An efficient synthesis of enantiopure (+)- and (-)-syn-1,3-amino alcohols with a norbornane framework and their application in the asymmetric addition of ZnEt2 to benzaldehyde

Article abstract of DOI:10.1016/j.tetasy.2004.07.027

A series of new optically active (+)- and (-)-syn-1,3-amino alcohols with a norbornane framework has been synthesized. Their abilities as chiral catalysts in the enantioselective additions of ZnEt₂ to benzaldehyde were evaluated. High yields and enantiomeric excesses have been achieved (up to 91%). The influence of the configuration of the carbon bearing the hydroxyl group of the ligands has been studied. A plausible mechanism is also suggested for the observed enantioselectivity.

Full text of DOI:10.1016/j.tetasy.2004.07.027

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 2583–2590
An efficient synthesis of enantiopure (+)- and (ꢀ)-syn-1,3-amino
alcohols with a norbornane framework and their application in
the asymmetric addition of ZnEt2 to benzaldehyde
Luciane F. de Oliveira and Valentim E. U. Costa*
´
ˆ
´
Departamento de Quımica Organica, Instituto de Quımica, Universidade Federal do Rio Grande do Sul,
Av. Bento Gonc¸alves, 9500, 91501-970 Porto Alegre RS, Brazil
Received 22 June 2004; accepted 19 July 2004
Abstract—A series of new optically active (+)- and (ꢀ)-syn-1,3-amino alcohols with a norbornane framework has been synthesized.
Their abilities as chiral catalysts in the enantioselective additions of ZnEt2 to benzaldehyde were evaluated. High yields and enan-
tiomeric excesses have been achieved (up to 91%). The influence of the configuration of the carbon bearing the hydroxyl group of the
ligands has been studied. A plausible mechanism is also suggested for the observed enantioselectivity.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
report the synthesis of conformationally rigid enantio-
pure 1,3-amino alcohols and their evaluation as chiral
ligands in the alkylation of benzaldehyde by diethylzinc.
1,3-Amino alcohols are important and versatile syn-
thetic intermediates for many natural products1 possess-
ing potent biological activity such as nucleoside
antibiotics1a–d or in alkaloids.1e They also possess rele-
vance in the development of new enzyme inhibitors
and the HIV protease inhibitor, ritonavir and lopinavir.2
Consequently, these compounds became targets for the
synthetic chemists, with different methodologies for
their synthesis.3
2. Results and discussion
2.1. Synthesis of 1,3-amino alcohols
The reduction of ketone (+)-1, with known absolute
configuration9 and prepared by previously published
procedures,8 with NaBH4 furnished a mixture of endo:
exo (10:90) diastereomers. Separation of these isomers
by flash chromatography rendered exo-(ꢀ)-2 and
endo-(ꢀ)-2-alcohols (also of known absolute configura-
tion9) as pure isomers (Scheme 1). Alcohol exo-(ꢀ)-2
was then treated with APTS to give ketoalcohol (+)-3
(Scheme 2).
Since Noyori et al.4 demonstrated the high efficiency of
(ꢀ)-3-exo-(dimethylamino)isoborneol (DAIB) as a chi-
ral catalyst for the addition of diethylzinc to benzalde-
hyde, many 1,2-amino alcohols have been prepared
and applied as catalysts.5 Until recently, only a few
examples for the uses of 1,3-amino alcohols have been
reported.6 However, there has been increased interest
in the application of 1,3-amino alcohols as chiral ligands
for the catalyzed enantioselective addition of dialkylzinc
to benzaldehyde,7 although the reaction mechanism has
been less studied.7d–g
OMe
OMe
OMe
MeO
MeO
MeO
In continuation of our work on the chemistry of enan-
tiopure norbornane framework derivatives,8 we herein
i
+
OH
O
OH
(+)-1
exo-(-)-2
endo-(-)-2
*
Corresponding author. Tel.: +55 051 33166300; fax: +55 051
33167304; e-mail: valentim@iq.ufrgs.br
Scheme 1. Reagents and conditions: (i) NaBH4, MeOH, rt, 2.5h, 92%.
0957-4166/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.07.027

2584
L. F. de Oliveira, Valentim E. U. Costa / Tetrahedron: Asymmetry 15 (2004) 2583–2590
O
NOH
O
OMe
NH2
MeO
i
ii
i
OH
OH
OH
OH
OH
exo-(-)-2
(+)-3
(+)-3
(+)-4
(+)-5
Scheme 2. Reagents and conditions: (i) APTS, acetone/water, rt, 5h,
75%.
Scheme 4. Reagents and conditions: (i) NH2OHÆHCl, NaOAc, MeOH,
rt, 5h; (ii) (a) NaBH4, NiCl2Æ6H2O, ꢀ78ꢁC, 10h; (b) NaBH4, HCO2H,
rt, overnight, 90%.
Treatment10 of ketoalcohol (+)-3 with NH2OHÆHCl/
NaOAc afforded hydroxy oxime (+)-4, while its reduc-
tion11 with NaBH4/NiCl2Æ6H2O at room temperature
produced a mixture of syn and anti amino alcohols
(Scheme 3).
O
NOH
NHAc
i
ii
OH
OH
OH
NOH
O
(+)-6
(+)-3
(+)-4
i
Scheme 5. Reagents and conditions: (i) NH2OHÆHCl, NaOAc, MeOH,
rt, 5h; (ii) (a) NaBH4, NiCl2Æ6H2O, ꢀ78ꢁC, 10h; (b) Ac2O, reflux, 5h,
95%.
OH
OH
(+)-3
(+)-4
NH2
H2N
Acetamido alcohol (+)-6 was reduced with LiAlH4 to
produce amino alcohol (+)-7 with a yield of 91%. Amino
alcohol (+)-7 was treated with acetic anhydride to give
acetamido ester (ꢀ)-8. The reduction of acetamido ester
(ꢀ)-8 with LiAlH4 yielded diethylamino alcohol (+)-9 in
73% yield. By using an Eschweiler–Clarke reaction13
from (+)-7, N-methylethylamino alcohol (+)-10 was syn-
thesized (Scheme 6).
ii
+
OH
anti-(+)-5
OH
syn-(+)-5
Scheme 3. Reagents and conditions: (i) NH2OHÆHCl, NaOAc, MeOH,
rt, 5h; (ii) (a) NaBH4, NiCl2Æ6H2O, MeOH, rt, 5h.
In order to control the stereochemistry of this reaction,
the temperature was varied as shown in Table 1. The
best conditions to obtain the desired stereochemistry
(100% syn) was achieved at ꢀ78ꢁC.
The synthesis of dimethylamino alcohol (+)-11 was car-
ried out by methylation of (+)-5 with HCHO/HCOOH
following the Eschweiler–Clarke reaction13 (Scheme 7).
The description of this synthetic route is the same for the
synthesis of the respective (ꢀ)-enantiomers (Scheme 8).
The direct solvent extractions of hydroxy oxime (+)-4 or
the respective amino alcohol (+)-5 resulted in very
poor yields. To overcome this, an in situ oximation with
NH2OHÆHCl/NaOAc followed by reduction with
NaBH4/NiCl2Æ6H2O was carried out producing a mix-
ture with the respective amino alcohol (+)-5. At this
stage, treatment of the mixture followed two ways: (a)
NaBH4 in formic acid to furnish amino alcohol (+)-5
pure in 90% yield (Scheme 4), and (b) acetic anhydride
producing acetamido alcohol (+)-6 in 95% yield (Scheme
5). It is important to note that the amino alcohol race-
mic 5 has already been synthesized by Edwards et al.12
2.2. Enantioselective addition of diethylzinc to
benzaldehyde
Acetamido alcohol 6 and amino alcohols 7, 9, 10 and 11
were evaluated as chiral auxiliaries to determine their
ability to catalyze the enantioselective addition of dieth-
ylzinc to benzaldehyde (Scheme 9).
Initially the enantiomeric pairs of the 1,3-amino alcoh-
ols (ꢀ)-9, (+)-9, (ꢀ)-11 and (+)-11 were evaluated to
determine the influence of the configuration of the car-
bon bearing the hydroxyl group. The addition reactions
were carried out in toluene at room temperature in the
presence of 8mol% of these chiral ligands. The condi-
tions used and the results obtained (entries 3, 4, 7 and
8) are summarized in Table 2.
from
2,3-iminonorbornane(3-azatricyclo[3.2.1.02,4]-
octane), without isolating the pure product, which was
characterized only as its N-benzoyl- and N-benzyloxy-
carbonyl derivatives.
Table 1. Effect of temperature in distribution of products under
conditions of reductions
The catalysts afforded 1-phenylpropanol in high yields
(90–94%) and good enantiomeric excesses (78–87%). In
agreement with previous observations,4d,5f,h the abso-
lute configuration of the 1-phenylpropanol correlates
with the configuration of the hydroxyl-bearing stereo-
centre of the ligand. The (R)-1-phenylpropanol was
obtained in 87% ee in the presence of (+)-9 and (+)-11,
Temperature (ꢁC)
syn:anti
Yield (%)
30
10
70:30
87:13
90:10
100:0
76
75
76
90
0
ꢀ78

L. F. de Oliveira, Valentim E. U. Costa / Tetrahedron: Asymmetry 15 (2004) 2583–2590
2585
Ac
N
Et
N
NHEt
NHAc
Et
Et
iii
ii
i
OH
OH
OAc
OH
(+)-7
(+)-6
(-)-8
(+)-9
iv
Me
N
Et
OH
(+)-10
Scheme 6. Reagents and conditions: (i) LiAlH4, THF, reflux, 4h, 91%; (ii) AcO2, reflux, 7h, 95%; (iii) LiAlH4, THF, reflux, 6h, 73%; (iv) HCHO,
HCOOH, reflux, 5h, 73%.
Table 2. Addition of ZnEt2 to benzaldehyde catalyzed by ligands
(+)-6, (+)-7, (+)-9, (ꢀ)-9, (+)-10, (+)-11 and (ꢀ)-11
Me
NH2
N
Config.c
Me
Entry
Catalyst
Mol%
Time
(h)a
Yield
(%)b
Ee
(%)c
i
OH
OH
1
2
3
4
5
6
7
8
9
(+)-6
(+)-7
(+)-9
20
20
8
3
8
71
62
94
90
99
96
91
93
98
63
55
87
78
91
85
78
82
85
R
R
R
S
(+)-11
(+)-5
18
18
1
(ꢀ)-9
(ꢀ)-9
(+)-10
(ꢀ)-11
(+)-11
(+)-11
8
Scheme 7. Reagents and conditions: (i) HCHO, HCOOH, reflux,
3days 60%.
20
20
8
S
1
R
S
20
20
1
8
20
R
R
NH2
MeO
OMe
a The reaction was followed by GC.
b Determined by GC.
OH
O
c Determined by chiral GC (Supelco b-Dex 120 30m) 100ꢁC isother-
mal. 1-phenylpropanol: tR (R) = 20.05min, tR (S) = 22.78min.
(-)-5
(-)-1
Scheme 8.
The results show (Table 2) that overall moderate to
excellent yields (62–99%) and enantioselectivities (55–
91%) were obtained. N,N-Diethyl amino alcohol (ꢀ)-9
(Table 2, entry 5) was found to be the most efficient of
the series to catalyze the diethylzinc addition. However,
the substituents on the nitrogen atom influence only
slightly the selectivity of the transformation (Table 2,
entries 5, 6 and 9). Nevertheless, when applying the N-
ethylamino alcohol (+)-7 and acetamido alcohol (+)-6,
a decrease in the enantioselectivity and yield was ob-
tained (Table 2, entries 1 and 2), due to the formation
of the benzyl alcohol as byproduct. According to the lit-
erature,4c,d the acidic protons on the nitrogen may cause
complications due to different chiral intermediates while
parallel reaction pathways can be involved, thus compli-
cating the induction.5f
OH
*
catalyst
Et2Zn, toluene, rt
PhCHO
Ph
Scheme 9. Addition of diethylzinc to benzaldehyde.
respectively (Table 2, entries 3 and 8). The (S)-1-phenyl-
propanol was produced with (ꢀ)-9 and (ꢀ)-11 in 78% ee
(Table 2, entries 4 and 7).
To study the effect of the catalystꢀs concentration, the
enantiomers (ꢀ)-9 and (+)-11 were chosen. Comparing
in Table 2, entries 4 and 8 with entries 5 and 9, it is pos-
sible to observe that the increase of the concentration
from 8 to 20mol% provokes a faster reaction time with
excellent yields. The increase of the enantiomeric
excesses was more significant for enantiomer (ꢀ)-9.
Due to these observations, all the other reactions were
performed with 20mol% concentration.
2.3. Effect of conformation on facial selectivity
Several studies on the mechanism of the asymmetric or-
ganic additions to aldehydes catalyzed by amino alcoh-
ols have been reported.4,14 These studies explain the

2586
L. F. de Oliveira, Valentim E. U. Costa / Tetrahedron: Asymmetry 15 (2004) 2583–2590
origin of the asymmetric induction, revealing the inter-
mediates and the transition states involved in the reac-
tion. The 5/4/4 tricyclic transition state described by
Noyori and Yamakawa4f,4h explains the observed abso-
lute configuration as well as the level of stereoselection
in many of the cases. Panda et al.7d have carried out
transition structure calculations to examine the reason
for the selectivity for 1,3-amino alcohols and to verify,
which of these ligands possess 6/4/4 tricyclic transition
structures. In these cases, the Zn-atom is part of a more
flexible six-membered ring in the catalytic chelate. A
qualitative explanation of the results obtained for our
1,3-amino alcohols synthesized can be given by the
6/4/4 tricyclic transition structure.
nates with the amine lone pair to form a six-membered
ring (zinc aminoalkoxide 12). The alkoxy oxygen atom
12 coordinates to diethylzinc to give the ethylzinc
aminoalkoxide complex 13 (Fig. 1). Benzaldehyde
coordinates to the face of complex 13 in two ways:
anti (the two unreacting Et groups on the Zn atoms
are anti) or syn (the two unreacting Et groups are syn).
However, based on the Panda et al.7d studies, it is
possible to define that the most stable transition state
is anti.
As shown in Figure 2, in the transition states (R)-anti-15
and (S)-anti-17, ethyl migrates to the re-face or si-face,
respectively, of the benzaldehyde to form 16 and 18.
The transition model proposed in Figure 2 illustrates
the (ꢀ)-1,3-amino alcohols attacking directly the si-face
leading to the (S)-1-phenylpropanol, and the (+)-1,3-
The 1,3-amino alcohols initially react with diethylzinc
liberating ethane. The resulting zinc ion then coordi-
Ph
R
R
R
R
R
O
R
N
N
Et
N
Et
Zn
H
Zn
Zn
Et
Et
PhCHO
ZnEt2
O
O
O
ZnEt2
Zn
Et
14
12
13
Figure 1.
(-)-1,3-amino alcohol
(+) -1,3-amino alcohol
Ph
Me
R
O
R
R
R
R
Ph
O
N
S
N
Zn
Et
Zn
Zn
Et
Me
Zn
H
Et
H
O
O
Et
H
H
(R)-anti-15
(S)-anti-17
Ph
Ph
H
H
R
O
R
R
R
O
Zn
Et
S
Et
R
N
N
Zn
Et
Zn
Zn
Et
Et
O
O
Et
18
16
OH
OH
Ph
(R)-1-phenylpropanol
Figure 2. Facial selectivity of diethylzinc addition with (ꢀ) and (+)-1,3-amino alcohols.
Ph
(S)-1-phenylpropanol

L. F. de Oliveira, Valentim E. U. Costa / Tetrahedron: Asymmetry 15 (2004) 2583–2590
2587
amino alcohols attack directly to the re-face leading to
the (R)-1-phenylpropanol.
4.2. (ꢀ)-(1S,2R,4R)-7,7-Dimethoxynorbornan-2-exo-ol
(ꢀ)-2
Ketone8 (+)-1 (1.09g, 6.41mmol) was dissolved in meth-
anol (35mL). The solution was cooled at 0ꢁC and, in
small portions, powdered sodium borohydride (490mg,
12.85mmol) added under stirring. The solution was
stirred at 0ꢁC for 3h. The solvent was removed in a
rotatory evaporator and water (20mL) added to the
residue. The solution was acidified with HCl 5% (pH4)
and extracted with Et2O (3 · 60mL). The combined
organic extracts were dried over MgSO4, filtered and
the solvent evaporated under reduced pressure. The res-
idue, constituted as a 9:1 exo:endo mixture of diastereo-
isomers, was separated and purified by flash
chromatography (silica, cyclohex/AcOEt 5.6:1 and
4:1). A clear oil was obtained (1.01g, 5.90mmol, 92%),
which corresponded to compound (ꢀ)-2 as a 9:1
exo:endo mixture of diastereoisomers.
3. Conclusions
A series of new optically active bicyclic syn-1,3-amino
alcohols was synthesized with excellent yields. This
route can be used to prepare various kinds of derivatives
from these new ligands in enantiomerically pure forms.
We have shown that homochiral syn-1,3-amino alcohols
9, 10 and 11 are effective catalysts for the enantioselec-
tive addition of ZnEt2 to benzaldehyde. The obtained
results show clearly that the absolute configuration of
the 1-phenylpropanol correlates with the configuration
of the hydroxyl-bearing stereocentre of the ligand. The
application of Noyoriꢀs mechanism to our system is a
plausible model and can explain the facial selectivity ob-
served in the reaction. These chiral ligands have con-
formationally rigid molecular structures and potential
sites for metal coordinates. Therefore, they are very
promising as potential chiral ligands for other asymmet-
ric transformations.
20
exo-(ꢀ)-2: (silica, cyclohex/AcOEt 5.6:1), ½aꢁ ¼ ꢀ30 (c
D
1.36, AcOEt). FTIR (film): m (cmꢀ1): 3539 (OH). 1H
NMR (300MHz, CDCl3): d 1.10–1.13 (m, 2H), 1.61
(dm, J = 13.6Hz, 1H), 1.70–1.77 (m, 2H), 1.86 (dd,
J = 13.6Hz, 8.0Hz, 1H), 2.06 (d, J = 4.3Hz, 1H), 2.15
(t, J = 4.3Hz, 1H), 2.98 (s, OH), 3.28 (s, 3H), 3.31 (s,
3H), 3.72 (dd, J = 8.0Hz, 2.1Hz, 1H). 13C NMR
(75MHz, CDCl3): d 22.4 (CH2), 26.2 (CH2), 37.7
(CH), 40.9 (CH2), 44.2 (CH), 49.3 (OCH3), 50.6
(OCH3), 74.1 (CH), 114.7 (C). HRMS found: m/z
172.1080; calcd for C9H16O3 [M]+: 172.1099.
4. Experimental
4.1. General
The reaction with ZnEt2 requiring anhydrous conditions
were conducted under an atmosphere of argon. Glass-
ware, syringes and needles, for the transfer of the re-
agents, were dried at 180ꢁC and allowed to cool in a
desiccator over CaCl2 before use. THF and toluene were
distilled from sodium and benzophenone under argon.
Benzaldehyde was obtained from Aldrich and distilled
prior to use. NMR spectra were obtained with a Varian
YH-300 spectrometer in a magnetic field of 7.05T in
CDCl3 or CD3OD solution at 22ꢁC. A 5mm multi-
nuclear Varian probe was used. Chemical shifts are
expressed in d (ppm) relative to TMS as an internal
standard and coupling constants (J) are given in hertz.
Infrared spectra were recorded using a FTIR-Mattson
3020 spectrometer. Products were analyzed by GC on
a Shimadzu chromatograph, model GC-17A a flame-
ionization detector equipped with a column DB1
(15m · 0.53mm, 1.50lm) and ee values determined
by a Supelco b-Dex 120 chiral GC column (30
m · 0.25mm (i.d.), 0.25lm film column). Optical rota-
tions were measured with a Perkin–Elmer polarimeter
model 341 with a 1cm cell at 20ꢁC. Melting points were
determined on an Electrothermal IA 9100 digital melt-
ing point apparatus. HRMS spectra were obtained on
a Mass Spectrometer Jeol AX500 (EB), EI (70eV) or
NICI with isobutane (200eV).
20
endo-(ꢀ)-2: (silica, cyclohex/AcOEt and 4:1), ½aꢁ ¼ ꢀ1
D
1
(c 3.07, AcOEt). FTIR (film): m (cmꢀ1): 3409 (OH). H
NMR (200MHz, CDCl3): d 0.98 (m, 1H), 1.88 (m,
2H), 2.12 (m, 3H), 3.05 (s, 3H), 3.09 (s, 3H), 4.3 (m,
1H). 13C NMR (50MHz, CDCl3): d 17.5 (CH2), 27.6
(CH2), 38.4 (CH2), 38.5 (CH), 43.8 (CH), 50.0 (CH3),
50.5 (CH3), 70.1 (CH), 114.1 (C).
4.3. (+)-(1S,2R,4R)-2-exo-Hydroxynorbornan-7-one
(+)-3
To a solution of the alcohol exo-(ꢀ)-2 (453mg,
2.63mmol) in acetone (9mL) and water (1mL),
APTS (1.00g, 5.27mmol) was added. The mixture was
stirred at room temperature for 5h and then made
alkaline with a saturated NaHCO3 aqueous solution.
The resulting suspension was extracted with CHCl3.
The organic layer was dried over MgSO4, filtered
and the solvent evaporated under reduced pressure. The
crude product was purified by flash chromatography
(silica, cyclohex/AcOEt 4:1) yielding 249mg (1.98mmol,
20
D
75%) of (+)-3 as a colourless oil. ½aꢁ ¼ þ30 (c 1.18,
AcOEt). FTIR (film): m (cmꢀ1): 3394 (OH), 1769
1
The absolute configurations of all the compounds syn-
thesized are proposed based on the previous determina-
tion of the absolute configurations of ketone (+)-1 and
of alcohol (ꢀ)-2 by Lightner et al.9
(C@O). H NMR (300MHz, CDCl3): d 1.44–1.52 (m,
2H), 1.77–1.85 (m, 1H), 1.87–1.91 (m, 2H), 1.95 (d,
J = 4.2Hz, 1H), 2.08 (dd, J = 13.4Hz, 8.1Hz, 1H),
3.48 (s, OH), 4.07 (d, J = 8.1Hz, 1H). 13C NMR
(75MHz, CDCl3): d 18.3 (CH2), 22.7 (CH2), 37.3
(CH2), 37.8 (CH), 46.2 (CH), 69.4 (CH), 216.6 (C@O).
HRMS found: m/z 126.0693; calcd for C7H10O2 [M]+:
126.0681.
The descriptions of the experimental procedures are the
same for synthesis to the respective (ꢀ)- and (+)-
products.

2588
L. F. de Oliveira, Valentim E. U. Costa / Tetrahedron: Asymmetry 15 (2004) 2583–2590
20
D
4.4. (+)-(1R,2R,4R)-7-syn-Aminonorbornan-2-exo-ol
(+)-5
1.47mmol, 95%). Mp = 78.4–80.1ꢁC. ½aꢁ ¼ þ63 (c
1.17, AcOEt). FTIR (film): m (cmꢀ1): 3355 (OH, NH),
1649 (C@O), 1537 (C–N). 1H NMR (300MHz, CDCl3):
d 0.98–1.12 (m, 2H), 1.57–1.71 (m, 3H), 1.83 (dd,
J = 13.9Hz, 7.3Hz, 2H), 1.96 (s, 3H), 2.07–2.09 (m,
1H), 2.31 (b s, 1H), 3.51 (s, OH), 3.92–3.95 (m, 1H),
3.96–3.99 (m, 1H), 7.34 (b s, NH). 13C NMR
(75MHz, CDCl3): d 22.9 (CH2), 23.8 (CH3), 26.6
(CH2), 39.3 (CH2), 40.1 (CH), 45.7 (CH), 58.8 (CH),
75.9 (CH), 170.5 (C@O). The molecular ion was too
weak for an exact mass measurement, so the elemental
composition was confirmed by data from its substrate
(+)-5 and its product (+)-7.
To a stirred solution of the keto alcohol (+)-3 (189mg,
1.5mmol) in methanol (27mL) at room temperature,
solid NaOAc (195mg, 2.34mmol) was added. The
resulting mixture was stirred at room temperature until
all the solid was dissolved. To the clear solution, solid
NH2OHÆHCl (172mg, 2.48mmol) was added and the
mixture was stirred at room temperature for 5h. To this
mixture nickel(II) chloride hexahydrate (627mg,
2.64mmol) was added and after complete dissolution,
the solution was cooled to ꢀ78ꢁC. Powdered sodium
borohydride (521mg, 13.77mmol) was added in small
portions under efficient stirring. The stirring was contin-
ued for 12h at ꢀ78 ꢁC [at this point the mixture may be
treated (in situ) according to Section 4.5 producing (+)-
6, method (b)] and 85% formic acid (50mL) and pow-
dered sodium borohydride (1.35g, 35.71mmol) added.
The mixture was stirred overnight at room temperature.
The solvent was removed using a rotatory evaporator
and the resulting mixture cooled to 0ꢁC, slowly
quenched with 20% NaOH (20mL) and extracted with
Et2O. The organic layer was dried over MgSO4, filtered
and the solvent evaporated. The crude product was puri-
fied by chromatography (silica, CHCl3/MeOH 4:1)
4.6. (+)-(1R,2R,4R)-7-syn-Ethylaminonorbornan-
2-exo-ol (+)-7
In a 100mL three-necked round-bottomed flask under
argon, LiAlH4 (172mg, 4.53mmol) was suspended in
dry THF (10mL). Compound (+)-6 (253mg, 1.51mmol)
in dry THF (15mL) was added dropwise and the result-
ing mixture refluxed for 4.5h. The solution was cooled
to 0ꢁC, quenched slowly with 10% NaOH (20mL) and
diluted with CHCl3 (40mL). The resulting mixture was
stirred overnight at room temperature, filtered, dried
over MgSO4, filtered and the solvent evaporated under
reduced pressure. Compound (+)-7 was obtained as
giving 408mg (3.21mmol, 90%) of as yellow oil.
20
½aꢁ ¼ þ8 (c 1.15, AcOEt). FTIR (film): m (cmꢀ1):
white solid (213mg, 1.37mmol, 91%). Mp = 42–
D
20
3360 and 3296 (NH2, OH). 1H NMR (300MHz,
CDCl3): d 0.96–1.15 (m, 2H), 1.43–1.68 (m, 2H), 1.82
(dd, J = 13.4Hz, 7.1Hz, 1H), 1.91–1.94 (m, 1H), 2.09–
2.10 (m, 2H), 3.25 (b s, 4H; 1H, NH2, OH), 3.72 (s,
1H). 13C NMR (75MHz, CDCl3): d 23.2 (CH2), 27.1
(CH2), 40.2 (CH2), 40.9 (CH), 47.1 (CH), 60.5 (CH),
75.9 (CH). HRMS found: m/z 127.0975; calcd for
C7H13NO [M]+: 127.0997.
43.7ꢁC. ½aꢁ ¼ þ17 (c 1.45, AcOEt). FTIR (film): m
D
(cmꢀ1): 3296 (OH, NH). H NMR (300MHz, CDCl3):
d 0.80–1.10 (m, 2H), 1.06 (t, J = 7.1Hz, 3H), 1.37–1.58
(m, 3H), 1.75–1.83 (m, 1H), 2.10–2.20 (m, 2H), 2.62
(q, J = 7.1Hz, 2H), 2.88–2.92 (m, 1H), 3.19 (b s, OH,
NH), 3.62–3.68 (m, 1H). 13C NMR (75MHz, CDCl3):
d 15.2 (CH3), 22.9 (CH2), 27.1 (CH2), 39.1 (CH), 40.8
(CH2), 42.8 (CH2), 45.4 (CH), 67.7 (CH), 75.9 (CH).
HRMS found: m/z 155.1303; calcd for C9H17NO [M]+:
155.1310.
1
(+)-(1R,2R,4R)-2-exo-Hydroxynorbornan-7-one oxime
20
(+)-4: Mp = 143.6–144.6ꢁC. ½aꢁ ¼ þ41 (c 1.01,
D
MeOH). FTIR (KBr): m (cmꢀ1): 3306 (OH), 1707
(C@N). 1H NMR (300MHz, CD3OD): d 1.29–1.39
(m, 2H), 1.51–1.54 (m, 1H, syn), 1.55–1.57 (m, 1H, anti),
1.61–1.71 (m, 2H), 1.92 (dd, J = 11.4Hz, 7.4Hz, 1H),
2.27 (d, J = 4.7Hz, 1H, anti), 2.40 (t, J = 4.7Hz, 1H,
anti), 3.05 (d, J = 4.1Hz, 1H, syn), 3.10 (t, J = 4.1Hz,
1H, syn), 3.89 (dd, J = 7.4Hz, 2.2Hz, 1H). 13C NMR
(75MHz, CDCl3): d 22.3 (CH2, syn), 23.5 (CH2, anti),
26.7 (CH2, anti), 27.8 (CH2, syn), 32.7 (CH, anti), 37.4
(CH, syn), 40.6 (CH2, anti), 40.9 (CH2, syn), 41.3 (CH,
syn), 45.8 (CH, anti), 73.1 (CH, anti), 73.4 (CH, syn),
168.4 (C@NOH). HRMS found: m/z 141.0810; calcd
for C7H11NO2 [M]+: 141.0790.
4.7. (ꢀ)-(1R,2R,4R)-7-syn-(Acetylethyl)aminonorbornan-
2-exo-yl acetate (ꢀ)-8
Compound (+)-7 (160mg, 1.03mmol) was dissolved in
acetic anhydride (24mL) and refluxed for 6h. The resi-
due was neutralized with a solution of saturated potas-
sium carbonate and extracted with Et2O (3 · 30mL).
The organic layers were dried over MgSO4. After filtra-
tion and evaporation, the crude product was purified by
silica gel column chromatography using chloroform
and methanol (99:1) as the eluent to give the corre-
sponding compound (ꢀ)-8 (234mg, 1.28mmol, 95%).
20
D
½aꢁ ¼ ꢀ21 (c 1.09, AcOEt). FTIR (film): m (cmꢀ1):
1726 (C@O), 1648 (C@O amide), 1421 (C–N). 1H
NMR (300MHz, CDCl3): d 1.15 (t, J = 7.1Hz, 3H),
1.11–1.25 (m, 2H), 1.58–1.69 (m, 1H), 1.71–1.80 (m,
2H), 1.91 (t, J = 7.6Hz, 1H), 1.95 (s, 3H), 2.11 (s, 3H),
2.54–2.57 (m, 1H), 3.12 (s, 1H), 3.20–3.40 (m, 2H),
3.47 (b s, 1H), 4.69 (dd, J = 7.6Hz, 2.93Hz, 1H). 13C
NMR (75MHz, CDCl3): d 14.1 (CH3), 20.9 (CH), 22.8
(CH3), 23.2 (CH2), 25.6 (CH2), 37.7 (CH2), 37.8 (CH),
41.8 (CH2), 42.9 (CH3), 63.4 (CH), 76.9 (CH), 170.4
(C@O), 172.5 (C@O). HRMS found: m/z 239.1517;
calcd for C13H21NO3 [M]+: 239.1521.
4.5. (+)-(1R,2R,4R)-7-syn-Acetamidonorbornan-
2-exo-ol (+)-6
The mixture containing amino alcohol (+)-5 (190mg,
1.5mmol), obtained in Section 4.4, was treated in situ
with acetic anhydride (11mL) and refluxed for 5h. The
residue was neutralized with a solution of saturated
potassium carbonate and extracted with Et2O
(3 · 30mL), yielding, after solvent evaporation, a white
solid corresponding to compound (+)-6 (249mg,

L. F. de Oliveira, Valentim E. U. Costa / Tetrahedron: Asymmetry 15 (2004) 2583–2590
2589
4.8. (+)-(1R,2R,4R)-7-syn-Diethylaminonorbornan-2-
exo-ol (+)-9
2.20–2.22 (m, 2H), 3.57 (d, J = 6.8Hz, 1H). 13C NMR
(75MHz, CDCl3): d 22.8 (CH2), 27.1 (CH2), 37.6
(CH), 40.3 (CH2), 44.3 (CH3), 44.5 (CH), 75.8 (CH),
76.2 (CH). HRMS found: m/z 155.1311; calcd for
C9H17NO [M]+: 155.1310.
Following Section 4.6, 164mg (0.658mmol) of (ꢀ)-8
were reduced with 150mg (3.95mmol) of LiAlH4 in
dry THF (15mL). The mixture was refluxed for 6h.
After stirring, the solution was cooled to 0ꢁC, quenched
slowly with 10% NaOH (10mL) and diluted with CHCl3
(30mL). The resulting mixture was stirred overnight at
room temperature, filtered, dried over MgSO4, filtered
and the solvent evaporated under reduced pressure.
The crude product was purified by silica gel column
chromatography using chloroform and methanol
4.11. General procedure for the enantioselective
alkylation of benzaldehyde with diethylzinc
To the catalyst (0.125mmol), diethylzinc (2.0mL,
2.0mmol, 1M in hexane) was slowly added. The result-
ing solution was stirred at room temperature for 1h.
Benzaldehyde (0.625mmol, 0.066g, 0.064mL) was
added dropwise causing the solution to acquire a yellow
colour. The reaction mixture was stirred at rt and the
progress of the reaction monitored by GC (the solution
acquire a pale yellow colour). The reaction was
quenched with aqueous HCl (10%, 8mL) and extracted
with diethyl ether (4 · 5mL). The organic layer was
dried over MgSO4 and concentrated in vacuo to give
the crude reaction mixture, which was analyzed by
GC. GC conditions (Supelco b-Dex 120, 30m,
0.25mm i.d.); isotherm at 100ꢁC. tR: benzaldehyde
4.18min, benzyl alcohol 14.51min, (R)-(+)-1-phenylpro-
panol 22.05min, (S)-(+)-1-phenylpropanol 22.78min.
(95:5) as an eluent to give the corresponding compound
20
(+)-9 (112mg, 0.480mmol, 73%). ½aꢁ ¼ þ5 (c 1.04,
D
1
AcOEt). FTIR (film): m (cmꢀ1): 3365 (OH). H NMR
(300MHz, CDCl3): d 1.02 (t, J = 7.3Hz, 3H), 0.99–
1.10 (m, 2H), 1.48–1.57 (m, 2H), 1.82–1.84 (m, 2H),
2.31 (s, 1H), 2.35–2.37 (m, 1H), 2.70–2.71 (m, 1H),
2.76 (m, 2H), 3.70–3.73 (m, 1H). 13C NMR (75MHz,
CDCl3): d 22.6 (CH2), 27.1 (CH2), 37.4 (CH), 40.7
(CH2), 44.4 (CH), 70.9 (CH), 75.7 (CH). HRMS found:
m/z 183.1639; calcd for C11H21NO [M]+: 183.1623.
4.9. (+)-(1R,2R,4R)-7-syn-Ethylmethylaminonorbornan-
2-exo-ol (+)-10
To 200mg (1.29mmol) of (+)-7, 5mL of formaldehyde
(36% H2O solution) and 9mL of 85% formic acid were
added. The solution was then refluxed for 5h. The
resulting mixture was cooled to 0ꢁC, made alkaline with
20% NaOH (pH = 10) and extracted with Et2O. The
organic layer was dried over MgSO4, filtered and the
solvent evaporated. The crude product was purified by
column chromatography (silica, CHCl3/MeOH 99:1)
Acknowledgements
We thank CNPq and FAPERGS for financial support.
CNPq for fellowship to V.E.U.C. and CAPES for schol-
arship to L.F.O. Special thanks to Dr. Hubert Stassen
for reviewing this text. The authors are indebted to
Dr. Hassan Oulyadi and the Centre Regional Universi-
´
taire de Spectroscopie––Universite de Rouen for the
yielding 159mg (0.94mmol, 73%) of as colourless oil.
high resolution mass spectra and Amano Enzyme
USA Co. Ltd for providing the ꢁAmanoꢀ lipases used
in this work.
20
D
½aꢁ ¼ þ12 (c 1.13, AcOEt). FTIR (film): m (cmꢀ1):
1
3368 (OH). H NMR (300MHz, CDCl3): d 0.80–1.30
(m, 2H), 1.04 (t, J = 7.2Hz, 3H), 1.44–1.58 (m, 2H),
1.60–1.78 (m, 3H), 1.82 (dd, J = 13.4Hz, 6.8Hz, 1H)
2.22 (s, 3H), 2.28–2.32 (m, 2H), 2.38 (s, 1H), 3.66 (d,
J = 6.8Hz, 1H) 13C NMR (75MHz, CDCl3): d 11.5
(CH3), 22.9 (CH2), 26.8 (CH2), 27.2 (CH2), 37.5 (CH),
39.5 (CH3), 40.7 (CH2), 44.7 (CH), 74.5 (CH), 75.9
(CH). HRMS found: m/z 169.1459; calcd for
C10H19NO [M]+: 169.1467.
References
1. (a) Shibahara, S.; Kondo, S.; Maeda, K.; Umezawa, H.;
Ohno, M. J. Am. Chem. Soc. 1972, 94, 4353; (b) Knapp, S.
Chem. Rev. 1995, 95, 1859; (c) Wang, Y.-F.; Yzawa, T.;
Kobayashi, S.; Ohno, M. J. Am. Chem. Soc. 1982, 104,
6465; (d) Hashiguchi, S.; Kawada, A.; Natsugari, H. J.
Chem. Soc., Perkin Trans. 1 1991, 2435; (e) Kozikowski,
A. P.; Chen, Y.-Y. J. Org. Chem. 1981, 46, 5248; (f)
Benedetti, F.; Norbedo, S. J. Chem. Soc. 2001, 203; (g)
Carlier, P. R.; Lo, M. M.-C.; Lo, P. C.-K.; Richelson, E.;
Tatsumi, M.; Reynolds, I. J.; Sharma, T. A. Bioorg. Med.
Chem. Lett. 1997, 7, 1511; (h) Musso, D. L.; Mehta, N. B.;
Soroko, F. E. Bioorg. Med. Chem. Lett. 1997, 7, 1; (i)
Carlier, P. R.; Lo, M. M.-C.; Lo, P. C.-K.; Richelson, E.;
Tatsumi, M.; Reynolds, I. J.; Sharma, T. A. Bioorg. Med.
Chem. Lett. 1998, 8, 487.
2. (a) Kempf, D. J.; Sham, H. L.; Marsh, K. C.; Flentge, C.
A.; Betebenner, D. A.; Green, B. E.; McDonald, E.;
Vasavanonda, S.; Saldivar, A.; Widerburg, N. E.; Kati, W.
M.; Ruiz, L.; Zhao, C.; Fino, L.; Patterson, J.; Molla, A.;
Plattner, J. J.; Norbeck, D. W. J. Med. Chem. 1998, 41,
602; (b) Sham, H. L.; Kempf, D. J.; Molla, A.; Marsh, K.
C.; Kumar, G. N.; Chen, C.-M.; Kati, W.; Stewart, K.;
Lal, R.; Hsu, A.; Betebenner, D. A.; Korneyeva, M.;
4.10. (+)-(1R,2R,4R)-7-syn-Dimethylaminonorbornan-2-
exo-ol (+)-11
To 300mg (2.36mmol) of (+)-5, 9mL of formaldehyde
(36% H2O solution) and 17mL of 85% formic acid were
added and the solution refluxed for 3days. The resulting
mixture was cooled to 0ꢁC, made alkaline with 20%
NaOH (pH = 10) and extracted with Et2O. The organic
layer was dried over MgSO4, filtered and the solvent
evaporated. The crude product was purified by column
chromatography (silica, CHCl3/MeOH 5.6:1) giving
220mg (1.42mmol, 60%) of as yellow liquid.
20
D
½aꢁ ¼ þ22 (c 1.08, AcOEt). FTIR (film): m (cmꢀ1):
1
3376 (OH). H NMR (300MHz, CDCl3): d 0.90–1.01
(m, 2H), 1.34–1.51 (m, 2H), 1.62–1.67 (m, 1H), 1.73
(dd, J = 13.7Hz, 6.8Hz, 1H) 2.11 (s, 1H), 2.16 (s, 6H),

2590
L. F. de Oliveira, Valentim E. U. Costa / Tetrahedron: Asymmetry 15 (2004) 2583–2590
´
Vasavanonda, C.; McDonald, E.; Saldivar, A.; Wide-
burg, N.; Chen, X.; Niu, P.; Park, O.; Jayanti, V.;
Grabowski, B.; Granneman, G. R.; Sun, E.; Japour
A. J., J. M.; Leonard, J. M.; Plattner, J. J.; Norbeck
D. W. Antimicrob. Agents Chemother. 1998, 42, 3218; (c)
Sham, H. L.; Zhao, C.; Li, L.; Betebenner, D. A.; Saldivar,
A.; Vasavanonda, S.; Kempf, D. J.; Plattner, J. J.;
Norbeck, D. W. Bioorg. Med. Chem. Lett. 2002, 12,
3101.
Ginj, G.; Brocard, J.; Pelinski, L.; Novogrocki, G.
Tetrahedron: Asymmetry 2003, 14, 1701; (i) Joshi, S. N.;
Malhotra, S. V. Tetrahedron: Asymmetry 2003, 14, 1763;
(j) Sosa-Rivadeneyra, M.; Mun˜oz-Mun˜iz, O.; de Perrodi,
C. A.; Quintero, L.; Juaristi, E. J. Org. Chem. 2003, 68,
2369.
6. (a) Muchow, G.; Vannoorenberghe, Y.; Buono, G. Tet-
rahedron Lett. 1987, 28, 6163; (b) Oppolzer, W.; Radinov,
R. N. Tetrahedron Lett. 1988, 29, 5645; (c) Cicchi, S.;
Crea, S.; Goti, A.; Brandi, A. Tetrahedron: Asymmetry
1997, 8, 293; (d) Genov, M.; Kostova, K.; Dimitrov, V.
Tetrahedron: Asymmetry 1997, 8, 1869; (e) Cho, B. T.;
Kim, N. Tetrahedron Lett. 1994, 35, 4115; (f) Hulst, R.;
Heres, H.; Fitzpatrick, K.; Peper, N.; Kellogg, R. M.
Tetrahedron: Asymmetry 1996, 7, 2755.
7. (a) Philipova, I.; Dimitrov, V.; Simova, S. Tetrahedron:
Asymmetry 1999, 10, 1381; (b) Panev, S.; Linden, A.;
Dimitrov, V. Tetrahedron: Asymmetry 2001, 12, 1313; (c)
Dimitrov, V.; Dobrikov, G.; Genov, M. Tetrahedron:
Asymmetry 2001, 12, 1323; (d) Panda, M.; Phuan, P.-W.;
Kozlowski, M. C. J. Org. Chem. 2003, 68, 564; (e)
´
3. (a) Barluenga, J.; Fernandez-Marı, F.; Viado, A. L.;
Aguilar, E.; Olano, B. J. Org. Chem. 1996, 61, 5659; (b)
Toujas, J.-L.; Toupet, L.; Vaultier, M. Tetrahedron 2000,
56, 2665; (c) Gais, H.-J.; Loo, R.; Roder, D.; Das, P.;
Raabe, G. Eur. J. Org. Chem. 2003, 1500; (d) Veenstra, S.
J.; Kinderman, S. S. Synlett 2001, 1109; (e) Dudling, T.;
Hafez, A. M.; Taggi, A. E.; Wagerle, T. R.; Lectka, T.
Org. Lett. 2002, 4, 387; (f) Takemoto, Y.; Anzai, M.;
Yamada, R.; Fujii, N.; Ohno, H.; Ibuka, T. Tetrahedron
Lett. 2001, 42, 1725; (g) Kochi, T.; Tang, T. P.; Ellman, J.
A. J. Am. Chem. Soc. 2002, 124, 6518; (h) Ohno, H.;
Hansaguchi, H.; Tanaka, T. J. Org. Chem. 2001, 66, 1867;
(i) Kochi, T.; Tang, T. P.; Ellman, J. A. J. Am. Chem. Soc.
2003, 125, 11276; (j) Raghavan, S.; Rajender, A.; Joseph,
S. C.; Rasheed, M. A.; Kumar, K. R. Tetrahedron:
Asymmetry 2004, 15, 365.
´
Martınez, A. G.; Vilar, E. T.; Fraile, A. G.; Cerero, S. M.;
Maroto, B. L. Tetrahedron: Asymmetry 2004, 15, 753; (f)
´
Martınez, A. G.; Vilar, E. T.; Fraile, A. G.; Cerero, S. M.;
Maroto, B. L. Tetrahedron: Asymmetry 2003, 14, 1959; (g)
´
4. (a) Kitamura, M.; Kawai, K.; Noyori, R. J. Am. Chem.
Soc. 1986, 108, 6071; (b) Kitamura, M.; Okada, S.; Suga,
S.; Noyori, R. J. Am. Chem. Soc. 1989, 111, 4028; (c)
Noyori, R.; Suga, S.; Kawai, K.; Okada, S.; Kitamura,
M.; Oguni, N.; Hayashi, M.; Kaneko, T.; Matsuda, Y. J.
Organomet. Chem. 1990, 19, 19; (d) Noyori, R.; Kitamura,
M. Angew. Chem., Int. Ed. Engl. 1991, 30, 49; (e)
Kitamura, M.; Suga, S.; Niwa, M.; Noyori, R. J. Am.
Chem. Soc. 1995, 117, 4832; (f) Yamakawa, M.; Noyori,
R. J. Am. Chem. Soc. 1995, 117, 6327; (g) Kitamura, M.;
Suga, S.; Oka, H.; Noyori, R. J. Am. Chem. Soc. 1998,
120, 9800; (h) Yamakawa, M.; Noyori, R. Organometallics
1999, 18, 128; (i) Noyori, R. Angew. Chem., Int. Ed. 2002,
41, 2008.
Vilaplana, M. J.; Molina, P.; Arques, A.; Andres, C.;
Pedrosa, R. Tetrahedron: Asymmetry 2002, 13, 5.
8. Lapis, A. A. M.; Kreutz, O. C.; Pohlmann, A. R.; Costa,
V. E. U. Tetrahedron: Asymmetry 2001, 12, 557.
9. (a) Lightner, D. A.; Gawronski, J. K.; Bouman, T. D. J.
Am. Chem. Soc. 1980, 102, 1983; (b) Lightner, D. A.;
Crist, B. V.; Kalyanam, N.; May, L. M.; Jackman, D. E.
J. Org. Chem. 1985, 50, 3867.
10. Marchand, A. P.; Sharma, R.; Zope, U. R. J. Org. Chem.
1993, 58, 759.
11. Ipaktschi, J. J. Chem. Ber. 1984, 117, 856.
12. Edwards, O. E.; Elder, J. W.; Lesage, M.; Retallack, R. W.
Can. J. Chem. 1975, 53, 1019.
13. (a) Pine, S. H. J. Chem. Educ. 1968, 48, 118; (b) Pine, S.
H.; Sanchez, B. L. J. Org. Chem. 1971, 36, 829.
14. (a) Goldfuss, B.; Houk, K. N. J. Org. Chem. 1998, 63,
8998; (b) Goldfuss, B.; Steigelmann, M.; Khan, S. I.;
Houk, K. N. J. Org. Chem. 2000, 65, 77; (c) Goldfuss, B.;
Steigelmann, M.; Rominger, F. Eur. J. Org. Chem., 2000,
1785; (d) Goldfuss, B.; Steigelmann, M. J. Mol. Modell.
2000, 6, 166; (e) Vazquez, J.; Pericas, M. A.; Maseras, F.;
Lledos, A. J. Org. Chem. 2000, 65, 7303; (f) Brandt, P.;
Hedberg, C.; Lawonn, K.; Pinho, P.; Anderson, P. G.
Chem. Eur. J. 1999, 5, 1692.
5. Some recent examples are: (a) Soai, K.; Niwa, S. Chem.
Rev. 1992, 92, 833; (b) Pu, L.; Yu, H.-B. Chem. Rev. 2001,
101, 757; (c) Blaser, H.-U. Chem. Rev. 2002, 92, 933; (d)
Paleo, R. M.; Cabeza, I.; Sardina, F. J. J. Org. Chem.
2000, 65, 2108; (e) Rasmusen, T.; Norrby, P.-O. J. Am.
´
Chem. Soc. 2001, 123, 2464; (f) Martınez, A. G.; Vilar, E.
T.; Fraile, A. G.; Cerero, S. M.; Ruiz, P. M.; Villas, P. C.
´
Tetrahedron: Asymmetry 2002, 13, 1; (g) Martınez, A. G.;
Vilar, E. T.; Fraile, A. G.; Cerero, S. M.; Ruiz, P. M.
Tetrahedron: Asymmetry 2002, 13, 1457; (h) Bastin, S.;