The crude product was puri-
fied by column chromatography (silica gel, hexane/ethyl
26
acetate 30:1) to give 3 as an oil: ½aŠ ¼ ꢀ192:75 (c 0.99,
D
CHCl3); IR (film, cmꢀ1): 3029(m), 2946(m), 2888(m),
1667(vs), 1622(m), 1421(m), 1376(m), 1238(m); 1H
NMR (CDCl3): 0.69 (s, 3H at C-7 or C-8), 1.05 (s, 3H
at C-7 or C-8), 1.25 (td, J = 7.2, 1.5 Hz, 1H at C-5),
2.04 (s, 3H at C-9), 2.07 (d, J = 2.8 Hz, 1H at C-1),
2.59 (d, J = 20.0 Hz, 1H at C-4), 2.70 (dd, J = 20.1,
7.5 Hz, 1H at C-4), 9.91 (br s, 1H at C-10); 13C NMR
(CDCl3): 13.14 (C-7 or C-8), 13.41 (C-7 or C-8), 20.06
(C-6), 25.73 (C-5), 25.87 (C-9), 34.61 (C-1), 40.16 (C-4),
138.66 (C-3), 162.11 (C-2), 187.54 (C-10).
3.2. General procedure for the Grignard reaction
Aldehyde 3 (15 mmol) in anhydrous diethyl ether
(20 ml) was added dropwise to the Grignard reagent
formed from the appropriate halide (18 mmol) and

3356
B. Fra˛ckowiak et al. / Tetrahedron: Asymmetry 16 (2005) 3352–3360
magnesium (18 mmol) in anhydrous diethyl ether
3.2.4. (1R)-(ꢀ)-1-[(1R,5S)-3,6,6-Trimethylbicyclo[3.1.0]-
25
(60 ml). The mixture was stirred until TLC monitoring
showed the absence of substrate 3. Then NH4Cl solution
was added dropwise and the aqueous layer extracted
with diethyl ether. The organic solution was washed
with saturated NaCl solution and dried over MgSO4.
Each of the crude diastereoisomeric mixtures (RS)-4–
(RS)-6 were separated by column chromatography (elu-
ent: hexane–diethyl ether 9:1) to give pure compounds
(R)-4–(R)-6 and (S)-4–(S)-6.
hex-2-en-2-yl]butan-1-ol (R)-5. ½aŠ ¼ ꢀ98:5 (c 0.90,
CHCl3); IR (film, cmꢀ1): 3358(m),D3019(m), 2958(vs),
1
1660(w), 1457(m), 1373(m), 1021(s); H NMR (CDCl3):
0.66 (s, 3H at C-7 or C-8), 0.86 (t, J = 7.1 Hz, 3H at C-
13), 0.96 (s, 3H at C-7 or C-8), 1.13 (t, J = 6.9 Hz, 1H
at C-5), 1.23–1.27 (m, 2H at C-12), 1.43–1.47 (m, 2H at
C-11), 1.541 (s, 3H at C-9), 1.76 (d, J = 6.8 Hz, 1H at
C-1); 1.92 (d, J = 17.0 Hz, 1H at C-4), 2.38 (dd,
J = 17.8, 7.7 Hz, 1H at C-4), 4.30 (dd, J = 7.6, 5.1 Hz,
1H at C-10); 13C NMR (CDCl3): 13.74 (C-7 or C-8),
14.68 (C-7 or C-8), 14.77 (C-13), 19.77 (C-12), 21.39
(C-6), 27.30 (C-5), 36.77 (C-1), 37.04 (C-4), 38.77 (C-
11), 68.56 (C-9), 68.57 (C-10), 135.50 (C-3), 138.66
(C-2). Anal. Calcd for C13H22O: C, 80.35; H, 11.41.
Found: C, 80.09; H, 11.62.
3.2.1. (1S)-(ꢀ)-1-[(1R,5S)-3,6,6-Trimethylbicyclo[3.1.0]-
25
hex-2-en-2-yl]but-3-en-1-ol (S)-4. ½aŠ ¼ ꢀ56:2 (c 0.76,
D
CHCl3); IR (film, cmꢀ1): 3402(s), 3077(m), 2923(vs),
1641(w), 1433(m), 1375(s), 1037(s), 914(s); 1H NMR
(CDCl3): 0.72 (s, 3H at C-7 or C-8), 0.98 (s, 3H at C-7
or C-8), 1.13 (t, J = 7.2 Hz, 1H at C-5), 1.55 (s, 3H at
C-9), 1.62 (d, J = 6.7 Hz, 1H at C-1), 1.93 (d,
J = 17.9 Hz, 1H at C-4), 2.21–2.38 (m, 2H at C-11),
2.42 (dd, J = 18.4, 8.1 Hz, 1H at C-4), 4.34 (t,
J = 6.9 Hz, 1H at C-10), 5.02 (d, J = 5.6 Hz, 1H at C-
13), 5.10 (d, J = 13.1 Hz, 1H at C-13), 5.67–5.81 (m,
1H at C-12); 13C NMR (CDCl3): 12.98 (C-7 or C-8),
13.65 (C-7 or C-8), 20.44 (C-6), 26.22 (C-9), 26.27 (C-
5), 36.26 (C-1), 38.07 (C-4), 40.43 (C-11), 67.90 (C-12),
117.22 (C-13), 134.94 (C-10), 135.23 (C-3), 136.44 (C-
2). Anal. Calcd for C13H20O: C, 81.20; H, 10.48. Found:
C, 81.01; H, 10.67.
3.2.5. (1S)-(ꢀ)-1-[(1R,5S)-3,6,6-Trimethylbicyclo[3.1.0]-
25
hex-2-en-2-yl]-2-methylpropan-1-ol (S)-6. ½aŠ ¼ ꢀ134:2
D
(c 0.89, CHCl3); IR (film, cmꢀ1): 3464(m), 3019(m),
1
2954(vs), 1655(w), 1467(m), 1374(s), 1012(s), 999(s); H
NMR (CDCl3): 0.76 (s, 3H at C-7 or C-8), 0.78 (d,
J = 6.6 Hz, 3H at C-12 or C-13), 1.00 (s, 3H at C-7 or C-
8), 1.04 (d, J = 6.0 Hz, 3H at C-12 or C-13), 1.17 (t,
J = 7.2 Hz, 1H at C-5), 1.58 (s, 3H at C-9), 1.62 (dd,
J = 7.4, 2.7 Hz, 1H at C-1), 1.75–1.84 (m, 1H at C-11),
1.97 (d, J = 17.7 Hz, 1H at C-4), 2.48 (dd, J = 17.9,
7.6 Hz, 1H at C-4), 3.89 (d, J = 8.8 Hz, 1H at C-10); 13C
NMR (CDCl3): 13.07 (C-7 or C-8), 13.68 (C-7 or C-8),
18.94 (C-13), 19.24 (C-12), 20.36 (C-6), 26.24 (C-9), 26.25
(C-5), 33.14 (C-1), 38.04 (C-4), 36.24 (C-11), 74.30 (C-10),
135.57 (C-3), 136.32 (C-2). Anal. Calcd for C13H22O: C,
80.35; H, 11.41. Found: C, 80.17; H, 11.71.
3.2.2. (1R)-(ꢀ)-1-[(1R,5S)-3,6,6-Trimethylbicyclo[3.1.0]-
25
hex-2-en-2-yl]but-3-en-1-ol (R)-4. ½aŠ ¼ ꢀ83:1 (c 0.95,
D
CHCl3); IR (film, cmꢀ1): 3434(s), 3079(m), 2978(w),
1
1641(w), 1446(m), 1384(m), 1112(s), 910(s); H NMR
(CDCl3): 0.67 (s, 3H at C-7 or C-8), 0.97 (s, 3H at C-7
or C-8), 1.15 (td, J = 7.5, 1.1 Hz, 1H at C-5), 1.55 (s,
3H at C-9), 1.79 (dd, J = 6.7, 2.9 Hz, 1H at C-1), 1.92
(d, J = 18.2 Hz, 1H at C-4), 2.05–2.13 (m, 1H at C-11),
2.20–2.28 (m, 1H at C-11), 2.40 (dd, J = 17.9, 7.6 Hz,
1H at C-4), 4.34 (dd, J = 8.7, 4.3 Hz, 1H at C-10), 5.06
(d, J = 5.4 Hz, 1H at C-13), 5.10 (d, J = 13.7 Hz, 1H at
C-13), 5.72–5.86 (m, 1H at 12); 13C NMR (CDCl3):
12.96 (C-7 or C-8), 13.80 (C-7 or C-8), 20.53 (C-6),
26.18 (C-9), 26.52 (C-5), 36.26 (C-1), 38.02 (C-4), 40.36
(C-11), 66.97 (C-12), 117.75 (C-13), 135.12 (C-10),
135.25 (C-3), 136.96 (C-2). Anal. Calcd for C13H20O:
C, 81.20; H, 10.48. Found: C, 81.03; H, 10.65.
3.2.6. (1R)-(ꢀ)-1-[(1R,5S)-3,6,6-Trimethylbicyclo[3.1.0]-
25
D
hex-2-en-2-yl]-2-methylpropan-1-ol (R)-6. ½aŠ ¼ ꢀ146:0
(c 1.13, CHCl3); IR (film, cmꢀ1): 3402(m), 3018(m),
2955(vs), 1655(w), 1462(m), 1373(m), 1168(w), 1011(m);
1H NMR (CDCl3): 0.72 (s, 3H at C-7 or C-8), 0.80 (d,
J = 6.6 Hz, 3H at C-12 or C-13), 0.97 (s, 3H at C-7 or
C-8), 0.99 (d, J = 6.7 Hz, 3H at C-12 or C-13), 1.21 (t,
J = 10.6, Hz, 1H at C-5), 1.59 (s, 3H at C-9), 1.83 (dd,
J = 6.8, 2.8 Hz, 1H at C-1), 1.71–1.74 (m, 1H at C-11),
2.00 (d, J = 17.7 Hz, 1H at C-4), 2.41 (dd, J = 17.9,
8.0 Hz, 1H at C-4), 4.02 (d, J = 7.8 Hz, 1H at C-10); 13C
NMR (CDCl3): 13.30 (C-7 or C-8), 14.21 (C-7 or C-8),
18.56 (C-13), 19.03 (C-12), 20.84 (C-6), 26.34 (C-9),
26.93 (C-5), 33.06 (C-1), 38.13 (C-4), 37.03 (C-11), 73.75
(C-10), 136.02 (C-3), 136.99 (C-2). Anal. Calcd for
C13H22O: C, 80.35; H, 11.41. Found: C, 80.13; H, 11.73.
3.2.3. (1S)-(ꢀ)-1-[(1R,5S)-3,6,6-Trimethylbicyclo[3.1.0]-
25
hex-2-en-2-yl]butan-1-ol (S)-5. ½aŠ ¼ ꢀ141:5 (c 0.80,
D
CHCl3); IR (film, cmꢀ1): 3418(m), 3019(m), 2956(vs),
1659(w), 1456(m), 1374(m), 1022(m); 1H NMR (CDCl3):
0.72 (s, 3H at C-7 or C-8), 0.87 (t, J = 7.3 Hz, 3H at C-
13), 0.97 (s, 3H at C-7 or C-8), 1.13 (t, J = 6.7 Hz, 1H
at C-5), 1.24–1.30 (m, 2H at C-12), 1.44–1.47 (m, 2H at
C-11), 1.54 (s, 3H at C-9), 1.72–1.82 (m, 1H at C-1),
1.92 (d, J = 16.7 Hz, 1H at C-4), 2.42 (dd, J = 17.9,
7.7 Hz, 1H at C-4), 4.30 (t, J = 7.0 Hz, 1H at C-10);
13C NMR (CDCl3): 12.88 (C-7 or C-8), 13.63 (C-7 or
C-8), 13.99 (C-13), 18.94 (C-12), 20.36 (C-6), 26.19 (C-
5), 35.90 (C-1), 37.89 (C-4), 38.01 (C-11), 68.09 (C-9),
68.12 (C-10), 134.85 (C-3), 136.99 (C-2). Anal. Calcd
for C13H22O: C, 80.35; H, 11.41. Found: C, 80.11; H,
11.68.
3.3. General procedure for the syntheses of
p-nitrobenzoates
The appropriate alcohol (R)-4–(R)-6 and (S)-4–(S)-6 or
15 (6.6 mmol) was dissolved in anhydrous pyridine. p-
Nitrobenzoic chloride (7.5 mmol) was added to the solu-
tion in portions and the mixture stirred overnight. If the
substrate was detected in the TLC analysis, the reaction
was warmed up to 60 ꢁC and stirred for 2 more hours.
The mixture was then diluted with water (20 ml), satu-
rated NaHCO3 solution (7 ml) added and the product
extracted with diethyl ether. The combined organic

B. Fra˛ckowiak et al. / Tetrahedron: Asymmetry 16 (2005) 3352–3360
3357
layers were washed with a 5% H2SO4 solution, then with
water and dried over MgSO4. The crude product was
purified by column chromatography (if necessary) and
recrystallized from hexane for compounds (R)-7–(R)-9
and (S)-7–(S)-9 and from hexane–acetone 4:1 for com-
pound 15.
3.3.4. (1R)-(+)-1-[(1R,5S)-6,6-Dimethylbicyclo[3.1.0]hex-
20
2-en-2-yl]but-1-yl p-nitrobenzoate (R)-8. ½aŠ ¼ þ19:05
D
(c 0.60, CHCl3); mp = 56–59 ꢁC; 1H NMR (CDCl3):
0.78 (s, 3H at C-7 or C-8), 0.96 (t, J = 7.3 Hz, 3H at
C-13), 1.06 (s, 3H at C-7 or C-8), 1.22 (t, J = 7.7 Hz,
1H at C-5), 1.32–1.43 (m, 2H at C-12), 1.77 (dd,
J = 6.9, 2.9 Hz, 1H at C-1), 1.86–1.93 (m, 2H at C-11),
2.02 (d, J = 18.4 Hz, 1H at C-4), 2.47 (dd, J = 18.2,
7.8 Hz, 1H at C-4), 5.78 (dd, J = 8.1, 5.3 Hz), 8.20–
8.30 (m, 4H at C-16, C-17, C-19 and C-20); 13C NMR
(CDCl3): 13.21 (C-13), 13.86 (C-7 or C-8), 13.88 (C-5),
18.86 (C-12), 20.70 (C-6), 26.25 (C-7 or C-8), 26.86 (C-
1), 35.48 (C-4), 36.88 (C-9), 37.98 (C-11), 72.49 (C-10),
123.49 (C-17 and C-19), 130.70 (C-16 and C-20),
133.31 (C-3), 136.44 (C-2), 138.10 (C-15), 150.45 (C-
18), 164.28 (C-14). Anal. Calcd for C20H25NO4: C,
69.95; H, 7.34; N, 4.08. Found: C, 69.57; H, 7.42; N,
4.11.
3.3.1. (1S)-(ꢀ)-1-[(1R,5S)-6,6-Dimethylbicyclo[3.1.0]hex-
20
D
2-en-2-yl]but-3-en-1-yl p-nitrobenzoate (S)-7. ½aŠ
¼
ꢀ25:4 (c 0.88, CHCl3); mp = 97–100 ꢁC; 1H NMR
(CDCl3): 0.53 (s, 3H at C-7 or C-8), 0.99 (s, 3H at C-7
or C-8), 1.21 (t, J = 7.2 Hz, 1H at C-5), 1.72 (s, 3H at
C-9), 1.80 (dd, J = 6.7, 2.7 Hz, 1H at C-1), 1.99 (d,
J = 18.7 Hz, 1H at C-4), 2.47–2.71 (m, 1H at C-4 and
2H at C-11), 5.06–5.10 (m, 1H at C-13), 5.13–5.20 (m,
1H at C-13), 5.71–5.84 (m, 1H at C-10 and 1H at C-
12), 8.19–8.29 (m, 4H at C-16, C-17, C-19 and C-20);
13C NMR (CDCl3): 13.30 (C-5), 13.52 (C-7 or C-8),
20.58 (C-6), 26.27 (C-1), 26.34 (C-7 or C-8), 36.63
(C-9), 37.48 (C-4), 38.04 (C-11), 72.02 (C-10), 117.91
(C-13), 123.55 (C-17 and C-19), 130.53 (C-16 and C-
20), 132.42 (C-3), 133.39 (C-12), 136.34 (C-2), 138.43
(C-15), 150.48 (C-18), 163.85 (C-14). Anal. Calcd for
C20H23NO4: C, 70.36; H, 6.79; N, 4.10. Found: C,
70.11; H, 6.81; N, 4.12.
3.3.5. (1S)-(ꢀ)-1-[(1R,5S)-6,6-Dimethylbicyclo[3.1.0]hex-
20
D
2-en-2-yl]-2-methylprop-1-yl p-nitrobenzoate (S)-9. ½aŠ
¼
ꢀ10:1 (c 1.60, CHCl3); mp = 126–128 ꢁC; 1H NMR
(CDCl3): 0.46 (s, 3H at C-7 or C-8), 0.93 (d, J = 6.7 Hz,
3H at C-12 or C-13), 0.94 (s, 3H at C-7 or C-8), 1.03 (d,
J = 6.6 Hz, 3H at C-12 or C-13), 1.18 (t, J = 7.2 Hz, 1H
at C-5), 1.73 (s, 3H at C-9), 1.72–1.76 (m, 1H at C-1),
1.98 (d, J = 18.5 Hz, 1H at C-4), 2.16–2.28 (m, 1H at C-
11), 2.52 (dd, J = 18.1, 7.8 Hz, 1H at C-4), 5.42 (d,
J = 9.4 Hz, 1H at C-10), 8.19–8.31 (m, 4H at C-16, C-
17, C-19 and C-20); 13C NMR (CDCl3): 13.31 (C-7 or
C-8), 13.42 (C-5), 18.66 (C-12 or C-13), 19.26 (C-12 or
C-13), 20.44 (C-6), 26.14 (C-7 or C-8), 26.33 (C-1), 30.94
(C-9), 36.86 (C-11), 38.01 (C-4), 78.28 (C-10), 123.55 (C-
17 and C-19), 130.52 (C-16 and C-20), 132.25 (C-2),
136.51 (C-3), 138.68 (C-15), 150.46 (C-18), 163.98 (C-14).
Anal. Calcd for C20H25NO4: C, 69.95; H, 7.34; N, 4.08.
Found: C, 69.65; H, 7.40; N, 4.09. Crystal data:
C20H25NO4, Mw = 343.41, T = 100(2) K, Mo-Ka radia-
3.3.2.
(1R)-(ꢀ)-1-[(1R,5S)-6,6-Dimethylbicyclo[3.1.0]-
20
D
hex-2-en-2-yl]but-3-en-1-yl p-nitrobenzoate (R)-7. ½aŠ
¼
ꢀ57:9 (c 1.04, CHCl3); mp = 72–73 ꢁC; 1H NMR
(CDCl3): 0.79 (s, 3H at C-7 or C-8), 1.07 (s, 3H at C-7
or C-8), 1.23 (t, J = 7. 4 Hz, 1H at C-5), 1.74 (s, 3H at
C-9), 1.79 (dd, J = 6.9, 2.7 Hz, 1H at C-1), 2.03 (d,
J = 18.1 Hz, 1H at C-4), 2.30–2.38 (m, 1H at C-11),
2.48 (dd, J = 18.1, 7.7 Hz, 1H at C-4), 2.57–2.65 (m, 1H
at C-11), 5.07–5.08 (m 1H at C-13), 5.10–5.18 (m 1H at
C-13); 5.73–5.87 (m, 1H at C-10 and 1H at C-12), 8.19–
8.29 (m, 4H at C-16, C-17, C-19 and C-20); 13C NMR
(CDCl3): 13.26 (C-5), 13.96 (C-7 or C-8), 20.72 (C-6),
26.22 (C-1), 26.87 (C-7 or C-8), 36.80 (C-9), 37.85
(C-4), 37.98 (C-11), 71.69 (C-10), 117.83 (C-13), 123.50
(C-17 and C-19), 130.70 (C-16 and C-20), 132.77 (C-3),
133.69 (C-12), 136.30 (C-2), 138.65 (C-15), 150.47
(C-18), 163.98 (C-14). Anal. Calcd for C20H23NO4: C,
70.36; H, 6.79; N, 4.10. Found: C, 70.08; H, 6.84; N,
4.11.
˚
tion, monoclinic, space group P21, a = 11.254(2) A,
˚
˚
b = 7.4550(10) A, c = 11.404(2) A, b = 105.27(3)ꢁ, V =
923.0(3) A , Z = 2, Dc = 1.236 Mgꢀ3, l = 0.086 mmꢀ1
,
3
˚
F(000) = 368, crystal size 0.27 · 0.25 · 0.20, 3.30 6 h 6
28.47, R = 0.100, wR = 0.089 (2715 reflections, all data)
for 326 parameters.
3.3.6. p-Nitrobenzenoate(1R)-(+)-[(1S,5R)-6,6-dimethylbi-
20
D
3.3.3. (1S)-(ꢀ)-1-[(1R,5S)-6,6-Dimethylbicyclo[3.1.0]hex-
cyclo[3.1.0]hex-2-en-2-yl]-2-methylprop-1-yl (R)-9. ½aŠ ¼
20
D
2-en-2-yl]but-1-yl p-nitrobenzoate (S)-8. ½aŠ ¼ ꢀ28:0 (c
þ100:0 (c 0.20, CHCl3); mp = 90–94 ꢁC; 1H NMR
(CDCl3): 0.83 (s, 3H at C-7 or C-8), 0.94 (d, J = 6.7 Hz,
3H at C-12 or C-13), 1.02 (d, J = 6.7 Hz, 3H at C-12 or
C-13), 1.05 (s, 3H at C-7 or C-8), 1.22 (t, J = 6.7 Hz, 1H
at C-5), 1.73 (s, 3H at C-9), 1.77 (dd, J = 7.1, 2.8 Hz, 1H
at C-1), 1.98 (d, J = 19.3 Hz, 1H at C-4), 2.06–2.11 (m,
1H at C-11), 2.44 (dd, J = 18.4, 7.8 Hz, 1H at C-4), 5.53
(d, J = 7.9 Hz, 1H at C-10), 8.21–8.31 (m, 4H C-16, C-17,
C-19 and C-20); 13C NMR (CDCl3): 13.49 (C-7 or C-8),
14.32 (C-5), 18.56 (C-12 or C-13), 19.93 (C-12 or C-13),
20.91 (C-6), 26.35 (C-7 or C-8), 27.25 (C-1), 31.78 (C-9),
37.69 (C-11), 38.02 (C-4), 77.45 (C-10), 123.54 (C-17 and
C-19), 130.69 (C-16 and C-20), 132.42 (C-2), 136.51 (C-3),
139.24 (C-15), 150.46 (C-18), 163.94 (C-14). Anal. Calcd
for C20H25NO4: C, 69.95; H, 7.34; N, 4.08. Found: C,
69.62; H, 7.39; N, 4.10.
1
0.60, CHCl3); mp = 45–49 ꢁC; H NMR (CDCl3): 0.52
(s, 3H at C-7 or C-8), 0.97 (t, J = 7.3 Hz, 3H at C-13),
0.98 (s, 3H at C-7 or C-8), 1.20 (t, J = 7.2 Hz, 1H at
C-5), 1.35–1.42 (m, 2H at C-12), 1.73 (s, 3H at C-9),
1.78 (dd, J = 6.9, 1.6 Hz, 1H at C-1), 1.99 (d, J =
16.5 Hz, 1H at C-4), 2.50 (dd, J = 18.1, 7.8 Hz, 1H at
C-4), 5.79 (t, J = 7.3 Hz, 1H at C-10), 8.17–8.30 (m, 4H
at C-16, C-17, C-19 and C-20); 13C NMR (CDCl3):
13.25 (C-13), 13.49 (C-7 or C-8), 13.86 (C-5), 18.84 (C-
12), 20.53 (C-6), 26.20 (C-7 or C-8), 26.35 (C-1), 34.98
(C-4), 36.56 (C-9), 38.03 (C-11), 72.70 (C-10), 123.52
(C-17 and C-19), 130.69 (C-16 and C-20), 132.92 (C-3),
136.53 (C-2), 137.97 (C-15), 150.45 (C-18), 163.99 (C-
14). Anal. Calcd for C20H25NO4: C, 69.95; H, 7.34; N,
4.08. Found: C, 69.59; H, 7.41; N, 4.10.

3358
B. Fra˛ckowiak et al. / Tetrahedron: Asymmetry 16 (2005) 3352–3360
3.3.7. (ꢀ)-[(1R,5S)-3,6,6-Trimethylbicyclo[3.1.0]hex-2-
25.78 (C-5), 38.12 (C-1), 38.62 (C-11), 40.00 (C-4),
135.00 (C-3), 155.27 (C-2), 200.84 (C-10). Anal. Calcd
for C13H20O: C, 81.20; H, 10.48. Found: C, 80.91; H,
10.56.
20
en-2-yl]methyl p-nitrobenzoate 16. ½aŠ ¼ ꢀ51:5 (c 5.10,
CHCl3); mp = 88–90 ꢁC; IR (KBr,D cmꢀ1): 3414(m),
3015(w), 2958(m), 1714(s), 1528(s), 1269(s), 1099(s),
1
726(m); H NMR (CDCl3): 0.75 (s, 3H at C-7 or C-8),
1.04 (s, 3H at C-7 or C-8), 1.22–1.28 (m, 1H at C-5),
1.74 (s, 3H at C-9), 1.78 (dd, J = 6.9, 2.9 Hz, 1H at C-
1), 2.08 (d, J = 6.0 Hz, 1H at C-4), 2.56 (dd,
J = 18.1 Hz, 7.6 Hz, 1H at C-4), 4.91 (s, 2H at C-10),
8.21–8.26 (m 4H at C-13, C-14, C-16 and C-17); 13C
NMR (CDCl3): 13.02 (C-7 or C-8), 13.42 (C-5), 20.66
(C-6), 26.27 (C-1), 26.61 (C-7 or C-8), 38.01 (C-4), 38.99
(C-9), 62.20 (C-10), 123.53 (C-14 and C-16), 129.74 (C-
12), 130.65 (C-13 and C-17), 136.05 (C-3), 140.08 (C-2),
150.51 (C-15), 164.69 (C-11). Anal. Calcd for
C17H19NO4: C, 67.76; H, 6.36; N, 4.65. Found: C,
67.49; H, 6.45; N, 4.68.
3.5. Synthesis of (ꢀ)-1-[(1R,5S)-3,6,6-trimethylbicyclo-
[3.1.0]hex-2-en-2-yl]but-2-en-1-one 13
DBU (0.05 mmol) was added to the solution of the
crude ketone 10 (0.16 mmol) in anhydrous dichloro-
methane (3 ml). The reaction mixture was stirred over-
night, saturated aqueous CuSO4 then added and the
mixture extracted with CH2Cl2 three times. The com-
bined organic layers were washed with brine and dried
over MgSO4. The crude product 13 was purified by col-
umn chromatography (eluent: hexane–diethyl ether
25
30:1). ½aŠ ¼ ꢀ38:4 (c 0.50, CHCl3); IR (film, cmꢀ1):
D
3025(m), 2971(s), 1668(s), 1585(s), 1458(m), 1379(m),
1
3.4. General procedure for the oxidation of alcohols
to ketones
970(m); H NMR (CDCl3): 0.82 (s, 3H at C-8 or C-9),
0.89–0.94 (m, 1H at C-5), 1.10 (s, 3H at C8 or C-9),
1.18–1.28 (m, 1H at C-1), 1.91 (dd, J = 6.9, 1.4 Hz, 3H
at C-13), 1.97 (s, 3H at C-9), 2.17 (d, J = 19.5 Hz, 1H
at C-4), 2.68 (dd, J = 19.5, 7.8 Hz, 1H at C-4), 6.42
(dd, J = 15.4, 1.5 Hz, 1H at C-11), 6.84–6.96 (m, 1H
at C-12). Anal. Calcd for C13H18O: C, 82.06; H, 9.53.
Found: C, 81.88; H, 9.74.
The commercially available (Aldrich) Dess–Martin peri-
odinane (1.24 mmol) was added to the appropriate
alcohol (RS)-4–(RS)-6 (1.03 mmol) in anhydrous dichloro-
methane (2.5 ml). The reaction was stirred at room
temperature for 30 min. Then a 1:1 mixture of saturated
aqueous NaHCO3 and saturated aqueous Na2S2O3 was
added and the reaction stirred until a clear mixture was
obtained. The aqueous phase was extracted with CH2Cl2
three times and the combined organic phases washed
with brine and dried with MgSO4. The crude products
11 and 12 were purified by column chromatography
(eluent: hexane–diethyl ether 30:1). The crude product
10 was used in the next reaction.
3.6. Synthesis of (ꢀ)-4-[(1R,5S)-3,6,6-trimethylbicyclo-
[3.1.0]hex-2-en-2-yl]but-3-en-2-one 14
Diethyl (2-oxopropyl)phosphonate (39.92 mmol) was
added to the pulverized Ba(OH)2Æ8H2O (8.02 mmol)
(earlier warmed at 130 ꢁC for 4 h) in tetrahydrofuran
(130 ml). The suspension was stirred at room tempera-
ture for 30 min. Next the solution of aldehyde 3
(13.34 mmol) in THF–H2O 40:1 (140 ml) was added
and stirring continued at room temperature for 15 h.
The reaction mixture was diluted with dichloromethane
and washed with water. The aqueous layer was extracted
three times with CH2Cl2 and the combined organic
phases washed with saturated aqueous NaHCO3, brine
and dried over MgSO4. The crude product 13 was puri-
3.4.1. (ꢀ)-1-[(1R,5S)-3,6,6-Trimethylbicyclo[3.1.0]hex-2-
25
en-2-yo]butan-1-one 11. ½aŠ ¼ ꢀ85:4 (c 0.96, CHCl3);
D
IR (film, cmꢀ1): 3022(m), 2960(s), 1678(s), 1607(s),
1455(m), 1375(m), 1179(m); 1H NMR (CDCl3): 0.77
(s, 3H at C-7 or C-8), 0.92 (t, J = 7.4 Hz, 3H at C-13),
1.08 (s, 3H at C-7 or C-8), 1.21 (t, J = 7.3 Hz, 1H at
C-5), 1.55–1.67 (m, 2H at C-12), 1.93 (d, J = 6.8 Hz,
1H at C-1), 1.98 (s, 3H at C-9), 2.14 (d, J = 20.7 Hz,
1H at C-4), 2.41–2.51 (m, 2H at C-11), 2.59 (dd,
J = 20.7, 9.0 Hz, 1H at C-4); 13C NMR (CDCl3):
13.24 (C-7 or C-8), 13.87 (C-7 or C-8), 17.06 (C-12)
20.13 (C-6), 25.84 (C-5), 26.15 (C-9), 38.77 (C-1),
39.96 (C-4), 44.39 (C-11), 135.83 (C-3), 153.75 (C-2),
200.60 (C-10). Anal. Calcd for C13H20O: C, 81.20; H,
10.48. Found: C, 80.89; H, 10.59.
fied by column chromatography (eluent: hexane–diethyl
25
ether 30:1). ½aŠ ¼ ꢀ52:5 (c 1.77, CHCl3); IR (film,
D
cmꢀ1): 3021(m), 2944(s), 1685(vs), 1588(vs), 1360(s),
1279(s), 1169(m), 969(m). 1H NMR (CDCl3): 0.69
(s, 3H at C-7 or C-8), 1.09 (s, 3H at C-7 or C-8), 1.28
(t, J = 6.7 Hz, 1H at C-5), 1.81-1-83 (m, 1H at C-1),
1.84 (s, 3H at C-9), 2.17 (d, J = 19.7 Hz, 1H at C-4),
2.31 (s, 3H at C-13), 2.65 (dd, J = 19.9, 7.5 Hz, 1H at
C-4), 6.17 (d, J = 15.6 Hz, 1H at C-11), 7.42 (d, J =
15.6 Hz, 1H at C-10); 13C NMR (CDCl3): 13.05 (C-7
or C-8), 13.94 (C-5), 20.43 (C-6), 26.27 (C-7 or C-8),
27.37 (C-13), 36.56 (C-9), 39.60 (C-4), 127.20 (C-11),
134.39 (C-3), 137.34 (C-10), 150.24 (C-2), 199.28 (C-
12). Anal. Calcd for C13H18O: C, 82.06; H, 9.53. Found:
C, 81.84; H, 9.76.
3.4.2. (ꢀ)-1-[(1R,5S)-3,6,6-Trimethylbicyclo[3.1.0]hex-2-
25
en-2-yl]-2-methylpropan-1-one 12. ½aŠ ¼ ꢀ120:0 (c 0.90,
D
CHCl3); IR (film, cmꢀ1): 3021(m), 2970(s), 1674(s),
1
1596(s), 1466(m), 1381(m), 971(m); H NMR (CDCl3):
0.73 (s, 3H at C-7 or C-8), 0.98 (s, 3H at C-7 or C-8),
1.01 (d, J = 2.1 Hz, 3H at C-12 or C-13), 1.03 (d,
J = 2.7 Hz, 3H at C-12 or C-13), 1.16 (t, J = 5.5, Hz,
1H at C-5), 1.94 (s, 3H at C-9), 1.91 (d, J = 2.8 Hz, 1H
at C-1), 2.89 (m, 1H at C-11), 2.10 (d, J = 19.7 Hz, 1H
at C-4); 2.58 (dd, J = 18.8, 7.9 Hz, 1H at C-4); 13C
NMR (CDCl3): 13.33 (C-7 or C-8), 14.21 (C-7 or C-8),
15.92 (C-13), 18.07 (C-12), 20.19 (C-6), 26.34 (C-9),
3.7. Synthesis of (ꢀ)-[(1R,5S)-3,6,6-trimethylbicyclo-
[3.1.0]hex-2-en-2-yl]methanol 15
Aldehyde 3 (0.12 mol) in anhydrous diethyl ether (180 ml)
was added to the suspension of lithium aluminium

B. Fra˛ckowiak et al. / Tetrahedron: Asymmetry 16 (2005) 3352–3360
3359
hydride (0.14 mol) in anhydrous diethyl ether (60 ml).
purified by column chromatography (eluent: hexane–
20
The reaction mixture was stirred until the TLC monitor-
ing did not show the presence of the substrate, and then
quenched with distilled water. The precipitate was filtered
off, the organic layer collected and the water layer
extracted three times with diethyl ether. The combined
organic layers were dried over MgSO4, the crude product
converted to p-nitrobenzoate 16 and after recrystalliza-
tion (the procedure and spectroscopic data described
above) compound 16 (0.05 mol) was diluted in methanol
(120 ml) and potassium hydroxide (0.06 mol) added. The
reaction mixture was stirred overnight and after TLC
analysis did not show the presence of p-nitrobenzoate
16, the solvent was removed. Next water was added
and the aqueous phase extracted three times with diethyl
ether and the organic phase dried over MgSO4. After
acetone 10:1). ½aŠ ¼ þ251:5 (c 2.20, CHCl3); IR (film,
cmꢀ1): 3322(vb),D 3074(v), 3015(v), 1644(m), 1054(s);
1H NMR (CDCl3): 0.84 (s, 3H at C-7), 1.00 (s, 3H at
C-8), 1.02 (s, 3H at C-9), 1.25–1.34 (m, 2H at C-1 and
C-5), 1.47 (s, 1H at –OH), 1.52–1.62 (m, 1H at C-4),
1.70–1.85 (m, 2H at C-4 and 2H at C-11), 3.64–3.79
(m, 2H at C-12), 4.76 (s, 1H at C-10), 4.88 (s, 1H at
C-10); 13C NMR (CDCl3): 16.56 (C-5), 23.46 (C-7 or
C-8), 24.25 (C-6), 27.09 (C-7 or C-8), 29.70 (C-9),
38.22 (C-1), 38.31 (C-4), 47.50 (C-11), 52.47 (C-3),
60.33 (C-12), 105.61 (C-10), 158.92 (C-2). Anal. Calcd
for C12H20O: C, 79.94; H, 11.18. Found: C, 79.65; H,
11.26.
3.10. General procedure for the esterification of alcohols
to acetates
removing the solvent the alcohol 15 was 94% pure
20
(GC). ½aŠ ¼ ꢀ208:4 (c 5.10, CHCl3); bp = 72–73 ꢁC/
D
0.5 mmHg; n2D0 ¼ 1:4878; IR (film, cmꢀ1): 3334(s),
Acetyl chloride (0.2 ml) was added dropwise to a cooled
(water-ice bath) mixture of the appropriate alcohol
(3.28 mmol) and anhydrous pyridine (0.5 ml) in anhy-
drous diethyl ether (15 ml). The reaction was stirred
overnight, then diluted with diethyl ether and washed
with an HCl solution. The ethereal solution was then
collected. The product was additionally extracted from
the aqueous layer with diethyl ether. The combined
organic layers were washed with a 5% H2SO4 solution,
saturated NaHCO3 solution, brine and dried (MgSO4).
The crude product was purified by vacuum column
chromatography (eluent: hexane–acetone from 100:1
to 70:1).
1
3019(m), 2876(vs), 1445(m), 1373(m), 997(s); H NMR
(CDCl3): 0.77 (s, 3H at C-7), 1.05 (s, 3H at C-8), 1.21
(td, J = 7.2, 1.2 Hz, 1H at C-5), 1.63 (s, 3H at C-9), 1.75
(dd, J = 6.0, 2.8 Hz, 1H at C-1), 2.01 (d, J = 18.1 Hz,
1H at C-4), 2.49 (dd, J = 17.9, 7.6 Hz, 1H at C-4), 4.14
(s, 2H at C-10); 13C NMR (CDCl3): 13.06 (C-7 or
C-8), 13.46 (C-5), 20.60 (C-6), 26.56 (C-7 or C-8), 31.77
(C-9), 38.00 (C-4), 38.59 (C-1), 59.18 (C-10), 136.26 (C-
3), 137.78 (C-2). Anal. Calcd for C10H16O: C, 78.90; H,
10.59. Found: C, 78.63; H, 10.67.
3.8. Synthesis of ethyl (+)-[(1R,5S)-3,6,6-trimethyl-2-
mehtylenebicyclo[3.1.0]hex-3-yl]acetate 18
3.10.1. Methyl (ꢀ)-[(1R,5S)-3,6,6-trimethylbicyclo[3.1.0]-
20
hex-2-en-2-yl]acetate 17. ½aŠ ¼ꢀ111:6 (c 3.15, CHCl3);
D
The mixture of alcohol (0.05 mol), triethyl orthoacetate
(0.04 mol) and propionic acid (one drop) was heated at
138 ꢁC until TLC analysis did not show the presence
of the substrate 15. The unreacted orthoacetate was
then distilled off and the crude product 18 was purified
IR (film, cmꢀ1): 3021(v), 2942(vb), 1742(vs), 1445(m),
1234(vb), 956(v); 1H NMR (CDCl3): 0.74 (s, 3H at C-7),
1.04 (d, J = 7.4 Hz, 2H at C-4), 1.21 (td, J = 17.3,
1.9 Hz, 1H at C-5), 1.65 (s, 3H at C-9), 1.71 (dd,
J = 6.8, 2.7 Hz, 1H at C-1), 2.06 (s, 3H at C-12), 2.51
(dd, J = 18.1, 7.6 Hz, 2H at C-4), 4.59 (s, 2H at C-10).
Anal. Calcd for C12H18O2: C, 74.19; H, 9.34. Found: C,
73.97; H, 9.52.
by column chromatography (eluent: hexane–diethyl
20
ether from 100:1 to 50:1). ½aŠ ¼ þ151:2 (c 5.50,
D
CHCl3); bp = 70 ꢁC/0.5 mmHg; n2D0 ¼ 1:4697; IR
(film, cmꢀ1): 3076(w), 2957(s), 1735(vs), 1646(m),
1
1452(m), 1367(m), 1185(s). H NMR (CDCl3): 0.85 (s,
3.10.2. Ethyl (+)-2-[(1R,3S,5S)-3,6,6-trimethyl-2-meth-
3H at C-7 or C-8), 1.03 (s, 3H at C-7 or C-8), 1.12
(s, 3H at C-9), 1.26 (t, J = 7.1 Hz, 3H at C-14), 1.29–
1.36 (m, 1H at C-5), 1.58–1.68 (m, 1H at C-1), 1.80
(d, J = 6.7, 1H at C-4), 2.11 (dd, J = 14.5, 7.5 Hz, 1H
at C-4), 2.24 and 2.37 (AB, 2d, J = 13.1 Hz, 2H at C-
11), 4.1 (q, J = 7.1 Hz, 2H at C-13), 4.76 (s, 1H at C-
10), 4.86 (s, 1H at C-10); 13C NMR (CDCl3): 14.31
(C-7 or C-8), 16.23 (C-5), 22.53 (C-7 or C-8), 24.42
(C-6), 27.09 (C-14), 29.35 (C-9), 36.69 (C-4), 37.51
(C-1), 48.17 (C-11), 53.18 (C-3), 59.95 (C-13), 106.02
(C-10), 157.84 (C-2), 171.75 (C-12). Anal. Calcd for
C14H22O2: C, 75.63; H, 9.97. Found: C, 75.37; H,
10.01.
20
ylene-bicyclo[3.1.0]hex-3-yl]acetate 20. ½aŠ ¼ þ243:3
D
(c 1.95, CHCl3); IR (film, cmꢀ1): 3322(vb), 3074(v),
3015(m), 1453(m), 1239(vs), 1031(m); 1H NMR
(CDCl3): 0.84 (s, 3H at C-7), 1.00 (s, 3H at C-8), 1.02
(s, 3H at C-9), 1.25–1.35 (m, 2H at C-1 and C-5),
1.57–1.87 (m, 4H at C-4 and C-11), 2.03 (s, 3H at C-
14), 4.03–4.20 (m, 2H at C-12), 4.72 (s, 1H at C-10),
4.89 (s, 1H at C-10); 13C NMR (CDCl3): 16.33 (C-5),
21.08 (C-7 or C-8), 23.35 (C-4), 24.28 (C-6), 27.06 (C-7
or C-8), 29.64 (C-9), 37.99 (C-4), 38.18 (C-1), 42.89
(C-11), 52.24 (C-3), 62.32 (C-12), 105.90 (C-10), 157.72
(C-2), 171.16 (C-13). Anal. Calcd for C14H22O2: C,
75.63; H, 9.97. Found: C, 75.31; H, 10.04.
3.9. Synthesis of (+)-2-[(1R,5S)-3,6,6-trimethylbicyclo-
[3.1.0]hex-3-yl]ethanol 19
Acknowledgements
The procedure was analogous as in the reduction of
aldehyde 3 to alcohol 15. The crude product 19 was
Authors wish to express their thanks to the Polish State
Committee for Scientific Research for supporting this

3360
B. Fra˛ckowiak et al. / Tetrahedron: Asymmetry 16 (2005) 3352–3360
8. Jayaraman, M.; Deshmukh, A. R. A. S.; Bhawal, B. M.
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9. Popov, S. A.; Gatilov, Y. V.; Rybalova, T. V.; Kholdeeva,
O. A.; Tkachev, A. V. Tetrahedron: Asymmetry 2001, 12,
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work (Grant No. 3T09B 092 28) and Professor Jozef
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of odour characteristics.
10. Popov, S. A.; Gatilov, Y. V.; Rybalova, T. V.; Tkachev,
A. V. Tetrahedron: Asymmetry 2003, 14, 233–238.
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