The enantiomers of Iralia: preparation and odour evaluation

Article abstract of DOI:10.1016/j.tetasy.2007.04.022

The enantiomers of methyl ionones 1 and 2 were prepared by an enzyme-catalysed approach. Their odour properties were evaluated by skilful perfumers.

Full text of DOI:10.1016/j.tetasy.2007.04.022

Tetrahedron: Asymmetry 18 (2007) 1145–1153
The enantiomers of Iraliaꢀ: preparation and odour evaluation
Agnese Abate, Elisabetta Brenna,* Claudio Fuganti, Luciana Malpezzi and Stefano Serra
Dipartimento di Chimica, Materiali, Ingegneria Chimica, Politecnico di Milano, ed Istituto CNR per la Chimica
del Riconoscimento Molecolare, Via Mancinelli 7, I-20131 Milano, Italy
Received 5 April 2007; accepted 20 April 2007
Available online 16 May 2007
Abstract—The enantiomers of methyl ionones 1 and 2 were prepared by an enzyme-catalysed approach. Their odour properties were
evaluated by skilful perfumers.
ꢁ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
enantioselectivity in the odour perception of chiral odo-
urants have been identified.4
Methyl ionones 1 and 2 (Scheme 1) are important violet
odourants, which have not been found in nature. They
were first prepared by Tiemann in 18931 by reaction of cit-
ral with ethyl methyl ketone, followed by cyclisation. They
were commercialised as a mixture by Firmenich in 1903 un-
der the trade name of Iraliaꢀ. In 1905, Franc¸ois Coty made
use of Violettoneꢀ (a-ionone, 3) and Iraliaꢀ to create the
great classic L’Origan,2 a perfume with a warm oriental
character.
Herein we report on the preparation of the enantiomers of
the chiral methyl ionones 1 and 2, and on the evaluation of
their odour properties by skilful perfumers.
2. Results and discussion
Commercial a-isomethylionone 1 (Isoraldeine 95—Givau-
dan) was reduced with sodium boron hydride in CH2Cl2/
methanol 2:1 to give a 1:1 mixture of the two diastereoiso-
meric alcohols ( )-4a and ( )-4b (Scheme 2). These latter
derivatives were converted into 4-nitrobenzoates ( )-5a
and ( )-5b, and were crystallised from methanol (four crys-
tallizations). The crystalline product was found to be the
single diastereoisomer ( )-5a (de = 98%, 1H NMR), whose
relative configuration was established by X-ray diffraction
analysis (Fig. 1). The mother liquors were enriched in the
other diastereoisomer ( )-5b, which was recovered with
de = 94% (1H NMR), after three crystallizations from
hexane.
O
O
O
1
2
3
Scheme 1.
Modern fine and functional perfumery is always searching
new odourants to enrich the panel of odourous molecules
to be used in commercial products. This search is per-
formed either by an accurate investigation of the relation-
ship between odour and structure or by serendipitous
discoveries.3 With the aim of providing a contribution to
the knowledge of the odour properties of molecules, we
have been preparing in recent years the enantiomerically
pure stereoisomers of chiral commercial fragrances by
enzyme-mediated methods. Unpredictable examples of
Racemic alcohol 4a, obtained by saponification of ester
( )-5a, was submitted to Lipase PS—mediated transesteri-
fication in t-butyl methyl ether in the presence of vinyl ace-
tate. After 24 h, acetate (ꢀ)-6a and alcohol (+)-4a were
recovered as pure compounds from the reaction mixture
by column chromatography. According to the same proce-
dure, acetate (+)-6b and alcohol (ꢀ)-4b were obtained
starting from racemic 5b. Then, MnO2 oxidation of alcohol
(ꢀ)-4a, prepared from (ꢀ)-6a (Scheme 3), afforded (ꢀ)-1
(ee = 98%, chiral GC), while the reaction of (+)-4b,
*
Corresponding author. Fax: +39 02 23993080; e-mail: elisabetta.
brenna@polimi.it
0957-4166/$ - see front matter ꢁ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.04.022

1146
A. Abate et al. / Tetrahedron: Asymmetry 18 (2007) 1145–1153
O
OH
O
O
ii
i
NO2
( )-5a + ( )- 5b
( )-4a + ( )-4b
1
OAc
O
O
OH
iv
(-)-6a
iii
NO2
+
OH
( )-4a
( )-5a
(+)-4a
(+)-6b
OAc
O
O
OH
iv
iii
NO2
+
OH
( )-5b
( )-4b
(-)-4b
Scheme 2. Reagents: (i) NaBH4, CH2Cl2, MeOH; (ii) p-nitrobenzoyl chloride, pyridine; (iii) MeOH, KOH; (iv) t-ButOMe, vinyl acetate, lipase PS; column
chromatography.
obtained from (+)-6b, gave enantiomer (+)-1 (ee = 94%,
chiral GC). Oxidation of (+)-4a and of (ꢀ)-4b afforded
(+)- and (ꢀ)-1, respectively, showing ee = 89% and 87%
(chiral GC). The enantiomeric excesses of (ꢀ)-6a, (+)-4a,
(+)-6b and (ꢀ)-4b were thus derived from the enantiomeric
excesses of their corresponding oxidation products.
Racemic a-methyl ionone 2 was prepared according to the
sequence reported in Scheme 4. Commercial a-ionone 3
was submitted to ipobromite degradation to give carbox-
ylic acid 7. The latter was converted into ethyl ester 8
and reduced with Redal to give alcohol 9, which was oxi-
dised to afford the unsaturated aldehyde 10. Addition of
ethyl magnesium bromide gave a-methylionol as a 1:1 mix-
ture of the two diastereoisomers ( )-11a and ( )-11b.
These latter derivatives were converted into the 4-nitro-
benzoate esters ( )-12a and ( )-12b. Repeated crystalliza-
tions from methanol gave diastereoisomer ( )-12a as a
single crystalline compound, whose relative configuration
was established by X-ray diffraction analysis (Fig. 2).
Nitrobenzoate ( )-12a was hydrolysed (Scheme 5) to af-
ford ( )-11a, which was submitted to Lipase PS mediated
acetylation in the presence of vinyl acetate in t-butylmethyl
ether solution.
Figure 1.
OH
OH
OAc
OAc
O
ii
i
(-)-4a
(-)-6a
(S)-(-)-1
(R)-(+)-1
O
ii
i
(+)-4b
(+)-6b
Acetate (ꢀ)-13a (ee = 98%, chiral GC) and unreacted alco-
hol (+)-11a (ee = 93%, chiral GC of the corresponding ace-
Scheme 3. Reagents: (i) MeOH, KOH; (ii) MnO2, CH2Cl2.

A. Abate et al. / Tetrahedron: Asymmetry 18 (2007) 1145–1153
1147
O
COOEt
COOH
iii
i
ii
3
9
7
8
OH
OH
CHO
vi
v
iv
11
10
NO2
NO2
O
O
O
O
vii
( )-12a + ( )-12b
( )-12a
Scheme 4. Reagents: (i) NaOH aq, Br2; (ii) EtOH, H2SO4; (iii) REDAL; (iv) MnO2, CH2Cl2; (v) EtMgBr, THF (vi) p-nitro benzoyl chloride, pyridine; (vii)
crystallisations from methanol.
GC), which were hydrolysed and converted into benzoates
(2R)-14a and (2R)-14b. These derivatives were submitted to
ozonolysis, followed by treatment with PPh3. After column
chromatography, (R)-(ꢀ)-155 was recovered. An (R)-con-
figuration was thus assigned to the stereogenic carbon
atom bearing the OH group acetylated by lipase PS in both
diastereoisomers. The X-ray analysis of p-nitrobenzoate
( )-12a allowed us to establish the relative configuration
of the two stereogenic centres, thus the (S)-configuration
could be assigned to the ionone enantiomer obtained from
(ꢀ)-6a.
The same procedure was applied to the 1:1 mixture of 11a
Figure 2.
and 11b: the ozonolysis of benzoates (3R)-16a and (3R)-16b
afforded (R)-(+)-17.6 At the end of the correlation, an (S)-
configuration was assigned to the ionone enantiomer
tate) were recovered after column chromatography. Alco-
obtained from (ꢀ)-13a.
hol (ꢀ)-11a, obtained by hydrolysis of (ꢀ)-13a, and its
enantiomer (+)-11a were converted into (ꢀ)- and (+)-2,
respectively, by oxidation with Mn(IV)oxide. The enantio-
3. Olfactory evaluation
meric excesses of these two samples of ionone 2 were de-
rived from those of the starting materials (ꢀ)-13a and
(+)-11a.
(R)-(+)-1 (ee = 94%): odour threshold 0.079 ng/L air: typ-
ical dry warm ionone note, irisone, clean tea-like, also on
blotter more intense and dryer than (ꢀ)-1.
2.1. Configuration assignment
(S)-(ꢀ)-1 (ee = 98%): odour threshold 0.83 ng/L air; about
ten times weaker floral note in the direction of iris and
ionone, with hesperidic—citric elements and sweet fruity
damascone-like aspects. More rich and complex in odour
than (+)-1.
The absolute configurations of the enantiomers of methyl
ionones 1 and 2 were established according to Scheme 6.
We assumed that in the two series of compounds, Lipase
PS acetylated the stereocentre showing the same configura-
tion in both diastereoisomers. The 1:1 mixture of ( )-4a
and ( )-4b was submitted to Lipase PS acetylation to af-
ford two enantiopure diastereoisomeric acetates (chiral
(R)-(+)-2 (ee = 93%): odour threshold 0.53 ng/L air; woo-
dy, powdery, floral odour in the direction of the ionone

1148
A. Abate et al. / Tetrahedron: Asymmetry 18 (2007) 1145–1153
NO2
OAc
OH
OH
O
O
i
ii
(-)-13a
+
( )-12a
( )-11a
(+)-11a
OAc
OH
OH
O
i
iii
(-)-13a
(-)-11a
(S)-(-)-2
O
iii
(+)-11a
(R)-(+)-2
Scheme 5. Reagents: (i) MeOH, KOH; (ii) t-ButOMe, vinyl acetate, lipase PS; column chromatography; (iii) MnO2, CH2Cl2.
O
OAc
2
OH
O
i
ii
(2R)-6a+(2R)-6b
(2R)-4a+(2R)-4b
(2R)-14a+(2R)-14b
O
O
iii
O
(R)-(-)-15
OAc
O
OH
O
i
3
ii
(3R)-13a+(3R)-13b
(3R)-16a+(3R)-16b
(3R)-11a+(3R)-11b
O
O
iii
O
H
(R)-(+)-17
Scheme 6. Reagents: (i) KOH, MeOH; (ii) PhCOCl, pyridine; O3, CH2Cl2–MeOH; then PPh3.
family, but less powerful and less intense. Dry-down linear,
after 4 h woody-ionone, somewhat orris-like, and after 24 h
woody-ionone, fruity, raspberry-type.
(S)-(ꢀ)-2 (ee = 98%): odour threshold 0.24 ng/L air; woo-
dy, powdery, floral odour in the direction of the ionone
family, but less powerful and less intense. Dry-down linear,

A. Abate et al. / Tetrahedron: Asymmetry 18 (2007) 1145–1153
1149
after 4 h woody-ionone, somewhat orris-like, and after 24 h
woody-ionone, only very slightly fruity.
g cmꢀ3, F(000) = 384, l (CuKa) = 0.644 mmꢀ1; colourless
crystal (0.6 · 0.4 · 0.2 mm).
Crystal data for ( )-12a: C21H27NO4, Mr = 357.4; triclinic,
˚
4. Conclusion
P1, a = 8.538(1), b = 10.212(1), c = 12.603(1) A, a =
91.07(1)ꢂ,
b = 109.32(1)ꢂ,
c = 103.03(1)ꢂ,
V =
3
˚
The enantiomers of methyl ionones 1 and 2 were prepared
by an enzyme-mediated approach, and their absolute con-
figurations were established by chemical correlation. The
odour properties of each single enantiomer were evaluated
by skilful perfumers. In a previous work,7 we reported the
odour descriptions of a-ionone enantiomers: they showed
very similar odour (floral-woody note, with an additional
honey aspect), with (R)-3 being slightly weaker (odour
threshold: 3.2 ng/L air) than its (S)-enantiomer (odour
threshold: 2.7 ng/L air).
1005.05(2) A , Z = 2, Dc = 1.181 g cmꢀ3, F(000) = 384, l
(CuKa) = 0.656 mmꢀ1
0.3 mm).
;
colourless crystal (0.6 · 0.4 ·
For both structures, diffraction data were collected on a
Siemens P4 diffractometer with graphite monochromated
CuKa radiation (k = 1.54179 A), using h/2h scan tech-
˚
nique. The structures were solved by direct methods9 and
refined by full-matrix least-squares on F2 (SHELX97,
SHELDRICK, 1999)10. In ( )-5a, the atoms of the cyclohex-
enyl group show very high atomic displacement factors
possibly due to positional disorder. However, there were
no remarkable peaks in the difference Fourier map and
the disorder remained unresolved.
As for methyl ionone 1, the (R)-enantiomer was found to
be one order of magnitude stronger than its enantiomer,
while the two enantiomers of compound 2 proved to be
very similar both in odour and strength, as the enantiomers
of parent compound 3. The odour thresholds of the enan-
tiomers of 1 and 2 are lower than those of (R)- and (S)-3.
Subtle structural variations, such as the addition of one
methyl group, can produce interesting effects on the odour
strength of a compound.
5.1.1. (RS,E)-3-Methyl-4-((SR)-2,6,6-trimethylcyclohex-2-
enyl)but-3-en-2-ol ( )-4a and (RS,E)-3-methyl-4-((RS)-
2,6,6-trimethylcyclohex-2-enyl)but-3-en-2-ol ( )-4b. NaBH4
(1.72 g, 0.045 mol) was added to a solution of commercial 1
(25.0 g, 0.121 mol) in CH2Cl2/MeOH (150 mL) at 0 ꢂC.
The reaction mixture was stirred at room temperature for
1 h, poured into ice and extracted with CH2Cl2. The organic
phase was dried over NaSO4 and evaporated, to give a 1:1
mixture (23.1 g, 92%) of ( )-4a and ( )-4b: 1H NMR
(400 MHz, CDCl3): d 5.35 (br s, 1H, CHC@C of the cyclo-
hexene ring of both diastereomers), 5.20 (d, 1H,
J = 10.5 Hz, CH–CH@C of both diastereomers), 4.26 (m,
1H, CHOH of both diastereomers), 2.44 (d, 1H,
J = 10.5 Hz, H–C(1) cyclohexene ring of both diastereo-
mers), 2.00 (m, 2H, CH2C@ of both diastereomers), 1.71 (s,
3H, CH3C@C of both diastereomers), 1.58–1.50 (m, 3H,
CH3C@C of both diastereomers), 1.45 (m, 1H, H–C(5) cyclo-
hexene ring of both diastereomers), 1.27 (d, 3H, J = 6.4 Hz,
CH3CH of both diastereomers), 1.18 (dt, 1H, J = 13.1,
5.4 Hz, H–C(5) cyclohexene ring of both diastereomers),
0.89 (s, 3H, one CH3–C(6) cyclohexene ring of both dia-
stereomers), 0.80 and 0.77 (2s, 3H, one CH3–C(6) cyclohex-
ene ring of both diastereomers); GC/MS tR = 16.84 min
(single peak), m/z (%) 208 (M+, 4), 181 (27), 150 (75), 109
(100).
5. Experimental
5.1. General
(E)-3-Methyl-4-(2,6,6-trimethylcyclohex-2-enyl)but-3-en-2-
one (a-isomethyl ionone or c-methylionone) was a com-
mercial product (Isoraldeine 95, Givaudan). Lipase PS
from Pseudomonas cepacia (Amano Pharmaceuticals Co.,
Japan) was employed in this work. GC/MS analyses were
performed on a HP 6890 gas-chromatograph equipped
with a 5973 mass-detector, using a HP-5MS column
(30 m · 0.25 mm · 0.25 lm). The following temperature
program was employed: 60ꢂ (1 min)/6ꢂ/min/150ꢂ (1 min)/
1
12ꢂ/min/280ꢂ (5 min). H and 13C NMR spectra were re-
corded on a Bruker ARX 400 spectrometer (400 MHz
1H, 100.6 MHz 13C), in CDCl3 solution at rt unless other-
wise stated, using TMS as an internal standard; J values
are given in Hertz. All the chromatographic separations
were carried out on silica gel columns. Chiral GC analyses
were performed on a DANI-HT-86.10 gas chromatograph
using a Chirasil-DEX-CB column in the following condi-
tions: (i) compounds 1 and 13a: 70 ꢂC (1 min) ꢀ3.5 ꢂC/
min ꢀ140 ꢂC (6 min) ꢀ20 ꢂC/min ꢀ180 ꢂC (5 min), (ꢀ)-1
tR = 14.31 min, (+)-1 tR = 14.79 min; (ꢀ)-13a tR =
17.85 min, (+)-13a tR = 17.94 min. Optical rotations were
measured on Dr. Kernchen Propol digital automatic polar-
imeter. Microanalyses were determined on a Carlo Erba
1106 Analyzer. Derivative 7 was prepared from a-ionone
5.1.2. (RS,E)-3-Methyl-4-((SR)-2,6,6-trimethylcyclohex-2-
enyl)but-3-en-2-yl 4-nitrobenzoate ( )-5a and (RS,E)-3-
methyl-4-((RS)-2,6,6-trimethylcyclohex-2-enyl)but-3-en-2-yl
4-nitrobenzoate ( )-5b. A solution of p-nitro benzoyl
chloride (30.7 g, 0.166 mol) in CH2Cl2 (100 mL) was added
at 0 ꢂC to a solution of the 1:1 mixture of diastereoisomeric
alcohols ( )-4a and ( )-4b (23.0 g, 0.110 mol) in pyridine
(100 mL). The reaction mixture was stirred at room tem-
perature for 1 h, poured into ice, and extracted with
CH2Cl2. The organic phase was dried over Na2SO4 and
concentrated under reduced pressure, to give a residue
which was crystallised four times from methanol affording
( )-5a (de = 98%, by 1H NMR): 8.03 g, 20%. From
the mother liquors of the first crystallisation, compound
( )-5b showing de = 70% (1H NMR) was recovered, and
8
3 according to Ref. and was converted into ethyl ester 8
by reaction with ethanol/H2SO4 cat.
Crystal data for ( )-5a: C21H27NO4, Mr = 357.4; mono-
˚
clinic, P21/n, a = 7.387(1), b = 6.355(1), c = 43.730(6) A,
3
˚
b = 94.21(1)ꢂ, V = 2044.8(5) A , Z = 4, Dc = 1.161

1150
A. Abate et al. / Tetrahedron: Asymmetry 18 (2007) 1145–1153
brought to de = 94% by means of three crystallisations
from hexane (5.89 g, 15%).
CH@C), 4.25 (q, 1H, J = 6.3 Hz, CHOH), 2.44 (d, 1H,
J = 10.8 Hz, H–C(1) cyclohexene ring), 2.00 (m, 2H,
CH2C@), 1.71 (s, 3H, CH3C@C), 1.52 (s, 3H, CH3C@C),
1.44 (m, 1H, H–C(5) cyclohexene ring), 1.27 (d, 3H,
J = 6.3 Hz, CH3CH), 1.20 (m, 1H, H–C(5) cyclohexene
ring), 0.90 (s, 3H, CH3–C(6) cyclohexene ring), 0.80 (s,
3H, CH3–C(6) cyclohexene ring); 13C NMR (100.6 MHz,
CDCl3): 139.1, 135.1, 126.2, 120.2, 73.5, 48.3, 32.2, 31.8,
27.1, 26.6, 22.9, 22.6, 21.7, 11.8. C14H24O: Calcd C,
80.71; H, 11.61. Found: C, 80.79; H, 11.69.
Data of ( )-5a: mp 85–88 ꢂC; 1H NMR (400 MHz,
CDCl3): d 8.35–8.15 (m, 4H, aromatic hydrogens), 5.54
(q, 1H, J = 6.4 Hz, CHOCO), 5.43–5.28 (m, 2H, vinylic
hydrogens), 2.47 (d, 1H, J = 10.9 Hz, H–C(1) cyclohexene
ring), 2.00 (m, 2H, CH2C@), 1.80 (d, 3H, J = 1.5 Hz,
CH3C@C), 1.52 (m, 3H, CH3C@C), 1.48 (d, 3H,
J = 6.4 Hz, CH3CH), 1.40 (dt, 1H, J = 13.0, 7.4 Hz, H–
C(5) cyclohexene ring), 1.18 (dt, 1H, J = 13.0, 5.4 Hz, H–
C(5) cyclohexene ring), 0.89 (s, 3H, CH3–C(6) cyclohexene
ring), 0.75 (s, 3H, CH3–C(6) cyclohexene ring); 13C NMR
(100.6 MHz, CDCl3): 163.7, 150.3, 136.2, 134.6, 134.5,
130.5, 129.5, 123.4, 120.7, 77.6, 48.4, 32.4, 32.1, 27.3,
26.4, 22.9, 22.6, 19.4, 12.4; GC/MS: tR = 28.15 min, m/z
(%) 301 (M+-56, 42), 190 (32), 150 (50), 134 (100).
C21H17NO4: Calcd C, 70.56; H, 7.61; N, 3.92. Found: C,
70.65; H, 7.73; N, 3.81.
5.1.5. (R,E)-3-Methyl-4-((S)-2,6,6-trimethylcyclohex-2-enyl)-
but-3-en-2-yl acetate (ꢀ)-6a and (S,E)-3-methyl-4-((R)-
2,6,6-trimethylcyclohex-2-enyl)but-3-en-2-ol (ꢀ)-4a. A mix-
ture of ( )-4a (3.60 g, 0.017 mol), lipase PS (1.00 g), and
vinyl acetate (10 mL) in tBuOMe (50 mL) was stirred at rt
for 24 h. The reaction mixture was filtered, concentrated
under reduced pressure and submitted to column chroma-
tography (hexane/ethyl acetate 9/1). The first eluted frac-
tions gave acetate (ꢀ)-6a (1.44 g, 34%). The last eluted
fractions afforded unreacted alcohol (+)-4a (1.09 g, 31%).
Data of ( )-5b: mp 43–45 ꢂC; 1H NMR (400 MHz,
CDCl3): d 8.35–8.15 (m, 4H, aromatic hydrogens), 5.55
(q, 1H, J = 6.4 Hz, CHOCO), 5.42–5.33 (m, 2H, vinylic
hydrogens), 2.46 (d, 1H, J = 10.9 Hz, H–C(1) cyclohexene
ring), 2.00 (m, 2H, CH2C@), 1.79 (d, 3H, J = 1.5 Hz,
CH3C@C), 1.53 (m, 3H, CH3C@C), 1.48 (d + m, 4H,
J = 6.4 Hz, CH3CH + H–C(5) cyclohexene ring), 1.20 (dt,
1H, J = 13.0, 5.4 Hz, H–C(5) cyclohexene ring), 0.88 (s,
3H, CH3–C(6) cyclohexene ring), 0.79 (s, 3H, CH3–C(6)
cyclohexene ring); 13C NMR (100.6 MHz, CDCl3): 163.8,
150.3, 136.3, 134.6, 134.1, 130.5, 130.2, 123.4, 120.7, 77.9,
48.6, 32.4, 32.0, 27.3, 26.5, 22.9, 22.6, 19.2, 12.2; GC/MS:
tR = 28.04 min, m/z (%) 301 (M+-56, 30), 190 (35), 150
(45), 134 (100), 119 (100). C21H17NO4: Calcd C, 70.56;
H, 7.61; N, 3.92. Found: C, 70.48; H, 7.52; N, 4.05.
20
1
Data of (ꢀ)-6a: ½aꢁD ¼ ꢀ203:1 (c 1.05, CHCl3). H NMR
(400 MHz, CDCl3): d 5.36 (br s, 1H, CHC@C of the cyclo-
hexene ring), 5.29–5.17 (m, 2H, CH–CH@C + CHOAc),
2.44 (d, 1H, J = 10.9 Hz, H–C(1) cyclohexene ring), 2.04
(s, 3H, OAc), 1.99 (m, 2H, CH2C@), 1.70 (d, 3H,
J = 1.5 Hz, CH3C@C), 1.53 (m, 3H, CH3C@C), 1.43 (dt,
1H, J = 13.1, 7.4 Hz, H–C(5) cyclohexene ring), 1.31 (d,
3H, J = 6.5 Hz, CH3CH), 1.20 (dt, 1H, J = 13.1, 5.2 Hz,
H–C(5) cyclohexene ring), 0.88 (s, 3H, CH3–C(6) cyclohex-
ene ring), 0.75 (s, 3H, CH3–C(6) cyclohexene ring); 13C
NMR (100.6 MHz, CDCl3): 170.2, 135.1, 134.9, 128.2,
120.5, 75.5, 48.4, 32.4, 32.2, 27.4, 26.3, 22.9, 22.6, 21.3,
19.4, 12.5; GC/MS: tR = 18.98 min, m/z (%) 190 (M+- 60,
50), 134 (100), 119 (95). C16H26O2: Calcd C, 76.75; H,
10.47. Found: C, 76.84; H, 10.38.
5.1.3. (RS,E)-3-Methyl-4-((SR)-2,6,6-trimethylcyclohex-2-
enyl)but-3-en-2-ol ( )-4a. Derivative ( )-5a (7.90 g,
0.022 mol) was hydrolysed with KOH (1.88 g, 0.033 mol)
in methanol (100 mL). After the usual work-up, racemic
alcohol ( )-4a (3.79 g, 83%) was recovered: mp 58–60 ꢂC;
1H NMR (400 MHz, CDCl3): d 5.35 (br s, 1H, CHC@C
of the cyclohexene ring), 5.19 (d, 1H, J = 10.5 Hz, CH–
CH@C), 4.26 (q, 1H, J = 6.4 Hz, CHOH), 2.44 (d, 1H,
J = 10.5 Hz, H–C(1) cyclohexene ring), 2.00 (m, 2H,
CH2C@), 1.71 (d, 3H, J = 1.5 Hz, CH3C@C), 1.56 (m,
3H, CH3C@C), 1.46 (m, 1H, H–C(5) cyclohexene ring),
1.27 (d, 3H, J = 6.4 Hz, CH3CH), 1.18 (dt, 1H, J = 13.1,
5.4 Hz, H–C(5) cyclohexene ring), 0.89 (s, 3H, CH3–C(6)
cyclohexene ring), 0.77 (s, 3H, CH3–C(6) cyclohexene ring);
13C NMR (100.6 MHz, CDCl3): 139.2, 135.1, 126.5, 120.2,
73.7, 48.3, 32.4, 31.8, 27.1, 26.6, 22.9, 22.6, 21.7, 11.8.
C14H24O: Calcd C, 80.71; H, 11.61. Found: C, 80.66; H,
11.54.
20
Data of (+)-4a: mp 59–63 ꢂC; ½aꢁD ¼ þ292:9 (c 1.02,
CHCl3). 1H, 13C NMR and MS spectra were in accordance
with those of the corresponding racemic compound.
5.1.6. (R,E)-3-Methyl-4-((R)-2,6,6-trimethylcyclohex-2-enyl)-
but-3-en-2-yl acetate (+)-6b and (S,E)-3-methyl-4-((S)-2,6,
6-trimethylcyclohex-2-enyl)but-3-en-2-ol (ꢀ)-4b. A mixture
of ( )-4b (2.70 g, 0.013 mol), lipase PS (0.800 g), and vinyl
acetate (10 mL) in tBuOMe (50 mL) was stirred at rt for
24 h. The reaction mixture was filtered, concentrated under
reduced pressure and submitted to column chromatography
(hexane/ethyl acetate 9/1). The first eluted fractions gave
acetate (+)-6b (1.01 g, 31 %). The last eluted fractions affor-
ded unreacted alcohol (ꢀ)-4b (0.757 g, 28%).
20
1
Data for (+)-6b: ½aꢁD ¼ þ278:8 (c 1.10, CHCl3); H NMR
(400 MHz, CDCl3): d 5.36 (m, 1H, CHC@C of the cyclo-
hexene ring), 5.31–5.20 (m, 2H, CH–CH@C + CHOAc),
2.42 (d, 1H, J = 10.9 Hz, H–C(1) cyclohexene ring), 2.03
(s, 3H, OAc), 2.00 (m, 2H, CH2C@), 1.69 (d, 3H,
J = 1.4 Hz, CH3C@C), 1.51 (m, 3H, CH3C@C), 1.44 (m,
1H, H–C(5) cyclohexene ring), 1.30 (d, 3H, J = 6.2 Hz,
CH3CH), 1.20 (m, 1H, H–C(5) cyclohexene ring), 0.88 (s,
3H, CH3–C(6) cyclohexene ring), 0.78 (s, 3H, CH3–C(6)
5.1.4. (RS,E)-3-Methyl-4-((RS)-2,6,6-trimethylcyclohex-2-
enyl)but-3-en-2-ol ( )-4b. Derivative ( )-5b (5.70 g,
0.016 mol) was hydrolysed with KOH (1.34 g, 0.024 mol)
in methanol (80 mL). After the usual work-up, racemic
alcohol ( )-4b (2.82 g, 85%) was recovered: mp 71–75 ꢂC;
1H NMR (400 MHz, CDCl3): d 5.34 (br s, 1H, CHC@C
of the cyclohexene ring), 5.20 (d, 1H, J = 10.8 Hz, CH–

A. Abate et al. / Tetrahedron: Asymmetry 18 (2007) 1145–1153
1151
cyclohexene ring); 13C NMR: 170.2, 134.9, 134.8, 128.9;
120.5; 75.7; 48.4; 32.3; 32.0; 27.3; 26.4; 22.9; 22.6; 21.3;
19.2; 12.2. C16H26O2: Calcd C, 76.75; H, 10.47. Found:
C, 76.66; H, 10.54. GC/MS: tR = 18.78 min, m/z (%) 190
(M+-60, 46), 134 (100), 119 (95).
5.1.11. (E)-3-(2,6,6-Trimethylcyclohex-2-enyl)prop-2-en-1-
ol 9. Compound 8 (60.0 g, 0.270 mol) was reduced with
Redal (92 mL, 3.5 M in toluene) at 0 ꢂC in toluene solution
(500 mL). After the usual work-up, alcohol 9 was recov-
ered and purified by column chromatography (hexane/
ethyl acetate 7/3) (33.6 g, 69%). 1H NMR (400 MHz,
CDCl3): d 5.64 (dt, 1H, J = 15.2, 5.7 Hz, C@CHCH2),
5.49 (dd, 1H, J = 15.2, 5.7 Hz, CH@CHCH2), 5.40 (m,
1H, C@CH of the cyclohexene ring), 4.13 (m, 2H,
CH2OH), 2.12 (d, 1H, J = 9.0 Hz, H–C(1) cyclohexene
ring), 1.99 (m, 2H, CH2C@), 1.59 (s, 3H, CH3C@C), 1.43
(dt, 1H, J = 13.6, 8.0, H–C(5) cyclohexene ring), 1.17 (dt,
1H, J = 13.6, 4.8, H–C(5) cyclohexene ring), 0.89 (s, 3H,
CH3–C(6) cyclohexene ring), 0.82 (s, 3H, CH3–C(6) cyclo-
hexene ring); GC/MS: tR = 14.93 min, m/z (%) 180 (M+,
10), 165 (5), 124 (100). C12H20O: Calcd C, 79.94; H,
11.18. Found: C, 79.88; H, 11.23.
20
Data for (ꢀ)-4b: mp = 78–81 ꢂC; ½aꢁD ¼ ꢀ285:3 (c 0.95,
CHCl3); 1H, 13C NMR and MS spectra were in accordance
with those of the corresponding racemic compound.
5.1.7.
(R,E)-3-Methyl-4-((S)-2,6,6-trimethylcyclohex-2-
enyl)but-3-en-2-ol (ꢀ)-4a. Hydrolysis of (ꢀ)-6a (1.30 g,
5.2 mmol) with KOH (0.437 g, 7.8 mmol) in MeOH
(30 mL) gave after the usual work-up a residue which
was crystallised from hexane, to afford alcohol (ꢀ)-4a
20
(0.894 g, 86 %): mp 60–62 ꢂC; ½aꢁD ¼ ꢀ321:5 (c 1.08,
CHCl3). 1H, 13C NMR and MS spectra were in accordance
with those of the corresponding racemic compound.
5.1.12. (E)-3-(2,6,6-Trimethylcyclohex-2-enyl)acrylaldehyde
10. A mixture of alcohol 9 (33.4 g, 0.186 mol) and MnO2
(1.2 equiv) in dichloromethane (300 mL) was refluxed for
2 h. The reaction mixture was filtered and concentrated un-
der reduced pressure to give a residue, which was purified
by column chromatography (hexane/ethyl acetate 95:5) to
afford aldehyde 10 (23.4 g, 71%): 1H NMR (400 MHz,
CDCl3): d 9.53 (d, 1H, J = 7.9, CHO), 6.68 (dd, 1H,
J = 15.2, 9.6, CH@), 5.49 (dd, 1H, J = 15.2, 7.9 Hz,
C@CHCHO), 5.54 (m, 1H, C@CH of the cyclohexene
ring), 2.42 (d, 1H, J = 9.6 Hz, H–C(1) cyclohexene ring),
2.06 (m, 2H, CH2C@), 1.58 (m, 3H, CH3C@C), 1.47 (m,
1H, H–C(5) cyclohexene ring), 1.24 (m, 1H, H–C(5) cyclo-
hexene ring), 0.95 (s, 3H, CH3–C(6) cyclohexene ring), 0.88
(s, 3H, CH3–C(6) cyclohexene ring); GC/MS:
tR = 14.83 min, m/z (%) 178 (M+, 25), 163 (19), 122 (81),
107 (100). C12H18O: Calcd C, 80.85; H, 10.18. Found: C,
80.78; H, 10.24.
5.1.8.
(R,E)-3-Methyl-4-((R)-2,6,6-trimethylcyclohex-2-
enyl)but-3-en-2-ol (+)-4b. Hydrolysis of (+)-6b (0.740 g,
2.96 mmol) with KOH (0.248 g, 4.44 mmol) in MeOH
(25 mL) gave, after the usual work, up a residue, which
was crystallised from hexane, to afford alcohol (+)-4b
20
(0.535 g, 87%): mp = 80–83 ꢂC; ½aꢁD ¼ þ308:3 (c 0.95,
CHCl3); 1H, 13C NMR and MS spectra were in accordance
with those of the corresponding racemic compound.
5.1.9. (S,E)-3-Methyl-4-(2,6,6-trimethylcyclohex-2-enyl)but-
3-en-2-one (ꢀ)-1. A mixture of alcohol (ꢀ)-4a (0.870 g,
4.18 mmol) and MnO2 (1.2 equiv) in CH2Cl2 (20 mL) was
refluxed for 2 h. The reaction mixture was filtered and con-
centrated under reduced pressure to give a residue, which
was purified by column chromatography (hexane/ethyl ace-
tate 95:5) to afford (ꢀ)-2 (0.724 g, 84%): ee = 98% (chiral
20
1
GC); ½aꢁD ¼ ꢀ450 (c 1.31, CHCl3). H NMR (400 MHz,
CDCl3): d 6.42 (dd, 1H, J = 10.9, 1.3 Hz, CH@CCO),
5.47 (m, 1H, CH@C of the cyclohexene ring), 2.66 (d,
1H, J = 10.9 Hz, H–C(1) cyclohexene ring), 2.31 (s, 3H,
OAc), 2.07 (m, 2H, CH2C@), 1.86 (d, 3H, J = 1.5 Hz,
CH3C@C), 1.58–1.45 (m, 4H, CH3C@C + H–C(5) cyclo-
hexene ring), 1.27 (dt, 1H, J = 13.1, 5.2 Hz, H–C(5) cyclo-
hexene ring), 0.94 (s, 3H, CH3–C(6) cyclohexene ring), 0.82
(s, 3H, CH3–C(6) cyclohexene ring); 13C NMR
(100.6 MHz, CDCl3): 200.2, 145.2, 137.8, 133.2, 121.9,
50.2, 32.7, 31.7, 27.1, 26.9, 25.6, 22.9, 22.7, 11.7; GC/MS:
tR = 17.31 min, m/z (%) 206 (M+, 12), 191 (5), 150 (67),
135 (100). C14H22O: Calcd C, 81.50; H, 10.75. Found: C,
81.56; H, 10.69.
5.1.13.
(SR,E)-1-((RS)-2,6,6-Trimethylcyclohex-2-enyl)-
pent-1-en-3-ol 11a and (RS,E)-1-((RS)-2,6,6-trimethylcyclo-
hex-2-enyl)pent-1-en-3-ol 11b. Aldehyde 10 (23.0 g,
0.129 mol) was dropped into a solution of ethylmagnesium
bromide (from 0.193 mol of ethyl bromide and 0.219 mol
of Mg) in Et2O (500 mL) at 10 ꢂC. The mixture was re-
fluxed for 1 h, poured into ice, quenched with saturated
NH4Cl solution, and extracted with Et2O. The organic
phase was dried over Na2SO4 and evaporated to give a resi-
due, which was submitted to column chromatography
(hexane/ethyl acetate 7:3). A 1:1 mixture of alcohols 11a
1
and 11b was obtained (21.7 g, 81%): H NMR (400 MHz,
CDCl3): d 5.47–5.42 (m, 2H, CH@CH of both diastereo-
mers), 5.40 (m, 1H, C@CH of the cyclohexene ring of both
diastereomers), 4.05–3.99 (m, 1H, CHOH of both diaste-
reomers), 2.11 (m, 1H, H–C(1) cyclohexene ring of both
diastereomers), 2.00 (m, 2H, CH2C@ of both diastereo-
mers), 1.67–1.37 (m, 6H, CH3C@C of both diastereo-
5.1.10. (R,E)-3-Methyl-4-(2,6,6-trimethylcyclohex-2-enyl)-
but-3-en-2-one (+)-1.
A mixture of alcohol (+)-4b
(0.490 g, 2.36 mmol) and MnO2 (1.2 equiv) in CH2Cl2
(20 mL) was refluxed for 2 h. The reaction mixture was fil-
tered and concentrated under reduced pressure to give a
residue, which was purified by column chromatography
(hexane/ethyl acetate 95:5) to afford (+)-2 (0.427 g, 88%):
mers + CH2CH3
of
both
diastereomers + H–C(5)
cyclohexene ring of one diastereomers), 1.20–1.14 (m,
H–C(5) cyclohexene ring of both diastereomers), 0.93–
0.88 (m, 6H, CH3CH2 of both diastereomers + one CH3–
C(6) cyclohexene ring of both diastereomers), 0.84 and
0.81 (2s, 3H, one CH3–C(6) cyclohexene ring of both
20
1
ee = 94% (chiral GC); ½aꢁD ¼ þ430 (c 1.25, CHCl3). H,
13C NMR and MS spectra were in accordance with those
of the corresponding enantiomer. C14H22O: Calcd C,
81.50; H, 10.75. Found: C, 81.56; H, 10.69.

1152
A. Abate et al. / Tetrahedron: Asymmetry 18 (2007) 1145–1153
diastereomers); GC/MS: tR = 16.16 min (single peak) m/z
C@CHCHOCO), 5.13 (q, 1H, J = 7.2, CHOAc), 2.09 (d,
1H, J = 8.9, H–C(1) cyclohexene ring), 2.03 (s, 3H, OAc),
1.98 (m, 2H, CH2C@), 1.63 (m, 2H, CH2CH3), 1.55 (m,
3H, CH3C@C), 1.40 (dt, 1H, J = 12.6, 8.2, H–C(5) cyclo-
hexene ring), 1.16 (dt, 1H, J = 12.6, 4.5, H–C(5) cyclohex-
ene ring), 0.89 (t, 3H, J = 7.1, CH3CH2), 0.88 (s, 3H, CH3–
C(6) cyclohexene ring), 0.80 (s, 3H, CH3–C(6) cyclohexene
ring); 13C NMR (100.6 MHz, CDCl3): d 170.2, 134.9, 133.6,
129.7, 121.1, 76.1, 54.0, 31.8, 31.7, 27.5, 27.3, 26.9, 22.9,
22.7, 21.2, 9.5. GC/MS: tR = 18.32 min, m/z (%) 190
(M+-60, 6), 190 (80), 123 (86), 105 (100). C16H26O2: Calcd
C, 76.75; H, 10.47. Found: C, 76.82; H, 10.41.
(%) 208 (M+, 6), 190 (10), 152 (73), 123 (67), 95 (100).
5.1.14. (RS,E)-1-((SR)-2,6,6-Trimethylcyclohex-2-enyl)pent-
1-en-3-yl 4-nitrobenzoate 12a and (RS,E)-1-((RS)-2,6,
6-trimethylcyclohex-2-enyl)pent-1-en-3-yl 4-nitrobenzoate
12b. To a solution of the 1:1 mixture of alcohols
11a and 11b (21.6 g, 0.103 mol) in pyridine (100 mL), a
solution of 4-nitrobenzoyl chloride (28.6 g, 0.155 mol) in
CH2Cl2 (50 mL) was added at 0 ꢂC. After 2 h at room tem-
perature, the usual work-up allowed the recovery of the
corresponding mixture of 4-nitrobenzoates 12a and 12b,
which was crystallised four times from methanol to afford
derivative, to afford derivative 12a as a single diastereoiso-
Data for (+)-11a: [a]D = +274.2 (c 1.06, CHCl3); ee = 93%
mer (de = 98%, H NMR; 7.72 g, 21%): mp 64–67 ꢂC; d
(chiral GC of the corresponding acetate). H, 13C NMR
1
1
8.31–8.16 (m, 4H, aromatic hydrogens), 5.64 (dd, 1H,
and MS spectra were in accordance with those of the cor-
responding racemic compound.
J = 14.7, 9.4, CH–CH@C), 5.49 (dd, 1H, J = 14.7, 7.4,
C@CHCHOCOAr),
5.45–5.38
(m,
2H,
CHO-
COAr + C@CH of the cyclohexene ring), 2.13 (d, 1H,
J = 9.4, H–C(1) cyclohexene ring), 1.99 (m, 2H, CH2C@),
1.90–1.72 (m, 2H, CH2CH3), 1.54 (m, 3H, CH3C@C),
1.38 (dt, 1H, J = 13.3, 7.8, H–C(5) cyclohexene ring),
1.16 (dt, 1H, J = 13.3, 5.1, H–C(5) cyclohexene ring),
0.99 (t, 3H, J = 7.4, CH3CH2), 0.89 (s, 3H, CH3–C(6)
cyclohexene ring), 0.82 (s, 3H, CH3–C(6) cyclohexene ring);
GC/MS: tR = 27.50 min, m/z (%) 301 (M+-56, 6), 190 (27),
134 (100), 119 (100). C12H27NO4: Calcd C, 70.56; H, 7.61;
N, 3.92. Found: C, 70.62; H, 7.68; N 3.86.
5.1.17. (R,E)-1-((S)-2,6,6-Trimethylcyclohex-2-enyl)pent-1-
en-3-ol (ꢀ)-11a. Acetate (ꢀ)-13a (1.23 g, 4.92 mmol) was
hydrolysed by reaction with KOH (0.413 g, 7.38 mmol) in
methanol (30 mL). After the usual work up, alcohol (ꢀ)-
11a (0.941 g, 92%) was recovered by column chromatogra-
phy (hexane/ethyl acetate 7/3): [a]D = ꢀ289.3 (c 1.21,
CHCl3); ee = 98% (chiral GC of the corresponding ace-
1
tate). H, 13C NMR and MS spectra were in accordance
with those of the corresponding racemic compound.
5.1.18. (R,E)-1-(2,6,6-Trimethylcyclohex-2-enyl)pent-1-en-
3-one (+)-2. A mixture of alcohol (+)-11a (0.950 g,
4.57 mmol) and MnO2 (1.2 equiv) in CH2Cl2 (20 mL) was
refluxed for 2 h. The reaction mixture was filtered and con-
centrated under reduced pressure to give a residue, which
was purified by column chromatography (hexane/ethyl ace-
tate 95:5) to afford (+)-3 (0.762 g, 81%): [a]D = +376.8 (c 0
1.05, CHCl3); ee = 93% (chiral GC of the corresponding
alcohol); 1H NMR (400 MHz, CDCl3) d 6.65 (dd, 1H,
J = 15.6, 9.5, CH–CH@C), 6.07 (d, 1H, J = 15.6,
C@CHCO), 5.49 (m, 1H, CH@C of the cyclohexene ring),
2.59 (q, 2H, J = 7.3, CH2CH3), 2.27 (d, 1H, J = 9.5, H–
C(1) cyclohexene ring), 2.04 (m, 2H, CH2C@), 1.56 (m,
3H, CH3C@C), 1.45 (dt, 1H, J = 13.4, 8.3, H–C(5) cyclo-
hexene ring), 1.21 (dt, 1H, J = 13.4, 4.8, H–C(5) cyclohex-
ene ring), 1.11 (t, 3H, J = 7.3, CH3CH2), 0.93 (s, 3H, CH3–
C(6) cyclohexene ring), 0.85 (s, 3H, CH3–C(6) cyclohexene
ring); 13C NMR (100.6 MHz, CDCl3): d 201.0, 147.6,
131.9, 131.1, 122.5, 54.2, 33.1, 32.4, 31.1, 27.7, 26.7, 22.9,
22.7, 8.1; GC/MS: tR = 17.07 min, m/z (%) 206 (M+, 33),
191 (13), 150 (30), 135 (35), 121 (100). C14H22O: Calcd C,
81.50; H, 10.75. Found: C, 81.45; H, 10.79.
5.1.15.
(SR,E)-1-((RS)-2,6,6-Trimethylcyclohex-2-enyl)-
pent-1-en-3-ol 11a. p-Nitroderivative 12a (7.62 g, 0.0213
mol) was hydrolysed by reaction with KOH (1.79 g,
0.032 mol) in methanol (50 mL) at room temperature.
After the usual work-up, alcohol 11a was recovered by col-
umn chromatography (hexane/ethyl acetate 7/3) (3.46 g,
1
78%): H NMR (400 MHz, CDCl3) d 5.47–5.27 (m, 3H,
vinylic hydrogens), 4.03–3.89 (m, 1H, CHOH), 2.06 (m,
1H, H–C(1) cyclohexene ring), 1.95 (m, 2H, CH2C@),
1.62–1.32 (m, 6H, CH3C@C + CH2CH3 + H–C(5) cyclo-
hexene ring), 1.13 (dt, 1H, J = 13.1, 4.8, H–C(5) cyclohex-
ene ring), 0.87 (t, 3H, J = 7.1, CH3CH2), 0.85 (s, 3H, CH3–
C(6) cyclohexene ring), 0.78 (s, 3H, CH3–C(6) cyclohexene
ring); 13C NMR (100.6 MHz, CDCl3): d 134.5, 133.8,
132.4, 120.8, 74.3, 53.9, 31.7, 31.4, 30.8, 27.4, 26.7, 22.9,
22.7, 9.6. C14H24O: Calcd C, 80.71; H, 11.61. Found: C,
80.78; H, 11.57.
5.1.16. (R,E)-1-((S)-2,6,6-trimethylcyclohex-2-enyl)pent-1-
en-3-yl acetate and (ꢀ)-13a and (S,E)-1-((R)-2,6,6-trimeth-
ylcyclohex-2-enyl)pent-1-en-3-ol (+)-11a. A mixture of
( )-11a (3.36 g, 0.016 mol), lipase PS (1 g), and vinyl ace-
tate (10 mL) in tBuOMe (50 mL) was stirred at rt for
24 h. The reaction mixture was filtered, concentrated under
reduced pressure and submitted to column chromatogra-
phy (hexane/ethyl acetate 9/1). The first eluted fractions
gave acetate (ꢀ)-13a (1.33 g, 33%). The last eluted fractions
afforded unreacted alcohol (+)-11a (0.971 g, 29%).
5.1.19. (S,E)-1-(2,6,6-Trimethylcyclohex-2-enyl)pent-1-en-3-
one (ꢀ)-2. A mixture of alcohol (ꢀ)-11a (0.930 g,
4.47 mmol) and MnO2 (1.2 equiv) in CH2Cl2 (20 mL) was
refluxed for 2 h. The reaction mixture was filtered and con-
centrated under reduced pressure to give a residue, which
was purified by column chromatography (hexane/ethyl ace-
tate 95:5) to afford (ꢀ)-3 (0.718 g, 78%): [a]D = ꢀ397.1 (c
1.20, CHCl3); ee = 98% (chiral GC of the corresponding
alcohol); 1H, 13C NMR and MS spectra were in accordance
with those of the enantiomer. C14H22O: Calcd C, 81.50; H,
10.75. Found: C, 81.58; H, 10.80.
Data for (ꢀ)-13a: [a]D = ꢀ178.5 (c 01.14, CHCl3); ee = 98%
1
(chiral GC); H NMR (400 MHz, CDCl3) d 5.51 (dd, 1H,
J = 15.6, 8.9, CH–CH@C), 5.40 (m, 1H, CH@C of the
cyclohexene ring), (5.35, dd, 1H, J = 15.6, 7.2,

A. Abate et al. / Tetrahedron: Asymmetry 18 (2007) 1145–1153
1153
5.1.20. (R,E)-3-Methyl-4-((RS)-2,6,6-trimethylcyclohex-2-
enyl)but-3-en-2-yl benzoates (2R)-14a and (2R)-14b.
8.20–8.00 (m, 2H, aromatic hydrogens), 7.40–7.30 (m,
3H, aromatic hydrogens), 5.25 (q, 1H, J = 6.5, CHOCO),
2.20 (s, 3H; CH3CO), 1.50 (d, 3H, J = 6.5, CH3CH);
GC/MS: tR = 16.31 min, m/z (%) 192 (M+, 2), 149 (25),
105 (100).
A
1:1 mixture of (2R)-4a and (2R)-4b (1.00 g, 4.81 mmol) (ob-
tained from the acetates produced by lipase PS acetylation
of the 1:1 mixture of racemic 4a and 4b) was dissolved in
pyridine (10 mL) and treated with PhCOCl (1.01 g,
7.21 mmol) at 0 ꢂC. After the usual work-up a 1:1 mixture
5.1.23. (R)-1-Oxobutan-2-yl benzoate (R)-17. The 1:1
mixture of benzoates (3R)-16a and (3R)-16b (1.10 g,
3.52 mmol) was treated with O3 at ꢀ78 ꢂC in CH2Cl2/
MeOH 1:1 solution (50 mL). The mixture was quenched
with PPh3 (2.77 g, 0.0106 mol) and after the usual work-
1
of (2R)-14a and (2R)-14b (1.27 g, 85%) was obtained. H
NMR (400 MHz, CDCl3) d 8.20–8.00 (m, 2H, aromatic
hydrogens), 7.60–7.25 (m, 3H, aromatic hydrogens), 5.50
(m, 1H, CHOCO of both diastereomers), 5.40–5.30 (m,
2H, vinylic hydrogens of both diastereomers), 2.42 (d,
1H, J = 10.9 Hz, H–C(1) cyclohexene ring of both diaste-
reomers), 1.99 (m, 2H, CH2C@ of both diastereomers),
1.80–1.35 (m, 7H, CH3C@C + CH3CH + H–C(5) cyclo-
hexene ring of both diastereomers), 1.20 (m, 1H,
J = 13.0, 5.4 Hz, H–C(5) cyclohexene ring of both diaste-
reomers), 0.88 (s, 3H, CH3–C(6) cyclohexene ring of both
diastereomers), 0.77 and 0.75 (2s, 3H, CH3–C(6) cyclohex-
ene ring of both diastereomers); GC/MS: tR = 25.16 and
25.24 min, m/z (%) 312 (M+, 2), 256 (15), 190 (30), 135
(29), 105 (100). C21H28O2: Calcd C, 80.73; H, 9.03. Found:
C, 80.67; H, 9.11.
up, the residue was submitted to CC (hexane/AcOEt 8:2),
20
to obtain (+)-(R)-17 (0.372 g, 55%): ½aꢁD ¼ þ41:0 (c 1.00,
20
CHCl3), for (R)-17 lit.6a ½aꢁD ¼ þ43:2 (c 1.0, CHCl3), lit.6b
20
1
½aꢁD ¼ þ41 (c 0.07, CHCl3); H NMR:6a,b 9.30 (s, 1H,
CHO), 8.20–8.00 (m, 2H, aromatic hydrogens), 7.40–7.30
(m, 3H, aromatic hydrogens), 5.18 (m, 1H, CHOCO),
2.00–1.90 (m, 2H, CH2CH3), 1.23 (t, 3H, J = 6.5,
CH3CH2).
Acknowledgement
We thank Dr. Philip Kraft (Givaudan Schweiz AG—Fra-
grance Research—Duebendorf) for the kind gift of Isoral-
deine 95 and for the odour evaluations of all the samples.
5.1.21. (R,E)-1-((RS)-2,6,6-Trimethylcyclohex-2-enyl)pent-
1-en-3-yl benzoate (3R)-16a and (3R)-16b. A 1:1 mixture
of (3R)-11a and (3R)-11b (1.00 g, 4.81 mmol) (obtained
from the acetates produced by lipase PS acetylation of
the 1:1 mixture of racemic 11a and 11b) was dissolved in
pyridine (10 mL) and treated with PhCOCl (1.01 g,
7.21 mmol) at 0 ꢂC. After the usual work-up a 1:1 mixture
References
1. Tiemann, F. to Haarmann & Reimer, Ger. Patent 75,120,
1
of (3R)-16a and (3R)-16b (1.25 g, 83%) was obtained. H
1893.
NMR (400 MHz, CDCl3) d 8.20–8.00 (m, 2H, aromatic
hydrogens), 7.70–7.40 (m, 3H, aromatic hydrogens),
5.70–5.35 (m, 4H, CHOCO + vinylic hydrogens of both
diastereomers), 2.12 (d, 1H, J = 8.7 Hz, H–C(1) cyclohex-
ene ring of both diastereomers), 1.98 (m, 2H, CH2C@ of
both diastereomers), 1.78 (m, 2H, CH2CH3 of both diaste-
reomers), 1.57 (m, 3H, CH3CH of both diastereomers),
1.42 (m, 1H, H–C(5) of the cyclohexene ring of both diaste-
reomers), 1.15 (m, 1H, H–C(5) cyclohexene ring of both
diastereomers), 0.97 (t, J = 7.5, CH2CH3), 0.88, 0.87,
0.81, and 0.80 (4s, 6H, 2CH3–C(6) cyclohexene ring of both
diastereomers); GC/MS: tR = 24.69 min (single peak) m/z
(%) 312 (M+, 2), 256 (5), 190 (33), 105 (100). –C21H28O2:
Calcd C, 80.73; H, 9.03. Found: C, 80.79; H, 8.95.
2. Ohloff, G. ‘Dufte’, Wiley-VCH, Helvetica Chimica Acta,
¨
Zurich, 2004.
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3. Sell, C. S. Angew. Chem., Int. Ed. 2006, 45, 6254–6261.
4. Brenna, E.; Fuganti, C.; Serra, S. Tetrahedron: Asymmetry
2003, 14, 1–42; Abate, A.; Brenna, E.; Fuganti, C.; Gatti, F.
G.; Serra, S. Chem. Biodiv. 2004, 1, 1888–1898; Abate, A.;
Brenna, E.; Fuganti, C.; Gatti, F. G.; Serra, S. J. Mol. Cat. B:
Enzym. 2004, 32, 33–51; Brenna, E. Curr. Org. Chem. 2003, 7,
1347–1367.
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Tetrahedron: Asymmetry 1994, 5, 927–934; (b) Martre, A.-M.;
Mousset, G.; Rhlid, R. B.; Veschambre, H. Tetrahedron Lett.
1990, 31, 2599–2602.
7. Brenna, E.; Fuganti, C.; Serra, S.; Kraft, P. Eur. J. Org.
Chem. 2002, 967–978.
8. Buchecker, R.; Egli, R.; Regel-Wild, H.; Tscharner, C.;
Eugster, C.-H.; Uhde, G.; Ohloff, G. Helv. Chim. Acta 1973,
56, 2548–2562.
9. Altomare, A.; Burla, M. C.; Camalli, M.; Cascarano, G. L.;
Giacovazzo, C.; Guagliardi, A.; Moliterni, A. G. G.; Polidori,
G. P.; Spagna, R. J. Appl. Cryst. 1999, 32, 115–119.
10. Sheldrick, G. M. SHELXL-97. Program for the Refinement of
Crystal Structures; University of Go¨ttingen: Germany, 1997.
5.1.22. (R)-3-Oxobutan-2-yl benzoate. The 1:1 mixture of
benzoates (2R)-14a and (2R)-14b (1.10 g, 3.52 mmol) was
treated with O3 at ꢀ78 ꢂC in CH2Cl2/MeOH 1:1 solution
(50 mL). The mixture was quenched with PPh3 (2.77 g,
0.0106 mol) and after the usual work-up, the residue
was submitted to CC (hexane/AcOEt 8:2), to obtain (ꢀ)-
20
(R)-15 (0.350 g, 57%): ½aꢁD ¼ ꢀ33:1 (c 1.16, CH2Cl2),
20
1
lit.5 for (R)-15 ½aꢁD ¼ ꢀ35:7 (c 1.0, CH2Cl2). H NMR5: