Synthesis of chiral norbornane derivatives as γ-amino alcohol catalysts: the effect of the functional group positions on the chirality transfer

Article abstract of DOI:10.1016/j.tetasy.2006.06.029

Starting from (1S,4R) chiral ketone (+)-6, we developed a synthetic route to the synthesis of new chiral γ-amino alcohols (+)- and (-)-syn-2-amino-7-hydroxy norbornane derivatives with excellent yields and enantiomeric excesses (up to 99%). These compounds were tested as chiral catalysts in the enantioselective addition of diethylzinc to benzaldehyde presenting moderate results. The results obtained, compared with others previously reported, showed that the relative disposition of the amino and hydroxyl groups on C(2) and C(7) positions, play an important role in the catalytic activity.

Full text of DOI:10.1016/j.tetasy.2006.06.029

Tetrahedron: Asymmetry 17 (2006) 1817–1823
Synthesis of chiral norbornane derivatives as c-amino
alcohol catalysts: the effect of the functional group positions
on the chirality transfer
*
´
Jose E. D. Martins, Clarissa M. Mehlecke, Muriell Gamba and Valentim E. U. Costa
ˆ
´
Departamento de Quı´mica Organica, Instituto de Quımica, Universidade Federal do Rio Grande do Sul, Av. Bento
Gonc¸alves, 9500, 91501-970 Porto Alegre RS, Brazil
Received 29 April 2006; revised 13 June 2006; accepted 16 June 2006
Available online 25 July 2006
Abstract—Starting from (1S,4R) chiral ketone (+)-6, we developed a synthetic route to the synthesis of new chiral c-amino alcohols (+)-
and (ꢀ)-syn-2-amino-7-hydroxy norbornane derivatives with excellent yields and enantiomeric excesses (up to 99%). These compounds
were tested as chiral catalysts in the enantioselective addition of diethylzinc to benzaldehyde presenting moderate results. The results
obtained, compared with others previously reported, showed that the relative disposition of the amino and hydroxyl groups on C(2)
and C(7) positions, play an important role in the catalytic activity.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
NH2
7
Chiral amino alcohols are very important compounds used
4
5
3
in organic synthesis with several applications, such as chi-
ral auxiliaries,1 synthetic intermediates,2 and chiral legends
for asymmetric synthesis.3 They also posses high biological
activity, which is used in HIV protease inhibitors.4
OH
6
1
2
(+)-1
Me
N
NHAc
Nucleophilic addition of organometallic reagents to car-
bonyl compounds is a very important operation in organic
synthesis, and its asymmetric version is particularly useful.5
Since the initial work of Oguni and Omi with (S)-leucinol,6
followed by Noyori’s work with DAIB,7 the asymmetric
addition of diethylzinc to aldehydes catalyzed by chiral ami-
no alcohols has attracted considerable attention. The reac-
tion is one of the most reliable reactions for testing the
effectiveness of newly developed chiral ligands.5,8 c-Amino
alcohols have been studied less than b-amino alcohols but
have demonstrated satisfactory results.9 In a recent work,
we described the synthesis of new enantiopure c-amino
alcohols syn-2-hydroxy-7-amino norbornane derivatives
with high yields and enantiomeric excesses (Fig. 1).9c
Me
OH
Et
N
Me
N
OH
(+)-2
Et
Et
(+)-5
OH
OH
(+)-3
(+)-4
Figure 1. Synthesis of enantiopure c-amino alcohols.
presenting satisfactory results when the compound (+)-3
was used (91% ee).9c
Inspired by these results, we decided to synthesize a new
enantiopure norbornane derivative namely c-amino alco-
hol 2-amino-7-hydroxy derivative (ꢀ)-12, which presents
the functional groups in opposite positions when compared
with compound (+)-1. Its evaluation as a chiral inductor in
the enantioselective addition of diethylzinc to benzalde-
hyde is also described.
Their evaluation as chiral ligands in the enantioselective
addition of diethylzinc to benzaldehyde was also described,
*
Corresponding author. Tel.: +55 051 33166300; fax: +55 051
33167304; e-mail: valentim@iq.ufrgs.br
0957-4166/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.06.029

1818
J. E. D. Martins et al. / Tetrahedron: Asymmetry 17 (2006) 1817–1823
2. Results and discussion
ing the trifluoroacetamide (ꢀ)-9.11 Treatment of (ꢀ)-9 with
p-toluenesulfonic acid and acetone, at reflux, provided
ketone (+)-10. syn-Alcohol (ꢀ)-11 was obtained by reduc-
tion of (+)-10 with L-Selectride and finally, the 1,3-syn-ami-
no alcohol (ꢀ)-12 obtained through the treatment of (ꢀ)-11
with potassium carbonate in methanol.12 The (+)-12 enan-
tiomer was synthesized from (ꢀ)-6 by the same methodology
with similar yields and enantiomeric excesses.
Herein, compound (ꢀ)-12 was obtained following Scheme 1.
The oxime (ꢀ)-7 was obtained by the treatment of (1S,4R)
chiral ketone (+)-6 (up to 99% ee)9c,10c with hydroxylamine
chloridrate and sodium acetate. The reduction of (ꢀ)-7 with
NaBH4/NiCl2Æ6H2O, followed by treatment with formic
acid, provided amine (ꢀ)-8.9c Attempts at removing the ketal
group of (ꢀ)-8 failed at room temperature. When the reac-
tion was performed at reflux, decomposition occurred. To
overcome this problem, we protected the amino group by
the treatment of (ꢀ)-8 with trifluoroacetic anhydride provid-
After the synthesis of chiral c-amino alcohol (ꢀ)-12, we
decided to synthesize its derivative (ꢀ)-16, which is an iso-
mer of (+)-39c (Fig. 1), together with other derivatives to
OMe
OMe
No product
OMe
MeO
MeO
MeO
iii
i
ii
NH2
iv
92%
90%
Decomposition
-8
(-)
(+)-6
(-)-7
O
NOH
O
OH
OMe
MeO
O
O
O
vi
vii
v
CF3
NH
CF3
CF3
NH
NH
95%
85%
85%
10
(+)-
9
(-)-11
(-)-
7
OH
4
3
5
viii
NH2
6
85%
1
2
(-)-12
OH
OMe
MeO
7
4
1
NH2
O
6
2
5
3
12
(+)-
6
(-)-
Scheme 1. Reagents and conditions: (i) NH2OHÆHCl, NaOAc, CH3OH, 15 h, rt; (ii) (a) NaBH4/NiCl2Æ6H2O, CH3OH, 6 h, ꢀ78 ꢁC, (b) NaBH4, H2CO2;
(iii) p-toluenesulfonic acid, acetone/H2O, 24 h, rt; (iv) p-toluenesulfonic acid, acetone/H2O, reflux; (v) (CF3CO)2O, Et3N, CH2Cl2, 15 h, rt; (vi)
p-toluenesulfonic acid, acetone, reflux, 2 h; (vii) L-Selectride, THF, ꢀ78 ꢁC, 4 h; (viii) K2CO3, CH3OH/H2O, 2 h, reflux.
OH
OAc
OH
OAc
OH
Ac
i
ii
i
iv
65%
NEt
NH2
NHAc
NHEt
87%
93%
96%
N
(+)-13
(+)-15
(-)-12
(-)-14
(-)-18
v
90%
OH
ii
92%
OH
iii
60%
OH
Et
N
NHAc
Me
N
(+)-19
Et
Me
(-)- 16
(-)-17
Scheme 2. Reagents and conditions: (i) (CH3CO)2O, reflux, 3 h; (ii) LiAlH4, THF, reflux, 4 h; (iii) H2CO2, H2CO, reflux, 7 days; (iv) 1,5-diiodopentane,
K2CO3, CH3OH/H2O, reflux, 1 h; (v) HCl 20%, THF, 15 h.

J. E. D. Martins et al. / Tetrahedron: Asymmetry 17 (2006) 1817–1823
1819
study their abilities as chiral inductors (Scheme 2). The
treatment of (ꢀ)-12 with acetic anhydride provided com-
pound (+)-13. Compound (ꢀ)-14 was obtained by reduction
of (+)-13 with LiAlH4. The acetylation reaction of (ꢀ)-14,
furnished compound (+)-15. Finally the N,N-diethylated
amino alcohol (ꢀ)-16 was obtained by LiAlH4 reduction.
(77% ee) obtained with an isoborneol c-amino alcohol pip-
eridino derivative.9d
2.2. Mechanism and facial selectivity
Figure 2 shows the transition state proposed for c-amino
alcohols,9c,d,15 for the asymmetric reaction. Molecular
orbital and density functional calculations indicate that
the anti coordination of benzaldehyde (with respect to the
chiral ligand) and a 6/4/4 tricyclic transition state are most
favorable.15
On the other hand, treatment of (ꢀ)-12 with formic acid
and formaldehyde9c provided compound (ꢀ)-17. The pip-
eridino derivative (ꢀ)-18 was obtained by treatment of
(ꢀ)-12 with 1,5-diiodopentane and potassium carbonate.13
The hydrolysis of compound (+)-13 with 20% HCl pro-
vided hydroxy acetamide (+)-19.
Analysis of Figure 2 shows that, in the transition states
anti-(2R,7S)- and anti-(2S,7R)-, the ethyl group migration
occurs in the si-face and re-face, respectively, of benzalde-
hyde. The (2R,7S)-amino alcohol predominantly forms the
(S)-1-phenylpropanol while the (2S,7R)-amino alcohol pre-
dominantly forms the (R)-1-phenylpropanol. In other
words, the configuration of the 1-phenylpropanol corre-
lated with the configuration of the hydroxyl-bearing stereo-
center (C–O), which is in agreement with previous
observations.7d,9c,14
2.1. Enantioselective addition of diethylzinc to benzaldehyde
Using chiral compounds 16–19 as catalysts, we have
performed the enantioselective addition of diethylzinc to
benzaldehyde. The addition reactions were carried out in
toluene at room temperature in the presence of 20 or
40 mol % of these chiral ligands (Table 1).
The catalysts afforded 1-phenylpropanol in high yields
(83–98%) and moderate enantiomeric excesses (30–78%).
The absolute configuration of the major enantiomer of
1-phenylpropanol correlates with the configuration of
the hydroxyl-bearing stereocenter (C–O). This was already
observed by Vilar et al.14 who reported that the stereo-
chemical outcome is mainly controlled by the hydroxyl
group with regards to its relative position in the norborn-
ane skeleton.
It is well known that the stereo chemical outcome is mainly
controlled by the hydroxyl group,7d,9c,14 therefore, the C–O
stereocenter position is a fundamental parameter in the
1-phenylpropanol enantiomeric excess. Figure 3 compares
the results of the enantioselective addition of diethylzinc
to benzaldehyde catalyzed by (+)-19c and (ꢀ)-12
derivatives.
The exchange in the C2 and C7 positions of the amino and
hydroxyl functional groups leads to a significant decrease
in the enantiomeric excess of 1-phenylpropanol. The results
obtained show that the preferential position to the hydr-
oxyl group is attached to C-2, which provides a higher
enantioselectivity.
The reaction with c-amino alcohol catalysts seemed to be
very sensitive to steric hindrance, as already observed by
Aoyama.9d The best results were obtained with the enantio-
meric pairs of the N,N-diethylated compounds, (+)- and
(ꢀ)-16, and the piperidino derivatives (+)- and (ꢀ)-18.
An increase in the amount of catalyst amount did not pro-
vide a significant change in the enantiomeric excess of the
1-phenylpropanol.
3. Conclusions
As shown in Table 1, compound 16 induced 68% enantio-
meric excess in the 1-phenylpropanol in spite of the 91% ee
obtained by its isomer (+)-3.9c However, the presence of a
piperidinic ring caused a slight increase in the enantioselec-
tivity, probably due to steric effects (Table 1, entries 6–8).
Aoyama et al. observed the same enantiomeric excess
In this work, we have developed a synthetic route to the
synthesis of new chiral c-amino alcohols syn-2-amino-7-hy-
droxy norbornane derivatives with excellent yields and
enantiomeric excesses (up to 99%). The compounds were
evaluated as chiral inductors in the enantioselective addi-
tion of diethylzinc to benzaldehyde presenting moderate
Table 1. Enantioselective addition of diethylzinc to benzaldehyde catalyzed by 1,3-amino alcohols derived from (ꢀ)-12
Entry
Catalyst
Mol (%)
Timea (h)
Yieldb (%)
eec (%)
Config.c
1
2
3
4
5
6
7
8
9
(ꢀ)-16
(+)-16
(ꢀ)-16
(ꢀ)-17
(ꢀ)-17
(ꢀ)-18
(ꢀ)-18
(+)-18
(+)-19
20
20
40
20
40
20
40
20
20
15
15
15
18
18
19
20
20
19
84
83
98
85
89
92
93
90
95
68
68
67
44
40
78
76
77
30
S
R
S
S
S
S
S
R
S
a The reaction was followed by GC.
b Determined by GC.
c Determined by chiral GC (Supelco b-Dex 120 30 m) 100 ꢁC isothermal. 1-Phenylpropanol: tR (R) = 30.48 min, tR (S) = 31.99 min.

1820
J. E. D. Martins et al. / Tetrahedron: Asymmetry 17 (2006) 1817–1823
(2S,7R)-diethylzinc/ benzaldehyde complex
(2R,7S)-diethylzinc/ benzaldehyde complex
Me
Et
Et
Ph
Zn
Et
Me
Zn
Et
O
S
H
Ph
R
O
R
O
O
H
S
H
Zn
Zn
H
R
N
R
N
S
R
R
R
anti-(2S,7R)-
anti-(2R,7S)-
Ph
Et
Et
Et
Zn
S
O
Zn
Et
H
Ph
Et
O
R
O
O
Et
S
Zn
Zn
R
H
R
R
N
N
S
R
R
R
OH
OH
Ph
(S)-1-phenylpropanol
Ph
(R)-1-phenylpropanol
Figure 2. 6/4/4/Transition state and facial selectivity of the diethylzinc addition to benzaldehyde to c-amino alcohols.
results. The results obtained clearly show that the absolute
configuration of the 1-phenylpropanol correlates with the
configuration of the hydroxyl-bearing stereocenter of the
ligand, as observed in a previous work.7d,9c,14 We also ob-
served that the exchange in the C2 and C7 positions of the
amino and hydroxyl functional groups of (+)-19c deriva-
tives, leading to (ꢀ)-12 derivatives, led to a significant
decrease in enantiomeric excess of 1-phenylpropanol. The
presence of a piperidinic ring in the c-amino alcohol struc-
ture (compound 18) provided an increase in the enantio-
selectivity, probably, due to steric effects.
DB1 (15 m · 0.53 mm) and ee values were determinated by
a Supelco b-Dex 120 chiral GC column (30 m · 0.25 mm).
Optical rotations were measured in a Perkin–Elmer 341
polarimeter with a 0.1 dm cell at a temperature of 20 ꢁC.
High resolution mass spectrometric analysis was obtained
with a Jeol AX500 (EB), EI (70 eV) or NICI with isobutene
(200 eV) mass spectrometer. Lipase AY Amano 30 (Can-
dida rugosa), Lot. LAYY0405102S was kindly provided
by Amano Enzyme USA Co. Ltd.
Lipase catalyzed transesterification was the source of chi-
rality of the compound (+)-6 precursors providing excel-
lent enantiomeric excesses (up to 99%).9c,10c,16
These chiral ligands have very rigid molecular structures
and a favorable stereochemistry for metal coordination.
Therefore, we believe that compounds (+)- and (ꢀ)-12
are promising chiral ligand precursors, which may be used
in other types of asymmetric transformations.
The absolute configurations of all compounds synthesized
were proposed based on the previous determination of the
absolute configuration of ketone (+)-6 by Lightner et al.10a
4.2. (ꢀ)-7,7-Dimethoxy-2-oximo-norbornane (ꢀ)-7
4. Experimental
4.1. General
To a stirred solution of (+)-6 (1.7 g, 10 mmol) in methanol
(50 mL) were added NH2OHÆHCl (1.4 g, 20 mmol) and
NaOAc (1.7 g, 20.7 mmol). The resulting mixture was stir-
red for 15 h at room temperature and then the methanol
was evaporated. The resulting material was neutralized
with a 10% NaHCO3 solution and extracted with chloro-
form. The organic layer was dried over anhydrous MgSO4,
filtered, and evaporated providing 1.66 g (90%) of a light
yellow solid. All spectral data confirm the structure of
the chiral oxime (ꢀ)-7, however the melting point does
Melting points were measured on a BUCHI B-545 melting
point apparatus. NMR spectra were measured with a
VARIAN VXR200 (B0 = 4.7 T) and YH-300 (B0 = 7.05 T).
Chemical shifts are expressed as d (ppm) relative to TMS
as an internal standard and the J values are given in hertz.
The products were analyzed by GC on a Shimadzu GC-17A
gas chromatograph, equipped with a FID detector. Column

J. E. D. Martins et al. / Tetrahedron: Asymmetry 17 (2006) 1817–1823
1821
NH2
(CH2), 26.1 (CH2), 38.0 (CH), 38.9 (CH2), 44.8 (CH),
50.0 (CH), 50.4 (CH), 54.6 (CH), 114.2 (C). FTIR (CHCl3):
c (cmꢀ1) 3385 (NH). The HRMS was not obtained because
of rapid decomposition of the amine (ꢀ)-8, therefore the
elemental composition was confirmed by data from its
substrate (ꢀ)-7 and its product (ꢀ)-9.
OH
7
1
7
4
4
5
3
5
3
OH
NH2
6
1
6
2
2
( )-12
_
(+)-1
4.4. (ꢀ)-7,7-Dimethoxy-2-exo-trifluoroacetamide-norborn-
ane (ꢀ)-9
NHAc
OH
To a cooled solution (0 ꢁC) of (ꢀ)-8 (1 g, 5.8 mmol) in
CH2Cl2 (30 mL) were added 2 mL of trifluoroacetic an-
hydride (14.5 mmol) and 2 mL of Et3N (14.5 mmol). The
mixture was stirred for 15 h at room temperature and then
washed with 20 mL of water. The organic layer was
separated and dried over anhydrous MgSO4, filtered, and
evaporated providing 1.32 g (85%) of a yellow oil.
30% ee
63% ee
OH
NHAc
2
13
Et
N
OH
Et
20
1
½aꢁD ¼ ꢀ7:4 (c 1.2, AcOEt). H NMR (200 MHz, CDCl3):
d (ppm) 4.10 (m, 1H), 3.30 (s, 3H), 3.29 (s, 3H), 2.5 (s, 1H),
2.19 (s, 1H), 2.01 (s, 2H), 1.85 (m, 2H), 1.33 (m, 2H). 13C
NMR (75 MHz, CDCl3): d (ppm) 24.0 (CH2), 26.2
(CH2), 37.2 (CH2), 37.6 (CH), 43.0 (CH), 50.1 (CH), 50.7
(CH3), 50.8 (CH3), 115.9 (CF3) (q, JC–F = 287.3 Hz),
68%ee
91% ee
Et
OH
N
Et
3
16
Me
N
OH
155.6 (C) (q, JC–F = 36.4 Hz). FTIR (CHCl3): c (cmꢀ1
)
Me
3302 (NH), 1645 (C@O). HRMS found: m/z 267.1099;
Me
N
44% ee
calcd for C11H16NO3F3 [M+]: 267.1082.
85% ee
OH
Me
17
5
4.5. (+)-2-exo-Trifluoroacetamide-7-one-norbornane (+)-10
Figure 3. Results of the asymmetric addition of diethylzinc to benzalde-
hyde catalyzed by (+)-1 and (ꢀ)-12 derivatives.
To a solution of (ꢀ)-9 (1.5 g, 5.6 mmol) in acetone (30 mL),
p-toluenesulfonic acid was added (3.2 g, 16.8 mmol) and re-
fluxed for 2 h. The mixture was evaporated and the crude
product neutralized with a 10% NaHCO3 solution. The mix-
ture was extracted with chloroform, dried over anhydrous
MgSO4, filtered, and evaporated providing 1.5 g of a brown
oil. The crude product was purified by flash chromatography
not agree with that obtained by Marchand17 even after sev-
eral purifications. Mp: 109–112 ꢁC (lit.15 89–92).
20
½aꢁD ¼ ꢀ35:5 (c 1.07, AcOEt). 1H NMR (200 MHz,
CDCl3): d (ppm) 1.45 (m, 2H), 1.95 (m, 2H), 2.41 (s,
1H), 2.65 (m, 2H), 2.85 (s, 1H), 3.25 (s, 3H), 3.28 (s, 3H).
13C NMR (50 MHz, CDCl3): d (ppm) 25.1 (CH2), 26.7
(CH2), 33.5 (CH2), 38.4 (CH), 45.3 (CH), 50.8 (CH3),
51.6 (CH3). FTIR (CHCl3): c (cmꢀ1) 3269 (OH), 1693
(C@N). HRMS found: m/z 185.1055; calcd for
C9H15NO3 [M+]: 185.1082.
(silica, cyclohexane/AcOEt 4:1) yielding 1.1 g (95%) of a
20
brown solid. Mp: 127–129 ꢁC. ½aꢁD ¼ þ8:5 (c 2.0, AcOEt).
1H NMR (200 MHz, CDCl3): d (ppm) 4.14 (m, 1H), 2.00
(m, 8H). 13C NMR (75 MHz, CDCl3): d (ppm) 20.7 (CH2),
22.6 (CH2), 33.9 (CH2), 37.9 (CH), 43.6 (CH), 48.3 (CH),
115.6 (CF3) (q, JC–F = 287.3 Hz), 156.8 (C) (q, JC–F
=
37.5 Hz) 215.2 (C). FTIR (CHCl3): c (cmꢀ1) 3312 (NH),
1770 (C@O), 1706 (C@O). HRMS found: m/z 221.0653;
calcd for C9H10NO2F3 [M+]: 221.0664.
4.3. (ꢀ)-7,7-Dimethoxy-2-exo-amino-norbornane (ꢀ)-8
To a stirred solution of (ꢀ)-7, (1.8 g, 9.7 mmol) in metha-
nol (50 mL) was added NiCl2Æ6HCl (3.3 g, 19 mmol). The
mixture was stirred until all the nickel chloride had
dissolved after which it was cooled to ꢀ78 ꢁC. NaBH4
(3.3 g, 87 mmol) was added slowly and the mixture was
stirred for 6 h in this temperature. After 6 h, formic acid
was added (60 mL) followed by another amount of NaBH4
(3.7 g, 97 mmol) very slowly. The mixture was stirred over
night at room temperature and then evaporated. The crude
material was neutralized with a 10% NaOH solution and
extracted with Et2O. The organic layer was dried over
4.6. (ꢀ)-2-exo-Trifluoroacetamide-7-syn-hydroxy-norborn-
ane (ꢀ)-11
In a 100 mL three-necked round-bottomed flask under
argon, a solution of compound (+)-10 (1 g, 4.5 mmol) in
dry THF (25 mL) was cooled to ꢀ78 ꢁC and then 9 mL
of a 1 M solution of L-Selectride slowly added. The mix-
ture was stirred for 4 h at this temperature and then
quenched with 1 mL of a 10% HCl solution. The mixture
is extracted with Et2O, dried over anhydrous MgSO4,
filtered, and evaporated providing 1.3 g of an orange oil.
The crude product was purified by flash chromatography
anhydrous MgSO4, filtered, and evaporated providing
20
1.53 g (92%) of a yellow oil. ½aꢁD ¼ ꢀ18:1 (c 1.05, AcOEt).
(silica, cyclohexane/AcOEt 3:1) yielding 0.85 g (85%) of a
1H NMR (300 MHz, CDCl3): d (ppm) 3.28 (s, 3H), 3.26
(s, 4H), 2.13 (s, 1H), 1.92 (s, 1H), 1.785 (m, 2H), 1.25
(m, 4H). 13C NMR (75 MHz, CDCl3): d (ppm) 24.8
20
light yellow oil. ½aꢁD ¼ ꢀ3:6 (c 1.1, AcOEt). 1H NMR
(200 MHz, CDCl3): d (ppm) 4.17 (s, 1H), 4.12 (s, 1H),
2.19 (s, 1H), 2.08 (s, 1H), 1.95 (m, 2H), 1.65 (m, 2H),

1822
J. E. D. Martins et al. / Tetrahedron: Asymmetry 17 (2006) 1817–1823
1.25 (m, 2H). 13C NMR (75 MHz, CDCl3): d (ppm) 23.3
(CH2), 25.1 (CH2), 36.9 (CH2), 40.8 (CH), 45.3 (CH),
52.3 (CH), 80.1 (CH), 116.0 (CF3) (q, JC–F = 287.5 Hz),
4.10. (+)-2-exo-Acetylethylamino-7-syn-acetate-norbornane
(+)-15
155.6 (C) (q, JC–F = 36.6 Hz). FTIR (CHCl3): c (cmꢀ1
)
Compound (ꢀ)-14 (0.35 g, 2.2 mmol) was dissolved in ace-
tic anhydride (15 mL) and refluxed for 4 h. The mixture
was neutralized with a 10% NaHCO3 solution and ex-
tracted with chloroform, dried over anhydrous MgSO4, fil-
3308 (OH), 1641 (C@O). HRMS found: m/z 223.0910;
calcd for C9H13NO2F3 [M+]: 223.1957.
4.7. (ꢀ)-2-exo-Amino-7-syn-hydroxy-norbornane (ꢀ)-12
tered, and evaporated to provide 0.51 g (96%) of a yellow
20
oil. ½aꢁD ¼ þ2:0 (c 1.1, AcOEt). 1H NMR (200 MHz,
To a stirred solution of (ꢀ)-11 (0.7 g, 3.1 mmol) in methanol
(20 mL) were added 2.1 g of K2CO3 (15.5 mmol) dissolved
in 5 mL of H2O. The solution was refluxed for 2 h and then
evaporated. The crude mixture was treated with 2 mL of
H2O and extracted with chloroform, dried over anhydrous
MgSO4, filtered, and evaporated to provide 338 g (85%) of
CDCl3): d (ppm) 4.67 (s, 1H), 4.09 (m, 1H), 3.42 (q, 2H,
J = 7.0 Hz), 2.22 (s, 1H), 2.15 (s, 3H), 2.14 (s, 1H), 2.03
(s, 3H), 1.98 (s, 2H), 1.21 (m, 2H), 1.07 (m, 2H). (The
CH3 from N-ethyl group appears only in 13C.) 13C NMR
(50 MHz, CDCl3): d (ppm) 15.7 (CH3), 21.1 (CH3), 22.3
(CH3), 24.2 (CH2), 25.3 (CH2), 35.1 (CH2), 38.3 (CH),
38.9 (CH2), 43.0 (CH), 57.5 (CH), 80.4 (CH), 170.1 (C),
170.7 (C). FTIR (CHCl3): c (cmꢀ1) 1733 (C@O), 1625
(C@O). HRMS found: m/z 239.1537; calcd for
C13H21NO3 [M+]: 239.1521.
20
1
a light yellow oil. ½aꢁD ¼ ꢀ5:0 (c 1.2, AcOEt). H NMR
(200 MHz, CDCl3): d (ppm) 3.97 (s, 1H), 3.25 (d, 1H,
J = 6.8 Hz), 2.20 (s, 1H), 1.91 (s, 1H), 1.78 (m, 2H), 1.58
(m, 2H), 1.08 (m, 2H). 13C NMR (75 MHz, CDCl3): d
(ppm) 22.9 (CH2), 25.5 (CH2), 37.5 (CH2), 41.4 (CH), 44.8
(CH), 55.1 (CH), 81.1 (CH). FTIR (CHCl3): c (cmꢀ1
)
4.11. (ꢀ)-2-exo-N,N-Diethylamino-7-syn-hydroxy-norborn-
ane (ꢀ)-16
3327 (OH/NH). HRMS found: m/z 127.0996; calcd for
C7H13NO [M+]: 127.0997.
In a 100 mL three-necked round-bottomed flask under
argon, LiAlH4 (0.39 g, 10.4 mmol) was suspended in dry
THF (25 mL). Compound (+)-15 (0.54 g, 2.6 mmol) was
dissolved in dry THF and added dropwise. The resulting
mixture was refluxed for 4 h. The solution was cooled to
0 ꢁC, quenched slowly with a 10% NaOH solution (1 mL)
and diluted with chloroform (30 mL). The solution was
stirred over night at room temperature, filtered, dried over
4.8. (+)-2-exo-Acetamide-7-syn-acetate-norbornane (+)-13
Compound (ꢀ)-12 (0.37 g, 3 mmol) was dissolved in acetic
anhydride (16 mL) and refluxed for 4 h. The mixture was
neutralized with a 10% NaHCO3 solution and extracted
with chloroform, dried over anhydrous MgSO4, filtered,
and evaporated to provide 0.54 g (87%) of a yellow solid.
20
1
Mp: 98–99 ꢁC. ½aꢁ ¼ þ22:0 (c 1.2, AcOEt). H NMR (200
MHz, CDCl3): dD(ppm) 4.82 (s, 1H), 4.08 (m, 1H), 2.33
(s, 1H), 2.25 (s, 1H), 2.14 (s, 3H), 2.10 (m, 2H), 2.04 (s,
3H), 1.64 (m, 2H), 1.25 (m, 2H). 13C NMR (50 MHz,
CDCl3): d (ppm) 21.1 (2CH3), 23.3 (CH2), 24.6 (CH2),
37.4 (CH2), 38.3 (CH), 43.8 (CH), 51.7 (CH), 81.5 (CH),
168.5 (C), 169.8 (C). FTIR (CHCl3): c (cmꢀ1) 3313 (NH),
1738 (C@O), 1645 (C@O). HRMS found: m/z 211.1213;
calcd for C11H17NO3 [M+]: 211.1208.
anhydrous MgSO4, filtered, and evaporated to provide
20
0.36 g (92%) of a yellow oil. ½aꢁD ¼ ꢀ41:0 (c 1.1, AcOEt).
1H NMR (200 MHz, CDCl3): d (ppm) 3.92 (s, 1H), 2.71.
(q, 4H, J = 7.1 Hz), 2.34 (s, 1H), 2.16 (s, 1H), 1.93
(m, 2H), 1.63 (m, 2H), 1.16 (m, 2H), 1.04 (t, 6H,
J = 7.1 Hz). 13C NMR (50 MHz, CDCl3): d (ppm) 10.9
(2CH3), 23.7 (CH2), 25.7 (CH2), 34.3 (2 CH2), 40.0 (CH),
41.2 (CH), 43.2 (CH2), 65.5 (CH), 80.8 (CH). FTIR
(CHCl3): c (cmꢀ1) 3323 (OH). HRMS found: m/z
183.1627; calcd for C11H21NO [M+]: 183.1623.
4.9. (ꢀ)-2-exo-Ethylamino-7-syn-hydroxy-norbornane
(ꢀ)-14
4.12. (ꢀ)-2-exo-N,N-Dimethylamino-7-syn-hydroxy-
norbornane (ꢀ)-17
In a 100 mL three-necked round-bottomed flask under
argon, LiAlH4 (0.36 g, 9.6 mmol) was suspended in dry
THF (20 mL). Compound (+)-13 (0.52 g, 2.4 mmol) was
dissolved in dry THF, added dropwise and the resulting
mixture refluxed for 4 h. The solution was cooled to 0 ꢁC,
quenched slowly with a 10% NaOH solution (1 mL) and
diluted with chloroform (30 mL). The solution was stirred
over night at room temperature, filtered, dried over anhy-
To 140 mg (1.1 mmol) of (ꢀ)-12, 2 mL of formaldehyde
(36% H2O solution) and 8 mL of 85% formic acid were
added. The solution was refluxed for 7 days. The resulting
mixture was cooled to 0 ꢁC, made alkaline by the addition
of 20% NaOH (pH = 10) and extracted with Et2O. The
organic layer was dried over anhydrous MgSO4, filtered,
and the solvent evaporated. The crude product was puri-
drous MgSO4, filtered, and evaporated to provide 0.35 g
fied by silica gel chromatographic column (CHCl3/MeOH
20
20
(93%) of a yellow oil. ½aꢁD ¼ ꢀ20:0 (c 1.0, AcOEt).
9:1) giving 102 mg (60%) of yellow oil. ½aꢁD ¼ ꢀ25:0
1H NMR (200 MHz, CDCl3): d (ppm) 3.86 (s, 1H), 2.84
(m, 1H), 2.60 (q, 2H, J = 7.3 Hz), 2.09 (s, 1H), 1.92
(s, 1H), 1.60 (m, 2H), 1.54 (m, 2H), 1.19 (s, 2H), 1.1.03
(t, 3H, J = 7.1 Hz). 13C NMR (50 MHz, CDCl3): d (ppm)
15.0 (CH3), 22.9 (CH2), 25.8 (CH2), 35.8 (CH2), 40.8
(CH), 41.3 (CH2), 42.4 (CH), 61.9 (CH), 80.7 (CH). FTIR
(CHCl3): c (cmꢀ1) 3293 (OH). HRMS found: m/z
155.1292; calcd for C9H17NO [M+]: 155.1310.
(c 1.2, AcOEt). 1H NMR (200 MHz, CDCl3): d (ppm)
3.80 (1H), 2.21 (d, 1H, J = 6.0 Hz), 2.14 (s, 6H), 2.05
(m, 2H), 1.80 (m, 2H), 1.45 (m, 2H), 1.00 (m, 2H). 13C
NMR (50 MHz, CDCl3): d (ppm) 23.3 (CH2), 25.4
(CH2), 34.0 (CH2), 40.1 (CH), 41.0 (CH), 43.4 (CH),
71.0 (2CH3), 80.5 (CH). IV (CHCl3): (cmꢀ1) 3403 (OH).
HRMS found: m/z 155.1324; calcd for C9H17NO [M+]:
155.1310.

J. E. D. Martins et al. / Tetrahedron: Asymmetry 17 (2006) 1817–1823
1823
´
4.13. (ꢀ)-2-exo-Piperidine-7-syn-hydroxy-norbornane
(ꢀ)-18
Universite de Rouen for the high resolution mass spectra,
Dr. Hubert Karl Stassen from Universidade Federal do
Rio Grande do Sul for English revising and Amano En-
zyme USA Co. Ltd, for kindly providing the lipase AY
‘Amano’ 30 (Candida rugosa).
To a solution of 107 mg (0.8 mmol) of (ꢀ)-12 in acetoni-
trile, 0.14 mL (0.92 mmol) of 1,5-diiodopentane and 290
mg (2.1 mmol) of K2CO3 were added and the solution re-
fluxed for 1 h. The mixture was filtered and the excess of
acetonitrile was evaporated. The residue was washed with
5 mL of H2O and extracted with chloroform. The organic
layer was dried over anhydrous MgSO4, filtered and the
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20
½aꢁD ¼ ꢀ30:0 (c 1.0, AcOEt). 1H NMR (300 MHz, CDCl3):
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4.14. (ꢀ)-2-exo-Acetamide-7-syn-hydroxy-norbornane
(ꢀ)-19
To a solution of 180 mg (0.84 mmol) of (+)-13 in 5 mL of
THF, 6 mL of 20% HCl solution is added and the solution
is stirred for 15 h. The mixture is neutralized with a 10%
NaHCO3 solution and extracted with Et2O. The organic
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solvent evaporated to give 135 mg of a yellow solid
20
(95%). Mp: 101–102 ꢁC. ½aꢁD ¼ þ5:4 (c 1.1, AcOEt).
1H NMR (200 MHz, CDCl3): d (ppm) 4.15 (s, 1H), 3.48
(s, 1H), 2.20 (s, 2H), 2.00 (s, 3H), 2.75 (m, 2H), 2.60
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found: m/z 169.1109; calcd for C9H15NO2 [M+]: 169.1103.
4.15. General procedure for the enantioselective addition of
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room temperature and monitored by GC. The reaction
was quenched with aqueous HCl (10%, 5 mL) and ex-
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was analyzed by GC.
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The authors thank Conselho Nacional de Desenvolvimento
´
´
Cientıfico e Tecnologico (CNPq), Coordenac¸ao de Aper-
˜
feic¸oamento de Pessoal de Ensino Superior (CAPES) and
`
Fundac¸ao de Amparo a Pesquisa do Estado do Rio
˜
Grande do Sul (FAPERGS) for the financial support.
The authors are also indebted to Dr. Hassan Oulyadi
and Centre Regional Universitaire de spectroscopie–