Chiral aminoalcohols with a menthane skeleton as catalysts for the enantioselective addition of diethylzinc to benzaldehyde

Article abstract of DOI:10.1016/S0957-4166(01)00206-3

Novel chiral aminoalcohols were synthesized by highly diastereoselective addition of Me₃SiCN and LiCH₂CN to (-)-menthone followed by LiAlH₄ reduction. The addition of CH₂=CH-MgBr and PhCH=CH-MgBr to menthone and the following epoxidation, provided useful hydroxy epoxides, one of which could be aminolyzed to afford an aminodiol. In one case, the configuration of the newly formed epoxidic stereogenic center was determined by X-ray crystallography. When applied as catalysts in the enantioselective addition of Et₂Zn to benzaldehyde, the aminoalcohols induced enantiomeric excesses (e.e.s) of up to 77%.

Full text of DOI:10.1016/S0957-4166(01)00206-3

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 1313–1321
Chiral aminoalcohols with a menthane skeleton as catalysts for
the enantioselective addition of diethylzinc to benzaldehyde†
Stefan Panev,a Anthony Lindenb and Vladimir Dimitrova,*
aInstitute of Organic Chemistry, Bulgarian Academy of Sciences, BG-1113 Sofia, Bulgaria
bInstitute of Organic Chemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland
Received 17 April 2001; accepted 8 May 2001
Abstract—Novel chiral aminoalcohols were synthesized by highly diastereoselective addition of Me3SiCN and LiCH2CN to
(−)-menthone followed by LiAlH4 reduction. The addition of CH2ꢀCH-MgBr and PhCHꢀCH-MgBr to menthone and the
following epoxidation, provided useful hydroxy epoxides, one of which could be aminolyzed to afford an aminodiol. In one case,
the configuration of the newly formed epoxidic stereogenic center was determined by X-ray crystallography. When applied as
catalysts in the enantioselective addition of Et2Zn to benzaldehyde, the aminoalcohols induced enantiomeric excesses (e.e.s) of up
to 77%. © 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
aminopropyl lithium to (−)-menthone, catalyzed the
enantioselective addition of diethylzinc to several alde-
hydes with excellent enantioselectivities of up to 95%.
We were therefore interested in preparing (−)-menthone
derived b- and g-aminoalcohols and testing them as
chiral ligands.
Catalytic asymmetric carbonꢁcarbon bond formation
has been one of the most studied fields in synthetic
organic chemistry over recent years.1–3 The enantiose-
lective addition of dialkylzinc compounds to aldehydes
in reactions catalyzed by different types of chiral lig-
ands has been investigated intensively because the
preparation of enantiomerically pure or enriched alco-
hols is of considerable interest for the synthesis of
bioactive compounds and natural products.4 Aminoal-
cohols have been shown to be highly efficient chiral
catalysts and among them the b-aminoalcohols have
been thought to provide the best results. In general,
since Noyori demonstrated the high activity of (−)-3-
exo-dimethylaminoisoborneol and suggested a mecha-
nistic model for the catalytic cycle, b-aminoalcohols
have usually been employed.5 Until recently, only a few
examples of the use of g-6 and d-aminoalcohols7,8 have
been reported. However, there has been increased inter-
est in the preparation of d-aminoalcohols, and their
utility as catalysts for the asymmetric addition of
dialkylzincs to aldehydes has been demonstrated.9 The
d-aminoalcohol N,N-dimethylaminopropyl neomen-
thol,8 prepared in one step by the addition of dimethyl-
The synthetic strategy used for the study presented
herein was developed during recent investigations.10
This strategy involves the addition of suitable
organometallic reagents to (−)-menthone, which pro-
ceeds highly diastereoselectively,11 and further transfor-
mation of the products to afford the desired
aminoalcohols.
2. Results and discussion
The first step in the investigation was, based on previ-
ous experiences,10 the addition of Me3SiCN, LiCH2CN,
CH2ꢀCH-MgBr and PhCHꢀCH-MgBr to (−)-men-
thone. For a successful reaction with Me3SiCN, the
(−)-menthone 1 needed to be activated with an equimo-
lar quantity of BF3·OEt2. Interestingly, the attack of
the reagent occurred predominantly from the axial face
of the menthane skeleton leading to the axial and
equatorial addition products presented in Scheme 1. In
the case of the equatorial addition product, it was not
possible during the hydrolytic work-up to cleave com-
pletely the initially formed silyl ether 3, to give the
corresponding cyanohydrin 2 (ratio 2:3:4=20:11:69 in
* Corresponding author. E-mail: vdim@orgchm.bas.bg
Dedicated to Professor Heinz Heimgartner on the occasion of his
†
60th birthday.
0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00206-3

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S. Pane6 et al. / Tetrahedron: Asymmetry 12 (2001) 1313–1321
the crude product by NMR). Similar behavior was
observed in the addition of the Me3SiCN/BF3·OEt2
reagent to (+)-camphor and (−)-fenchone.10g The com-
pounds 2, 3 and 4 could be isolated after column
chromatography in the yields given in Scheme 1.
The addition of PhCHꢀCH-MgBr, prepared from mag-
nesium and b-bromostyrene (mixture of trans/cis-iso-
mers=85:15), to CeCl3 activated 1 provided a mixture
of the equatorial addition products 8a and 8b, from
which 8a was isolated in 73% yield after column chro-
matography. Compound 8a has been reported previ-
ously;14 however, no experimental or analytical data is
available.
As described previously,11a the addition of LiCH2CN to
1 afforded compounds 5 and 6 in excellent yields,
depending on the reaction conditions. Compound 5
could be isolated with 92% d.e.; however, 6 was
obtained in a diastereoisomerically pure form after
simple recrystallization.11a In an earlier work,12
CH2ꢀCH-MgBr was added to 1 to give 92% of 7, 4% of
its diastereoisomer formed as a result of axial attack of
the reagent, and 4% of unreacted menthone was
returned. However, it was reported later13 that the same
reaction proceeds exclusively from the equatorial side
of the carbonyl group, with only 77% yield. In the
present investigation, compound 7 was prepared by the
addition of the vinyl Grignard reagent to (−)-menthone,
activated with anhydrous CeCl3, which was prepared
and applied according to our recently published proce-
For the preparation of b-aminoalcohols (Scheme 2)
compounds 2 and 4 were reduced with LiAlH4 to the
corresponding 9 and 12, which were isolated in moder-
ate yields (38 and 59%, respectively). Unfortunately, in
both cases, considerable amounts of menthol 10 and
neomenthol 11 were also isolated. This indicates the
formation of menthone as a side product under the
reaction conditions, which gives 10 and 11 on reduc-
tion. The cyanomethyl addition products 5 and 6 were
reduced to the corresponding g-aminoalcohols 14 and
15, respectively, with very good yields. The preparation
of N,N-dimethylaminoalcohols succeeded only in the
case of 13 and 16, however in low yields, by the
reaction of NaBH3CN/HCHO with 12 and 14,
respectively.
dure.10a,10d,11b In this manner, compound
7 was
obtained quantitatively as a single diastereoisomer (as
determined by NMR).
1. BF3•OEt2
2. Me3SiCN
+
+
CN
CN
OH
3. hydrolysis
OH
OSiMe3
CN
2
3
4
(17%)
(9%)
(47%)
1. LiCH2CN / -78°C
2. hydrolysis at -78°C
CN
OH
5
(quant.)
10
1. LiCH2CN / -78°C
4
5
6
2. 1.5 h at r.t.
3
2
1
8
OH
CN
7
O
3. hydrolysis at r.t.
9
1
6
(68%)
1. CeCl3 / THF
2. CH2=CH-MgBr
3. hydrolysis
OH
7
(quant.)
1. CeCl3 / THF
2. PhCH=CH-MgBr
Ph
+
3. hydrolysis
OH
OH
Ph
8a
8b
(73%)
(content not determined)
Scheme 1.

S. Pane6 et al. / Tetrahedron: Asymmetry 12 (2001) 1313–1321
1315
1. LiAlH4
+
+
OH
CN
OH
NH2
2. hydrolysis
OH
OH
OH
OH
CN
79 : 21
(54%)
9
10
10
11
11
2
4
(38%)
1. LiAlH4
+
+
OH
OH
2. hydrolysis
NH2
76 : 24
(22%)
12
(59%)
NaBH3CN / HCHO
OH
OH
NMe2
NH2
13
12
(24%)
1. LiAlH4
CN
2. hydrolysis
OH
NH2
OH
14
(73%)
5
6
1. LiAlH4
OH
OH
CN
2. hydrolysis
NH2
15
(84%)
NaBH3CN / HCHO
OH
NMe2
OH
NH2
14
16
(39%)
Scheme 2.
has (R)-configuration at the epoxide stereogenic center.
So far we have been unable to obtain crystals of 17 of
sufficient quality for X-ray crystal structure analysis.
The allylic alcohols 7 and 8a were epoxidized with
tert-butyl hydroperoxide and VO(acac)2 as catalyst to
the corresponding hydroxy epoxides 17 and 18 in very
good yields and diastereoselectivity (98% d.e. for 17
and 82% d.e. for 18 in the crude product). The pure
The aminolysis of 17 with Et2NH in the presence of
LiClO4 afforded aminodiol 19 in only 19% yield. The
cleavage proceeded with excellent regioselectivity at the
less substituted carbon atom of the epoxide and there-
fore, with retention of the configuration, according to
previously published data.10f,17 Attempts to aminolyze
the hydroxy epoxide 18 with Et2NH in the presence of
metal salts or with LiAl(NEt2)4 in THF were
unsuccessful.
diastereoisomers were
chromatography.
obtained
after column
The configuration of the newly formed stereogenic cen-
ters in 18 was determined by X-ray crystallographic
analysis (Fig. 1), where the known (S)-configuration at
C(2) was used to define the enantiomer employed in the
model for the crystal structure refinement. Therefore,
the hydroxy group directed V5+-promoted epoxidation
occurs, in accordance with the cyclic transition state,16
from the re-side of the double bond (Scheme 3). The
si-face is obviously highly hindered by the iso-propyl
group of the menthane skeleton. Therefore, we assume
that the predominantly formed diastereoisomer 17 also
The aminoalcohols 9, 12–16 and 19 were applied as
catalysts (3 mol%) in the enantioselective addition of
diethylzinc to benzaldehyde (Table 1). The addition
reactions were carried out in hexane with 1 M solution
of Et2Zn in hexane according to the published proce-
dure.10f The yields of the isolated 1-phenyl-1-propanol

1316
S. Pane6 et al. / Tetrahedron: Asymmetry 12 (2001) 1313–1321
ides, aminoalcohols) starting from (−)-menthone and
by using relatively simple transformation reactions. The
aminoalcohols provided only moderate enantioselectiv-
ity for the addition of Et2Zn to benzaldehyde. The
preparation of further derivatives with possibly better
efficiency as chiral catalysts is in progress.
3. Experimental
3.1. General methods and starting materials
The reactions with air and moisture sensitive reagents
were carried out in flame-dried Schlenk flasks under an
argon atmosphere. The solvents were dried (sodium/
benzophenone for Et2O and THF) and distilled. Thin-
layer chromatography (TLC) was performed using
aluminum sheets precoated with silica gel 60 F254
(Merck). Column chromatography was carried out at
normal pressure, silica gel 60 (0.063–0.200 mm, Merck).
Melting points were obtained using a Kofler block
apparatus (uncorrected). [h]2D0 measurements were
obtained using a Perkin–Elmer 241 polarimeter. Mass
spectra (MS) analyses were obtained using a Finnigan
MAT 90 or Finnigan SSQ 700 and are reported as
fragmentation in m/z with relative intensities (%) in
parentheses. NMR spectra were recorded on a Bruker
Avance DRX-250 (1H at 250.1 MHz; 13C at 62.9 MHz;
TMS as internal standard); samples for NOE difference
experiments were prepared by blowing argon through
the CDCl3 solution. Elemental analyses were performed
by the Microanalytical Service Laboratory of the Insti-
tute of Organic Chemistry, Bulgarian Academy of
Sciences.
Figure 1. ORTEP15 plot of the molecular structure of 18 with
50% probability ellipsoids.
were high. The observed enantioselectivities were low to
moderate and in all cases the (S)-enantiomer was
formed predominantly. The best result was realized
with the g-aminoalcohol 16. It is important to note that
the enantioselectivity obtained with N,N-dimethyl-
aminoalcohol 13 was lower than with the correspond-
ing aminoalcohol 12, while 16 which is the N,N-
dimethyl analogue of 14 increased the asymmetric
induction remarkably.
The following starting materials were used (commer-
cially available or prepared according to the literature):
(−)-menthone, Me3SiCN, BF3·OEt2, TBHP (3 M in
iso-octane), VO(acac)2 and Et2Zn (1 M in hexane)
(Fluka AG); NaBH3CN (Merck); LiAIH4 (Aldrich);
CH2ꢀO (37% in water); CH2ꢀCHMgBr and
PhCHꢀCHMgBr were prepared from the correspond-
The unambiguous assignment of the proton and car-
bon-13 spectra (Table 2 and Section 3) was made on
the basis of DEPT, HSQC18 and NOESY experiments.
In conclusion, we have prepared some new enantiomer-
ically pure derivatives (cyanohydrins, hydroxy epox-
OH
Et2NH / LiClO4
CH3CN
O
VO(acac)2 / t-BuOOH
R
R
OH
OH
OH
OH
NEt2
7
17
19
(81%)
(19%)
R
O
VO(acac)2 / t-BuOOH
Ph
Ph
no aminolysis reaction
could be realized
R
S
S
S
OH
8a
18
(76%)
Si
stereochemical
course of the V5+-assisted
R
VO(acac)2 / t-BuOOH
R
R
O
epoxidation
OH
OH
Re
R = H, Ph
Scheme 3.

S. Pane6 et al. / Tetrahedron: Asymmetry 12 (2001) 1313–1321
1317
Table 1. Addition of Et2Zn to benzaldehyde catalyzed by aminoalcohols 9, 12–16 and 19
OH
3 mol % ligand
O
+
Et2Zn
Entry
Ligand
Time (h)
Yielda (%)
e.e.b (%)
1
2
3
4
5
6
7
9
12
13
14
15
16
19
120
120
51
98
72
79
67
89
69
72
98
87
9 (S)
40 (S)
3 (S)
19 (S)
0
22
48
77 (S)
40 (S)
a Yields of isolated 1-phenyl-1-propanol (after column chromatography).
b Determined by polarimetry based on the maximum value for the specific rotation of (S)-1-phenyl-1-propanol ([h]2D0=−47 (c 2.2, hexane) for 98%
e.e. in the Fluka catalogue 1999/2000, p. 1142).
Table 2. 13C NMR chemical shifts of compounds 2, 4, 7–9 and 12–19 (CDCl3, 300 K, l in ppm from TMS)a
Compound
No. C-atom
2
4
7
8a
9b
12
13
14
15
16
17
18
19
C(1)
C(2)
C(3)
C(4)
C(5)
C(6)
C(7)
C(8)
72.64
49.18
20.23
34.10
26.42
47.65
29.41
18.66
23.34
21.45
122.70
–
72.19
51.90
23.48
33.94
30.29
48.86
25.99
17.37
23.25
21.35
121.51
–
76.52
49.09
20.69
35.05
27.64
48.98
26.69
18.38
23.71
22.14
146.37
111.01
–
76.71
49.83
21.03
35.09
27.91
49.30
27.21
18.66
23.87
22.25
138.32
126.55
137.33
126.29
128.54
127.10
75.56
48.46
21.72
36.36
28.76
45.83
26.87
18.64
24.16
23.01
51.16
–
74.20
51.58
23.47
35.05
30.03
45.71
24.53
19.54
24.72
22.46
42.57
–
74.30
52.33
23.99
34.90
30.42
46.69
24.99
19.86
24.80
22.12
61.13
47.94
–
74.50
50.01
20.40
35.16
27.72
46.93
25.56
17.99
23.67
22.48
41.34
37.41
–
75.76
53.24
23.59
35.06
29.95
46.99
24.56
19.40
24.82
22.41
31.78
36.95
–
74.70
50.47
20.49
35.38
27.81
47.38
25.94
18.02
23.80
22.67
34.54
55.22
–
71.65
47.44
20.20
34.93
27.11
46.71
27.01
17.90
23.34
22.07
58.25
44.52
–
72.77
47.54
20.10
35.07
27.27
46.67
27.52
17.99
23.45
22.17
55.79
68.91
137.24
125.43
128.47
128.02
76.27
46.13
20.10
34.97
27.71
41.31
25.49
18.09
23.50
22.71
68.94
55.05
47.19
11.50
–
C(9)
C(10)
C(11)
C(12)
C(13)
C(14)
C(15)
C(16)
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
a For the numbering of the menthane moiety see Scheme 1; the carbon atoms of the substituents were numbered continuously.
b In CD3OD.
ing organic halides by known procedures;19 anhydrous
CeCl3.10a,10d,11b
(0.50 g, 47%). Compounds 2 and 4 were distilled (70°C,
0.001 Torr) and obtained as colorless crystals.
Data for 2: Mp 45–46°C. [h]2D0=+1.9 (c 1.02, CHCl3).
Anal. calcd for C11H19NO (181.28): C, 72.88; H, 10.56;
N, 7.73. Found: C, 72.95; H, 10.54; N, 7.58%. MS (CI:
NH3) m/z (rel. int.): 199 ([M+18]+, 49), 181 ([(M−
3.2. (1S,2S,5R)-1-Hydroxy-2-iso-propyl-5-methylcyclo-
hex-1-yl-carbonitrile 2 and (1R,2S,5R)-1-hydroxy-2-iso-
propyl-5-methylcyclohex-1-yl-carbonitrile 4
1
H2O)+18]+, 5), 172 ([(M−HCN)+18]+, 100). H NMR
To 1 (0.90 g, 5.83 mmol) was added BF3·OEt2 (0.83 g,
5.85 mmol) and Me3SiCN (0.64 g, 6.45 mmol) at rt.
The mixture was stirred for 1 h at rt then heated to
60°C and stirred for a further 0.5 h. After hydrolysis
with 2N aqueous HCl, the mixture was extracted with
Et2O (3×15 mL). The organic extract was washed with
5% aq. NaHCO3, H2O and dried (MgSO4). After evap-
oration of the solvent, the crude product (1.04 g,
2:3:4=20:11:69 by NMR) was chromatographed (¥=
24 mm, h=520 mm, 84 g silica gel, petroleum ether/
Et2O=3:1) to give 3, (0.13 g, 9%) 2, (0.18 g, 17%), a
mixed fraction (0.01 g) (2:4=62:38 by NMR) and 4
(CDCl3, 300 K): l 0.90–1.04 (m, 1H, H-4ax), 0.91 (d,
3H, H-10, J=6.4 Hz), 0.97 (d, 3H, H-8, J=6.9 Hz),
1.03 (d, 3H, H-9, J=6.9 Hz), 1.38–1.48 (m, 1H, H-2),
1.40–1.60 (m, 2H, H-3eq, H-3ax), 1.53 (t, 1H, H-6ax,
J=12.0 Hz), 1.68–1.87 (m, 2H, H-4eq, H-5), 2.11 (dt,
1H, H-6eq, J=13.7, 2.9 Hz), 2.23 (quintd, 1H, H-7,
J=6.9, 2.0 Hz), 2.62 (s, 1H, OH).
Data for 4: Mp 40–42°C. [h]2D0=−12.9 (c 1.05, CHCl3).
Anal. calcd for C11H19NO (181.28): C, 72.88; H, 10.56;
N, 7.73. Found: C, 72.61; H, 10.23; N, 7.44%. MS (CI:

1318
S. Pane6 et al. / Tetrahedron: Asymmetry 12 (2001) 1313–1321
NH3) m/z (rel. int.): 199 ([M+18]+, 32), 181 ([(M−
2.00 (quintd, 1H, H-7, J=6.9, 2.1 Hz), 6.23 (d, 1H,
H-11, J=16.1 Hz), 6.65 (d, 1H, H-12, J=16.1 Hz), 7.21
(tt, 1H, H-16, J=7.1, 1.9 Hz), 7.31 (tt, 2H, H-15,
J=7.3, 1.6 Hz), 7.36–7.42 (m, 2H, H-14).
1
H2O)+18]+, 3), 172 ([(M−HCN)+18]+, 100). H NMR
(CDCl3, 300 K): l 0.87–0.95 (m, 1H, H-4ax), 0.97 (d,
3H, H-10, J=6.4 Hz), 1.02 (d, 6H, H-8, H-9, J=7.1
Hz), 1.28–1.38 (m, 2H, H-2, H-3ax), 1.29 (t, 1H, H-6ax,
J=12.2 Hz), 1.70–1.90 (m, 3H, H-3eq, H-4eq, H-5), 2.18
(dm, 1H, H-6eq), 2.22 (quintd, 1H, H-7, J=7.0, 2.3 Hz),
2.45 (s, 1H, OH).
3.5. (1S,2S,5R)-1-Aminomethyl-2-iso-propyl-5-methyl-
cyclohexan-1-ol 9
To a slurry of LiAlH4 (0.42 g, 11.07 mmol) in Et2O (7
mL) was added a solution of 2 (0.33 g, 1.82 mmol) in
Et2O (3 mL) at rt and the mixture was stirred for 1.5 h
at the same temperature. It was hydrolyzed with 2N
HCl and the acidic layer was washed with Et2O (3×10
mL) and rendered alkaline by treatment with aq.
NaOH. The alkaline layer was extracted (3×15 mL
CH2Cl2). The evaporation of the Et2O extract gave a
mixture of 10 and 11 (0.15 g, 54% 10:11=79:21 by
NMR). Evaporation of the CH2Cl2 layer afforded 9
(0.13 g, 38%) as colorless crystals. Mp 22–23°C. [h]2D0=
0.0 (c 1.04, MeOH). Anal. calcd for C11H23NO
(185.31): C, 71.30; H, 12.51; N, 7.56. Found: C, 67.95;
H, 12.09; N, 6.51%. MS (CI: NH3) m/z (rel. int.): 186
([M+H] , 100), 168 ([M−OH] , 2). H NMR (CD3OD,
300 K): l 0.75–0.90 (m, 1H, H-4ax), 0.90 (d, 3H, H-8,
J=6.9 Hz), 0.90 (d, 3H, H-10, J=6.1 Hz), 0.92 (d, 3H,
H-9, J=6.9 Hz), 1.00 (dd, 1H, H-6ax, J=13.3, 12.1 Hz),
1.10–1.20 (m, 1H, H-2), 1.43–1.58 (m, 2H, H-3eq, H-
3ax), 1.61 (ddd, 1H, H-6eq, J=13.2, 3.6, 2.4 Hz), 1.63–
1.84 (m, 1H, H-5), 1.68–1.82 (m, 1H, H-4eq), 2.04
(quintd, 1H, H-7, J=6.9, 1.9 Hz), 2.61 (d, 1H, Ha-11,
J=13.2 Hz), 2.74 (d, 1H, Hb-11, J=13.2 Hz).
3.3. (1R,2S,5R)-1-Vinyl-2-iso-propyl-5-methylcyclo-
hexan-1-ol 7
A mixture of 1 (0.64 g, 4.15 mmol) and anhydrous
CeCl3 (1.03 g, 4.18 mmol) in THF (20 mL) was stirred
for 40 min at rt, and then cooled to −10°C. To this
mixture was added a solution of CH2ꢀCH-MgBr in
THF (0.86 M, 8 mL, 6.88 mmol). The resulting mixture
was allowed to warm to rt and stirred at this tempera-
ture for 2 h. After hydrolysis (2N HCl), the mixture
was extracted with petroleum ether (3×15 mL), the
organic layer was washed with 5% aq. NaHCO3, H2O
and dried (Na2SO4). After evaporation of the solvent, 7
was obtained (0.76 g, quantitative). For determination
of [h]2D0, 7 was further purified by distillation (60°C,
0.001 Torr) to give a colorless liquid. [h]2D0=−19.2 (c
1.02, CHCl3). Anal. calcd for C12H22O (182.31): C,
+
+
1
’
1
79.06; H, 12.16. Found: C, 78.63; H, 11.86%. H NMR
(CDCl3, 300 K): l 0.72–0.97 (m, 1H, H-4ax), 0.85 (d,
3H, H-8, J=6.9 Hz), 0.87 (d, 6H, H-9, H-10, J=7.1
Hz), 1.05–1.20 (m, 2H, H-2, H-6ax), 1.23 (s, 1H, OH),
1.38–1.58 (m, 3H, H-3eq, H-3ax, H-6eq), 1.60–1.90 (m,
1H, H-5), 1.60–1.80 (m, 1H, H-4eq), 1.95 (quintd, 1H,
H-7, J=6.9, 2.0 Hz), 5.07 (dd, 1H, H-12cis, J=10.8, 1.5
Hz), 5.25 (dd, 1H, H-12trans, J=17.4, 1.5 Hz), 5.86 (dd,
1H, H-11, J=17.4. 10.8 Hz).
3.6. (1R,2S,5R)-1-Aminomethyl-2-iso-propyl-5-methyl-
cyclohexan-1-ol 12
To a slurry of LiAlH4 (0.70 g, 18.45 mmol) in Et2O (7
mL) was added 4 (0.57 g, 3.15 mmol) in Et2O (3 mL) at
rt and the mixture was stirred for 1.5 h. The mixture
was hydrolyzed with 2N HCl and the acidic layer was
extracted with Et2O (3×10 mL) and rendered alkaline
by treatment with aq. NaOH. The alkaline layer was
extracted with CH2Cl2 (3×15 mL) and dried (MgSO4).
Evaporation of the Et2O extract gave of a 10/11-mix-
ture (0.11 g, 22%, 10/11=76:24 by NMR). Evaporation
of the CH2Cl2 layer afforded 12 as colorless crystals
(0.34 g, 59%). Mp 38–40°C. [h]2D0=−26.2 (c 1.10,
MeOH). Anal. calcd for C11H23NO (185.31): C, 71.30;
H, 12.51; N, 7.56. Found: C, 66.68; H, 11.21; N, 6.13%.
3.4. (1S,2S,5R)-1-(E-2-Phenylethenyl)-2-iso-propyl-5-
methylcyclohexan-1-ol 8a
A mixture of 1 (0.45 g, 2.92 mmol) and CeCl3 (0.76 g,
3.08 mmol) in THF (15 mL) was stirred for 40 min at
rt, then cooled to −10°C and treated with a solution of
PhCHꢀCH-MgBr in THF (0.78 M, 7.5 mL, 5.85
mmol). The mixture was allowed to warm to rt and
stirred at this temperature for 2 h. After hydrolysis (2N
HCl), the mixture was extracted with petroleum ether
(3×15 mL), the organic layer was washed with 5% aq.
NaHCO3, H2O and dried (Na2SO4). After evaporation
of the solvent, the crude product (0.99 g) was chro-
matographed (¥=17 mm, h=520 mm, 45 g silica gel,
petroleum ether/Et2O=10:1) to give a mixed fraction
(0.12 g, 8a:8b=65:35 by NMR) and 8a (0.55 g, 73%).
For the determination of [h]2D0, 8a was further purified
by distillation (70°C, 0.001 Torr) to give a colorless
liquid. [h]2D0=−54.7 (c 1.04, CHCl3). Anal. calcd for
C18H26O (258.40): C, 83.67; H, 10.14. Found: C, 82.44;
H, 9.74%. MS (CI: NH3+) m/z (rel. int.): 258 [(M−H2O)+
1
MS (CI: NH3) m/z (rel. int.): 186 ([M+H]+, 100). H
NMR (CDCl3, 300 K): l 0.77–0.97 (m, 1H, H-6ax), 0.79
(d, 3H, H-8, J=6.9 Hz), 0.85–1.00 (m, 1H, H-4ax), 0.89
(d, 3H, H-10, J=6.6 Hz), 0.96 (d, 3H, H-9, J=6.9 Hz),
1.11 (qd, 1H, H-3ax, J=12.9, 3.4 Hz), 1.27–1.49 (m, 1H,
H-5), 1.33 (ddd, 1H, H-2, J=13.0, 3.5, 2.0 Hz), 1.61
(dq, 1H, H-3eq, J=12.8, 3.3 Hz), 1.72 (dm, 1H, H-4eq,
J=12.7 Hz), 1.85 (dt, 1H, H-6eq, J=13.2, 2.7 Hz), 2.13
(quintd, 1H, H-7, J=6.9, 2.0 Hz), 2.70 (dd, 1H, H-11,
J=13.0, 1.2 Hz), 2.87 (d, 1H, H-11%, J=13.0 Hz).
+
1
’
18] , 15), 241 ([M−OH] , 100). H NMR (CDCl3, 300
K): l 0.88 (d, 6H, H-8, H-9, J=6.9 Hz), 0.89 (d, 3H,
H-10, J=6.4 Hz), 0.80–1.06 (m, 1H, H-4ax), 1.16–1.31
(m, 2H, H-2, H-6ax), 1.39 (s, 1H, OH), 1.51–1.63 (m,
2H, H-3eq, H-6eq), 1.54 (qd, 1H, H-3ax, J=13.2, 3.4
Hz), 1.66–1.89 (m, 1H, H-5), 1.72–1.88 (m, 1H, H-4eq),
3.7. (1R,2S,5R)-1-N,N-Dimethylaminomethyl-2-iso-pro-
pyl-5-methylcyclohexan-1-ol 13
To a mixture of 12 (0.097 g, 0.524 mmol) in MeCN (2
mL) and aq. CH2O (37 wt%, 0.35 mL) at rt was added

S. Pane6 et al. / Tetrahedron: Asymmetry 12 (2001) 1313–1321
1319
NaBH3CN (0.070 g, 1.114 mmol). The mixture was
stirred for 25 min and glacial acetic acid was added to
neutralize the reaction (pH paper). The mixture was
stirred for an additional 2 h at rt, then acidified (2N
HCl), washed with CH2Cl2 (3×10 mL), alkalized (aq.
NaOH), extracted with CH2Cl2 (3×7 mL) and the
organic layer dried (MgSO4). Evaporation of the
organic extract afforded 13 as colorless liquid (0.027 g,
24%). [h]2D0=−41.4 (c 1.14, CHCl3). Anal. calcd for
C13H27NO (213.36): C, 73.18; H, 12.75; N, 6.56. Found:
C, 73.95; H, 12.51; N, 6.15%. MS (EI:) m/z (rel. int.):
213 (M+, 21), 198 (11), 170 (5), 154 (9), 137 (11), 128
(67), 111 (9), 95 (28), 81 (34), 69 (34), 60 (59), 58
84%). [h]2D0=−17.4 (c 1.09, CHCI3). Anal. calcd for
C12H25NO (199.34): C, 72.30; H, 12.64; N, 17.03.
Found: C, 70.38; H, 11.62; N, 5.78%. MS (CI: NH3)
m/z (rel. int.): 399 ([2M+H]+, 28), 200 ([M+H]+, 100).
1H NMR (CDCl3, 300 K): l 0.82 (d, 3H, H-8, J=6.8
Hz), 0.88 (d, 3H, H-10, J=6.4 Hz), 0.90–1.05 (m, 1H,
H-6ax), 0.97 (d, 3H, H-9, J=6.9 Hz), 1.05–1.22 (m, 2H,
H-2, H-3ax), 1.20–1.40 (m, 1H, H-5), 1.53–1.65 (m, 1H,
H-3eq), 1.64–1.75 (m, 2H, H-4eq, H-11), 1.95 (d, 1H,
H-6eq, J=13.0 Hz), 2.21 (sept, 1H, H-7, J=6.8 Hz),
2.85–3.12 (m, 2H, H-12).
3.10. (1R,2S,5R)-1-(2%-N,N-Dimethylaminoethyl)-2-iso-
propyl-5-methylcyclohexan-1-ol 16
1
(C3H8N, 100), 55 (49). H NMR (CDCl3, 300 K): l
0.80 (d, 3H, H-8, J=7.1 Hz), 0.82–0.93 (m, 1H, H-4ax),
0.85–0.97 (m, 1H, H-3ax), 0.92 (d, 3H, H-10, J=6.5
Hz), 0.98 (d, 3H, H-9, J=6.8 Hz), 1.03 (t, 1H, H-6ax,
J=13.6 Hz), 1.25 (s, 1H, OH), 1.30 (dt, 1H, H-2,
J=12.9, 3.1 Hz), 1.37–1.47 (m, 1H, H-5), 1.64 (dq, 1H,
H-3eq, J=13.1, 3.3 Hz), 1.73 (dm, 1H, H-4eq, J=12.9
Hz), 2.10 (quintd, 1H, H-7, J=6.9, 2.5 Hz), 2.19 (d,
1H, H-6eq, J=13.6 Hz), 2.59 (s, 6H, NMe2), 2.69 (d,
1H, Ha-11, J=13.1 Hz), 2.81 (d, 1H, Hb-11, J=13.1
Hz).
To a mixture of 14 (0.16 g, 0.80 mmol, 92% d.e.) in
MeCN (4 mL) and aq. CH2O (37 wt%, 0.50 mL) were
added 0.10 g (1.59 mmol) solid NaBH3CN at rt. The
mixture was stirred for 25 min and glacial acetic acid
was added to neutral reaction of pH paper. The mix-
ture was stirred at rt for an additional 2 h, then
acidified (2N HCl), washed (3×10 mL CH2Cl2) and
rendered alkaline by treatment with aq. NaOH. The
mixture was extracted with CH2Cl2 (3×7 mL) and the
organic layer was dried (MgSO4). Evaporation of the
solvent afforded 16 (0.07 g, 39%, 92% d.e. by NMR) as
colorless liquid. [h]D20=−17.2 (c 1.00, CHCl3). Anal.
calcd for C14H29NO (227.39): C, 73.95; H, 12.85; N,
6.16. Found: C, 73.48; H, 11.13; N, 5.70%. MS (EI:)
3.8. (1R,2S,5R)-1-(2%-Aminoethyl)-2-iso-propyl-5-
methylcyclohexan-1-ol 14
To LiAlH4 (0.30 g, 7.91 mmol) in Et2O (5 mL) was
added 5 (0.40 g, 2.05 mmol, 92% d.e. by NMR) in Et2O
(5 mL) at rt and the mixture was stirred for 1.5 h. The
mixture was hydrolyzed with 2N HCl, the acidic layer
was washed with Et2O (3×10 mL) and rendered alkaline
with aq. NaOH. The alkaline layer was extracted with
CH2Cl2 (3×15 mL) and the extract dried (MgSO4).
Evaporation of the solvent afforded 14 (0.30 g, 73%,
92% d.e. by NMR) as a colorless glass-like solid. [h]2D0=
−12.6 (c 1.01, CHCl3). Anal. calcd for C12H25NO
(199.34): C, 72.30; H, 12.64; N, 7.03; Found: C, 71.10;
H, 12.40; N, 6.88%. MS (EI:) m/z (rel. int.): 199 (M+,
19), 184 (9), 164 (12), 152 (61), 138 (23), 137 (23), 114
(100), 109 (29), 96 (28), 95 (40), 87 (54), 85 (72), 81 (29),
+
’
+
’
m/z (rel. int.): 226 ([M−H] , 49), 210 ([M−OH] , 11),
182 (7), 168 (7), 154 (6), 140 (26), 126 (13), 109 (17), 101
(57), 95 (20), 81 (20), 74 (63), 69 (31), 58 (C3H8N, 100),
1
57 (46), 55 (56). H NMR (CDCl3, 300 K): l 0.70–0.90
(m, 1H, H-4ax), 0.79 (t, 1H, H-6ax, J=13.0 Hz), 0.85–
0.98 (m, 1H, H-2), 0.87 (d, 3H, H-10, J=6.1 Hz), 0.90
(d, 3H, H-9, J=6.9 Hz), 0.94 (d, 3H, H-8, J=6.9 Hz),
1.05–1.20 (m, 1H, Ha-11), 1.39–1.59 (m, 2H, H-3eq,
H-3ax), 1.69–1.80 (m, 2H, H-4eq, H-6eq), 1.70–1.88 (m,
1H, H-5), 2.08–2.23 (m, 1H, Hb-11), 2.10–2.20 (m, 1H,
H-7), 2.13–2.29 (m, 1H, Ha-12), 2.25 (s, 6H, NMe2),
2.73–2.90 (m, 1H, Hb-12).
3.11. (1S,2S,5R)-1-Epoxyethyl-2-iso-propyl-5-methylcy-
clohexan-1-ol 17
1
69 (33), 55 (42). H NMR (CDCl3, 300 K): l 0.72–0.97
(m, 1H, H-4ax), 0.77–0.94 (m, 1H, H-6ax), 0.85–1.02 (m,
1H, H-2), 0.87 (d, 3H, H-10, J=6.1 Hz), 0.89 (d, 3H,
H-9, J=7.1 Hz), 0.92 (d, 3H, H-8, J=6.9 Hz), 1.32–
1.47 (m, 1H, Ha-11), 1.37–1.55 (m, 2H, H-3eq, H-3ax),
1.67–1.82 (m, 1H, H-4eq), 1.67–1.88 (m, 1H, H-5),
1.68–1.80 (m, 1H, H-6eq), 1.84–1.99 (m, 1H, Hb-11),
2.16 (septd, 1H, H-7, J=6.9, 1.9 Hz), 2.90–3.00 (m, 2H,
H-12).
To a mixture of 7 (0.930 g, 5.10 mmol) and VO(acac)2
(0.027 g, 0.10 mmol) in CH2Cl2 (40 mL) at rt was
added a solution of TBHP in iso-octane (3 M, 4 mL,
12.00 mmol). The mixture was stirred for 27 h at rt,
washed with a solution of NaCl (1 g) and NaOH (3 g)
in H2O (10 mL) then further washed with H2O, and the
organic layer dried (MgSO4). After evaporation of the
solvent, the crude product (0.980 g) was chro-
matographed (¥=24 mm, h=520 mm, 87 g silica gel,
petroleum ether/Et2O=2:1) to give 17 as colorless crys-
tals (0.820 g, 81%) and its diastereoisomer (0.008 g,
<1%). For determination of [h]2D0, 17 was additionally
purified by distillation (70°C, 0.001 Torr). Mp 66–67°C.
[h]2D0=−4.8 (c 0.99, CHCl3). Anal. calcd for C12H22O2
(198.30): C, 72.68; H, 11.18. Found: C, 72.55; H,
11.09%. MS (CI: NH3) m/z (rel. int.): 216 ([M+18]+,
3.9. (1S,2S,5R)-1-(2%-Aminoethyl)-2-iso-propyl-5-
methylcyclohexan-1-ol 15
To a suspension of LiAlH4 (0.28 g, 7.38 mmol) in Et2O
(4 mL) was added a solution of 6 (0.19 g, 0.97 mmol) in
Et2O (4 mL) at rt and the mixture was stirred for 2 h.
It was hydrolyzed with 2N HCl, the acidic layer was
washed (3×10 mL Et2O) and alkalized with aq. NaOH.
The alkaline layer was extracted (3×15 mL CH2Cl2) and
the organic extract was dried (MgSO4). Evaporation of
the solvent afforded 15 as a colorless liquid (0.16 g,
1
100), 199 ([M+H]+, 19), 181 (31), 163 (28), 137 (9). H
NMR (CDCl3, 300 K): l=0.87 (d, 3H, H-8, J=6.9
Hz), 0.89 (d, 3H, H-10, J=6.1 Hz), 0.91 (d, 3H, H-9,

1320
S. Pane6 et al. / Tetrahedron: Asymmetry 12 (2001) 1313–1321
3
−3
,
J=6.9 Hz), 1.10 (d, 1H, OH, J=1.5 Hz), 1.13 (dd, 1H,
H-6ax, J=13.3, 12.1 Hz), 1.21–1.32 (m, 1H, H-2), 1.43–
1.60 (m, 2H, H-3eq, H-3ax), 1.67 (ddd, 1H, H-6eq, J=
13.5, 3.3, 2.5 Hz), 1.72–1.87 (m, 2H, H-4eq, H-5), 2.01
(septd, 1H, H-7, J=6.9, 2.1 Hz), 2.76–2.84 (m, 2H,
H-11, Ha-12), 2.95 (dd, 1H, Hb-12, J=4.8, 3.3 Hz).
113.262(2)°, V=819.10(9) A , Z=2, Dc=1.112 Mg m ,
v(Mo Ka)=0.0703 mm−1, F(000)=300, T=160(1) K,
colorless prism, dimensions: 0.13×0.25×0.28 mm, Non-
ius KappaCCD diffractometer, Mo Ka radiation, u=
,
0.71073 A, 2qmax=50°, 10705 measured reflections of
which 2782 were unique. The intensities were corrected
for Lorentz and polarization effects, but not for absorp-
tion. Structure solution by direct methods using
SHELXS-9720 and refined on F by full-matrix least-
squares methods using teXsan,21 non-H atoms refined
anisotropically, hydroxy H-atom refined isotropically,
all other H-atoms fixed in calculated positions. The
refinement of 185 parameters using 2460 observed
reflections with I>2|(I) gave R=0.060, wR=0.071, S=
3.12. (1S,2S,5R,1%R,2%S)-1-(2%-Phenylepoxyethyl)-2-iso-
propyl-5-methylcyclohexan-1-ol 18
To a mixture of 8a (0.420 g, 1.63 mmol) and VO(acac)2
(0.011 g, 0.04 mmol) in CH2Cl2 (17 mL) were added at
rt a solution of TBHP in iso-octane (3 M, 1.3 mL, 3.90
mmol). The mixture was stirred for 47 h at rt, washed
with a solution of NaCl (1 g) and NaOH (3 g) in H2O
(10 mL), then with H2O, and the organic layer dried
(MgSO4). After evaporation of the solvent, the crude
product (0.440 g, 82% d.e. by NMR) was chro-
matographed (¥=13 mm, h=430 mm, 26 g silica gel,
petroleum ether/Et2O=2:1) to give 18 (0.340 g, 76%) as
a single diastereoisomer (colorless crystals). For deter-
mination of [h]2D0, 18 was further purified by distillation
(70°C, 0.001 Torr). Mp 109–112°C. [h]2D0=−31.2 (c 1.06,
CHCl3). Anal. calcd for C18H26O2 (274.40): C, 78.79; H,
9.55. Found: C, 78.49; H, 9.62%. MS (CI: NH3) m/z
3.300, weights: [|2(Fo)+(0.0075Fo)2]−1, max and min
Dz=0.18; −0.17 e A . Crystallographic data (excluding
−3
,
structure factors) for the structures of 18 have been
deposited with the Cambridge Crystallographic Data
Center as supplementary publication No. CCDC-
161028. Copies of the data can be obtained free of
charge on application to the CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK (fax: +44-(0)1223-336033;
email: deposit@ccdc.cam.ac.uk).
+
+
1
’
(rel. int.): 292 ([M+18] , 6), 257 ([M−OH] , 100). H
NMR (CDCl3, 300 K): l 0.78–0.98 (m, 1H, H-4ax), 0.84
(d, 3H, H-9, J=6.9 Hz), 0.92 (d, 3H, H-10, J=6.4 Hz),
0.97 (d, 3H, H-8, J=6.8 Hz), 1.16 (dd, 1H, H-6ax,
J=13.9, 13.0 Hz), 1.21–1.30 (m, 1H, H-2), 1.31 (d, 1H,
OH, J=1.2 Hz), 1.50–1.63 (m, 2H, H-3eq, H-3ax), 1.71–
1.88 (m, 3H, H-4eq, H-5, H-6eq), 1.98 (quintd, 1H, H-7,
J=6.9, 2.2 Hz), 2.79 (d, 1H, H-12, J=2.2 Hz), 4.06 (d,
1H, H-11, J=2.2 Hz), 7.25–7.41 (m, 5H, Ph).
Acknowledgements
Support of this work by the Bulgarian Fund for Scien-
tific Research (project X-711) is gratefully acknowl-
edged. The authors would like to thank Mr. N. Bild,
Institute of Organic Chemistry, University of Zurich,
for recording the mass spectra and for very helpful hints
concerning the mass spectrometry.
3.13. (1S,2S,5R)-1-(2%-N,N-Diethylamino-1%-hydroxy-
ethyl)-2-iso-propyl-5-methylcyclohexan-1-ol 19
References
To a mixture of 17 (0.72 g, 3.63 mmol) and LiClO4 (1.55
g, 14.57 mmol) in acetonitrile (3 mL) was added Et2NH
(0.57 g, 7.79 mmol). The mixture was heated at 60°C for
4 h and the solvent was evaporated. After the residue
was acidified with 2N HCl, the acidic phase was washed
with CH2Cl2 (3×10 mL), rendered alkaline by treatment
with aq. NaOH, extracted with CH2Cl2 (3×10 mL) and
the organic layer was dried (Na2SO4). Evaporation of
the solvent afforded 19 as yellowish highly hygroscopic
crystals (0.19 g, 19%). [h]2D0=0.0 (c 1.03, CHCl3). MS
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1
(CI: NH3) m/z (rel. int.): 272 ([M+H]+, 100). H NMR
(CDCl3, 300 K): l 0.77–0.90 (m, 1H, H-4ax), 0.88 (d,
3H, H-10, J=6.6 Hz), 0.91 (d, 6H, H-8, H-9, J=7.1
Hz), 1.05 (t, 6H, H-14, J=7.2 Hz), 1.02–1.17 (m, 1H,
H-6ax), 1.30–1.50 (m, 1H, H-2), 1.35–1.55 (m, 2H, H-3eq,
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H-4eq), 1.70–1.87 (m, 1H, H-5), 2.26 (quintd, 1H, H-7,
J=6.9, 1.5 Hz), 2.52 (dd, 1H, Ha-12, J=12.5, 7.8 Hz),
2.61 (qd, 4H, H-13, J=7.2, 0.9 Hz), 2.70 (dd, 1H,
Hb-12, J=12.7, 6.6 Hz), 3.91 (t, 1H, H-11, J=7.2 Hz).
3.14. X-Ray crystallographic details for compound 18
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,
a=11.7748(6), b=5.8362(4), c=12.9741(9) A, i=

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