Synthesis and olfactory properties of (-)-(1R,2S)-Georgywood

Article abstract of DOI:10.1016/j.tetasy.2004.11.003

The enantiomers of Georgywood were synthesized from (E)-2-methyl-6-methylene-nona-2,7-diene and methacrylaldehyde followed by oxidation of the Diels-Alder adduct and classical racemate separation of the acid with optically-active N-methylephedrine. Conversion to the final ketone and olfactory evaluation showed that the (-)-(1R,2S)-enantiomer is more powerful by a factor of >100 than its antipode. The absolute configuration was determined by conformational studies and CD-analysis.

Full text of DOI:10.1016/j.tetasy.2004.11.003

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 3967–3972
Synthesis and olfactory properties of (ꢀ)-(1R,2S)-Georgywood
*
Georg Frater, Urs Muller and Fridtjof Schroder
´
¨
¨
¨
Givaudan Schweiz AG, Fragrance Research Chemistry, Uberlandstrasse 138, CH8600 Du¨bendorf, Switzerland
Received 13 October 2004; accepted 3 November 2004
Abstract—The enantiomers of Georgywoodꢀ were synthesized from (E)-2-methyl-6-methylene-nona-2,7-diene and methacrylalde-
hyde followed by oxidation of the Diels–Alder adduct and classical racemate separation of the acid with optically-active N-meth-
ylephedrine. Conversion to the final ketone and olfactory evaluation showed that the (ꢀ)-(1R,2S)-enantiomer is more powerful by a
factor of >100 than its antipode. The absolute configuration was determined by conformational studies and CD-analysis.
ꢁ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
bond of pseudo-Georgywood 3 to give intermediate 4,
which readily undergoes subsequent cyclization to 2.
Steric constraints between the methyl group of C(2)
and the methyl groups of the 4-methyl-pent-4-enyl side
chain of 3 are thus circumvented, in analogy to our stud-
ies on the acid-promoted cyclization of similarly substi-
tuted 1,5-dienes.3 Recent improvements on the
cyclization reaction (Scheme 1b) have given excellent
selectivities towards the desired isomer 1.4
The woody-ambery odorant Georgywoodꢀ,1,2 as pro-
duced from homomyrcene 5 at Givaudan,2a is a racemic
regioisomer mixture consisting of the olfactorily-active
isomer 1 and iso-Georgywood 2 in about equal amounts
(Scheme 1). The latter isomer is less powerful by a factor
of >10,000. The formation of 2 can be rationalized
through a preisomerization of the endocyclic double
The olfactory quality of fragrance compounds however,
can be also improved by preparation of the enantiomers
or their enriched mixtures, which can then exhibit more
powerful or totally different scents.5 Indeed a sniff-test at
the outlet of a chiral GC-column showed that one of the
enantiomers of 1 was ca. 200 times more powerful than
the other, both having the same kind of woody-ambery
tonality. For an unambiguous assignment of their abso-
lute configuration, however, both enantiomers of 1 had
to be prepared.
O
+
5
a
O
b
2
1
30 pg/L
O
3
4
1
2
H+
b
b
2. Results and discussion
O
O
The synthesis of the enantiomers was closely analogous
to that described in Scheme 1, starting from (E)-2-
methyl-6-methylene-nona-2,7-diene 5.2
500 ng/L
Scheme 1. Givaudan synthesis of Georgywoodꢀ. Reagents and
conditions: (a) AlCl3, CH2Cl2, 10ꢂC, 2h, 85%; (b) H3PO4, toluene,
115ꢂC, 1h, 74%.
Diels–Alder reaction of 5 with methacrylaldehyde in the
presence of substoichiometric amounts of aluminium
chloride gave racemate 6 in excellent yield and selecti-
vity. Chromic acid oxidation6 of 6 gave acid 7. The
cis-configuration of compounds 6 and 7, as expected
from the endo-transition state of the corresponding
*
Corresponding author. Tel.: +41 1 8242371; fax: +41 1 8242926;
e-mail: georg.frater@givaudan.com
0957-4166/$ - see front matter ꢁ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.11.003

´
G. Frater et al. / Tetrahedron: Asymmetry 15 (2004) 3967–3972
3968
(-)-7
a
CHO
b
c, d
2
CHO
CO2H
1
+
(+)-7
95%
80%
5
6
7
O
O
1
2
2
3
(1R,2S)
(1S,2R)
O
(-)-3
(-)-2
(-)-1
e
f
65-75%
80%
O
O
O
(+)-3
(+)-2
(+)-1
Scheme 2. Synthesis and resolution of racemate 6 and further conversion of the enantiomers. Reagents and conditions: (a) AlCl3, CH2Cl2, 1.2equiv
methacrylaldehyde, ꢀ50ꢂC to ꢀ30ꢂC, 0.5h; (b) JonesÕ reagent, acetone, 30ꢂC, 0.5h; (c) 1equiv (+)- or (-)-N-methyl ephedrine, MeOH, 65ꢂC,
evaporation, then crystallization from hexane/methyl tert-butyl ether; (d) 2M HCl/methyl tert-butyl ether; (e) MeLi, ꢀ50ꢂC to 30ꢂC, 1h; (f) cryst.
H3PO4, toluene, 120ꢂC, 0.5h.
Diels–Alder reaction, was later deduced from the same
known2 relative configuration of the following com-
pounds 1–3. Acid 7 was subjected to optical resolution
with (+)- and (ꢀ)-N-methylephedrine.7 The (+)- or
(ꢀ)-methylephedrine salts of 7 were successively crystal-
lized until melting points and specific rotations reached
their maximum values. HCl-treatment of the resolved
salts and ether extraction gave the crude acids (ꢀ)-7 or
(+)-7.8
Table 1. Olfactory evaluation of the Georgywood
Enantiomers
(ꢀ)-1
(+)-1
22
D
½aŠ
ꢀ39.2+41.2
Eea
88%b
92%b
Odour description
Bottom note
Woody-ambery
Fresh, minty,
green, sweet
20pg/L
Weakly woody
Musty
Odour threshold valuec
Absolute configuration
3.5ng/Lb
(1S,2R)
(1R,2S)
The resolved enantiomers (ꢀ)-7 or (+)-7 were separately
converted to the methyl ketones (ꢀ)-3 or (+)-3, which
gave after acid-catalyzed cyclization (ꢀ)-1 or (+)-1 to-
gether with their rearranged by-products (ꢀ)-2 or (+)-
2, respectively (1/2 ratios of 59:41). By-products (ꢀ)-2
or (+)-2 were separated from the desired enantiomers
(ꢀ)-1 or (+)-1 by flash chromatography (Scheme 2).
a Determined by chiral GC.
b We are aware of the fact that the separated enantiomers contain 4–
6% of their antipodes. This means, however, that the factor of the
odour threshold values is >175, because (+)-1 is even weaker.
c Determined on the sniff-outlet of a chiral GC-column with a panel of
three experienced fragrance chemists.
The olfactory evaluation showed that (ꢀ)-1 was the
more powerful enantiomer, possessing the typical
woody-ambery odour of Georgywood 1 with a fresh,
minty, green and sweet bottom note (Table 1). The
odour threshold value of 20pg/L air for (ꢀ)-1 fitted
nicely with the 30pg/L determined for the racemate.
Antipode (+)-1 was less powerful by a factor of 175.
For the determination of the absolute configuration, the
conformation of ketone 1 was first determined by means
of NOEs and computational geometry optimization.9 It
was found that in both isomers 1 and 2, the methyl
groups at C(1) and C(2) are pseudoaxial, with the carbo-
nyl-group being eclipsed with the C(2)–C(3)-bond of 1
or the C(1)–C(2)-bond of 2. An analogous conformation
was found by X-ray structure analysis of oxime 8 (Fig.
1), which was prepared from 1. In contrast to this typical
conformation of the more constrained bicycles 1, 2 and
8, the more flexible monocyclic precursor 3 has pseudo-
equatorial methyl-groups with an axial acetyl-group
with the oxygen-atom located above the endocyclic dou-
ble bond.
Figure 1. X-ray crystal structure of oxime 8. The C(2)–C(3)-bond and
the C@N-bond are inplane.
former of the (1R,2S)-enantiomer of 1 (Fig. 2), which
was found in the CD-spectrum measured of (ꢀ)-1 at
k = 295.5nm with a Demax at +0.6 (20ꢂC, hexane). Meas-
urements in CHCl3 did not change the CD-spectra of
Application of the octant rule predicts a positive n ! p*
transition for the carbonyl group of the most stable con-

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G. Frater et al. / Tetrahedron: Asymmetry 15 (2004) 3967–3972
3969
of the absolute configuration. The results obtained were
independently confirmed by Corey et al., who has re-
cently synthesized both enantiomers of Georgywood
(ꢀ)-1 and (+)-1 via an asymmetric Diels–Alder reaction
of homomyrcene 5, stating that the (ꢀ)-enantiomer with
its typical woody-ambery odour has a (1R,2S)-configu-
ration and that its antipode is practically odourless.11
The much lower olfactory threshold in comparison to
its antipode renders (ꢀ)-1 as a promising candidate
for fragrance applications, provided an industrially
feasible and inexpensive asymmetric synthesis can be
developed.
4. Experimental
4.1. General
Reagents and solvents were purchased from commercial
suppliers and used without further purification. Solvents
for moisture-sensitive reactions contained <0.1% water.
Moisture-sensitive reactions were conducted in oven-
dried (130ꢂC) glassware under nitrogen. The given tem-
peratures refer to reaction thermometers. All reactions
were carried out under stirring. The silica gel used for
flash chromatography was Sorbsil, 0.04–0.063mm
(Merck). JonesÕ reagent was prepared as described in
the literature.6 Homomyrcene 5 was prepared and
enriched as described in Ref. 2.
1H and 13C NMR: Bruker-DPX-400MHz spectrometer;
all spectra were recorded at 400MHz and in CDCl3; d in
ppm rel. to SiMe4; coupling constants J in Hz. GC/MS:
Agilent 5973 MSD with 6890 GC; relative intensities in
% of the base peak. High resolution GC/MS: Finnigan
MAT95 with HP 5890 series II GC. IR: Bruker FT-IR
Vector 22 spectrometer, mꢁ in cmꢀ1. Peak intensities
are assigned as strong (s), middle (m) and weak (w).
Optical rotations: Perkin–Elmer 241 Polarimeter. Chiral
GC: Column OV-1701/Octakis (6-methyl-2,3-pentyl)-c-
CD 1:1; 25m · 0.25mm; produced by Ko¨nig (University
of Hamburg);12 0.7bar H2; split 1:50; flow 2.75mL/min;
GC F 2150 from Carlo Erba Instruments; 80ꢂC iso-
therm; retention times 156.6min for (+)-1 and
160.8min for (ꢀ)-1. Chiral Sniff-GC: Column OV 61/
b-CDM produced by Givaudan, 20m · 0.32mm; split
1:25 at 250ꢂC; 120ꢂC isotherm; 0.5lL injection with
80ng/lL starting concentration; 0.3kPa H2; flow 2mL/
min; GC 8185 from Carlo Erba Instruments; retention
times 34.9min for (+)-1 and 36.2min for (ꢀ)-1.
CD-spectra: recorded in the range 200–400nm on a
Jobin-Yvon instrument; 0.1cm cell; solvent hexane at
20ꢂC.
Figure 2. Chemdraw 3D plot of the energy-minimized conformer of
Georgywood 1 with (a) view upon the carbonyl-axis with the oxygen-
atom pointing towards the observer. Depicted are the 4 backside
sectors, the 4 forefront sectors are practically empty. (b) Orthogonal
view upon the carbonyl-axis. Depicted are the 4 upper sectors. NOEÕs:
Me(a)–C(8)/H(a)–C(1), H(a)–C(1)/Me(a)–C(2), Me(a)–C(2)/H(a)–
C(4).
(ꢀ)-1 or (+)-1, at ꢀ90ꢂC, which only made the maxima
slightly more pronounced;10 another indication that the
assignment is based on the most stable conformer.
The octant rule is less applicable on the most stable con-
former of by-product 2 because positive and negative
contributions from the different sectors are more bal-
anced here, giving relatively low DeÕs at k = 285nm.
The (2S,3R)-configuration of (ꢀ)-2, however, follows
from its 1H NMR- and NOE-data and the preisomeriza-
tion mechanism shown in Scheme 1.
4.2. ( )-(1S*,2R*)-1,2-Dimethyl-4-(4-methyl-pent-3-
enyl)-cyclohex-3-enecarbaldehyde 6
3. Conclusion
A suspension of AlCl3 (26.6g, 0.2mol) in CH2Cl2
(450mL) was cooled to ꢀ50ꢂC. Methacrylaldehyde
(58g, 0.8mol) in CH2Cl2 (100mL) was added dropwise
within 15min, followed by 70% (E)-2-methyl-6-methyl-
ene-nona-2,7-diene 5 (100g, 0.47mol). The mixture
was quenched after another 15min at ꢀ25ꢂC with water
The first synthesis of the olfactorily active (ꢀ)-(1R,2S)-
enantiomer of Georgywood 1 has been accomplished
via classical racemate resolution. Conformational stud-
ies and CD measurements allowed the determination

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G. Frater et al. / Tetrahedron: Asymmetry 15 (2004) 3967–3972
3970
22
(5.9g, 36%); mp 39–43ꢂC. ½aŠ ¼ ꢀ145:9 (c 2.2, EtOH).
and extracted with hexane. Washing with NaHCO3,
drying over MgSO4, filtration and evaporation of the
solvent gave an oily residue, which was distilled under
high vacuum to give 6 (102g, 98%) as a colourless oil
at 105ꢂC/0.2mbar. 1H NMR: d 0.98 (d, 3H, J = 7.5),
1.06 (s, 3H), 1.53 (ddd, 1H, J = 7/7/13.5), 1.6 (s, 3H),
1.67 (s, 3H), 1.84 (ddd, 1H, J = 7/7/13.5), 1.9–2.2 (6H),
2.2 (m, 1H) 5.07 (dd, 1H, J = 7/7), 5.32(m, 1H), 9.67
(s, 1H). 13C NMR: d 17.0 (q), 17.6 (q), 19.8 (q), 25.3
(t), 25.6 (q), 26.3 (t), 27.9 (t), 36.9 (d), 37.2 (t), 47.1
(s), 124.0 (d), 125.1 (d), 131.4 (s), 136.5 (s), 207.3 (d).
MS (EI): m/z (%) 220 (M+, 8), 205 (10), 191 (12), 177
(23), 123 (32), 107 (87), 69 (100). IR (film): m = 2965
(s), 2922 (s), 2724 (w), 1725 (s), 1453 (m), 1375 (m),
1103 (w) cmꢀ1. HRMS calcd for C15H24O: 220.1824;
found 220.1827. Anal. Calcd for C15H24O: C, 81.76;
H, 10.98. Found: C, 81.82; H, 10.95.
D
The spectral data of (ꢀ)-7 was superimposable on the
ones of racemate 7.
4.3.1.2. (+)-(1R,2S)-1,2-Dimethyl-4-(4-methyl-pent-3-
enyl)-cyclohex-3-enecarboxylic acid (+)-7. The mother
liquor ML-1 of procedure 4.3.1.1. was treated with
2M HCl and extracted with methyl tert-butyl ether.
Drying of the organic phase over MgSO4 and evapora-
tion of the solvent in vacuo gave slightly enriched acid
22
D
(20.8g, 0.11mol) with ½aŠ ¼ þ57:5 (c 2.1, EtOH). The
crude acid (25g, 0.11mol) and (+)-(1S,2R)-methylephe-
drine (20g, 0.11mol) were dissolved in methanol at
65ꢂC. The methanol was evaporated in vacuo. The resi-
due was dissolved in methyl tert-butyl ether (60mL) and
hexane (180mL) and crystallized at ꢀ80ꢂC. The mixture
was warmed up to 30ꢂC and kept for 36h at 0ꢂC. Filtra-
tion and recrystallization from methyl tert-butyl ether/
hexane at 30–50ꢂC followed by filtration and evapora-
4.3. ( )-(1S*,2R*)-1,2-Dimethyl-4-(4-methyl-pent-3-
enyl)-cyclohex-3-enecarboxylic acid 7
tion of the solvents gave 19g (+)-methylephedrine salt;
22
D
mp 88ꢂC with ½aŠ ¼ þ112:7 (c 2.1, EtOH). The thus-
JonesÕ reagent6 (230mL, 0.6mol CrO3) was added at
30ꢂC under vigorous stirring to aldehyde 6 (90g,
0.4mol) in acetone (40mL). At 85% conversion, water
was added. After extraction with methyl tert-butyl ether,
the organic phase was washed with water and extracted
with 15% K2CO3. The aqueous layer was acidified to
pH3 and extracted with methyl tert-butyl ether. The
resulting organic phase was dried over MgSO4, filtered
and evaporated to give 79.8g of a crystalline mass,
which was recrystallized from methanol at ꢀ70ꢂC to
obtained (+)-methylephedrine salt was treated with
2M HCl and extracted with methyl tert-butyl ether.
Drying of the organic phase over MgSO4, filtration
and evaporation of the solvent gave (+)-7 as crystalline
22
D
residue (6.2g, 50%); mp 40–43 ꢂC. ½aŠ ¼ þ157:3 (c
2.0, EtOH). NMR, IR and MS-spectra of (+)-7 were
superimposable on the ones of the racemate 7.
4.4. Conversion of the acids (ꢀ)-7 or (+)-7 to the ketones
(ꢀ)-3 or (+)-3
1
give 7 (61g, 65%) as white crystals; mp 64–67ꢂC. H
NMR: d 0.96 (d, 3H, J = 8), 1.23 (s, 3H), 1.57 (m,
1H), 1.6 (s, 3H), 1.67 (s, 3H), 1.88 (m, 1H), 1.9–2.0
(4H), 2.07 (m, 2H), 2.2 (m, 2H), 5.07 (dd, 1H,
J = 7/7), 5.32(d, 1H, J = 5). 13C NMR: d 17.7 (q),
18.2 (q), 19.8 (q), 22.1 (q), 25.1 (t), 25.3 (t), 25.7 (q),
26.4 (t), 37.2 (t), 37.6 (d), 43.9 (s), 124.2 (d), 124.6 (d),
131.4 (s), 134.2(s), 184.6 (s). MS (EI): m/z (%) 236
(M+, 10), 221 (7), 193 (23), 147 (22), 121 (88), 107
(40), 69 (70), 41 (100). IR (KBr): m = 2962 (m), 2912
(m), 2873 (m), 1696 (s), 1449 (w), 1374 (w), 1295 (m),
1146 (w), 936 (w) cmꢀ1. HRMS calcd for C15H24O2:
236.1776; found 236.1774. Anal. Calcd for C15H24O2:
C, 76.23; H, 10.24. Found: C, 75.74; H, 10.08.
4.4.1. (ꢀ)-(1S,2R)-1-[1,2-Dimethyl-4-(4-methyl-pent-3-
enyl)-cyclohex-3-enyl]-ethanone (ꢀ)-3. Methyllithium
0.9M in diethyl ether (110mL, 0.1mol) was added drop-
wise at ꢀ50ꢂC to a solution of (ꢀ)-7 (6.5g, 28mmol) in
methyl tert-butyl ether (70mL). After 1h at 35ꢂC, ace-
tone (5mL) was added under cooling, followed by
water. Hexane extraction, drying of the organic phase
over MgSO4, filtration and evaporation of the solvent
gave an oily residue, which was purified by bulb-to-bulb
distillation giving (ꢀ)-3 (4.9g, 70%) as a colourless oil
22
D
at 120ꢂC/0.1mbar. ½aŠ ¼ ꢀ170:4 (c 2.1, EtOH). 1H
NMR: d 0.81 (d, 3H, J = 7.4), 1.12(s, 3H), 1.5 (m,
1H), 1.6 (s, 3H), 1.67 (s, 3H), 1.92(m, 1H), 1.96 (4H),
2.07 (m, 2H), 2.13 (s, 3H), 2.21 (m, 1H), 5.07 (dd, 1H,
J = 6.4/6.4), 5.32(d, 1H, J = 5.2). 13C NMR: d 17.5
(q), 18.0 (q), 20.9 (q), 23.6 (t), 25.2 (t), 25.4 (q), 25.5
(q), 26.2 (t), 37.1 (t), 37.2 (d), 48.9 (s), 124.0 (d), 124.4
(d), 131.1 (s), 135.0 (s), 213.5 (s). MS (EI): m/z (%) 234
(M+, 6), 219 (2), 191 (40), 165 (8), 121 (45), 121 (88),
107 (100). IR (film): m = 2966 (m), 2931 (m), 2875 (m),
1705 (s), 1454 (m), 1354 (m), 1239 (w), 1108 (w), 1086
(w) cmꢀ1. HRMS calcd for C16H26O: 234.1984; found
234.1979. Anal. Calcd for C16H26O: C, 81.99; H,
11.18. Found: C, 82.04; H, 11.19.
4.3.1. Resolution of the racemate 7
4.3.1.1. (ꢀ)-(1S,2R)-1,2-Dimethyl-4-(4-methyl-pent-3-
enyl)-cyclohex-3-enecarboxylic acid (ꢀ)-7. (ꢀ)-(1R,
2S)-Methylephedrine (25g, 0.14mol) and racemate 7
(33g, 0.14mol) were dissolved in methanol at 65ꢂC.
The methanol was evaporated in vacuo and the residue
dissolved in methyl tert-butyl ether (50mL) and hexane
(150mL). The solution was cooled to ꢀ30ꢂC, where
crystallization occurred, giving after filtration mother
liquor ML-1 and the crystalline (ꢀ)-methylephedrine
salt. Two recrystallizations from tert-butyl ether/hexane
at 4 and 45ꢂC, filtration and drying raised the mp to 86–
22
87ꢂC with ½aŠ ¼ ꢀ102:4 (c 2.1, EtOH). The thus ob-
4.4.2. (+)-(1R,2S)-1-[1,2-Dimethyl-4-(4-methyl-pent-3-
enyl)-cyclohex-3-enyl]-ethanone (+)-3. Acid (+)-7 (6g,
25mmol) was treated in analogy to procedure 4.4.1. with
methyllithium (100mL, 90mmol) to give after work-up
and distillation (+)-3 (3.8g, 65%) as a colourless oil.
D
tained (ꢀ)-methylephedrine salt was treated with 2M
HCl and extracted with methyl tert-butyl ether. Drying
of the organic phase over MgSO4, filtration and evapo-
ration of the solvent gave (ꢀ)-7 as crystalline residue

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3971
22
½aŠ ¼ þ189:8 (c 2.1, EtOH). Physical and spectral data
234 (M+, 8), 219 (14), 191 (100), 177 (10), 161 (8), 135
(20), 121 (32), 105 (25), 91 (19). IR (film): m = 2964
(m), 2943 (m), 2905 (m), 2893 (m), 2873 (m), 2835 (w),
1697 (s), 1456 (w), 1430 (w), 1379 (w), 1361 (m), 1216
(w), 1201 (w), 1121 (w), 1091 (w), 1081 (w), 970 (w)
cmꢀ1. CD: kmax (De) 285 (ꢀ0.1), 245 (0), 230 (0.3), 219
(ꢀ0.1). HRMS calcd for C16H26O: 234.1984; found
234.1978. Anal. Calcd for C16H26O: C, 81.99; H,
11.18. Found: C, 81.98; H, 11.20.
D
are identical to the ones of antipode (ꢀ)-3.
4.5. Acid-catalyzed cyclization of the ketones (ꢀ)-3 or
(+)-3
4.5.1. (ꢀ)-(1R,2S)-1-(1,2,8,8-Tetramethyl-1,2,3,4,5,6,7,8-
octahydro-naphthalen-2-yl)-ethanone (ꢀ)-1. Crystalline
phosphoric acid (2.9g, 30mmol) and ketone (ꢀ)-3
(4.6g, 20mmol) in toluene (8mL) were rapidly heated
to 120ꢂC and kept at this temperature for 30min. The
mixture was cooled below 0ꢂC and hydrolyzed with
ice. After extraction with methyl tert-butyl ether, the
organic layers were washed until pH7, dried over
MgSO4, filtered and evaporated in vacuo. Bulb-to-bulb
distillation of the residue at 150ꢂC/0.1mbar gave 4g of
a colourless oil (1/2 ratio 59:41), which was purified by
flash chromatography over silica gel with hexane/methyl
tert-butyl ether 95:5 as eluent. All fractions containing
>80% 1 were pooled, the solvents evaporated in vacuo
and the residue crystallized 4 times from methanol at
ꢀ80ꢂC to give after evaporation of the solvent below
0ꢂC, white crystals, which were liquefied above 0ꢂC to
give (ꢀ)-1 as a colourless oil (1g, 22%). Olfactory evalu-
4.5.4. (+)-(2R,3S)-1-(2,3,8,8-Tetramethyl-1,2,3,4,5,6,7,8-
octahydro-naphthalen-2-yl)-ethanone (+)-2. Evapora-
tion of the prefractions of the flash chromatography of
procedure 4.5.2. in vacuo gave (+)-2 (0.2g, 7%) as a col-
22
D
ourless oil. ½aŠ ¼ þ10:2 (c 2.0, EtOH). CD: kmax (De)
285 (0.1), 245 (0), 232 (ꢀ0.3), 221 (0.1). NMR, IR and
MS spectra were identical to the ones of antipode (ꢀ)-2.
4.6. ( )-E-(1R*,2S*)-1-(1,2,8,8-Tetramethyl-1,2,3,4,5,6,
7,8-octahydro-naphthalen-2-yl)-ethanone oxime 8
Georgywood 1 (1g, 4.3mmol) was added dropwise to a
slurry of hydroxylamine hydrochloride (3g, 40mmol),
sodium acetate (4g, 50mmol) and water (3mL). After
addition of ethanol (20mL), the mixture was heated
for 1.5h to reflux until complete conversion was
detected by GC. After addition of water (100mL) and
extraction with methyl tert-butyl ether, filtration and
evaporation of the filtrate under reduced pressure a crys-
talline residue was obtained, which was dissolved in hot
ethanol (10mL). Upon cooling, the oxime crystallized.
Filtration, washing with cold ethanol and drying of
the crystals under high vacuum gave oxime 8 (0.85g,
ation 0.2% in diethylphthalate: typical Georgywood,
22
fresh, minty, sweet. ½aŠ ¼ ꢀ39:2 (c 2.0, EtOH). 88%
D
1
ee (chiral GC). H NMR: d 0.85 (d, 3H, J = 6.9), 0.99
(s, 3H), 1.02 (s, 3H), 1.06 (s, 3H), 1.4–2.2 (10H), 2.15
(s, 3H,), 2.36 (q, 1H, J = 6.9Hz). 13C NMR: d 19.15
(t), 19.7 (q), 21.1 (q), 22.5 (t), 24.9 (q), 27.7 (t), 28.4
(q), 29.4 (q), 30.8 (t), 34.0 (s), 35.4 (d), 40.1 (t), 50.7
(s), 125.9 (s), 136.95 (s), 214.5 (s). MS (EI): m/z (%)
234 (M+, 25), 219 (15), 191 (100), 161 (20), 135 (65),
121 (40), 105 (40), 91 (30). IR (film): m = 2930 (m),
1700 (s), 1460 (m), 1377 (m), 1357 (m), 1240 (w), 1220
(w), 1090 (m) cmꢀ1. CD: kmax (De) 295.5 (0.6), 240 (0),
212 (ꢀ1.7). HRMS calcd for C16H26O: 234.1984; found
236.1981.
1
79%); mp 145ꢂC. H NMR: d 0.86 (d, 3H, J = 7), 0.97
(s, 3H), 0.99 (s, 3H), 1.06 (s, 3H), 1.4–1.55 (3H), 1.57–
1.67 (m, 2H), 1.7–1.8 (m, 1H), 1.82–1.87 (1H), 1.89 (s,
3H), 1.9–2.07 (2H), 2.15–2.22 (dd, 1H, J = 6.4, 12.8),
9.57 (s, 1H). 13C NMR: d 10.2(q), 19.3 (t), 19.4 (q),
21.7 (q), 23.9 (t), 28.1 (t), 28.5 (q), 29.7 (q), 30.9 (t),
34.2(s), 35.3 (d), 40.3 (t), 43.5 (s), 126.0 (s), 137.2(s),
164.2(s). MS (EI): m/z (%) 249 (M+, 40), 234 (52), 232
(78), 2.6 (65), 191 (18), 150 (18), 135 (100), 121 (37),
112(55). IR (film): IR (film): m = 3237 (m), 2931 (s),
2900 (s), 2869 (s), 2829 (m), 1662 (w), 1450 (m), 1379
(m), 1261 (w), 984 (w), 740 (s) cmꢀ1. HRMS calcd for
C16H27NO: 249.2093; found 249.2095. Anal. Calcd for
C16H27NO: C, 77.06; H, 10.91; N, 5.62. Found: C,
77.00; H, 10.86; N, 5.67.
4.5.2. (+)-(1S,2R)-1-(1,2,8,8-Tetramethyl-1,2,3,4,5,6,7,8-
octahydro-naphthalen-2-yl)-ethanone (+)-1. Cryst. phos-
phoric acid (1.7g, 18mmol) and ketone (+)-3 (4.6g,
20mmol) in toluene (5mL) were treated as described in
procedure 4.5.1. to give, after bulb-to-bulb distillation,
flash chromatography and crystallization, (+)-1 as
22
D
colourless oil (0.7g, 23%). ½aŠ ¼ þ41:2 (c 2.0, EtOH).
92% ee (chiral GC). CD: kmax (De) 295.5 (ꢀ0.6), 240
(0), 212 (1.7). NMR, IR and MS spectra were identical
to the ones of antipode (ꢀ)-1.
Crystal data: C16H27NO, formula weight 249.39, crystal
size 0.3 · 0.4 · 0.3mm, monoclinic, space group
P2(1)/n, Z = 4, a = 9.398 (19)A, b = 14.160 (3)A,
4.5.3. (ꢀ)-(2S,3R)-1-(2,3,8,8-Tetramethyl-1,2,3,4,5,6,7,8-
octahydro-naphthalen-2-yl)-ethanone (ꢀ)-2. Evapora-
tion of the prefractions of the flash chromatography de-
scribed in procedure 4.5.1. in vacuo gave (ꢀ)-2 (0.25g,
˚
˚
˚
c = 11.386 (2)A, a = c = 90ꢂ, b = 94.97 (3)ꢂ, V =
1509.5(5)A, d = 1.097g/cm3, absorption coefficient =
3
˚
22
D
1
0.512mmꢀ1, F (000) = 552, k = 1.54178A (CuKa, rotat-
˚
5%) as a colourless oil. ½aŠ ¼ ꢀ9:1 (c 2.0, EtOH). H
NMR: d 0.75 (d, 3H, J = 6.8), 0.99 (s, 3H), 0.97 (s,
3H), 1.01 (s, 3H), 1.06 (s), 1.5 (m, 2H), 1.6 (m, 2H),
1.65–1.85 (4H), 1.94 (ddd, J = 3.5/6.8/6.8, 1H), 2.22 (d,
J = 17.2, 1H), 2.35 (d, J = 17.2, 1H). 13C NMR: d 16.6
(q), 19.2 (t), 22.2 (q), 24.7 (q), 27.0 (q), 27.9 (t), 28.0
(q), 30.9 (t), 33.2(d), 33.5 (s), 35.4 (t), 39.5 (t), 49.5
(s), 123.6 (s), 131.6 (s), 213.9 (s). NOEÕs: H(a)–C(1)/
Me(a)–C(3), Me(b)–C(2)/H(b)–C(4). MS (EI): m/z (%)
ing anode), 3466 reflections collected (0 6 h 6 12,
0 6 k 6 18, ꢀ14 6 l 6 14) on a Siemens P4 diffraction
measurement device. T = 293 (2)K. Theta range for data
collection: 5.00ꢂ–80.36ꢂ. Independent reflections: 1891
[R(int) = 0.2358]. Refinement method: Full-matrix
least-squares on F2. Completeness to theta = 80.36:
99.0%. Data/restraints/parameters: 3270/0/168. Good-
ness-of-fit on F2: 1.073. Final R indices [I > 2sigma(I)]:

´
3972
G. Frater et al. / Tetrahedron: Asymmetry 15 (2004) 3967–3972
4. Barras, J.-P.; Schro¨der, F. Patent Application GB
R indices (all data):
R1 = 0.1111, wR2= 0.2685.
0319277; priority 18/8/2003. A more detailed description
R1 = 0.1592, wR2= 0.3193. Largest diff. peak and hole:
0.421 and ꢀ0.445eAꢀ3. Full crystallographic results
˚
will be published soon.
5. Brenna, E.; Fuganti, C.; Serra, S. Tetrahedron: Asymmetry
2003, 14, 1–43.
6. (a) Bowers, A.; Halsall, T. G.; Jones, E. R. H.; Lemin, A.
J. Chem. Soc. 1953, 2548–2560; (b) Bower, H.; Jones;
Lemin J. Chem. Soc. 1953, 2548.
have been deposited as CIF-file at the Cambridge Crys-
tallographic Data Centre, UK.13
7. Kimura, Y.; Suzuki, M.; Matsumoto, T.; Abe, R.;
Terashima, S. Bull. Chem. Soc. Jpn. 1986, 59, 415–421.
8. The resolved enantiomers (ꢀ)-7 or (+)-7 have the tendency
to crystallize as racemates. Crystallization would have
given a certain enrichment in the mother liquor, but the
crude enantiomers (ꢀ)-7 or (+)-7 were further converted
as such, because they had sufficient enantiopurity, as
deduced from the ee-values of the final Georgywood
enantiomers (ꢀ)-1 or (+)-1.
Acknowledgements
We would like to thank M. Lovchik (University of Zur-
¨
ich) for conducting some of the chemical experiments,
K. Gubernator and K. Noack (Hoffmann LaRoche)
for molecular modelling and CD measurements, M.
Hennig and A. M. Alker (Hoffmann LaRoche) for X-
ray analysis, Prof. W. A. Ko¨nig (University of Ham-
burg) for a gift of chiral GC-columns and especially
our analytical department at Givaudan.
9. Energy minimized with Molecular Mechanics (MM2) and
further optimization using Molecular Dynamics or
MOPAC. Program: CS Chem3D Ultraꢀ, 2001 Cam-
bridgeSoft Corp., Cambridge, MA 02140, USA.
10. Circular Dichroism, Principles and Applications; Nakani-
shi, K., Berova, N., Woody, R. W., Eds.; VCH:
New York, 1994.
References
´
1. (a) Frater, G.; Bajgrowicz, J. A.; Kraft, P. Tetrahedron
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12. Ko¨nig, W. A. Gas Chromatographic Enantiomer Separa-
tions with Modified Cyclodextrins; Hu¨thigVerlag,
Heidelberg, 1992.
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Denis, C.; Frater, G. Angew. Chem., Int. Ed. 2000, 39,
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13. CCDC 251423 contains the supplementary crystallo-
graphic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif,
by emailing data_request@ccdc.cam.ac.uk, or by contact-
ing The Cambridge Crystallographic Data Centre, 12,
Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223
336033.
Chimia 2001, 55, 379–387.
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1996; Chem. Abstr. 1997, 126, 103856h; (b) Bella, M.;
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