Induced circular dichroism in chiral N-methyl amides possessing an achiral binaphthyl chromophore and its application to absolute configuration determination of aliphatic chiral amines

Article abstract of DOI:10.1016/j.tetasy.2012.06.013

Induced circular dichroism (ICD) was observed in binaphthyl N-methyl amides of chiral primary amines. The CD spectra showed split curves centered at 225 nm. A good correlation was found between the sign of the exciton chirality of the binaphthyl derivative and the absolute configuration of the original amine. Furthermore, the screw sense of the two naphthyl groups in the most stable conformer obtained from molecular mechanics (MM) calculation was in agreement with those expected from the exciton chirality, indicating that the method based on MM calculations can be used to determine unknown absolute configurations of aliphatic chiral amines. The practical use of the present method was demonstrated by the determination of the absolute configurations of the natural products, d- and l-cycloserines. 2012 Elsevier Ltd.

Full text of DOI:10.1016/j.tetasy.2012.06.013

Tetrahedron: Asymmetry 23 (2012) 981–991
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Induced circular dichroism in chiral N-methyl amides possessing an achiral
binaphthyl chromophore and its application to absolute configuration
determination of aliphatic chiral amines
Toshio Fujiwara a, Yuka Taniguchi a, Yukiteru Katsumoto b, Takeyuki Tanaka c, Manabu Node a,
a,
Minoru Ozeki a, Masayuki Yamashita a, , Shinzo Hosoi
⇑
⇑
a Pharmaceutical Manufacturing Chemistry, Kyoto Pharmaceutical University, 1 Shichono-cho, Misasagi, Yamashina-ku, Kyoto 607-8412, Japan
b Department of Chemistry, Graduate School of Science, Hiroshima University, Higashi-Hiroshima 739-8526, Japan
c Integrated Center for Science, Ehime University, 3-5-7 Tarumi, Matsuyama, Ehime 790-8566, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Induced circular dichroism (ICD) was observed in binaphthyl N-methyl amides of chiral primary amines.
The CD spectra showed split curves centered at 225 nm. A good correlation was found between the sign
of the exciton chirality of the binaphthyl derivative and the absolute configuration of the original amine.
Furthermore, the screw sense of the two naphthyl groups in the most stable conformer obtained from
molecular mechanics (MM) calculation was in agreement with those expected from the exciton chirality,
indicating that the method based on MM calculations can be used to determine unknown absolute con-
figurations of aliphatic chiral amines. The practical use of the present method was demonstrated by the
Received 11 May 2012
Accepted 15 June 2012
Available online 19 July 2012
determination of the absolute configurations of the natural products, D- and L-cycloserines.
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
properties of 2,20-binaphthyl chromophoric systems remain unex-
plored. We have shown that the ICD of 2,20-binaphthyl chromoph-
ores could be used to establish the absolute stereochemistry of
chiral mono-alcohols,8 and have reported the successful applica-
tion of the ICD of binaphthyl chromophores in combination with
molecular mechanics (MM) calculations, CONFLEX algorism, for
the determination of the absolute configurations of several types
of natural products possessing a secondary alcohol.13 In a previous
paper, we reported that the method was applicable to a chiral pri-
mary mono-amine, indicating a possible application for the deter-
mination of the absolute configurations of N-methylated
binaphthyl derivatives.14 Herein, further investigations of its scope
and limitations and its application to natural products are de-
scribed in detail.
The detection and assignment of molecular chirality are of par-
ticular importance from the viewpoint of differences in pharmaco-
kinetic and pharmacodynamic activities toward
a pair of
enantiomeric drugs. Various methods based on NMR spectroscopy
and circular dichroism (CD) are utilized as reliable tools, together
with the X-ray diffraction method. Exciton-coupled circular
dichroism (ECCD), in particular, has been extensively applied to or-
ganic molecules, including natural products, as a microscale meth-
od to determine their absolute configurations in a non-empirical
manner.1–3 In the past, the application of ECCD was limited to com-
pounds that have two or more chiral functional groups. However,
recent studies have clearly indicated that this method can be ap-
plied to molecules that have only one chiral site.4–11
Over the course of our stereochemical studies on chiral mono-
functional molecules by the ECCD method, induced CD (ICD) was
observed in dinitrodiphenic7 and 2,20-binaphthyl8 esters of chiral
secondary alcohols, indicating that the chirality of the substrates
was efficiently transferred to the biaryl chromophores. For 1,10-
binaphthyls, the relationship between the sign of the CD couplet
and the dihedral angle between the two naphthalene chromoph-
ores was investigated in great detail.12 In contrast, the chiroptical
2. Results and discussion
2.1. Preparation of binaphthyl amides
First, chromophoric reagent 1, designed by us, was applied to
chiral primary amines. A general procedure of derivatization of chi-
ral secondary alcohols with acyl cyanide 1 failed to proceed in the
absence of a base, such as 4-dimethylaminopyridine (DMAP).8
However, for chiral primary amines, the derivatization proceeded
as expected even in the absence of a base due to the larger nucle-
ophilicity. Thus, the condensation of amines 2a–j with reagent 1 in
⇑
Corresponding authors. Tel.: +81 75 595 4639; fax: +81 75 595 4775 (M.Y.).
E-mail address: yamasita@mb.kyoto-phu.ac.jp (M. Yamashita).
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.06.013

982
T. Fujiwara et al. / Tetrahedron: Asymmetry 23 (2012) 981–991
(R)
Me
CONH
MeOOC
3a
(S)
Me
CONH
MeOOC
3b
Figure 1. UV and CD spectra of binaphthyl amides 3a and 3b in cyclohexane.
Figure 2. Conformational analysis of binaphthyl derivatives 3a, 3b and N-methyl derivatives 4a, 4b.
CH3CN gave the corresponding amides 3a–j almost quantitatively
(Scheme 1).
to the x-axis, indicating that the two isomers are enantiomeric to
each other in solution; (2) the CD spectra showed bisignate curves
at around 240 nm and the spectroscopic pattern was basically iden-
tical for all of the compounds examined, except for their signs of the
Cotton effect. However, the curves obtained here do not show a
diagnostic split, which is clearly obtained for chiral secondary alco-
hols.8 In an empirical manner, we could guess the absolute config-
uration of the compounds as listed in Table 1 by referring to the
exciton chirality at around 240 nm, but this estimation is not proper
in terms of the basic idea of the ECCD method. Thus, we needed the
assistance of computational chemistry.
2.2. UV and CD spectra of binaphthyl amides
The UV spectra of the derived compounds showed absorption
maxima at ca. 227 and 333 nm. The 1H NMR spectra of the amides
derived from an antipodal pair of chiral primary amines (e.g., 2a and
2b) in CDCl3 were identical. The CD spectra of the derivatives in
cyclohexane exhibited the following features (Table 1 and Fig. 1):
(1) for all of the antipodal pairs, the CD spectra were symmetrical

T. Fujiwara et al. / Tetrahedron: Asymmetry 23 (2012) 981–991
983
Table 1
UV and CD spectra of binaphthyl amides 3a–j in cyclohexane
Compound
UV
kmax
(
e) nm
CD
kext
(D
e
) nm
Absolute configuration
258.6
244.1
228.8
219.5
258.8
244.1
228.8
219.5
233.7
223.6
216.9
212.6
231.9
224
217.7
211.2
239.5
223.6
217.1
211.6
242.1
224.4
217.1
213.4
255.4
240.7
229.0
220.1
256.8
242.1
228.6
218.3
257.6
242.7
225.6
217.1
258.8
242.7
225.4
216.9
(ꢀ10.0)
(0)
(R)
(S)
(R)
(S)
(R)
(S)
(R)
.(S)
(R)
(S)
3a
333.0
228.2
(670)
(22,400)
(ꢀ27.9)
(0)
(10.3)
(0)
3b
3c
3d
3e
3f
333.0
227.6
(801)
(22,400)
(ꢀ28.9)
(0)
(0)
227.0
226.8
226.8
226.6
226.6
226.8
227.8
227.6
(21,200)
(21,700)
(22,200)
(22,200)
(21,900)
(22,500)
(21,000)
(21,800)
(ꢀ19.3)
(0)
(6.9)
(0)
(16.7)
(0)
(ꢀ10.3)
(0)
(ꢀ8.8)
(0)
(3.9)
(0)
(9.4)
(0)
(ꢀ4.3)
(ꢀ6.0)
(0)
(13.7)
(0)
(5.0)
(0)
3g
3h
3i
(ꢀ16.8)
(0)
(ꢀ5.3)
(0)
(15.1)
(0)
(5.6)
(0)
3j
(ꢀ15.8)
(0)
COCN
MeOOC
CONHR*
MeOOC
CH3CN
r.t.
+
R*NH2
2a-j
1 (1 eq)
3a-j
R*NH2 =
NH2
NH2
NH2
NH2
NH2
3a: 99%
3c: 97%
3e: 97%
3g: 99%
3i: 100%
3j: 100%
NH2
NH2
NH2
NH2
NH2
: 99%
3b
3d: 97%
3f: 97%
3h: 99%
Scheme 1. Preparation of binaphthyl amide derivatives 3a–j.

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T. Fujiwara et al. / Tetrahedron: Asymmetry 23 (2012) 981–991
Me
CONHR*
MeOOC
CONR*
MeOOC
NaH (6eq)
MeI (20eq)
DMSO
r.t.
3a-j
4a-j
NHR =
HN
HN
N
H
HN
HN
4g: 90%
4a: 97%
4c: 91%
4e: 97%
4i: 91%
4j: 92%
HN
HN
HN
N
HN
H
4b: 95%
4d: 95%
4f: 94%
4h: 94%
Scheme 2. Preparation of N-methyl binaphthyl derivatives 4a–j.
2.3. Conformational analysis of binaphthyl amides
number of conformers are found as a result of MM calculations, in
which the screw sense of the conformers is not always uniform.
However, the calculation result reveals that the conformers with
the same screw sense of the most stable conformer are always
the majority as shown in Figure 2.
In order to gain further structural information on the binaph-
thyl derivatives, semi-empirical molecular orbital calculations
(AM1)15 were performed, in which the geometries for the most sta-
ble conformers were used as the initial estimate. The distance be-
tween the nitrogen atom of the amide and the carbonyl oxygen
atom of the ester was found to be ca. 3.2 Å in the binaphthyl
amides 3a, 3b (Fig. 2). This distance lies in the range of the hydro-
Conformational analysis was performed using molecular
mechanics calculations (CONFLEX-MM215) to assess the most sta-
ble conformer of the target derivative and to examine the screw
senses between the two longitudinal 1Bb electric transition mo-
ments of the 2-naphthoyl groups in the stable conformer.16 By
referring to the calculation result for each compound, we found a
clear correlation between the screw sense of the most stable con-
former and the sign of the apparent exciton chirality at around
240 nm, that is, the positive exciton chirality is correlated with
the clockwise (C) turn and the negative one with the counterclock-
wise (CC) turn. For each binaphthyl amide examined here, a greater
gen-bonding distance between C@O and N–H in the
a-helical
(R)
Me
CONMe
MeOOC
4a
(S)
Me
Me
CON
MeOOC
4b
Figure 3. UV and CD spectra of binaphthyl amides 4a and 4b in cyclohexane.

T. Fujiwara et al. / Tetrahedron: Asymmetry 23 (2012) 981–991
985
Table 2
UV and CD spectra of N-methyl derivatives 4a–j in cyclohexane
Compound
UV
kmax
(
e
) nm
CD
kex
(
D
e
) nm
Exciton chirality
+
Absolute configuration
t
4a
334.4
257.0
223.0
(500)
(18,300)
(15,600)
251.3
236.6
226.1
216.0
251.3
236.8
225.9
216.2
237.0
227.1
216.6
237.2
227.5
216.2
236.6
226.7
216.0
236.4
226.7
215.4
236.6
226.5
215.4
236.8
225.7
215.4
235.4
222.9
215.2
235.4
220.9
215.4
(0)
(24.8)
(0)
(R)
(ꢀ20.4)
4b
335.2
257.0
223.0
(600)
(19,400)
(16,600)
(0)
ꢀ
(S)
(ꢀ27.8)
(0)
(21.1)
(21.0)
(0)
(ꢀ20.9)
(ꢀ22.8)
(0)
(17.9)
(18.1)
(0)
(ꢀ16.3)
(ꢀ17.7)
(0)
(15.3)
(23.4)
(0)
(ꢀ20.7)
(ꢀ24.6)
(0)
(18.1)
(13.1)
(0)
4c
4d
4e
4f
257.4
221.8
(16,900)
(17,200)
+
(R)
(S)
(R)
(S)
(R)
(S)
(R)
(S)
257.4
221.6
(17,000)
(17,400)
ꢀ
+
257.2
221.8
(18,700)
(18,000)
257.2
221.8
(18,600)
(17,700)
ꢀ
+
4g
4h
4i
257.2
221.6
(18,100)
(17,700)
257.2
221.8
(18,200)
(17,800)
ꢀ
+
256.8
222.6
(19,400)
(18,200)
(ꢀ5.6)
(ꢀ12.1)
(0)
4j
256.8
222.6
(18,300)
(17,400)
ꢀ
(3.8)
structure of a protein (2.9 Å to 3.2 Å) based on X-ray crystallo-
graphic analysis.17 Thus, it can be expected that the binaphthyl
amides 3a–j form an intramolecular hydrogen-bond, which may
play an important role in the conformational stability and in the
resulting CD spectrum.
that for 4a is C (Fig. 2). Thus, the replacement of the amide hydro-
gen with a methyl group has results not only in the CD spectrum
but also in the conformational stability of the compound. This
change might be attributable to the loss of hydrogen bonding
and/or the steric effect of the methyl group. For the most stable
conformers of N-methyl amides 4a and 4b, the calculated screw
senses between the two 1Bb electric transition moments of the
naphthyl groups were in good accordance with those expected
from their exciton chiralities (Fig. 2), that is, N-methyl amide 4a
with a positive exciton chirality had a C turn, whereas 4b with a
negative exciton chirality had a CC turn. These results suggested
that the N-methylation could be established as a novel alternative
method for the determination of the absolute configuration of
compounds that have a primary amine based on induced CD exci-
ton chirality. In the following section, the potential of the method
is demonstrated.
2.4. UV and CD spectra of N-methyl derivatives
In order to investigate the influence of the intramolecular
hydrogen-bond on the CD spectra, N-methylation of the amides
was performed. Binaphthyl amides 3a–j were methylated with so-
dium hydride and iodomethane in DMSO to give the corresponding
N-methyl derivatives 4a–j in excellent yields (Scheme 2). In con-
trast with the CD spectra of 3a and 3b, those of the N-methyl deriv-
atives 4a and 4b in CH3CN showed simple diagnostic split curves
centered at 225 nm (Fig. 3). In the CD spectra of N-methyl deriva-
tives 4c–j, the same simple split curves were noted. In all cases, N-
methyl derivatives with an (R)-configuration exhibited positive
exciton chirality, while those with an (S)-configuration exhibited
negative exciton chirality (Table 2). It should be noted that the
wavelengths of the marker bands used for the derivatives 4a–j
were different from those for 3a–j. These results indicate that the
CD bands observed for 3a–j were not the values expected in the
ECCD method, in which the exciton coupling between the two
1Bb electric transition moments of the 2-naphthyl groups is consid-
ered. In fact, the replacement of the amide hydrogen with a methyl
group gave rise to the diagnostic split CDs that enabled us to deter-
mine the clear exciton chirality listed in Table 2. Therefore, it is im-
plied that the intramolecular hydrogen-bonding of the binaphthyl
amides affects their CD spectra.
2.5. Application of the ICD method to D- and L-cycloserines
2.5.1. Derivatization of D- and L-cycloserines to the
corresponding binaphthyl amides
The ICD method with N-methylation was applied to natural
products with a primary amine.
tized in MeCN even at 50 °C due to its insolubility in MeCN. The
optimum reaction conditions for -cycloserine were thus deter-
D-Cycloserine was hardly deriva-
D
mined (Table 3). The reaction was carried out in MeCN/DMF/H2O
(2/2/1) for 24 h at ambient temperature to give binaphthyl amide
5 in 40% yield (entry 6). When DMF or DMSO was employed as
the dipolar aprotic solvent, the reaction was found to proceed al-
most quantitatively (entries 8 and 9). Unfortunately, DMSO was
difficult to remove from the product. Therefore, DMF was used in
The MM calculations revealed that the screw sense of the most
stable conformer of each N-methyl amides 4a–j is antipole, for
example, the most stable conformer for 3a has the CC turn, while
the subsequent derivatizations. For
product was obtained in 98% yield.
L-cycloserine, the derivatized

986
T. Fujiwara et al. / Tetrahedron: Asymmetry 23 (2012) 981–991
Table 3
Derivatization of D-cycloserine to the corresponding binaphthyl amides 5a
O
H
N
O
O
MeO2C
C
NH
O
H2N
base
in solvent
+ 1
NH
O
D-cycloserine
5
Entry
Solvent
Temp (°C)
Base
Time (h)
HPLC area%b
Yieldc (%)
5
1
Others
1
2
3
4
5
6
7
8
9
MeCN
MeCN
MeCN
MeCN
MeCN/DMF/H2O
MeCN/DMF/H2O
MeCN/H2O
DMF
rt
50 °C
rt
—
—
1
1
1
1
1
24
24
24
24
NDd
2.0
97.6
96.2
14.4
5.5
37.9
0.3
82.5
0.2
1.1
2.4
1.8
70.0
71.0
6.9
10.4
6.6
3.2
—
—
—
—
—
DMAP (3.0)
Et3N (3.0)
15.6
23.5
55.2
89.3
10.9
96.6
92.9
rt
rt
rt
rt
rt
rt
—
—
—
—
—
40
—
98
e
DMSO
6.0
—
a
b
c
D
-Cycloserine: 20 mg.
Column: Cosmosil ARII 4.6 mm ꢁ 150 mm; temp: 40 °C; detection: UV 254 nm; eluent: MeOH/H2O/MSA = 90/10/0.1; flow rate: 1 mL/min.
Isolated yield.
Not detected.
d
e
DMSO could not be removed completely from the product.
O
O
Me
N
Me
N
O
H
N
O
O
O
Me
Me
C
C
N
N
C
MeO2C
MeO2C
NH
MeO2C
Me
NaH
MeI
O
O
O
+
in DMF
6
7
5
Y : 14%
Scheme 3. Preparation of N-methyl binaphthyl derivative 6.
Y : 86%
binaphthyl amides 5
N-methyl binaphthyl derivative 6
30
0
3
15
0
2
D-Cycloserine
L-Cycloserine
D-Cycloserine
L-Cycloserine
2.5
2
1.5
1
1.5
1
-
-
30
60
-
-
15
30
0.5
0
0.5
0
200
250
300
350
400
200
250
300
350
400
λ / nm
λ / nm
Figure 4. UV and CD spectra of binaphthyl amide 5 and N-methyl binaphthyl derivative 6 in MeOH.
2.5.2. N-Methylation of binaphthyl amides
CD spectra (Scheme 3). The expected N-methylated derivative 6
was furnished in only 14% yield, along with a large amount of
by-product 7 in which a third methyl group was introduced onto
Similar to the case of the amines described above, the N-meth-
ylation of cycloserine binaphthyl derivatives was performed in or-
der to investigate the influence of the amide hydrogen atom on the
the
a-position of the isoxazolidinone moiety of cycloserine. The

T. Fujiwara et al. / Tetrahedron: Asymmetry 23 (2012) 981–991
987
CD of by-product 7 was found to be inactive. On the other hand, the
CD spectrum of N-methylated derivative 6 showed the typical
diagnostic split centered at 225 nm, which was in good agreement
(254 nm) and then developed by spraying 10% H2SO4 and/or 5%
phosphomolybdic acid ethanol solution and heating the plate at
100 °C until coloration took place. Preparative TLC (PTLC) was per-
formed with precoated silica gel plates, Merck 60 F254 (0.5 mm
thick). Elemental analyses were performed by Kyoto Pharmaceuti-
cal University. Chemical purity was determined by HPLC (Shima-
dzu LC-2010C HT system; UV (254 nm), Cosmosil C18AR-II
with the other amines studied here; the
with an (R)-configuration showed positive exciton chirality
whereas the -cycloserine derivative with an (S)-configuration
D-cycloserine derivative
L
exhibited a negative one (Fig. 4). It is worth noting that when N-
methylated derivative 6 was exposed to methylation conditions
(NaH, MeI/DMF), no reaction took place. Recovered compound 6
was found to maintain its enantiomeric purity by comparing the
intensity of the Cotton effects. This result could be interpreted as
follows: once generated, the N-methylated derivative 6 resisted
further methylation due to A1,3-strain in its enolate form, although
enolization was presumed to proceed faster than N-methylation.
4.6 mm ꢁ 150 mm, 5
lm, 90.0% MeOH in H2O, 35 min; flow rate
1.0 mL/min; 40 °C).
4.2. Preparation of the binaphthyl-type chromophoric reagent 1
4.2.1. Dinaphtho[2,3-c:20,30-e]oxepine-6,8-dione
A stirred suspension of 2,20-binaphthalene-3,30-dicarboxylic
acid (4.77 g, 13.90 mmol) in acetic anhydride (48 mL) was heated
at reflux for 2.5 h. After cooling down to below 10 °C, the reaction
mixture was stirred at the same temperature for 2.5 h. The precip-
itated crystals were collected by filtration and washed with diethyl
ether. After being dried in vacuo at room temperature, dinaph-
tho[2,3-c:20,30-e]oxepine-6,8-dione (3.43 g, 76%) was obtained as
an ochreous solid that was used in the following step without fur-
ther purification.
3. Conclusion
Bisignate CD curves were observed at around 240 nm for all of
the binaphthyl amides examined. In a conformational analysis
based on MM calculations for each derivative, a strong correlation
was obtained between the signs of the exciton chirality and the
screw sense of the two 2-naphthoyl groups (positive/clockwise;
negative/counterclockwise) in the most stable conformer. Semi-
empirical molecular orbital calculations (AM1) suggested the exis-
tence of an intramolecular hydrogen-bond in the binaphthyl
amide. After N-methylation, the center of the bisignate CD curve
shifted to 225 nm, which showed excellent correlation between
the signs of exciton chirality and the absolute configurations of
the amines [positive/(R)-configuration; negative/(S)-configuration]
for all of the N-methyl derivatives. Furthermore, the calculated
screw senses between the electric transition moments of the
binaphthyl system in the N-methyl derivatives were in good accor-
dance with those expected from their exciton chiralities. The ICD
method was proven to be applicable to natural products possessing
4.2.2. 30-(Methoxycarbonyl)-2,20-binaphthalene-3-carboxylic
acid
A stirred suspension of dinaphtho[2,3-c:20,30-e]oxepine-6,8-
dione (3.40 g, 10.54 mmol) in methanol (68 mL) was heated at re-
flux for 4 h, followed by removal of the solvent in vacuo. The resi-
due was dissolved in methanol (25 mL) and chloroform (80 mL) at
60 °C. After the addition of activated carbon (3.0 g), the solution
was stirred at 60 °C for 1.5 h. Next, the activated carbon was fil-
tered off with heating and washed with chloroform/methanol
(3:1, v/v). The combined filtrates were concentrated to dryness.
After precipitation by the addition of ethyl acetate (10 mL), the sol-
vent was evaporated to give 30-(methoxycarbonyl)-2,20-binaphtha-
lene-3-carboxylic acid (3.47 g, 92%), which was used in the
following step without further purification.
a primary amine, such as D- and L-cycloserines. This method will be
a powerful tool to determine the absolute configurations of various
natural products with an amino group.
4. Experimental
4.1. General
4.2.3. Methyl 30-(cyanocarbonyl)-2,20-binaphthalene-3-carbox-
ylate 1 (improved procedure)
To a stirred suspension of 30-(methoxycarbonyl)-2,20-binaph-
thalene-3-carboxylic acid (2.40 g, 6.73 mmol) in methylene chlo-
ride (50 mL) were added dropwise thionyl chloride (2.40 g,
20.20 mmol) and pyridine (0.11 g, 1.35 mmol), and the reaction
mixture was stirred at temperatures below 10 °C for 2 h. After
the confirmation of complete dissolution, the solvent was removed
in vacuo. To a solution of the crude acid chloride in dichlorometh-
ane (60 mL) were added trimethylsilyl cyanide (2.00 g, 20.2 mmol)
and zinc iodide (0.02 g, 0.07 mmol) at temperatures below 10 °C,
and the reaction mixture was stirred at the same temperature for
2 h and then at room temperature for 1 h. After removal of the sol-
vent in vacuo, the crude product was stirred in cyclopentyl methyl
ether (12 mL) at room temperature for 1 h. The precipitated crys-
tals were collected by filtration and washed with cyclopentyl
methyl ether (7 mL). Drying the crystals in vacuo at room temper-
ature gave methyl 30-(cyanocarbonyl)-2,20-binaphthalene-3-car-
boxylate 1 (1.75 g, 71% over two steps), which was almost pure
and did not need further purification.
Unless otherwise noted, the following procedures were
adopted. Non-aqueous reactions were carried out under an inert
atmosphere of dry N2 and/or Ar. 1H NMR spectra were recorded
at 400 MHz or 500 MHz in CDCl3 with TMS as the internal refer-
ence (0.00 ppm). Chemical shifts are reported in ppm (d) and cou-
pling constants, J, are reported in Hz. Infrared spectra of samples in
CHCl3 solution were recorded on a Shimadzu FTIR-8300 spectrom-
eter. Peaks are reported in units of cmꢀ1 with the following relative
intensities: br (broad), s (strong 67–100%), m (medium 33–67%), or
w (weak 0–33%). UV spectra were recorded on a Shimadzu UV-
1600 spectrometer and data are given in kmax
UV spectra were measured on a JASCO J-725 spectrometer and data
are given in kext ) (nm). Mass spectra (MS) and high-resolution
(e) (nm). CD and
(De
MS (HRMS) were recorded on a JEOL JMS-SX 102A QQ, a Shimadzu
GCMS-Q505, and a JEOL JMS-GC-mate mass spectrometer. MS (EI)
were recorded with the ionization voltage of 70 eV. MS (FAB) were
recorded with NBA as the matrix. Data are reported in the form of
m/z (intensity relative to base = 100%). Column chromatography
was carried out with silica gel (Wakogel C-200). Recycling high
performance liquid chromatography (RHPLC) was performed on
JAI LC-908 with a JAIGEL H column using CHCl3 as the mobile
phase. For thin-layer chromatography (TLC), Merck precoated
plates GF254 were used. Spots were monitored under UV light
4.3. General procedure
4.3.1. Amidation
To a solution of amine (ca. 0.03 mmol) in acetonitrile (0.5 mL)
was added acyl cyanide 1 (1.1 equiv) and the whole mixture was

988
T. Fujiwara et al. / Tetrahedron: Asymmetry 23 (2012) 981–991
stirred at room temperature for 2–3 h under an argon atmosphere.
After removal of the solvent in vacuo, the crude product was puri-
fied by silica gel chromatography to give the corresponding
binaphthyl amides in 97–100% yields.
J = 6.9 Hz, 1.4H), 0.74 (s, 5.2H), 0.28 (s, 3.7H), 0.12 (d, J = 6.9 Hz,
1.6H); UV (cyclohexane) kmax ) nm 227.0 (21,200), 334.8 (700);
CD kext(nm)( )(cyclohexane) 212.6 (+6.9), 216.9 (0), 223.6
(e
D
e
(ꢀ19.3), 233.7 (0), 234.8 (+0.8), 240.0 (ꢀ0.8), 260.2 (+3.5), 287.4
(+1.0), 298.8 (+2.1); ½a D23
¼ þ8:4 (c 1.000, CHCl3); ESI-MS m/z 439
ꢂ
4.3.2. N-Methylation
(M+, 0.7), 382 (35), 339 (100), 295 (70), 280 (71), 252 (31); HRMS
To a suspension of 60% sodium hydride (6 equiv) in dimethyl
sulfoxide (0.5 mL) was added a solution of binaphthyl amide (ca.
10–20 mg) and then methyl iodide (20 equiv), after which the
whole mixture was stirred at room temperature for 1 day. The
reaction was quenched with ice-water and adjusted to pH 3–4
with solid ammonium chloride. The resulting aqueous solution
was extracted with diethyl ether (20 mL ꢁ 3) and dried over anhy-
drous magnesium sulfate. Removal of the solvent in vacuo gave a
residue that was purified by silica gel column chromatography to
give N-methyl amides in 90–97% yields.
(ESI) Anal. Calcd for
439.2150.
C
29H29NO3 m/z 439.2147 [M]+. Found:
4.3.3.2. Methyl 30-{[(2S)-3,3-dimethylbutan-2-yl]carbamoyl]-
2,20-binaphthalene-3-carboxylate 3d.
Colorless amorphous.
Rf (hexane/EtOAc, 2/1 (v/v)) 0.49. HPLC purity: 99.6%; Anal. Calcd
for C29H29NO3: C, 79.24; H, 6.65; N, 3.19. Found: C, 78.97; H,
6.61; N, 3.30. IR (film)
m
3342 w, 3059 w, 2957 m, 1711 m, 1647
m, 1529 m, 901 w, 768 w cmꢀ1
;
1H NMR (400 MHz, CDCl3) d
8.46 (s, 0.3H), 8.43 (s, 0.7H), 8.30 (s, 0.3H), 8.23 (s, 0.7H), 7.97–
7.95 (m, 2H), 7.84–7.77 (m, 3H), 7.63–7.51 (m, 5H), 6.57 (d,
J = 9.6 Hz, 0.5H), 6.37 (d, J = 9.6 Hz, 0.5H), 3.83–3.79 (m, 0.3H),
3.76 (s, 1.8H), 3.75 (s, 1.2H), 3.73–3.69 (m, 0.7H), 0.89 (d,
J = 6.9 Hz, 1.4H), 0.73 (s, 5.7H), 0.28 (s, 3.3H), 0.12 (d, J = 6.9 Hz,
4.3.2.1. Methyl 30-{[(1R)-1-cyclohexylethyl]carbamoyl}-2,20-
binaphthalene-3-carboxylate 3a.
Colorless amorphous. Rf
(hexane/EtOAc, 2/1 (v/v)): 0.39. HPLC purity: 100.0%; Anal. Calcd
for C31H31NO3: C, 79.97; H, 6.71; N, 3.01. Found: C, 79.19; H, 6.99;
1.6H); UV (cyclohexane) kmax
(e) nm 226.8 (21,700), 335.0 (800);
N, 3.11. IR (film)
m
2920 m, 2845 m, 1705 m, 1643 m, 1519 m,
CD kext(nm)(
De
)(cyclohexane) 211.2 (ꢀ10.3), 217.7 (0), 224.0
897 w, 890 w, 747 m cmꢀ1
;
1H NMR (500 MHz, CDCl3) d 8.45 (s,
(+16.7), 231.9 (0), 234.6 (ꢀ2.1), 259.8 (ꢀ4.3), 287.0 (ꢀ2.0), 299.4
1H), 8.29 (s, 0.58H), 8.24 (s, 0.42H), 7.98–7.93 (m, 2H), 7.82 (t,
J = 7.8 Hz, 2H), 7.80–7.74 (m, 1H), 7.63–7.50 (m, 5H), 6.52 (br d,
J = 8.8 Hz, 0.58H), 6.45 (br d, J = 8.8 Hz, 0.42H), 3.80 (m, 0.58H),
3.77 (s, 1.74H), 3.76 (s, 1.26H), 3.71 (m, 0.42H), 1.71–1.39 (m,
1.38H), 1.32–1.19 (m, 0.58H), 1.12–0.97 (m, 3.1H), 0.91 (d,
J = 6.3 Hz, 1.74H), 0.94–0.69 (m, 2.94H), 0.63–0.42 (m, 1.74H),
0.32–0.15 (m, 1.26H), 0.25 (d, J = 6.3 Hz, 1.26H); UV (cyclohexane)
(ꢀ3.2); ½a 2D4
ꢂ
¼ ꢀ8:5 (c 1.030, CHCl3); ESI-MS m/z 439 (M+, 0.8),
382 (33), 339 (100), 295 (69), 280 (66); HRMS (ESI) Anal. Calcd
for C29H29NO3 m/z 439.2147 [M]+. Found: 439.2151.
4.3.3.3. Methyl 30-[(2R)-butan-2-ylcarbamoyl]-2,20-binaphtha-
lene-3-carboxylate 3e.
EtOAc, 2/1 (v/v)) 0.30. HPLC purity: 100.0%; IR (film)
2960 m, 2915 w, 1706 m, 1646 m, 1631 m, 1525 m, 893 w
cmꢀ1 1H NMR (500 MHz, CDCl3) 8.45, 8.25 (each s, 0.42H), 8.44,
Colorless amorphous. Rf (hexane/
m
3000 m,
kmax(e) nm 228.2 (22,400), 333.0 (700); CD kext(nm)(De)(cyclohex-
ane) 214.0 (ꢀ11.6), 219.5 (0), 228.8 (+27.9), 244.1 (0), 258.6
;
(ꢀ10.0), 288.4 (ꢀ2.8), 300.6 (ꢀ3.9); ½a D28
ꢂ
¼ ꢀ15:7 (c 0.216, CHCl3);
8.23 (each s, 0.58H), 7.98–7.93 (m, 2H), 7.85–7.76 (m, 3H), 7.63–
7.55 (m, 3H), 7.55–7.51 (m, 2H), 6.47 (br d, J = 8.3 Hz, 0.58H),
6.40 (br d, J = 8.3 Hz, 0.42H), 3.77 (m, 1H), 3.77 (s, 3H), 1.23 (m,
1.17H), 0.92 (d, J = 6.4 Hz, 1.25H), 0.80 (m, 0.83H), 0.76 (t,
J = 7.3 Hz, 1.75H), 0.29 (d, J = 6.4 Hz, 1.75H), 0.20 (t, J = 7.3 Hz,
ESI-MS m/z 465 (M+, 22), 339 (100), 296 (44), 295 (48), 281 (38),
280 (72), 252 (27); HRMS (ESI) Anal. Calcd for C31H31NO3 m/z
465.2304 [M]+. Found: 465.2308.
4.3.2.2. Methyl 30-{[(1S)-1-cyclohexylethyl]carbamoyl}-2,20-
1.25H); UV kmax(e) nm 226.8 (22,200), 333.6 (1000); CD
binaphthalene-3-carboxylate 3b.
ane/EtOAc, 2/1 (v/v)): 0.39; HPLC purity: 100.0%; Anal. Calcd for
31H31NO3: C, 79.97; H, 6.71; N, 3.01. Found: C, 79.19; H, 6.99; N,
3.11. IR (film)
cmꢀ1 2920 m, 2845 w, 1701 m, 1645 m, 1520 m,
Pale yellow gum. Rf (hex-
kext(nm)(
D
e
)(cyclohexane) 211.6 (+3.9), 217.1 (0), 223.6 (ꢀ8.8),
239.5 (0), 256.8 (+2.5), 288.0 (+1.0), 298.8 (+1.5); ½a D30
¼ ꢀ2:4 (c
ꢂ
C
0.206, CHCl3); ESI-MS m/z 411 (M+, 57), 339 (100), 296 (64), 295
m
(57), 281 (43), 280 (88), 252 (36); HRMS (ESI) Anal. Calcd for
747 m; 1H NMR (500 MHz, CDCl3) d 8.45 (s, 1H), 8.29 (s, 0.58H),
8.24 (s, 0.42H), 7.98–7.93 (m, 2H), 7.82 (t, J = 7.8 Hz, 2H), 7.80–
7.74 (m, 1H), 7.63–7.50 (m, 5H), 6.52 (br d, J = 8.8 Hz, 0.58H), 6.45
(br d, J = 8.8 Hz, 0.42H), 3.80 (m, 0.58H), 3.77 (s, 1.74H), 3.76 (s,
1.26H), 3.71 (m, 0.42H), 1.71–1.39 (m, 1.38H), 1.32–1.19 (m,
0.58H), 1.12–0.97 (m, 3.1H), 0.91 (d, J = 6.3 Hz, 1.74H), 0.94–0.69
(m, 2.94H), 0.63–0.42 (m, 1.74H), 0.32–0.15 (m, 1.26H), 0.25 (d,
C
27H25NO3 m/z 411.1834 [M]+. Found: 411.1830.
4.3.3.4. Methyl 30-[(2S)-butan-2-ylcarbamoyl]-2,20-binaphtha-
lene-3-carboxylate 3f. Colorless amorphous. Rf (hexane/
EtOAc, 2/1 (v/v)) 0.30; HPLC purity: 100.0%; IR (film) 3000 m,
2955 m, 2920 m, 1711 s, 1647 s, 1631 m, 1531 m, 892 m cmꢀ1
m
;
1H NMR (500 MHz, CDCl3) 8.45, 8.25 (each s, 0.42H), 8.44, 8.23
(each s, 0.58H), 7.98–7.93 (m, 2H), 7.85–7.76 (m, 3H), 7.63–7.55
(m, 3H), 7.55–7.51 (m, 2H), 6.47 (br d, J = 8.3 Hz, 0.58H), 6.40 (br
d, J = 8.3 Hz, 0.42H), 3.77 (m, 1H), 3.77 (s, 3H), 1.23 (m, 1.17H),
0.92 (d, J = 6.4 Hz, 1.25H), 0.80 (m, 0.83H), 0.76 (t, J = 7.3 Hz,
1.75H), 0.29 (d, J = 6.4 Hz, 1.75H), 0.20 (t, J = 7.3 Hz, 1.25H); UV
J = 6.3 Hz, 1.26H); UV (cyclohexane) kmax(e) nm 227.6 (22,400),
333.0 (800); CD kext(nm)( )(cyclohexane) 214.6 (+9.8), 219.5 (0),
D
e
228.8 (ꢀ28.9), 244.1 (0), 258.8 (+10.3), 289.2 (+2.7), 301.0 (+3.5);
½
a 2D8
ꢂ
¼ þ17:5 (c 0.230, CHCl3); ESI-MS m/z 465 (M+, 25),339 (100),
296 (41), 295 (47), 281 (38), 280 (70); HRMS (ESI) Anal. Calcd for
C
31H31NO3 m/z [M]+ 465.2304. Found: 465.2303.
kmax(e) nm 226.6 (22,200), 333.6 (1000); CD kext(nm)(De)(cyclo-
hexane) 213.4 (ꢀ4.3), 217.1 (0), 224.4 (+9.4), 238.4 (+0.9), 242.1
4.3.3.1. Methyl 30-{[(2R)-3,3-dimethylbutan-2-yl]carbamoyl]-
2,20-binaphthalene-3-carboxylate 3c.
Colorless amorphous.
(0), 256.6 (ꢀ1.6), 277.8 (+0.5), 298.6 (ꢀ0.8); ½a D30
¼ þ2:5 (c 0.238,
ꢂ
CHCl3); ESI-MS m/z 411 (M+, 59), 339 (100), 296 (63), 295 (55),
Rf (hexane/EtOAc, 2/1 (v/v)) 0.49. HPLC purity: 99.6%; Anal. Calcd
for C29H29NO3: C, 79.24; H, 6.65; N, 3.19. Found: C, 79.01; H,
281 (42), 280 (87), 252 (36); HRMS (ESI) Anal. Calcd for
C
27H25NO3 m/z 411.1834 [M]+. Found: 411.1835.
6.66; N, 3.21. IR (film)
m
3342 w, 3059 w, 2955 m, 1711 m, 1647
m, 1529 m, 901 w, 839 w cmꢀ1
;
1H NMR (400 MHz, CDCl3) d
4.3.3.5. Methyl 30-[(2R)-hexan-2-ylcarbamoyl]-2,20-binaphtha-
lene-3-carboxylate 3g. Colorless amorphous. Rf (hexane/
EtOAc, 2/1 (v/v)) 0.54. HPLC purity: 99.5%; Anal. Calcd for
29H29NO3: C, 79.24; H, 6.65; N, 3.19. Found: C, 79.07; H, 6.60;
N, 3.23. IR (film) 3337 w, 3059 m, 2957 m, 2932 m, 2858 m,
8.46 (s, 0.3H), 8.43 (s, 0.7H), 8.30 (s, 0.3H), 8.23 (s, 0.7H), 7.97–
7.95 (m, 2H), 7.84–7.77 (m, 3H), 7.63–7.51 (m, 5H), 6.57 (d,
J = 9.6 Hz, 0.5H), 6.37 (d, J = 9.6 Hz, 0.5H), 3.83–3.79 (m, 0.3H),
3.76 (s, 1.8H), 3.75 (s, 1.2H), 3.73–3.69 (m, 0.7H), 0.89 (d,
C
m

T. Fujiwara et al. / Tetrahedron: Asymmetry 23 (2012) 981–991
989
1711 m, 1647 m, 1535 m, 901 w, 787 w cmꢀ1
;
1H NMR (400 MHz,
J = 9.8 Hz, 0.58H), 0.29 (m, 0.42H), 0.20 (d, J = 7.3 Hz, 1.74H), 0.13
(d, J = 9.8 Hz, 0.42H); UV (cyclohexane) kmax nm 227.6
(21,800), 330.6 (1300); CD kext(nm)( )(cyclohexane) 209.6
CDCl3) d 8.44 (s, 1H), 8.25 (d, J = 10.1 Hz, 1H), 7.97–7.95 (m, 2H),
7.84–7.77 (m, 3H), 7.60–7.52 (m, 5H), 6.50 (d, J = 10.5 Hz, 0.5H),
6.48 (d, J = 10.5 Hz, 0.5H), 3.83–3.75 (m, 1H), 3.78 (s, 1.8H), 3.77
(s, 1.2H), 1.16–1.10 (m, 2H), 0.94 (d, J = 6.4 Hz, 1.6H), 0.80 (t,
J = 6.4 Hz, 1.3H), 0.75–0.46 (m, 4H), 0.39 (t, J = 7.3 Hz, 1.7H), 0.30
(e)
D
e
(+3.2), 216.9 (0), 225.4 (ꢀ15.8), 242.7 (0), 258.8 (+5.6), 287.6
(+1.6), 299.6 (+2.0); ½a D30
¼ þ25:2 (c 0.266, CHCl3); ESI-MS m/z
ꢂ
491 (M+, 46), 339 (100), 296 (47), 295 (60), 281 (59), 280 (76);
HRMS (ESI) Anal. Calcd for C33H33NO3 m/z 491.2460 [M]+. Found:
491.2460.
(d, J = 6.9 Hz, 1.4H); UV (cyclohexane) kmax
(e) nm 226.6 (21,900),
334.0 (900); CD kext(nm)(
D
e
)(cyclohexane) 214.2 (ꢀ7.0), 220.1
(0), 229.0 (+13.7), 240.7 (0), 255.4 (ꢀ6.0), 290.2 (ꢀ1.8), 301.0
(ꢀ2.3); ½a 2D0
ꢂ
¼ ꢀ17:7 (c 0.884, CHCl3); ESI-MS m/z 440 (M+, 12),
4.3.3.9. Methyl 30-{[(1R)-1-cyclohexylethyl](methyl)carbamoyl}-
439 (33), 339 (90), 296 (61), 295 (65), 281 (71), 280 (100), 252
(39); HRMS (ESI) Anal. Calcd for C29H29NO3 m/z 439.2147 [M]+.
Found: 439.2152.
2,20-binaphthalene-3-carboxylate 4a.
Colorless amorphous.
Rf (CHCl3/EtOAc, 9/1 (v/v)) 0.48. HPLC purity: 98.7%; IR (film)
2925 m, 2850 m, 1725 m, 1623 m, 750 m cmꢀ1 1H NMR
m
;
(500 MHz, CDCl3) d 8.58–8.38 (m, 1H), 8.17–7.71 (m, 6H), 7.64–
7.47 (m, 5H), 4.29 (m, 0.7H), 3.69 (s, 2.1H), 3.68 (s, 0.9H), 3.52
(m, 0.3H), 2.67 (br s, 0.9H), 2.48 (br s, 2.1H), 1.79–0.48 (m,
4.3.3.6. Methyl 30-[(2S)-hexan-2-ylcarbamoyl]-2,20-binaphtha-
lene-3-carboxylate 3h.
EtOAc, 2/1 (v/v)) 0.54. HPLC purity: 99.7%; Anal. Calcd for
29H29NO3: C, 79.24; H, 6.65; N, 3.19. Found: C, 79.13; H, 6.49;
N, 3.26. IR (film) 3335 w, 3059 m, 2955 m, 2932 m, 2856 m,
1711 m, 1647 m, 1535 m, 901 w, 787 w cmꢀ1 1H NMR
Colorless amorphous. Rf (hexane/
13.1H), 0.12 (br d, J = 4.4 Hz, 0.9H); UV (cyclohexane) kmax
(e) nm
C
223.0 (15,600), 257.0 (18,300), 334.4 (500); CD kext(nm)( )(cyclo-
De
m
hexane) 216.0 (ꢀ20.4), 226.1 (0), 236.6 (+24.8), 251.3 (0), 256.8
;
(ꢀ3.8), 263.1 (0), 278.0 (+2.2), 286.5 (0), 292.6 (ꢀ4.1), 303.8
(400 MHz, CDCl3) d 8.44 (s, 1H), 8.25 (d, J = 10.1 Hz, 1H), 7.97–
7.95 (m, 2H), 7.84–7.77 (m, 3H), 7.60–7.52 (m, 5H), 6.50 (d,
J = 10.5 Hz, 0.5H), 6.48 (d, J = 10.5 Hz, 0.5H), 3.83–3.75 (m, 1H),
3.78 (s, 1.8H), 3.77 (s, 1.2H), 1.16–1.09 (m, 2H), 0.94 (d,
J = 6.4 Hz, 1.6H), 0.80 (t, J = 6.9 Hz, 1.3H), 0.75–0.46 (m, 4H), 0.39
(t, J = 6.9 Hz, 1.7H), 0.30 (d, J = 6.4 Hz, 1.4H); UV (cyclohexane)
(ꢀ9.0); ½a 2D4
ꢂ
¼ þ20:6 (c 0.206, CHCl3); ESI-MS m/z 479 (M+, 34),
339 (100), 295 (57), 281 (35), 280 (64); HRMS (ESI) Anal. Calcd
for C32H33NO3 m/z 479.2460 [M]+. Found: 479.2458.
4.3.3.10. Methyl 30-{[(1S)-1-cyclohexylethyl](methyl)carbam-
oyl}-2,20-binaphthalene-3-carboxylate 4b.
Colorless amor-
phous. Rf (CHCl3/EtOAc, 9/1 (v/v)) 0.50. HPLC purity: 99.1%; IR
(film) 2925 m, 2850 m, 1724 m, 1617 m, 1615 m, 888 w,
749 m cmꢀ1 1H NMR (500 MHz, CDCl3) d 8.58–8.38 (m, 1H),
kmax(e) nm 226.8 (22,500), 334.0 (900); CD kext(nm)(De)(cyclohex-
ane) 213.8 (+3.5), 218.3 (0), 228.6 (ꢀ16.8), 242.1 (0), 256.8 (+5.0),
m
289.22 (+0.5), 300.4 (+1.0); ½a D20
ꢂ
¼ þ15:4 (c 0.739, CHCl3); ESI-MS
;
m/z 440 (M+, 13), 439 (37), 339 (100), 296 (67), 295 (72), 281
(71), 280 (95), 252 (41); HRMS (ESI) Anal. Calcd for C29H29NO3
m/z 439.2147 [M]+. Found: 439.2142.
8.17–7.71 (m, 6H), 7.64–7.47 (m, 5H), 4.29 (m, 0.7H), 3.69 (s,
2.1H), 3.68 (s, 0.9H), 3.52 (m, 0.3H), 2.67 (br s, 0.9H), 2.48 (br s,
2.1H), 1.79–0.48 (m, 13.1H), 0.12 (br d, J = 4.4 Hz, 0.9H); UV (cyclo-
hexane) kmax
(e) nm 223.0 (16,600), 257.0 (19,400), 335.2 (600); CD
4.3.3.7.
clo[3.1.1]hept-3-yl]carbamoyl}-2,20-binaphthalene-3-carboxyl-
ate 3i. Colorless amorphous Rf (hexane/EtOAc, 2/1 (v/v)) 0.31.
HPLC purity: 98.6%; IR (film) 2995 m, 2910 m, 2860 m, 1710 s,
1646 s, 1584 m, 1534 m, 897 m cmꢀ1 1H NMR (500 MHz, CDCl3)
Methyl
30-{[(1R,2R,3R,5S)-2,6,6-trimethylbicy-
kext(nm)(
De
)(cyclohexane) 216.2 (+21.1), 225.9 (0), 236.8 (ꢀ27.8),
251.3 (0), 256.8 (+4.3), 263.7 (0), 275.8 (ꢀ2.4), 286.5 (0), 293.0
(+4.8), 303.8 (+10.0); ½a D25
¼ ꢀ23:8 (c 0.248, CHCl3); ESI-MS m/z
ꢂ
m
479 (M+, 32), 339 (100), 295 (59), 281 (33), 280 (64); HRMS (ESI)
;
Anal. Calcd for C32H33NO3 m/z 479.2460 [M]+. Found: 479.2464.
d 8.44 (s, 0.42H), 8.42 (s, 0.58H), 8.27 (s, 1H), 7.98–7.93 (m, 2H),
7.85–7.76 (m, 3H), 7.63–7.51 (m, 5H), 6.71 (br d, J = 8.3 Hz,
0.58H), 6.58 (br d, J = 8.3 Hz, 0.42H), 4.07 (m, 1H), 3.78 (s, 1.74H),
3.77 (s, 1.26H), 2.50 (m, 0.58H), 2.17 (m, 0.58), 2.09–1.95 (m,
1H), 1.80 (m, 0.58H), 1.61 (m, 1.16H), 1.47–1.34 (m, 2.10H), 1.07
(s, 1.74H), 1.05 (s, 1.26H), 1.00 (d, J = 7.3 Hz, 1.26H), 0.86 (s, 3H),
0.63 (m, 0.58H), 0.38 (d, J = 9.8 Hz, 0.58H), 0.29 (m, 0.42H), 0.20
(d, J = 7.3 Hz, 1.74H), 0.13 (d, J = 9.8 Hz, 0.42H); UV (cyclohexane)
4.3.3.11. Methyl 30-{[(2R)-3,3-dimethylbutan-2-yl](methyl)car-
bamoyl]-2,20-binaphthalene-3-carboxylate
4c.
Colorless
amorphous. Rf (hexane/EtOAc, 2/1 (v/v)) 0.46. HPLC purity:
99.0%; Anal. Calcd for C30H31NO3: C, 79.44; H, 6.89; N, 3.09. Found:
C, 79.19; H, 6.99; N, 3.11. IR (film)
m 2953 m, 1720 m, 1609 m, 897
w, 754 w cmꢀ1; 1H NMR (400 MHz, CDCl3) d 8.52 (s, 0.6H), 8.43 (s,
0.4H), 8.05–7.80 (m, 6H), 7.61–7.50 (m, 5H), 4.59–4.57 (m, 0.5H),
3.70 (s, 3H), 3.76–3.69 (m, 0.5H), 2.73 (s, 1.2H), 2.62 (s, 1.8H),
1.25 (s, 1.2H), 1.00–0.80 (m, 0.5H), 0.74 (s, 7.8H), 0.10–0.01 (m,
kmax(e) nm 227.8 (21,000), 331.4 (1100); CD kext(nm)(De)(cyclo-
hexane) 212.8 (ꢀ4.5), 217.1 (0), 225.6 (+15.1), 242.7 (0), 257.6
(ꢀ5.3), 286.6 (ꢀ1.8), 299.4 (ꢀ2.3); ½a D30
ꢂ
¼ ꢀ20:9 (c 0.238, CHCl3);
2.5H); UV (cyclohexane) kmax
(16,900), 335.0 (700); CD kext(nm)(De
(
e
)
nm 221.8 (17,200), 257.4
)(cyclohexane) 216.6
ESI-MS m/z 491 (M+, 46), 339 (100), 296 (48), 295 (61), 281 (59),
280 (77); HRMS (ESI) Anal. Calcd for C33H33NO3 m/z 491.2460
[M]+. Found: 491.2461.
(ꢀ20.9), 227.1 (0), 237.0 (+21.0), 269.8 (+1.8), 287.5 (0), 287.5
(0), 294.0 (ꢀ5.3), 304.6 (ꢀ9.7); ½a D26
¼ þ10:8 (c 1.870, CHCl3);
ꢂ
ESI-MS m/z 453 (M+, 0.5), 396 (33), 339 (100), 295 (77), 280 (74);
HRMS (ESI) Anal. Calcd for C30H31NO3 m/z 453.2304 [M]+. Found:
453.2299.
4.3.3.8.
clo[3.1.1]hept-3-yl]carbamoyl}-2,20-binaphthalene-3-carboxyl-
ate 3j. Colorless amorphous Rf (hexane/EtOAc, 2/1 (v/v)) 0.35.
HPLC purity: 99.6%; Anal. Calcd for C33H33NO3: C, 80.62; H, 6.77; N,
2.85. Found: C, 79.19; H, 6.99; N, 3.11. IR (film) 3325 w, 2945 m,
2915 m, 2870 m, 1702 m, 1640 m, 1638 m, 1524 m, 895 m,
748 m cmꢀ1 1H NMR (500 MHz, CDCl3) d 8.44 (s, 0.42H), 8.42 (s,
Methyl
30-{[(1S,2S,3S,5R)-2,6,6-trimethylbicy-
4.3.3.12. Methyl 30-{[(2S)-3,3-dimethylbutan-2-yl](methyl)car-
m
bamoyl]-2,20-binaphthalene-3-carboxylate
4d.
Colorless
amorphous. Rf (hexane/EtOAc, 2/1 (v/v)) 0.46. HPLC purity:
99.2%; Anal. Calcd for C30H31NO3: C, 79.44; H, 6.89; N, 3.09. Found:
;
0.58H), 8.27 (s, 1H), 7.98–7.93 (m, 2H), 7.85–7.76 (m, 3H), 7.63–
7.51 (m, 5H), 6.71 (br d, J = 8.3 Hz, 0.58H), 6.58 (br d, J = 8.3 Hz,
0.42H), 4.07 (m, 1H), 3.78 (s, 1.74H), 3.77 (s, 1.26H), 2.50 (m,
0.58H), 2.17 (m, 0.58), 2.09–1.95 (m, 1H), 1.80 (m, 0.58H), 1.61
(m, 1.16H), 1.47–1.34 (m, 2.10H), 1.07 (s, 1.74H), 1.05 (s, 1.26H),
1.00 (d, J = 7.3 Hz, 1.26H), 0.86 (s, 3H), 0.63 (m, 0.58H), 0.38 (d,
C, 79.77; H, 6.93; N, 3.09. IR (film)
m 3059 m, 1722 m, 1603 m, 897
w, 727 w cmꢀ1 1H NMR (CDCl3) d 8.52 (s, 0.6H), 8.43 (s, 0.4H),
;
8.04–7.80 (m, 6H), 7.61–7.50 (m, 5H), 4.58–4.56 (m, 0.5H), 3.70
(s, 3H), 3.76–3.69 (m, 0.5H), 2.73 (s, 1.2H), 2.62 (s, 1.8H), 1.25 (s,
1.2H), 1.00–0.80 (m, 0.5H), 0.74 (s, 7.8H), 0.10–0.01 (m, 2.5H);
UV (cyclohexane) kmax(e) nm 221.6 (17,400), 257.4 (17,100),

990
T. Fujiwara et al. / Tetrahedron: Asymmetry 23 (2012) 981–991
334.8 (700); CD kext(nm)(
D
e
)(cyclohexane) 216.2 (+17.9), 227.5
339 (71), 310 (52), 295 (73), 281 (38), 280 (100), 252 (35); HRMS
(ESI) Anal. Calcd for
453.2308.
(0), 237.2 (ꢀ22.8), 287.3 (0), 295.0 (+4.4), 304.6 (+8.7);
C
30H31NO3 m/z 453.2304 [M]+. Found:
½
a 2D6
ꢂ
¼ ꢀ10:0 (c 2.180, CHCl3); ESI-MS m/z 453 (M+, 0.7), 396
(40), 340 (26), 339 (100), 295 (68), 280 (59); HRMS (ESI) Anal.
Calcd for C30H31NO3 m/z 453.2304 [M]+. Found: 453.2301.
4.3.3.17. Methyl 30-{methyl[(1R,2R,3R,5S)-2,6,6-trimethylbicy-
clo[3.1.1]hept-3-yl]-carbamoyl}-2,20-binaphthalene-3-carboxyl-
4.3.3.13. Methyl 30-[(2R)-butan-2-yl(methyl)carbamoyl]-2,20-
binaphthalene-3-carboxylate 4e.
(hexane/EtOAc, 2/1 (v/v)) 0.38. HPLC purity: 100.0%; IR (film)
2953 m, 2936 m, 1722 m, 1614 m, 895 w, 721 w cmꢀ1 1H NMR
(CDCl3) d 8.50 (s, 0.8H), 8.46 (s, 0.2H), 7.99–7.79 (m, 6H), 7.61–
7.50 (m, 5H), 4.60–4.50 (m, 1H), 3.71 (s, 3H), 2.66 (s, 1.2H), 2.47
(s, 1.8H), 1.40–1.20 (m, 2.3H), 1.10–0.60 (m, 3.2H), 0.30–0.20 (m,
ate 4i.
HPLC purity: 99.0%; IR (film)
895 w cmꢀ1 1H NMR (CDCl3) d 8.50 (s, 1H), 8.03–7.77 (m, 6H),
Colorless amorphous. Rf (hexane/EtOAc, 2/1 (v/v)) 0.57.
Colorless amorphous. Rf
m
2951 m, 2924 m, 1722 m, 1620 m,
m
;
;
7.60–7.51 (m, 5H), 5.20–5.00 (m, 1H), 3.70 (s, 3H), 2.84 (s, 0.5H),
2.65 (s, 2.5H), 2.22–2.20 (m, 1H), 1.70–1.50 (m, 2.3H), 1.32–1.19
(m, 2.8H), 1.13 (s, 3H), 1.10–1.00 (m, 1H), 1.02 (s, 3H), 0.90–0.83
(m, 1.4H), 0.74 (d, J = 10.9 Hz, 1H), 0.70–0.55 (m, 0.5H); UV (cyclo-
2.5H); UV (cyclohexane) kmax
(18,700), 336.2 (900); CD kext(nm)(
(
e
)
nm 221.8 (18,000), 257.2
)(cyclohexane) 216.0
hexane) kmax
(e) nm 222.6 (18,200), 256.8 (19,400), 335.2 (700); CD
D
e
kext(nm)(
De
)(cyclohexane) 215.2 (ꢀ5.6), 222.9 (0), 235.4 (+13.1),
(ꢀ16.3), 226.7 (0), 236.6 (+18.1), 253.1 (0), 256.0 (ꢀ1.6), 261.5
245.3 (0), 255.2 (ꢀ5.0), 267.3 (0), 271.4 (+0.3), 283.1 (0), 291.6
(0), 274.2 (+2.4), 287.1 (0), 293.2 (ꢀ3.1), 304.0 (ꢀ7.0);
(ꢀ2.1), 302.8 (ꢀ3.9); ½a D26
¼ þ0:2 (c 2.020, CHCl3);ESI-MS m/z 505
ꢂ
½
a 2D3
ꢂ
¼ ꢀ8:0 (c 0.891, CHCl3); ESI-MS m/z 425 (M+, 30), 339 (42),
(M+, 58), 339 (100), 310 (33), 295 (77), 280 (87); HRMS (ESI) Anal.
310 (39), 295 (63), 280 (100), 252 (40); HRMS (ESI) Anal. Calcd
Calcd for C34H35NO3 m/z 505.2617 [M]+. Found: 505.2612.
for C28H27NO3 m/z 425.1991 [M]+. Found: 425.1986.
4.3.3.18. Methyl 30-{methyl[(1S,2S,3S,5R)-2,6,6-trimethylbicy-
4.3.3.14. Methyl 30-[(2S)-butan-2-yl(methyl)carbamoyl]-2,20-
clo[3.1.1]hept-3-yl]-carbamoyl}-2,20-binaphthalene-3-carboxyl-
binaphthalene-3-carboxylate 4f.
(hexane/EtOAc, 2/1 (v/v)) 0.38. HPLC purity: 100.0%; IR (film)
2953 m, 2936 m, 1722 m, 1612 m, 895 w, 725 w cmꢀ1 1H NMR
Colorless amorphous. Rf
ate 4j.
HPLC purity: 98.8%; IR (film)
894 w cmꢀ1 1H NMR (CDCl3) d 8.50 (s, 1H), 8.01–7.77 (m, 6H),
Colorless amorphous. Rf (hexane/EtOAc, 2/1 (v/v)) 0.57.
m
m
2951 m, 2924 m, 1722 m, 1620 m,
;
;
(CDCl3) d 8.50 (s, 0.8H), 8.46 (s, 0.2H), 7.99–7.79 (m, 6H), 7.61–
7.50 (m, 5H), 4.60–4.50 (m, 1H), 3.70 (s, 3H), 2.66 (s, 1.2H), 2.47
(s, 1.8H), 1.40–1.20 (m, 2.3H), 1.10–0.60 (m, 3.2H), 0.30–0.20 (m,
7.60–7.51 (m, 5H), 5.20–5.00 (m, 1H), 3.70 (s, 3H), 2.84 (s, 0.5H),
2.65 (s, 2.5H), 2.24–2.19 (m, 1H), 1.70–1.50 (m, 2.3H), 1.30–1.19
(m, 2.8H), 1.13 (s, 3H), 1.10–1.00 (m, 1H), 1.02 (s, 3H), 0.90–0.83
(m, 1.4H), 0.74 (d, J = J = 10.9 Hz, 1H), 0.70–0.55 (m, 0.5H); UV
2.5H); UV (cyclohexane) kmax
(18,600), 335.2 (1000); CD kext(nm)(
(
e
)
nm 221.8 (17,700), 257.2
)(cyclohexane) 215.4
D
e
(cyclohexane) kmax
(700); CD kext(nm)(De
(
e
) nm 222.6 (17,400), 256.8 (18,300), 335.6
)(cyclohexane) 215.4 (+3.8), 220.9 (0),
(+15.3), 226.7 (0), 236.4 (ꢀ17.7), 257.0 (+2.5), 286.3 (0), 293.2
(+3.7), 304.0 (+7.6); ½a D20
ꢂ
¼ þ9:0 (c 0.748, CHCl3); ESI-MS m/z 425
235.4 (ꢀ12.1), 245.5 (0), 256.2 (+4.0), 266.1 (0), 278.4 (ꢀ0.6),
(M+, 30), 339 (44), 310 (40), 295 (59), 281 (36), 280 (100), 252
(42); HRMS (ESI) Anal. Calcd for C28H27NO3 m/z 425.1991 [M]+.
Found: 425.1999.
285.5 (0), 290.4 (+1.1), 302.0 (+2.9); ½a D26
¼ ꢀ0:7 (c 1.640, CHCl3);
ꢂ
ESI-MS m/z 505 (M+,23), 339 (58), 295 (71), 280 (100), 252 (36);
HRMS (ESI) Anal. Calcd for C34H35NO3 m/z 505.2617 [M]+. Found:
505.2609.
4.3.3.15. Methyl 30-[(2R)-hexan-2-yl(methyl)carbamoyl]-2,20-
binaphthalene-3-carboxylate 4g.
Colorless amorphous. Rf
4.3.3.19. Methyl 30-{[(4R)-3-oxoisoxazolidin-4-yl]carbamoyl}-
(hexane/EtOAc, 2/1 (v/v)) 0.49. HPLC purity: 99.2%; Anal. Calcd
for C30H31NO3: C, 79.44; H, 6.89; N, 3.09. Found: C, 79.16; H,
2,20-binaphthalene-3-carboxylate 5.
Colorless amorphous.
Rf (hexane/EtOAc, 1/3 (v/v)) 0.41. HPLC purity: 100.0%; IR (film)
3296 m, 3059 m, 2953 m, 2933 m, 1715 m, 1663 m, 1508 m, 901
w, 667 w cmꢀ1 1H NMR (CDCl3) d 8.54 (s, 0.5H), 8.48 (s, 0.5H),
m
7.00; N, 3.20. IR (film)
m 2955 m, 2932 m, 1722 m, 1614 m, 895
w, 721 w cmꢀ1 1H NMR (CDCl3) d 8.50 (s, 0.8H), 8.46 (s, 0.2H),
;
;
7.95–7.78 (m, 6H), 7.59–7.51 (m, 5H), 4.61–4.56 (m, 1H), 3.70 (s,
1.8H), 3.69 (s, 1.2H), 2.66 (s, 1.2H), 2.47 (s, 1.8H), 1.36–0.22 (m,
8.24 (s, 0.5H), 8.21 (s, 0.5H), 7.98–7.94 (m, 2H), 7.84–7.75 (m,
3H), 7.67–7.53 (m, 5H), 7.20–7.16 (m, 1H), 4.71–4.65 (m, 1H),
4.44–4.37 (m, 1H), 3.88–3.85 (m, 0.5H), 3.76 (s, 1.5H), 3.74 (s,
12H); UV (cyclohexane) kmax
(e
)
nm 221.6 (17,700), 257.2
)(cyclohexane) 215.4
(18,100), 335.0 (900); CD kext(nm)(
D
e
1.5H), 3.13–3.08 (m, 0.5H); UV (cyclohexane) kmax
(e) nm 242.0
(ꢀ20.7), 226.5 (0), 236.6 (+23.47), 250.7 (0), 257.2 (ꢀ4.9), 264.1
(10,400), 333.0 (300); CD kext(nm)(De)(cyclohexane) 205.6
(0), 279.0 (+1.7), 285.7 (0), 293.0 (ꢀ5.1), 303.8 (ꢀ9.9);
(ꢀ9.3), 229.8 (ꢀ17.2), 239.4 (0), 249.2 (+21.2); ½a D26
¼ ꢀ6:2 (c
ꢂ
½
a 2D6
ꢂ
¼ þ7:4 (c 1.870, CHCl3); ESI-MS m/z 454 (M+, 11), 453 (35),
4.220, CHCl3); ESI-MS m/z 440 (M+, 11), 296 (100), 280 (39); HRMS
(ESI) Anal. Calcd for C26H20N2O5 m/z 440.1372 [M]+. Found:
440.1379.
339 (56), 310 (43), 295 (68), 281 (39), 280 (100), 252 (40); HRMS
(ESI) Anal. Calcd for
453.2310.
C
30H31NO3 m/z 453.2304 [M]+. Found:
4.3.3.20. 30-{Methyl[(4R)-2-methyl-3-oxoisoxazolidin-4-yl]car-
4.3.3.16. Methyl 30-[(2S)-hexan-2-yl(methyl)carbamoyl]-2,20-
binaphthalene-3-carboxylate 4h. Colorless amorphous. Rf
(hexane/EtOAc, 2/1 (v/v)) 0.49. HPLC purity: 99.7%; Anal. Calcd
for C30H31NO3: C, 79.44; H, 6.89; N, 3.09. Found: C, 79.91; H,
bamoyl}-2,20-binaphthalene-3-carboxylate
6.
amorphous. Rf (hexane/EtOAc, 1/3 (v/v)) 0.79; HPLC purity:
100.0%; IR (film) 3059 w, 3026 w, 1713 m, 1663 m, 1512 m,
895 w cmꢀ1 1H NMR (CDCl3) d 8.54 (s, 0.6H), 8.45 (s, 0.4H),
Colorless
m
;
6.89; N, 3.17. IR (film)
m
2955 m, 2932 m, 1722 m, 1612 m, 895
8.06–7.80 (m, 6H), 7.63–7.55 (m, 5H), 5.40–5.32 (m, 0.5H), 4.35–
4.21 (m, 0.5H), 3.88 (s, 1.5H), 3.77 (s, 1.5H), 3.73 (s, 3H), 3.31–
w, 721 w, cmꢀ1 1H NMR (CDCl3) d 8.49 (s, 0.8H), 8.45 (s, 0.2H),
;
7.94–7.77 (m, 6H), 7.61–7.50 (m, 5H), 4.60–4.58 (m, 1H), 3.70 (s,
1.8H), 3.69 (s, 1.2H), 2.65 (s, 1.2H), 2.47 (s, 1.8H), 1.36–0.21 (m,
3.24 (m, 2H), 2.74 (s, 1.2H), 2.56 (s, 1.8H); UV (cyclohexane) kmax
nm 224.2 (5400), 248.6 (5400), 335.0 (200); CD
kext(nm)(
)(cyclohexane) 213.6 (ꢀ8.1), 219.8 (0), 233.0 (+8.9),
(e)
12H); UV (cyclohexane) kmax
(18,300), 334.8 (900); CD kext(nm)(
(
e
)
nm 221.8 (17,800), 257.2
)(cyclohexane) 215.4
De
D
e
245.6 (0), 250.4 (ꢀ0.9), 256.4 (0), 265.6 (+2.5), 288.4 (0), 304.6
(+18.1), 225.7 (0), 236.8 (ꢀ24.6), 251.7 (0), 257.0 (+4.0), 262.7
(ꢀ2.3); ½a 3D0
ꢂ
¼ þ51:2 (c 0.430, CHCl3); ESI-MS m/z 468 (M+, 30),
(0), 279.6 (ꢀ2.6), 286.9 (0), 293.2 (+4.2), 303.8 (+9.0);
310 (94), 295 (76), 281 (48), 280 (100); HRMS (ESI) Anal. Calcd
½
a 2D6
ꢂ
¼ ꢀ7:7 (c 1.760, CHCl3); ESI-MS m/z 454 (M+, 18), 453 (53),
for C28H24N2O5 m/z 468.1691 [M]+. Found: 468.1685.

T. Fujiwara et al. / Tetrahedron: Asymmetry 23 (2012) 981–991
991
7. Hosoi, S.; Kamiya, M.; Kiuchi, F.; Ohta, T. Tetrahedron Lett. 2001, 42, 6315–6317.
8. Hosoi, S.; Kamiya, M.; Ohta, T. Org. Lett. 2001, 3, 3659–3662.
9. Gawronski, J.; Kwit, M.; Gawronska, K. Org. Lett. 2002, 4, 4185–4188.
10. Huang, X.; Fujioka, N.; Pescitelli, G.; Koehn, F. E.; Williamson, R. T.; Nakanishi,
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11. Zhang, J.; Holmes, A. E.; Sharma, A.; Brooks, N. R.; Rarig, R. S.; Zubieta, J.;
Canary, J. W. Chirality 2003, 15, 180–189.
12. Mason, S. F.; Seal, R. H.; Roberts, D. R. Tetrahedron 1974, 30, 1671–1682.
13. Hosoi, S.; Serata, J.; Kiuchi, F.; Sakushima, A.; Ohta, T. J. Nat. Prod. 2004, 67,
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Acknowledgments
This work was financially supported by Grants-in-Aid for Scien-
tific Research (C) (no. 20590030) from the Japan Society for the
Promotion of Science and MEXT-Supported Program for the Strate-
gic Research Foundation at Private Universities, 2009–2012.
References
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15. Calculations were performed with CONFLEX and MOPAC implemented in
CAChe ver. 4.1.1 for Apple Macintosh; Fujitsu Co., Ltd, Chiba, Japan.
Conformational analysis using CONFLEX was carried out under the following
conditions: search limit: 0.01%; maximum configurations: 5000; highest steric
energy: 25.0 kcal/mol; energy comparison: 1.5 kcal/mol; dihedral comparison:
10.0°; force field: augmented MM2; optimization: conjugate gradient for no
more than 3000 updates or until convergence to 0.001 kcal/mol; cut-off
distance for vdw interactions: 9.0 Å.
16. The most stable conformers of the derivatives, whose parent amines were in an
antipodal relationship, were enantiomeric to each other.
17. Niimura, N.; Minezaki, Y.; Nonaka, T.; Castagna, J.-C.; Cipriani, F.; Hoeghoej, P.;
Lehmann, M. S.; Wilkinson, C. Nat. Struct. Biol. 1997, 4, 909–914.
5. Kurtan, T.; Nesnas, N.; Li, Y. Q.; Huang, X.; Nakanishi, K.; Berova, N. J. Am. Chem.
Soc. 2001, 123, 5962–5973.
6. Kurtan, T.; Nesnas, N.; Koehn, F. E.; Li, Y. Q.; Nakanishi, K.; Berova, N. J. Am.
Chem. Soc. 2001, 123, 5974–5982.