Asymmetric synthesis of novel 1,4-aminoalcohol ligands with norbornene and norbornane backbone: use in the asymmetric diethylzinc addition to benzaldehyde

Article abstract of DOI:10.1016/j.tetasy.2007.09.019

The asymmetric synthesis of cis-1,4-aminoalcohols with norbornene and norbornane backbone was performed starting with (2S,3R)-(-)-cis-hemiester 1 (98% ee). Chemoselective amination with HMPTA followed by Grignard reactions and subsequent LAH reductions af

Full text of DOI:10.1016/j.tetasy.2007.09.019

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Tetrahedron: Asymmetry 18 (2007) 2349–2357
Asymmetric synthesis of novel 1,4-aminoalcohol ligands with
norbornene and norbornane backbone: use in the asymmetric
diethylzinc addition to benzaldehyde
Cihangir Tanyeli,* Serhat Odabaßs, Mine Erdem, Esen C¸ akır and Eda Keskin
Department of Chemistry, Middle East Technical University, 06531 Ankara, Turkey
Received 17 August 2007; accepted 14 September 2007
Available online 10 October 2007
Abstract—The asymmetric synthesis of cis-1,4-aminoalcohols with norbornene and norbornane backbone was performed starting with
(2S,3R)-(ꢀ)-cis-hemiester 1 (98% ee). Chemoselective amination with HMPTA followed by Grignard reactions and subsequent LAH
reductions afforded compounds 5a–d. cis-Hemiester 1 was also transformed into chiral ligands 7a–f and 9a–d with the DCC coupling
method followed by LAH reduction using acyclic, heterocyclic amines and various aniline derivatives and p-toluenesulfonamide, respec-
tively. The chiral ligands were subjected to asymmetric diethylzinc addition to examine their effectiveness as chiral catalysts. Among
these, arylamine and tosyl substituted chiral ligands 9a–d exhibited the highest selectivities (up to 97% ee).
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
(Fig. 1).11 Their evaluation as chiral ligands in the addition
of diethylzinc to benzaldehyde was also described, showing
satisfactory results with compound (+)-2a (88% ee).
Aminoalcohols have been used extensively in asymmetric
synthesis as chiral ligands1 and auxiliaries.2 The hetero-
atoms allow great ability to bind a transition metal or achi-
ral starting compound. They also play an important role in
asymmetric C–C bond forming reactions, which have
always been one of the most challenging areas in organic
synthesis. Among these, the enantioselective addition of
diethylzinc to aldehydes catalyzed by chiral aminoalcohols
which was initiated by Oguni and Omi with (S)-leucinol,3
and followed by Noyori with DAIB,4 has attracted consid-
erable attention. Chiral 1,2-aminoalcohols indicate high
chiral catalytic activity of enantioselective alkylation,5
however, only a few examples of 1,4-aminoalcohols with
high catalytic activity have been identified.6 Most of the
chiral 1,4-aminoalcohol ligands are derived from mono-
terpenes, that is, pulegone,7 camphor,8 fenchone,9 and
limonene,10 and have successfully been used as chiral
catalysts, although their use is limited, since in most cases,
only one enantiomer of the starting compound is commer-
cially available. In recent work, we described the synthesis
of new chiral 1,4-aminoalcohols including a norbornene
backbone with high yields and enantiomeric excesses
CO2H
NMe2
OH
(+)-2a
NMe2
OH
CO2Me
Ph
Ph
(-)-2c
(-)-1
NH2
OH
(-)-2b
Figure 1. Synthesis of 1,4-aminoalcohols.
In connection with the aforementioned work,11 we decided
to synthesize a series of new enantiopure 1,4-aminoalcohol
derivatives, which present the various substituents on a hy-
droxyl group attached to a methylene carbon and on the
nitrogen moiety. Herein, we report the synthesis of novel
functionalized derivatives and also the evaluation results
*
Corresponding author. Tel.: +90 312 210 3222; fax: +90 312 210 3200;
e-mail: tanyeli@metu.edu.tr
0957-4166/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.09.019

2350
C. Tanyeli et al. / Tetrahedron: Asymmetry 18 (2007) 2349–2357
as a chiral catalyst in the enantioselective addition of dieth-
ylzinc to benzaldehyde.
2.2. Asymmetric synthesis of 1,4-aminoalcohols having
substituents on the hydroxymethylene carbon
In the synthesis of sterically and electronically modified
chiral ligands, the N,N-dimethylamine moiety was kept
constant, whereas the ester moiety was functionalized with
various substituents. For this purpose, cis-monoester (ꢀ)-1
was reacted with hexamethylphosphorus triamide, which
transformed the carboxylic acid group into the correspond-
ing N,N-dimethyl amide derivative (ꢀ)-3 with a yield of
88%.13 Using a Grignard method, the ester group of (ꢀ)-
3 was functionalized with methyl and ethylmagnesium
iodide to give dimethyl and diethyl substituted derivatives
(+)-4a and (+)-4b, respectively. The five- and six-mem-
bered ring construction on the ester carbon of (ꢀ)-3 was
accomplished by using 1,4-dibromobutane and 1,5-dibromo-
pentane with magnesium in ether to afford (+)-4c and
(+)-4d, respectively. Subsequent reduction of (+)-4a–d by
LiAlH4 in ether afforded the resultant chiral ligands (+)-
5a–d (Scheme 1).
2. Results and discussion
2.1. Asymmetric synthesis of 1,4-aminoalcohols with
norbornene and norbornane backbone
In our synthetic route to the novel chiral 1,4-aminoalco-
hols, homochiral cis-monoester (ꢀ)-1 was chosen as the
starting compound. Recently, Bolm et al.12 reported a
highly efficient and widely applicable method for the
desymmetrization of meso-anhydrides via quinine- or quin-
idine-mediated opening with methanol. Although both
enantiomers of cis-monoester-1 could be synthesized with
quite high enantiomeric excesses (up to 99% ee), in our
study we only used cis-monoester (ꢀ)-1 obtained from qui-
nine-mediated desymmetrization of norborneneanhydride
(98% ee). The data have previously been reported.11
The main structural characteristic of the target 1,4-amino-
alcohols 5a–d, 7a–f, 9a–d is to possess various acyclic
and cyclic substitutions on the methylene carbon bearing
a hydroxyl group and an N,N-dialkyl, N-aryl and hetero-
cyclic amine. Additionally, the catalytic activity has been
evaluated and compared to those previously reported by
us for (+)-2a, (ꢀ)-2b, and (ꢀ)-2c.11 The obtained results
are related to the previous studies reported by us, and allow
us to compare the role of substitutions on both the hydroxy-
methylene side and the nitrogen moiety.
2.3. Asymmetric synthesis of N-functionalized 1,4-amino-
alcohol derivatives
Following our synthetic work, we also synthesized a new
set of novel chiral N-functionalized 1,4-aminoalcohols de-
rived from cis-monoester (ꢀ)-1. The key step for the N-
functionalization of (ꢀ)-1 was the DCC coupling method,
which transformed the carboxylic acid group into the cor-
responding N,N-disubstituted acyclic and cyclic amides
(ꢀ)-6a–c by using diethyl, diallyl, and dibenzyl amines as
(-)-1
a
CONMe2
CO2Me
(-)-3
b
CONMe2
OH
CONMe2
OH
CONMe2
OH
CONMe2
OH
Et
Et
(+)-4a
(+)-4b
(+)-4c
(+)-4d
c
c
c
c
NMe2
OH
NMe2
OH
NMe2
OH
NMe2
OH
(+)-5a
Et
Et
(+)-5c
(+)-5b
(+)-5d
Scheme 1. Reagents and conditions: (a) HMPTA, benzene, reflux; (b) (i) MeI, Mg, Et2O for (+)-4a; (ii) EtI, Mg, Et2O for (+)-4b; (iii) 1,4-dibromobutane,
Mg, Et2O for (+)-4c; (iv) 1,5-dibromopentane, Mg, Et2O for (+)-4d; (v) 1 M HCl for compounds (+)-4a–d; (c) LiAlH4, Et2O, reflux.

C. Tanyeli et al. / Tetrahedron: Asymmetry 18 (2007) 2349–2357
2351
the first set and pyrrolidine, piperidine, and morpholine
(ꢀ)-6d–f as the second set, respectively. Subsequent reduc-
tion of (ꢀ)-6a–f by LiAlH4 in ether afforded the resultant
chiral ligands (ꢀ)-7a, (+)-7b, (ꢀ)-7c, (+)-7d, (ꢀ)-7e, and
(ꢀ)-7f (Scheme 2).
the secondary amine functionality of this group of 1,4-
aminoalcohols can be useful chiral ligand candidates for
asymmetric borane reduction reactions, after the LAH
step, the norbornene backbone was subsequently trans-
formed into the norbornane backbone via hydrogenation
in the presence of Pd/C. In the LAH step, the nitro group
of compound (+)-8a was reduced into the amine group,
whereas the chloride substituted derivative (+)-8b afforded
the corresponding dechlorinated and chlorinated products
(+)-9b and (+)-9c in a 1:2 molar ratio, respectively, after
the hydrogenation step (Scheme 3).
The next step consisted of preparing various N-aryl substi-
tuted 1,4-aminoalcohols. cis-Monoester (ꢀ)-1 was coupled
with o-, m-, and p-substituted aniline derivatives using the
DCC method to obtain the desired amide ester products.
Unfortunately, m- and p-substituted aniline derivatives,
that is, m-nitroaniline, p-toluidine, p-chloroaniline, and
aniline itself, afforded meso-imide type products, whereas
only o-substituted derivatives o-nitro and o-chloro anilines
except o-anisidine yielded the amide ester type products
(+)-8a and (+)-8b, respectively. In addition to the aniline
derivatives, p-toluenesulfonamide was also introduced to
the carboxylic acid group of cis-monoester (ꢀ)-1. Since
The absolute configurations of (+)-5a–d, (ꢀ)-7a, 7c, 7e, 7f,
(+)-7b, 7d, and (ꢀ)-9a, 9d, (+)-9b, 9c were determined as
(S) for the carboxylic acid group attached to the stereogen-
ic center and as (R) for the ester group attached one, by
comparing the specific rotation signs determined at equal
concentrations in the same solvent with cis-monoester
cis-monoester (-)-1
a
Ph
Ph
CO N
CO2Me
CO N
CO2Me
CO N
CO2Me
CO N
CO2Me
CO N
CO2Me
O
CO N
CO2Me
(-)-6c
(-)-6d
(-)-6e
(-)-6f
(-)-6b
(-)-6a
b
Ph
Ph
O
N
OH
N
OH
N
OH
N
OH
N
OH
N
OH
(-)-7c
(+)-7d
(-)-7e
(-)-7f
(+)-7b
(-)-7a
Scheme 2. Reagents and conditions: (a) DCC, DMAP, CH2Cl2, secondary acyclic and cyclic amines; (b) LiAlH4, Et2O, reflux.
O2N
O
a
a
cis-monoester (-)-1
CO NH S
CO NH
CO2Me
CO2Me
O
a
Cl
(+)-8c
(+)-8a
b, c
H2N
b, c
CO NH
CO2Me
O
(+)-8b
N
H
N S
H
O
b, c
OH
OH
(-)-9a
(-)-9d
Cl
N
N
H
+
H
OH
OH
(+)-9b
(+)-9c
Scheme 3. Reagents and conditions: (a) DCC, DMAP, CH2Cl2; (i) o-nitroaniline for (+)-8a, (ii) o-chloroaniline for (+)-8b, (iii) p-toluenesulfonamide for
(+)-8c; (b) LiAlH4, Et2O, reflux; (c) H2, Pd/C, CH2Cl2.

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C. Tanyeli et al. / Tetrahedron: Asymmetry 18 (2007) 2349–2357
(+)-1, which has already been reported in the literature.12,14
In our synthetic route, the carboxylic acid group was trans-
formed into the amine functionality and the ester group
into the alcohol moiety of the target 1,4-aminoalcohols.
Since the transformation of the cis-monoester (ꢀ)-1 to chi-
ral ligands (+)-5a–d, (ꢀ)-7a, 7c, 7e, 7f, (+)-7b, 7d, and (ꢀ)-
9a, 9d, (+)-9b, 9c has no effect on the stereocenters of the
norbornene backbone, the absolute configuration of each
ligand was not altered during the transformation reactions.
selectivity of chiral ligand (+)-5a was explored. At
ꢀ10 ꢁC, catalyst (+)-5a gave 35% ee (entry 5) while in
hexane at 0 ꢁC afforded 33% ee (entry 6). Both the enantio-
selectivity and the chemical yield were lower than entry 1.
We also examined the effect of the solvent using THF,
DCM, and hexane for catalysts (+)-5b–d. In THF, both
catalysts (+)-5b and (+)-5c gave <5% ee (entries 7 and 9,
respectively). In DCM, 7% and 13% ee values were
obtained for catalysts (+)-5b and (+)-5c, respectively
(entries 8 and 10). The best result was obtained at the opti-
mized temperature 0 ꢁC in hexane for catalyst (+)-5d (69%
ee) (Table 1, entry 11).
2.4. Enantioselective addition of diethylzinc to benzaldehyde
using 5a–d, 7a–f, and 9a–c
As the second set of chiral 1,4-aminoalcohols, the catalytic
properties of 7a–d possessing various acyclic and cyclic
substituents on the nitrogen atom were explored again
in asymmetric diethylzinc addition to benzaldehyde. The
results are summarized in Table 2.
The catalytic properties of all new chiral 1,4-aminoalcohols
5a–d, 7a–f, and 9a–d were studied in the asymmetric dieth-
ylzinc addition to benzaldehyde. As the first set of chiral
1,4-aminoalcohols, (+)-5a–d possessing various acyclic
and cyclic substitutions on hydroxy methylene carbon were
tested. The results are summarized in Table 1.
Table 2. Asymmetric diethylzinc addition to benzaldehyde using nor-
bornene-based 1,4-aminoalcohol catalysts (ꢀ)-7a, (+)-7b, (ꢀ)-7c, (+)-7d,
(ꢀ)-7e, and (ꢀ)-7f
Table 1. Asymmetric diethylzinc addition to benzaldehyde using nor-
bornene-based 1,4-aminoalcohol catalysts (+)-5a–d
O
O
H
H
HO
HO
1. ZnEt2, L*
1. ZnEt2, L*
H
H
S
S
2. work-up
2. work-up
L* = (+)-5a-d
L* = (-)-7a, (+)-7b, (-)-7c
(+)-7d, (-)-7e, (-)-7f
Entry Liganda Solvent Temperature (ꢁC) Yieldb (%) eec (%)
Entry
Liganda
Solvent
Temperature
Yieldb
(%)
eec
(%)
(ꢁC)
1
2
3
4
5
6
7
8
9
(ꢀ)-7a
(ꢀ)-7a
(+)-7b
(ꢀ)-7c
(+)-7d
(+)-7d
(ꢀ)-7e
(ꢀ)-7e
(ꢀ)-7f
(ꢀ)-7f
Toluene
Hexane
Toluene
Toluene
Toluene
Hexane
Toluene
Hexane
Toluene
Hexane
0
0
0
0
0
0
0
0
0
0
92
87
89
79
86
82
85
83
88
76
89
60
72
58
20
5
40
85
63
30
1
2
3
4
5
6
7
8
9
(+)-5a
(+)-5b
(+)-5c
(+)-5d
(+)-5a
(+)-5a
(+)-5b
(+)-5b
(+)-5c
(+)-5c
(+)-5d
Toluene
Toluene
Toluene
Toluene
Toluene
Hexane
THF
DCM
THF
DCM
Hexane
0
0
0
0
78
38
89
78
41
52
20
10
15
10
80
53
15
11
65
35
33
<5
7
ꢀ10
0
0
0
0
0
0
<5
13
69
10
10
11
a 10 mol % of chiral catalysts was used.
b Yields were calculated after column chromatography.
a 10 mol % of chiral catalysts was used.
c Enantiomeric ratios were determined by HPLC analysis using a chiral
b Yields were calculated after column chromatography.
c Enantiomeric ratios were determined by HPLC analysis using a chiral
column. The major product has the (S)-configuration.
column. The major product has the (S)-configuration.
All the ligands exhibited acceptable enantioselectivities (up
to 89% ee) and afforded (S)-1-phenylpropanol. The reac-
tions were carried out at 0 ꢁC and in two different solvents:
toluene and hexane. The best results were obtained with
aminoalcohol having diethyl substituents on the nitrogen
atom (ꢀ)-7a and piperidinyl substituted aminoalcohol
(ꢀ)-7e as 89% and 85% ee values, respectively (Table 2, en-
tries 1 and 8). We observed high solvent dependence
enantioselectivities for this set of chiral catalysts. Catalyst
(ꢀ)-7a gave 89% ee in toluene (entry 1), but a drastic de-
crease of enantioselectivity was observed in hexane (entry
2). In contrast to this case, chiral catalyst (ꢀ)-7e afforded
40% ee in toluene (entry 7) and a sharp increase was ob-
served in hexane with 85% ee (entry 8). Similar solvent
dependence was observed for ligands (+)-7d and (ꢀ)-7f
as 20% and 63% ee in toluene and 5% and 30% ee in
The asymmetric diethylzinc addition reactions were first
carried out in toluene with 10 mol % of chiral catalysts
(+)-5a–d at 0 ꢁC and compared with the result of (ꢀ)-2c
(49% ee), which has diphenyl substituents on the hydroxy-
methylene carbon reported in our previous study (entries
1–4).11 The best results were obtained with aminoalcohol
(+)-5a (53% ee), which has dimethyl substituents on the
hydroxymethylene carbon (entry 1) and with (+)-5d (65%
ee), which has a cyclohexyl moiety on the hydroxymethyl-
ene carbon (entry 4). Catalysts with diethyl and cyclopentyl
substituents on the hydroxymethylene carbon (+)-5b and
(+)-5c, respectively (entries 2 and 3), gave products with
lower ee values. We investigated the conditions to improve
the enantioselectivity of the chiral catalysts. For this pur-
pose, the temperature and solvent dependence enantio-

C. Tanyeli et al. / Tetrahedron: Asymmetry 18 (2007) 2349–2357
2353
hexane, respectively (entries 5, 6, 9, and 10). Diallyl and
dibenzyl substituted aminoalcohols (+)-7b and (ꢀ)-7c
afforded acceptable enantioselectivities 72% and 58% ee
at 0 ꢁC and in toluene, respectively (entries 3 and 4).
piperidine, and morpholine, and afforded high enantiose-
lectivities by comparing with hydroxymethylene substi-
tuted ligands (up to 89% ee). The best results were
obtained with the secondary arylamine and tosyl amine
substituted ligands (2R,3S)-9a–c and (2S,3R)-9d (up to
97% ee). We also examined the effect of the solvent using
hexane, toluene, THF, and DCM and found out that hex-
ane and toluene were the best solvents for these ligands. We
concluded that the substitution on the nitrogen moiety is
more preferable over substitution on the hydroxymethylene
carbon.
In the last part, we explored the catalytic activities of 9a–d
having a secondary arylamine functionality and norborn-
ane backbone in the asymmetric diethylzinc addition to
benzaldehyde. The results are summarized in Table 3.
Table 3. Asymmetric diethylzinc addition to benzaldehyde using nor-
bornene-based 1,4-aminoalcohol catalysts (ꢀ)-9a, (+)-9b, (+)-9c, and
(ꢀ)-9d
4. Experimental
O
H
HO
1
The H and 13C NMR spectra were recorded in CDCl3 on
1. ZnEt2, L*
H
S
a Brucker Spectrospin Avance DPX 400 spectrometer.
Chemical shifts are given in ppm downfield from tetra-
methylsilane. Apparent splittings are given in all cases.
Infrared spectra were obtained from KBr pellets on a Matt-
son 1000 FT-IR spectrophotometer. Mass spectra were
recorded on a Varian MAT 212. Melting points are
uncorrected. Optical rotations were measured in a 1 dm cell
using a Rudolph Research Analytical Autopol III polarim-
eter at 20 ꢁC. HPLC measurements were performed with
ThermoFinnigan Spectra System instrument. Separations
were carried out on Chiralcel OD-H analytical column
(250 · 4.60 mm) with hexane/2-propyl alcohol as eluent.
Column chromatography was performed on silica gel (60-
mesh, Merck). TLC was carried out on Merck 0.2-mm sil-
ica gel 60 F254 analytical aluminum plates. Elemental anal-
yses were carried out using a LECO 932-CHN instrument.
2. work-up
L* = (-)-9a, (+)-9b, (+)-9c, (-)-9d
Entry
Liganda
Solvent
Temperature
Yieldb
(%)
eec
(%)
(ꢁC)
1
2
3
4
5
6
7
8
(ꢀ)-9a
(ꢀ)-9a
(+)-9b
(+)-9b
(+)-9c
(+)-9c
(ꢀ)-9d
(ꢀ)-9d
Hexane
Toluene
Hexane
Toluene
Hexane
Toluene
Hexane
Toluene
0
0
0
0
0
0
0
0
93
97
87
91
79
82
96
97
91
95
84
92
76
80
97
96
a 10 mol % of chiral catalysts was used.
b Yields were calculated after column chromatography.
c Enantiomeric ratios were determined by HPLC analysis using a chiral
column. The major product has the (S)-configuration.
4.1. Synthesis of (2R,3S)-methyl 3-(dimethylcarbamoyl)-
bicyclo[2.2.1] hept-5-ene-2-carboxylate (ꢀ)-3
All the catalysts were tested at 0 ꢁC in hexane and toluene.
o-Aminoaniline substituted chiral ligand (ꢀ)-9a gave 91%
ee in hexane and 95% ee in toluene, respectively (Table 3,
entries 1 and 2). A drastic increase was observed for aniline
substituted ligand (+)-9b in hexane and toluene from 84%
to 92% ee, respectively (entries 3 and 4), whereas o-chloro
aniline substituted ligand (+)-9c showed a slight increase
in hexane and toluene from 76% to 80% ee, respectively
(entries 5 and 6). Tosyl substituted aminoalcohol catalyst
(ꢀ)-9d afforded almost the same enantioselectivities 97–
96% ee in hexane and toluene, respectively (entries 7 and 8).
To the solution of cis-monoester (ꢀ)-1 (2.00 g, 10.2 mmol)
in benzene (5 mL) was added hexamethylphosphorous tri-
amide (1.85 mL, 5.1 mmol) at a rate that maintained the re-
flux of the reaction. After 2 h, the resulting cloudy solution
was allowed to cool to room temperature and a saturated
NaHCO3 solution was added. The aqueous layer was ex-
tracted with DCM. The organic solutions were combined,
dried over MgSO4, and concentrated to give compound
20
(ꢀ)-3 (2.01 g, 88%). ½aꢁD ¼ ꢀ39:1 ðc 2:03; CHCl3Þ; mp
1
78–79 ꢁC; IR (KBr): 2998, 1742, 1637 cmꢀ1; H NMR: d
6.30 (dd, J ¼ 3:03, 5.34 Hz, 1H), 6.12 (dd, J ¼ 2:93,
5.39 Hz, 1H), 3.52 (s, 3H), 3.35 (dd, J ¼ 3:16, 9.91 Hz,
1H), 3.19 (dd, J ¼ 3:48, 9.92 Hz, 1H), 3.12 (s, 1H), 3.04
(s, 1H), 2.95 (s, 3H), 2.81 (s, 3H), 1.38 (d, J ¼ 8:5 Hz,
1H), 1.27 (d, J ¼ 8:5 Hz, 1H); 13C NMR: d 173.3, 172.4,
136.6, 133.9, 51.9, 49.2, 48.9, 47.3, 47.0, 46.9, 37.3, 36.0;
HRMS calcd for C12H18NO3 (M+H)+, 224.1287; found,
224.1277.
3. Conclusion
We have synthesized a series of chiral norbornene-based
1,4-aminoalcohols (2R,3S)-5a–d, (2R,3S)-7a–f, (2R,3S)-
9a–c, and (2S,3R)-9d where the amine moiety attached chi-
ral center has (S)-configuration while the alcohol moiety
attached stereogenic center has an (R)-configuration. These
compounds were used as ligands in the asymmetric diethyl-
zinc addition to benzaldehyde. Ligands (2R,3S)-5a–d
possess various acyclic and cyclic substituents on hydrox-
ymethylene carbon and gave moderate enantioselectivities
(up to 69% ee). The other set of ligands (2R,3S)-7a–f was
functionalized on the nitrogen atom by various acyclic sub-
stituents and heterocyclic systems, that is, pyrrolidine,
4.2. General procedure for Grignard reactions
Haloalkane (7.7 mmol) was dissolved in 10 mL of anhy-
drous diethyl ether and placed into the addition funnel.
This solution was added to magnesium (10.2 mmol) turn-
ings. Once the reaction had begun, the rest of the halo-
alkane solution was added dropwise at a rate that

2354
C. Tanyeli et al. / Tetrahedron: Asymmetry 18 (2007) 2349–2357
maintained gentle reflux. When the addition of the halo-
alkane solution was complete, the mixture was refluxed
for 20 min. Compound (ꢀ)-3 (2.6 mmol) was dissolved in
15 mL of anhydrous diethyl ether and added to the pre-
pared Grignard mixture. After all of compound (ꢀ)-3 solu-
tion had been added, the reaction mixture was refluxed for
2 h. The resultant mixture was poured into a mixture of ice
(25 g) and 3 M H2SO4 (30 mL). The organic phase was
washed with 5% NaHCO3 and then with brine, after which
it was dried over MgSO4, the solvent evaporated and the
crude product purified by column chromatography
(EtOAc).
overnight at room temperature. DCC precipitated as dic-
yclohexylurea. The mixture was filtered and the filtrate
was washed first with 1 M HCl, then with 1 M NaHCO3
and finally with brine. The organic phase was dried over
MgSO4 and evaporation of the solvent afforded the desired
amide ester product.
4.3.1. (2R,3S)-Methyl 3-(diethylcarbamoyl)bicyclo[2.2.1]-
hept-5-ene-2-carboxylate (ꢀ)-6a. (0.45 g, 35%); mp: 65–
20
68 ꢁC; ½aꢁD ¼ ꢀ32:4 ðc 3:00; CHCl3Þ; 1H NMR: d 6.30
(dd, J ¼ 3:03, 5.34 Hz, 2H), 3.56 (s, 3H), 3.46–3.37 (m,
2H), 3.23–3.19 (m, 2H), 3.12 (d, J ¼ 3:43 Hz, 1H), 3.10
(br s, 1H), 2.98 (br s, 1H), 1.45 (d, J ¼ 8:43 Hz, 1H),
1.33 (d, J ¼ 8:40 Hz, 1H), 1.21 (t, J ¼ 7:12 Hz, 3H), 1.06
(t, J ¼ 7:07 Hz, 3H); 13C NMR: d 173.0, 170.7, 135.2,
134.1, 51.2, 49.3, 48.6, 47.1, 46.3, 46.2, 41.5, 40.1, 14.5,
12.8.
4.2.1.
bicyclo[2.2.1]hept-5-ene-2-carboxamide
(2S,3R)-3-(2-Hydroxypropan-2-yl)-N,N-dimethyl-
(+)-4a. (0.38 g,
20
40%); mp 99–101 ꢁC; ½aꢁ ¼ þ84:6 ðc 1:84; CHCl3Þ; 1H
NMR:
d
6.46 (dd, JD¼ 2:90 Hz, 1H), 5.87 (dd,
J ¼ 2:90 Hz, 1H), 5.76 (s, 1H), 3.45 (dd, J ¼ 3:10,
9.30 Hz, 1H), 3.20 (s, 3H), 3.09 (s, 1H), 2.96 (s, 4H), 2.36
(d, J ¼ 9:34 Hz, 1H), 1.39 (d, J ¼ 8:10 Hz, 1H), 1.32 (d,
J ¼ 8:05 Hz, 1H), 1.26 (s, 3H), 1.09 (s, 3H); 13C NMR: d
175.9, 137.4, 130.4, 69.5, 58.4, 49.6, 47.1, 46.1, 43.8, 38.3,
36.6, 31.1, 30.9.
4.3.2. (2R,3S)-Methyl 3-(diallylcarbamoyl)bicyclo[2.2.1]-
hept-5-ene-2-carboxylate (ꢀ)-6b. (0.91 g, 65%) colorless
20
1
oil; ½aꢁD ¼ ꢀ43:90 ðc 2:03; CHCl3Þ; H NMR: d 6.27 (dd,
J ¼ 3:95, 14.80 Hz, 2H), 5.87–5.69 (m, 2H), 5.24 (t,
J ¼ 4:45 Hz, 2H), 5.11 (dd, J ¼ 2:98, 14.8 Hz, 2H), 4.05
(dd, J ¼ 5:08, 15.0 Hz, 1H), 3.99 (t, J ¼ 1:85 Hz, 1H),
3.88 (dt, J ¼ 2:14, 17.5 Hz, 1H), 3.78 (dd, J ¼ 6:47,
15.0 Hz, 1H), 3.56 (s, 3H), 3.40 (dd, J ¼ 3:18, 9.99 Hz,
1H), 3.22 (dd, J ¼ 3:29, 9.97 Hz, 1H), 3.16 (s, 1H), 3.05
(s, 1H), 1.43 (d, J ¼ 8:43 Hz, 1H), 1.32 (d, J ¼ 8:46 Hz,
1H). 13C NMR: d 172.8, 171.9, 134.9, 134.3, 133.5, 133.2,
117.0, 116.5, 51.3, 49.3, 48.8, 48.6, 48.1, 47.1, 46.1, 20.8.
4.2.2. (2S,3R)-3-(3-Hydroxypentan-3-yl)-N,N-dimethylbi-
cyclo[2.2.1]hept-5-ene-2-carboxamide (+)-4b. (0.29 g, 34%);
20
1
mp 82–83 ꢁC; ½aꢁD ¼ þ80:8 ðc 2:11; CHCl3Þ; H NMR: d
6.37 (dd, J ¼ 3:10, 5.20 Hz, 1H), 5.80 (dd, J ¼ 2:90,
5.30 Hz, 1H), 5.56 (s, 1H), 3.36 (dd, J ¼ 3:10, 9.30 Hz,
1H), 3.12 (s, 3H), 2.97 (s, 1H), 2.80 (s, 4H), 2.38 (dd,
J ¼ 2:43, 9.30 Hz, 1H), 1.65–1.55 (m, 2H), 1.45–1.36 (m,
2H), 1.32–1.16 (m, 2H), 0.78–0.72 (m, 6H); 13C NMR: d
176.0, 137.5, 130.2, 73.5, 54.8, 49.5, 47.1, 45.5, 43.6, 38.3,
36.6, 30.8, 30.1, 8.3,7.9.
4.3.3. (2R,3S)-Methyl 3-(dibenzylcarbamoyl)bicyclo[2.2.1]-
hept-5-ene-2-carboxylate (ꢀ)-6c. (1.03 g, 54%); mp 77–
20
80 ꢁC; ½aꢁD ¼ ꢀ34:9 ðc 2:03; CHCl3Þ; 1H NMR: d 7.40–
7.14 (m, 10H), 6.38 (dd, J ¼ 5:18, 3.21 Hz, 1H), 6.23 (dd,
J ¼ 5:25, 2.99 Hz, 1H), 4.40–4.63 (m, 4H), 3.54 (s, 4H),
3.17 (s, 2H), 3.01 (s,1H), 1.43 (d, J ¼ 13:69 Hz, 1H), 1.25
(d, J ¼ 8:34 Hz, 1H). 13C NMR: d 173.0, 172.2, 137.6,
136.7, 135.3, 134.0, 129.0, 128.7, 128.4, 127.6, 127.3,
126.4, 51.3, 49.7, 49.4, 48.7, 48.4, 47.3, 46.2, 45.9.
4.2.3. (2S,3R)-3-(1-Hydroxycyclopentyl)-N,N-dimethylbi-
cyclo[2.2.1]hept-5-ene-2-carboxamide (+)-4c. (0.21 g, 40%);
20
1
mp 104–105 ꢁC; ½aꢁD ¼ þ46:2 ðc 2:01; CHCl3Þ; H NMR:
d 6.38 (dd, J ¼ 3:60, 8.20 Hz, 1H), 5.80 (dd, J ¼ 3:50,
5.20 Hz, 1H), 5.26 (s, 1H), 3.38 (dd, J ¼ 3:20, 9.40 Hz,
1H), 3.12 (s, 3H), 2.98 (s, 1H), 2.87 (s, 4H), 2.31 (dd,
J ¼ 2:53, 9.40 Hz, 1H), 1.76–1.65 (m, 4H), 1.50–1.38 (m,
4H), 1.25 (d, J ¼ 5:50 Hz, 1H), 1.22 (d, J ¼ 6:30 Hz, 1H);
13C NMR: d 175.0, 138.0, 129.9, 80.8, 58.3, 50.0, 47.1,
47.0, 44.3, 41.6, 41.2, 38.2, 36.4, 24.3, 24.1.
4.3.4. (2R,3S)-Methyl 3-(pyrrolidine-1-carbonyl)bicyclo[2.2.1]-
hept-5-ene-2-carboxylate (ꢀ)-6d. (0.50 g, 39%); mp 51–
20
52 ꢁC; ½aꢁD ¼ ꢀ24:65 ðc 0:10; MeOHÞ; 1H NMR: d 6.32
(dd, J ¼ 3:00, 5.41 Hz, 1H), 6.26 (dd, J ¼ 2:94, 5.42 Hz,
1H), 3.58 (s, 3H), 3.42 (dt, J ¼ 8:43, 16.68 Hz, 4H), 3.33
(dd, J ¼ 3:17, 10.00 Hz, 1H), 3.24 (dd, J ¼ 3:40,
10.00 Hz, 1H), 3.17 (s, 1H), 3.10 (s, 1H), 1.93–1.91 (m,
2H), 1.84 (p, J ¼ 6:73 Hz, 2H), 1.44 (dd, J ¼ 1:42,
8.47 Hz, 1H), 1.32 (d, J ¼ 8:43 Hz, 1H); 13C NMR: d
172.8, 170.4, 135.5, 133.9, 51.4, 48.7, 48.5, 48.1, 46.3,
46.2, 45.7, 26.1, 24.2.
4.2.4.
(2S,3R)-3-(1-Hydroxycyclohexyl)-N,N-dimethylbi-
cyclo[2.2.1]hept-5-ene-2-carboxamide (+)-4d. (0.28 g, 40%)
20
colorless oil; ½aꢁD ¼ þ52:4 ðc 2:00; CHCl3Þ; 1H NMR: d
6.44 (dd, J ¼ 3:09, 5.30 Hz, 1H), 5.98 (dd, J ¼ 2:90,
5.20 Hz, 1H), 5.43 (s, 1H), 3.34 (dd, J ¼ 3:07, 9.18 Hz,
1H), 3.11 (s, 3H), 3.02 (s, 1H), 2.88 (s, 4H), 2.31 (d,
J ¼ 9:28 Hz, 1H), 1.75–1.08 (m, 12H); 13C NMR: d 176.0,
137.5, 130.2, 70.1, 57.9, 49.5, 47.0, 45.0, 43.5, 39.0, 38.8,
38.3, 36.6, 26.2, 22.2, 21.9.
4.3.5. (2R,3S)-Methyl 3-(piperidine-1-carbonyl)bicyclo-
[2.2.1]hept-5-ene-2-carboxylate (ꢀ)-6e. (1.18 g, 88%); mp
20
4.3. General procedure for DCC coupling reactions
77–78 ꢁC; ½aꢁD ¼ ꢀ21:95 ðc 2:00; MeOHÞ; 1H NMR: d
6.21 (dd, J ¼ 3:02, 5.19 Hz, 1H), 6.07 (dd, J ¼ 2:90,
5.27 Hz, 1H), 3.62–3.58 (m, 1H), 3.46 (s, 3H), 3.42 (s,
1H), 3.29 (dd, J ¼ 2:91, 9.78 Hz, 1H), 3.10 (dd, J ¼ 3:12,
9.83 Hz, 3H), 3.04 (s, 1H), 2.95 (s, 1H), 1.54–1.43 (m,
6H), 1.32 (d, J ¼ 7:92 Hz, 1H), 1.21 (d, J ¼ 1:21 Hz,
cis-Monoester (ꢀ)-1 (1.0 equiv) and amine (1.0 equiv) were
dissolved in DCM at 0 ꢁC under an argon atmosphere.
Then, DCC (1.1 equiv) and DMAP (0.25 equiv) were
added simultaneously at 0 ꢁC. The mixture was stirred

C. Tanyeli et al. / Tetrahedron: Asymmetry 18 (2007) 2349–2357
2355
1H); 13C NMR: d 172.9, 170.0, 135.8, 133.5, 51.3, 48.8,
48.3, 46.9, 46.8, 46.6, 42.7, 33.8, 26.3, 25.4, 25.0.
4.4.1. 2-((2R,3S)-3-((Dimethylamino)methyl)bicyclo[2.2.1]-
hept-5-en-2-yl)propan-2-ol (+)-5a. (0.14 g, 30%) colorless
20
oil; ½aꢁD ¼ þ17:4 ðc 1:37; CHCl3Þ; IR (KBr): 3445, 2968,
1
1729 cmꢀ1; H NMR: d 6.12 (dd, J ¼ 2:90, 5.70 Hz, 1H),
4.3.6. (2R,3S)-Methyl 3-(morpholine-4-carbonyl)bicyclo-
[2.2.1]hept-5-ene-2-carboxylate (ꢀ)-6f. (1.00 g, 74%); mp
5.97 (dd, J ¼ 2:90, 5.30 Hz, 1H), 2.71 (br s, 1H), 2.63 (br
s, 1H), 2.43 (s, 1H), 2.41 (s, 1H), 2.35 (dd, J ¼ 2:70,
5.30 Hz, 1H), 2.16 (s, 6H), 2.09 (s, 1H), 2.02 (dd,
J ¼ 2:90, 12.70 Hz, 1H), 1.37 (q, J ¼ 6:20 Hz, 2H), 1.19
(s, 3H), 0.95 (s, 3H); 13C NMR: d 135.6, 133.0, 70.3,
60.0, 54.5, 50.3, 46.7, 45.7, 43.8, 40.7, 31.9, 27.2. Anal.
Calcd for C13H23NO: C, 74.59; H, 11.07; N, 6.69. Found:
C, 74.27; H, 10.82; N, 6.53.
20
1
87–88 ꢁC; ½aꢁD ¼ ꢀ32:2 ðc 0:20; MeOHÞ; H NMR: d 6.34
(dd, J ¼ 3:01, 5.36 Hz, 1H), 6.10 (dd, J ¼ 2:92, 5.40 Hz,
1H), 3.60 (d, J ¼ 7:73 Hz, 4H), 3.50 (s, 3H), 3.47 (d,
J ¼ 14:35 Hz, 2H), 3.34 (d, J ¼ 9:13 Hz, 2H), 3.28 (dd,
J ¼ 3:12, 9.84 Hz, 1H), 3.18 (dd, J ¼ 3:47, 9.88 Hz, 1H),
3.12 (s, 1H), 3.02 (s, 1H), 1.40 (d, J ¼ 8:53 Hz, 1H), 1.26
(d, J ¼ 8:50 Hz, 1H); 13C NMR: d 172.2, 170.9, 136.3,
133.4, 66.8, 66.3, 51.5, 48.8, 48.4, 46.9, 46.8, 46.7, 45.8,
42.2.
4.4.2. 3-((2R,3S)-3-((Dimethylamino)methyl)bicyclo[2.2.1]-
hept-5-en-2-yl)pentan-3-ol (+)-5b. (0.10 g, 35%) colorless
20
oil; ½aꢁD ¼ þ17:35 ðc 1:30; CHCl3Þ; IR (KBr): 3409, 2965,
4.3.7. (2R,3S)-Methyl 3-(2-nitrophenylcarbamoyl)bicyclo-
[2.2.1]hept-5-ene-2-carboxylate (+)-8a. (0.97 g, 60%); mp
1
1725 cmꢀ1; H NMR: d 6.30 (dd, J ¼ 3:20, 5.30 Hz, 1H),
20
1
5.92 (dd, J ¼ 3:00, 5.30 Hz, 1H), 5.53 (s, 1H), 3.54–3.51
(m, 1H), 3.35 (dd, J ¼ 3:20, 9.80 Hz, 1H), 3.12 (br s,
1H), 3.08 (s, 3H), 2.97 (s, 1H), 2.90 (s, 1H), 2.88 (s, 3H),
2.43–2.37 (m, 1H), 1.59–1.48 (m, 2H), 1.40–1.18 (m, 4H),
0.89 (t, J ¼ 7:40 Hz, 6H); 13C NMR: d 136.6, 134.4, 74.6,
61.0, 51.0, 50.9, 47.2, 45.8, 44.5, 41.0, 31.8, 31.6, 30.8,
7.9, 7.7. Anal. Calcd for C15H27NO: C, 75.90; H, 11.46;
N, 5.90. Found: C, 75.67; H, 11.12; N, 5.53.
96–97 ꢁC; ½aꢁD ¼ þ7:9 ðc 2:00; CHCl3Þ; H NMR: d 10.52
(s, 1H), 8.74 (d, J ¼ 8:54 Hz, 1H), 8.21 (d, J ¼ 6:96 Hz,
1H), 7.64 (t, J ¼ 7:14 Hz, 1H), 7.18 (t, J ¼ 7:83 Hz, 1H),
6.33 (dd, J ¼ 5:41, 2.90 Hz, 1H), 6.19 (dd, J ¼ 5:37,
2.70 Hz, 1H), 3.73 (s, 3H), 3.37 (t, J ¼ 4:1 Hz, 1H), 3.31
(br s, 1H), 3.20 (br s, 1H), 2.72 (t, J ¼ 2:34 Hz, 1H), 1.80
(d, J ¼ 8:75 Hz, 1H), 1.55 (dd, J ¼ 8:80, 1.45 Hz, 1H);
13C NMR: d 173.5, 173.2, 137.5, 136.7, 136.1, 135.7,
134.8, 125.7, 123.2, 122.5, 52.1, 50.6, 49.3, 47.5, 47.0, 45.0.
4.4.3. 1-((2R,3S)-3-((Dimethylamino)methyl)bicyclo[2.2.1]-
hept-5-en-2-yl)cyclopentanol (+)-5c. (0.11 g, 54%) colorless
20
4.3.8. (2R,3S)-Methyl 3-(2-chlorophenylcarbamoyl)bicyclo-
[2.2.1]hept-5-ene-2-carboxylate (+)-8b. (1.06 g, 68 %); mp
oil; ½aꢁD ¼ þ11:1 ðc 2:56; CHCl3Þ; IR (KBr): 3409, 2960,
1
1464, 1074 cmꢀ1; H NMR: d 6.10 (dd, J ¼ 2:91, 5.53 Hz,
20
1
78–79 ꢁC; ½aꢁD ¼ þ58:9 ðc 2:00; CHCl3Þ; H NMR: d 8.25
(d, J ¼ 8:06 Hz, 1H), 8.20 (s, 1H), 7.25 (d, J ¼ 7:90 Hz,
1H), 7.16 (t, J ¼ 8:00 Hz, 1H), 6.91 (t, J ¼ 7:80 Hz, 1H),
6.19 (dd, J ¼ 2:90, 5.28 Hz, 1H), 6.07 (dd, J ¼ 2:95,
5.32 Hz, 1H), 3.61 (s, 3H), 3.18 (d, J ¼ 4:57 Hz, 2H),
3.01 (br s, 1H), 2.64 (t, J ¼ 1:63 Hz, 1H), 1.70 (d,
J ¼ 7:95 Hz, 1H), 1.44 (d, J ¼ 8:05 Hz, 1H); 13C NMR: d
174.0, 172.4, 137.7, 135.9, 135.0, 133.2, 127.6, 124.5,
122.8, 121.7, 49.8, 49.8, 48.9, 47.7, 47.5, 46.2.
1H), 5.99 (dd, J ¼ 2:86, 5.53 Hz, 1H), 2.73 (br s, 1H),
2.64 (d, J ¼ 3:40 Hz, 1H), 2.61 (d, J ¼ 2:55 Hz, 1H),
2.59–2.51 (m, 1H), 2.30 (t, J ¼ 12:43 Hz, 1H), 2.15 (br s,
7H), 1.95 (dd, J ¼ 2:40, 12.40 Hz, 1H), 1.80–1.40 (m, 8H),
1.35 (d, J ¼ 7:96 Hz, 2H); 13C NMR: d 135.6, 133.0, 70.3,
60.0, 54.5, 50.3, 46.7, 45.7, 43.8, 40.7, 31.9, 27.2. Anal.
Calcd for C15H25NO: C, 76.55; H, 10.71; N, 5.95. Found:
C, 76.67; H, 10.71; N, 5.64.
4.4.4. 1-((2R,3S)-3-((Dimethylamino)methyl)bicyclo[2.2.1]-
hept-5-en-2-yl)cyclohexanol (+)-5d. (0.14 g, 52%) colorless
4.3.9. (2R,3S)-Methyl 3-(tosylcarbamoyl)bicyclo[2.2.1]hept-
5-ene-2-carboxylate (+)-8c. (1.46 g, 82%); mp 76 ꢁC;
20
oil; mp 67–68 ꢁC; ½aꢁD ¼ þ3:7 ðc 2:16; CHCl3Þ, IR (KBr):
20
½aꢁD ¼ þ16:7 ðc 2:00; CHCl3Þ; 1H NMR:
d 7.88 (d,
3506, 2954, 1556, 1094 cmꢀ1
;
1H NMR: d 6.15 (dd,
J ¼ 8:28 Hz, 2H), 7.24 (d, J ¼ 8:15 Hz, 2H), 6.12 (dd,
J ¼ 3:20, 5.42 Hz, 1H), 6.01 (dd, J ¼ 3:17, 5.48 Hz, 1H),
3.61 (s, 3H), 3.14 (br s, 1H), 3.10 (t, J ¼ 4:26 Hz, 1H),
2.98 (br s, 1H), 2.38 (d, J ¼ 4:82 Hz, 1H), 2.36 (s, 3H),
1.50 (dd, J ¼ 8:95, 17.40 Hz, 1H), 1.33 (dd, J ¼ 8:62,
16.85 Hz, 1H); 13C NMR: d 174.3, 171.8, 144.8, 137.5,
136.0, 135.7, 129.5, 128.3, 52.3, 49.2, 48.5, 47.3, 46.2,
44.9, 33.8.
J ¼ 3:08, 5.70 Hz, 1H), 5.95 (dd, J ¼ 2:70, 5.70 Hz, 1H),
2.75 (br s, 1H), 2.62–2.55 (m, 2H), 2.39 (t, J ¼ 12:83 Hz,
1H), 2.25 (dd, J ¼ 2:84, 2.42 Hz, 1H), 2.15 (br s, 6H),
2.12 (s, 1H), 1.99 (dd, J ¼ 2:84, 2.39 Hz, 1H), 1.79–1.16
(m, 6H), 1.12 (dd, J ¼ 3:93, 3.95 Hz, 2H), 1.07–0.95 (m,
4H); 13C NMR: d 136.7, 133.9, 71.9, 61.5, 57.2, 51.3,
47.6, 46.0, 44.6, 41.8, 39.9, 36.1, 26.1, 22.0, 21.4. Anal.
Calcd for C16H27NO: C, 77.06; H, 10.91; N, 5.62. Found:
C, 76.81; H, 10.95; N, 5.67.
4.4. General procedure for LAH reduction reactions
4.4.5.
((2R,3S)-3-((Dimethylamino)methyl)bicyclo[2.2.1]-
To a suspension of LiAlH4 (3.0 equiv) in dry THF (10 mL)
was added a solution of amide or amidoester (1.0 equiv) in
THF (5 mL) at a rate which maintained gentle reflux. The
mixture was then refluxed for 1 day and hydrolized by the
cautious addition of water and 15% NaOH solution. The
fine white precipitate, which formed, was washed with
ether and discarded. The filtrate was concentrated and
purified by column chromatography.
hept-5-en-2-yl)methanol (ꢀ)-7a. (0.36 g, 95%) colorless
20
oil; ½aꢁD ¼ ꢀ6:4 ðc 1:80; CHCl3Þ; IR (KBr): 3412, 2968,
1645 cmꢀ1
;
1H NMR:
d
6.06 (s, 2H), 3.47 (d,
J ¼ 11:30 Hz, 1H), 3.19 (t, J ¼ 11:25 Hz, 1H), 2.74–2.67
(m, 4H), 2.61–2.52 (m, 2H), 2.44–2.35 (m, 2H), 2.32 (d,
J ¼ 7:50 Hz, 2H), 1.40 (s, 2H), 1.02 (t, J ¼ 7:14 Hz, 6H);
13C NMR: d 135.1, 134.0, 62.8, 54.2, 50.0, 47.7, 47.0,
46.4, 46.3, 39.4, 10.4. Anal. Calcd for C13H23NO: C,

2356
C. Tanyeli et al. / Tetrahedron: Asymmetry 18 (2007) 2349–2357
74.59; H, 11.07; N, 6.69. Found: C, 73.93; H, 10.85; N,
6.48.
4.5. General procedure for hydrogenation reactions
The compound was dissolved in CH2Cl2 (10 mL) at room
temperature and Pd/C (10% (w/w)) was then added to this
solution. H2 gas was allowed to pass into the reaction ves-
sel. The reaction was continued until the starting com-
pound was consumed as monitored by TLC. The mixture
was filtered on Celite and washed with CH2Cl2
(3 · 20 mL). Evaporation of the solvent afforded the de-
sired product.
4.4.6. ((2R,3S)-3-((Diallylamino)methyl)bicyclo[2.2.1]hept-
5-en-2-yl)methanol (+)-7b. (0.58 g, 75%) colorless oil;
20
½aꢁD ¼ þ15:7 ðc 1:00; CHCl3Þ; IR (KBr): 3458, 2962,
1
1642 cmꢀ1; H NMR: d 6.04 (dd, J ¼ 2:65, 5.52 Hz, 2H),
5.89–5.79 (m, 2H), 5.19 (d, J ¼ 8:18 Hz, 2H), 5.16 (d,
J ¼ 8:18 Hz, 2H), 3.48 (dd, J ¼ 2:95, 11.65 Hz, 1H), 3.38
(d, J ¼ 5:47 Hz, 1H), 3.34 (d, J ¼ 5:46 Hz, 1H), 3.17 (t,
J ¼ 11:40 Hz, 1H), 2.87 (q, J ¼ 8:03 Hz, 2H), 2.75 (br s,
1H), 2.69 (br s, 1H), 2.63–2.56 (m, 1H), 2.53–2.46 (m,
1H), 2.40 (t, J ¼ 12:60 Hz, 1H), 2.29 (dd, J ¼ 2:94,
12.78 Hz, 1H), 1.40 (dd, J ¼ 1:58, 8.32 Hz, 2H); 13C
NMR: d 135.4, 134.4, 133.7, 118.8, 62.9, 56.6, 54.4, 50.0,
47.7, 47.0, 46.3, 39.3. Anal. Calcd for C15H23NO: C,
77.21; H, 9.93; N, 6.00. Found: C, 76.56; H, 10.13; N, 6.16.
4.5.1.
((2R,3S)-3-((2-Aminophenylamino)methyl)bicyclo-
[2.2.1]heptan-2-yl)methanol (ꢀ)-9a. (0.67 g, 90%); mp
20
85 ꢁC; ½aꢁD ¼ ꢀ116:0 ðc 0:10; CHCl3Þ; IR (KBr): 3364,
1
2959, 1603 cmꢀ1; H NMR: d 6.72 (t, J ¼ 6:25 Hz, 1H),
6.58 (dd, J ¼ 1:42, 7.41 Hz, 1H), 6.54 (d, J ¼ 7:30 Hz,
1H), 6.50 (d, J ¼ 4:40 Hz, 1H), 3.54 (dd, J ¼ 4:89,
10.06 Hz, 1H), 3.27 (t, J ¼ 9:93 Hz, 1H), 3.02 (dd,
J ¼ 5:22, 10.79 Hz, 1H), 2.60 (t, J ¼ 10:60 Hz, 1H), 2.10
(br s, 1H), 1.99 (d, J ¼ 4:06 Hz, 1H), 1.52 (dd, J ¼ 4:54,
9.11 Hz, 1H), 1.51–1.43 (m, 1H), 1.39 (d, J ¼ 9:60 Hz,
1H), 1.25–1.18 (m, 1H), 1.18 (br s, 1H), 1.12 (br s, 1H),
1.12–1.10 (m, 1H), 1.04–0.98 (m, 1H); 13C NMR: d 138.1,
133.2, 120.9, 117.6, 116.3, 111.0, 49.3, 49.2, 48.1, 41.3,
39.4, 37.6, 30.1, 25.9, 22.7. Anal. Calcd for C15H22N2O:
C, 77.13; H, 9.00; N, 11.37. Found: C, 76.93; H, 8.65; N,
10.98.
4.4.7.
((2R,3S)-3-((Dibenzylamino)methyl)bicyclo[2.2.1]-
hept-5-en-2-yl)methanol (ꢀ)-7c. (0.66 g, 72%); mp 92 ꢁC;
20
½aꢁD ¼ ꢀ33:0 ðc 2:00; CHCl3Þ; IR (KBr): 3230, 2965,
1599, 1451 cmꢀ1 1H NMR: d 7.34–7.24 (m, 10H), 6.52
;
(br s, 1H), 6.02 (dd, J ¼ 7:00, 9.94 Hz, 2H), 3.91 (s, 1H),
3.87 (s, 1H), 3.39 (d, J ¼ 11:58 Hz, 1H), 3.24 (s, 1H),
3.21 (s, 1H), 2.86 (t, J ¼ 11:42 Hz, 1H), 2.71 (s, 1H),
2.53–2.44 (m, 3H), 2.24 (dd, J ¼ 2:84, 13.1 Hz, 2H), 1.36
(s, 2H); 13C NMR: d 136.9, 135.4, 134.3, 129.8, 128.4,
127.4, 62.7, 58.5, 55.6, 49.9, 47.9, 46.9, 46.4, 39.3. Anal.
Calcd for C23H27NO: C, 82.84; H, 8.16; N, 4.20. Found:
C, 82.20; H, 8.46; N, 4.45.
4.5.2. ((2R,3S)-3-((Phenylamino)methyl)bicyclo[2.2.1]heptan-
2-yl)methanol (+)-9b. After LAH reduction of (+)-8b,
without purification the mixture was subjected to hydro-
20
genation. (0.24 g, 30%); mp 68–69 ꢁC; ½aꢁD
¼
4.4.8. ((2R,3S)-3-(Pyrrolidin-1-ylmethyl)bicyclo[2.2.1]hept-
5-en-2-yl)methanol (+)-7d. (0.39 g, 95%); mp 65–66 ꢁC;
þ5:1 ðc 2:00; CHCl3Þ; IR (KBr): 3423, 2960, 1602 cmꢀ1
;
1H NMR: d 7.08 (t, J ¼ 7:90 Hz, 2H), 6.62 (t, J ¼
6:95 Hz, 1H), 6.51 (d, J ¼ 7:92 Hz, 2H), 3.58 (dd,
J ¼ 6:05, 10.09 Hz, 1H), 3.43 (t, J ¼ 9:51 Hz, 1H), 3.13
(br s, 1H), 3.00 (dd, J ¼ 6:21, 11.56 Hz, 1H), 2.70 (dd,
J ¼ 9:22, 11.46 Hz, 1H), 2.19 (s, 1H), 2.02 (d,
J ¼ 4:08 Hz, 1H), 1.62–1.56 (m, 1H), 1.55–1.47 (m, 1H),
1.41 (d, J ¼ 9:84 Hz, 1H), 1.32–1.22 (m, 3H), 1.17 (d,
J ¼ 9:84 Hz, 1H), 1.12–1.10 (m, 1H); 13C NMR: d 147.7,
128.2, 116.3, 111.9, 63.9, 48.4, 48.3, 46.9, 39.8, 38.0, 36.4,
28.9, 21.5. Anal. Calcd for C15H21NO: C, 77.88; H, 9.15;
N, 6.05. Found: C, 77.70; H, 9.28; N, 6.11.
20
½aꢁD ¼ þ1:6 ðc 2:00; MeOHÞ; 1H NMR: d 6.05 (s, 2H),
3.50 (t, J ¼ 6:87 Hz, 1H), 3.22 (t, J ¼ 11:25 Hz, 1H), 2.75
(s, 2H), 2.65–2.44 (m, 7H), 2.20 (d, J ¼ 12:54 Hz, 1H),
1.76 (br s, 4H), 1.40 (s, 2H); 13C NMR: d 135.4, 134.3,
63.0, 56.8, 53.8, 49.9, 47.7, 46.9, 46.2, 41.0, 23.3. Anal.
Calcd for C13H21NO: C, 75.32; H, 10.21; N, 6.76. Found:
C, 75.11; H, 9.95; N, 6.57.
4.4.9. ((2R,3S)-3-(Piperidin-1-ylmethyl)bicyclo[2.2.1]hept-5-
en-2-yl)methanol (ꢀ)-7e. (0.88 g, 89%); mp 61–62 ꢁC;
20
½aꢁD ¼ ꢀ3:6 ðc 2:00; MeOHÞ; 1H NMR: d 6.05 (s, 2H),
3.50 (d, J ¼ 10:65 Hz, 1H), 3.21 (t, J ¼ 11:45 Hz, 1H),
2.75 (s, 1H), 2.68 (s, 1H), 2.64–2.47 (m, 4H), 2.28–2.17
(m, 4H), 1.64–1.49 (m, 4H), 1.43–1.37 (m, 2H), 1.26 (s,
2H); 13C NMR: d 135.3, 134.4, 63.1, 60.0, 50.1, 47.6,
47.0, 46.4, 38.8, 29.6, 25.6, 24.2. Anal. Calcd for
C14H23NO: C, 75.97; H, 10.47; N, 6.33. Found: C, 75.32;
H, 10.13; N, 6.17.
4.5.3.
((2R,3S)-3-((2-Chlorophenylamino)methyl)bicyclo-
[2.2.1]heptan-2-yl)methanol (+)-9c. After LAH reduction
of (+)-8b, without purification the mixture was subjected
to hydrogenation. (0.59 g, 65%) colorless oil;
20
½aꢁD ¼ þ10:8 ðc 2:00; CHCl3Þ; IR (KBr): 3348, 2950,
1
1598 cmꢀ1; H NMR: d 7.15 (dd, J ¼ 6:25, 7.30 Hz, 1H),
7.03 (t, J ¼ 7:07 Hz, 1H), 6.52 (dd, J ¼ 7:33, 13.54 Hz,
2H), 4.76 (br s, 1H), 3.61 (dd, J ¼ 6:87, 9.98 Hz, 1H),
3.49 (t, J ¼ 9:41 Hz, 1H), 3.00 (dd, J ¼ 6:70, 11.62 Hz,
1H), 2.79 (dd, J ¼ 8:85, 11.47 Hz, 1H), 2.21 (s, 1H), 2.06
(s, 1H), 1.64 (br s, 1H), 1.58–1.49 (m, 1H), 1.43 (d,
J ¼ 9:90 Hz, 1H), 1.39–1.24 (m, 3H), 1.19 (d,
J ¼ 9:76 Hz, 1H), 1.13–1.06 (m, 1H); 13C NMR: d 144.5,
129.1, 127.8, 119.1, 116.9, 111.2, 64.8, 49.0, 48.9, 47.2,
40.8, 38.9, 37.3, 29.9, 22.5. Anal. Calcd for C15H20ClNO:
C, 67.79; H, 7.58; N, 5.27. Found: C, 67.59; H, 7.84; N,
5.42.
4.4.10. ((2R,3S)-3-(Morpholinomethyl)bicyclo[2.2.1]hept-5-
en-2-yl)methanol (ꢀ)-7f. (0.59 g, 70%) colorless oil;
20
½aꢁD ¼ ꢀ4:3 ðc 2:00; CHCl3Þ; 1H NMR: d 6.06 (s, 2H),
3.68 (br s, 4H), 3.50 (br s, 1H), 3.21 (t, J ¼ 11:21 Hz,
1H), 2.75 (s, 1H), 2.71 (s, 1H), 2.57–2.47 (m, 4H), 2.34–
2.26 (m, 4H), 1.43–1.38 (m, 2H); 13C NMR: d 134.9,
133.8, 66.0, 62.4, 59.3, 53.1, 49.5, 47.0, 46.4, 45.7, 37.6.
Anal. Calcd for C13H21NO2: C, 69.92; H, 9.48; N, 6.27.
Found: C, 69.62; H, 9.13; N, 6.18.

C. Tanyeli et al. / Tetrahedron: Asymmetry 18 (2007) 2349–2357
2357
4. (a) Kitamura, M.; Suga, S.; Kawai, K.; Noyori, R. J. Am.
Chem. Soc. 1986, 108, 6071–6072; (b) Kitamura, M.; Okada,
S.; Suga, S.; Noyori, R. J. Am. Chem. Soc. 1989, 111, 4028–
4036; (c) Noyori, R.; Suga, S.; Kaway, K.; Okada, S.;
Kitamura, M.; Oguni, N.; Hayashi, N.; Kaneko, T.; Matsu-
da, Y. J. Organomet. Chem. 1990, 382, 19–37; (d) Noyori, R.;
Kitamura, M. Angew. Chem., Int. Ed. Engl. 1991, 30, 49–69;
(e) Kitamura, M.; Suga, S.; Niwa, M.; Noyori, R. J. Am.
Chem. Soc. 1995, 117, 4832–4842; (f) Yamakawa, M.;
Noyori, R. J. Am. Chem. Soc. 1995, 117, 6327–6335; (g)
Kitamura, M.; Suga, S.; Oka, H.; Noyori, R. J. Am. Chem.
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Organometallics 1999, 18, 128–133; (i) Noyori, R. Angew.
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5. (a) Beliczey, J.; Giffels, G.; Kragl, U.; Wandrey, C. Tetra-
hedron: Asymmetry 1997, 8, 1529–1530; (b) Sola, L.; Vidal-
Ferran, A.; Moyano, A.; Perkas, M. A.; Riera, A. Tetra-
hedron: Asymmetry 1997, 8, 1559–1568; (c) Cho, B. T.; Chun,
Y. S. Tetrahedron: Asymmetry 1998, 9, 1489–1492; (d)
Nugent, A. W. J. Chem. Soc., Chem. Commun. 1999, 1369–
1370.
4.5.4. N-(((2S,3R)-3-(Hydroxymethyl)bicyclo[2.2.1]heptan-
2-yl)methyl)-4-methylbenzenesulfonamide (ꢀ)-9d. (1.18 g,
20
91%); mp 75.0 ꢁC; ½aꢁD ¼ ꢀ13:2 ðc 1:00; CHCl3Þ; IR
(KBr): 3459, 2958, 1627 cmꢀ1
;
1H NMR: d 7.67 (d,
J ¼ 8:12 Hz, 2H), 7.21 (d, J ¼ 8:10 Hz, 2H), 6.23 (br s,
1H), 3.61 (dd, J ¼ 4:50, 9.44 Hz, 1H), 3.36 (t,
J ¼ 10:09 Hz, 1H), 2.91 (dd, J ¼ 4:65, 15.83 Hz, 1H),
2.43 (t, J ¼ 10:96 Hz, 1H), 2.34 (s, 3H), 2.09 (br s, 1H),
1.85 (br s, 1H), 1.44–1.35 (m, 2H), 1.23–1.13 (m, 4H),
1.07 (dd, J ¼ 13:50, 24.50 Hz, 2H); 13C NMR: d 142.0,
135.9, 128.6, 126.1, 63.5, 48.0, 46.7, 46.6, 39.9, 38.3, 36.4,
28.9, 21.5, 20.5. Anal. Calcd for C16H23NO3S: C, 62.11;
H, 7.49; N, 4.53; S, 10.36. Found: C, 62.20; H, 7.82; N,
4.69; S, 9.92.
4.6. General procedure for diethylzinc addition reactions
The ligand (0.05 mmol) was dissolved in hexane (or tolu-
ene) (3 mL) at room temperature under argon atmosphere
and diethyl zinc (1.0 mmol, 1 M in hexane) was then added
to this solution. The mixture was stirred for 30 min, and
then cooled to 0 ꢁC. Benzaldehyde (0.5 mmol) was added
to the mixture and the reaction mixture was stirred for
48 h at 0 ꢁC. After adding 1 M HCl (10 mL), it was ex-
tracted with ethyl acetate (25 mL). The organic phase was
then dried over MgSO4 and the solvent was evaporated
to give the corresponding alcohol. HPLC-analysis of 1-
phenyl-1-propanol: Chiralcel OD-H at room temperature,
n-hexane/2-propanol = 98:2, 1.0 mL/min, 254 nm, t1 ¼
26:3 min ðRÞ, t2 ¼ 31:5 min ðSÞ.
6. (a) Genov, M.; Kostova, K.; Dimitrov, V. Tetrahedron:
Asymmetry 1997, 8, 1869–1876; (b) Genov, M.; Dimitrov, V.;
Ivanova, V. Tetrahedron: Asymmetry 1997, 8, 3703–3706; (c)
Knollmuller, M.; Ferencic, M.; Ga¨rtner, P. Tetrahedron:
¨
Asymmetry 1999, 10, 3969–3975; (d) Hanyu, N.; Aoki, T.;
Mino, T.; Sakamoto, M.; Fujita, T. Tetrahedron: Asymmetry
2000, 11, 2971–2979; (e) Scarpi, D.; Galbo, F. L.; Occhiato,
E. G.; Guarna, A. Tetrahedron: Asymmetry 2004, 15, 1319–
1324; (f) Faux, N.; Razafimahefa, D.; Picart-Goetgheluck, S.;
Brocard, J. Tetrahedron: Asymmetry 2005, 16, 1189–1197; (g)
Kasashima, Y.; Hanyu, N.; Aoki, T.; Mino, T.; Sakamoto,
M.; Fujita, T. J. Oleo Sci. 2005, 54, 495–504; (h) Zhong, J.;
Wang, M.; Guo, H.; Yin, M.; Bian, Q.; Wang, M. Synlett
2006, 1667–1670; (i) Martinez, A. G.; Vilar, E. T.; Fraile, A.
G.; Cerero, S. M.; Ruiz, P. M.; Morillo, C. D. Tetrahedron:
Asymmetry 2007, 18, 742–749.
Acknowledgement
7. He, X. C.; Eliel, E. L. Tetrahedron 1987, 43, 4979–4987.
8. Goldfuss, B.; Steigelman, M.; Khan, S. I.; Houk, K. N. J.
Org. Chem. 2000, 65, 77–82.
9. Hanyu, N.; Aoki, T.; Mino, T.; Sakamoto, M.; Fujita, T.
Tetrahedron: Asymmetry 2000, 11, 4127–4136.
We would like to thank the Turkish Scientific and Techni-
cal Research Council for a Grant [No. TBAG-105T247].
10. Steiner, D.; Sethofer, S. D.; Goralski, C. T.; Singaram, B.
Tetrahedron: Asymmetry 2002, 13, 1477–1483.
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