Folding of dihelicenetriamines in water

Article abstract of DOI:10.1016/S0957-4166(02)00249-5

Diastereomeric triamines containing two helicene moieties, 1,12-dimethylbenzo[c]phenanthrene, were synthesized and found to form folded structures in the water. Such folding was not observed for an achiral compound possessing a naphthalene moiety. The (M,M)-dihelicenetriamine with matching configuration at the helicene moieties formed a more stable folded structure than the (P,M)-isomer containing two enantiomeric helicene groups. The most stable folded conformation was predicted by the Monte Carlo method with Amber force field of the dihelicenetriamine.

Full text of DOI:10.1016/S0957-4166(02)00249-5

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 1043–1052
Folding of dihelicenetriamines in water
Shinobu Honzawa,a Hitoshi Okubo,a Keiichi Nakamura,a Shuzo Anzai,a Masahiko Yamaguchia,*
and Chizuko Kabutob
aDepartment of Organic Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba,
Sendai 980-8578, Japan
bInstrumental Analysis Center for Chemistry, Graduate School of Science, Tohoku University, Aoba, Sendai 980-8578, Japan
Received 4 April 2002; accepted 7 May 2002
Abstract—Diastereomeric triamines containing two helicene moieties, 1,12-dimethylbenzo[c]phenanthrene, were synthesized and
found to form folded structures in the water. Such folding was not observed for an achiral compound possessing a naphthalene
moiety. The (M,M)-dihelicenetriamine with matching configuration at the helicene moieties formed a more stable folded structure
than the (P,M)-isomer containing two enantiomeric helicene groups. The most stable folded conformation was predicted by the
Monte Carlo method with Amber force field of the dihelicenetriamine. © 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
treated with 1 equiv. of Boc2O followed by CbzCl giving
(M)-5. A half aldehyde (M)-6 was obtained by DIBAL
reduction of (M)-4. Compound (M)-5 was then con-
verted to the monoamine by selective removal of the
benzyloxycarbonyl group and coupled with (M)-6 in
refluxing toluene followed by NaBH4 reduction giving
(M,M)-7 in 70% yield. The nitrile (M,M)-7 was reduced
by a two-step procedure using NaBH4 and DIBAL, and
t-butoxycarbonylation of the crude product gave
(M,M)-8. The protecting groups of (M,M)-8 were
removed with trifluoroacetic acid, and treatment with
hydrochloric acid gave (M,M)-2. The antipode (P,P)-2
Non-bonding interactions and chiral recognition
between the helical p-electron systems play important
roles in the chemistry of helicenes, 1,12-dimethylben-
zo[c]phenanthrene derivatives. Electron-rich and elec-
tron-deficient helicenes formed a charge-transfer (CT)
complex in solution, and the (M)-helicene acceptor
exhibited higher affinity with the (M)-donor than the
(P)-donor.1 A CT-complex of the racemic electron-
deficient helicene and pyrene crystallized in the columnar
structure, each of which contained a single enantiomer
of the helicene.2 Macrocyclic alkynes containing three
helicene moieties aggregated in organic solvents by p-p
interactions, and the homo-aggregation of the (M,M,M)-
isomer turned out to be stronger than the hetero-aggre-
gation between the (M,M,M)-isomer and the
(P,P,P)-isomer.3 As an extension of helicene chem-
istry,4,5 the basic derivatives, 5,8-bis(aminomethyl)-1,12-
dimethylbenzo[c]phenanthrene 1 and its dimers 2, were
synthesized.6 The isomers 2 were found to form folded
structures in water, and the behavior of (M,M)-2 was
compared with that of (P,M)-2.
•2HCl
H2NCH2
D
CH2NH2
(M)-1
A
A
D
•3HCl
H
N
B
C
B
C
H2NCH2
CH2NH2
7
6
6
7
(M,M)-2
11
2
2
11
D
A
A
D
•3HCl
•3HCl
H
N
2. Results and discussion
B
C
B
C
H2NCH2
H2NCH2
CH2NH2
CH2NH2
7
6
6
7
The diamine 1, prepared by hydrogenation of the dinitrile
41 in 71% yield, was used for the synthesis of 2 (Scheme
1). In order to discriminate two amino groups, (M)-1 was
(P,M)-2
H
N
3
* Corresponding author. E-mail: yama@mail.pharm.tohoku.ac.jp
0957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00249-5

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S. Honzawa et al. / Tetrahedron: Asymmetry 13 (2002) 1043–1052
6-H and 7-H were shifted by more than 1 ppm; from l
8.3 (CD3OD) to l 7.0 (D2O) for 6-H, and from l 8.0
(CD3OD) to l 6.7 (D2O) for 7-H. The peaks were
assigned unambiguously using 2D-NMR of (M,M)-2 as
was synthesized by the same procedure starting from
(P)-4. The diastereoisomer (P,M)-2, a meso-compound,
was obtained from (P)-5 and (M)-6. An achiral dimer 3
was also synthesized from 2,7-naphthalenedicarboxylic
acid7 in order to compare its properties with those of 2.
1
well as H NMR of (M,M)-2-d obtained by NaBD4
reduction of (M,M)-7. The 1H NMR spectra of (M,M)-
2 in DMSO-d6, DMF-d7, and CD3CO2D were similar
1
The dimers 2 exhibited different H NMR spectra in
1
to that recorded in CD3OD. The H NMR spectra in
water and organic solvents. While the aromatic protons
of (M,M)-2 in CD3OD appeared at >l 7.4, they were
all shifted to higher field in D2O (Fig. 1). In particular,
in the spectra of (M,M)-2, the two singlet signals for
D2O were concentration independent between 0.1 and 5
mM indicating the intramolecular nature of the phe-
1
nomenon. In accordance, H NMR of the monomeric
(M)-1 did not show such solvent effects. UV, CD, and
fluorescence
spectra
of
(M,M)-2
exhibited
hypochromism on changing the solvent from methanol
to water (Figs. 2 and 3), which suggests the formation
of p-stacked structures in water. These observations are
consistent with the formation of folded, most likely
Scheme 1.
Figure 2. UV and CD spectra of (M,M)-2 (1.0×10−5 M, 25°C)
in CH3OH (black lines) and in H2O (red lines).
Figure 3. Fluorescence spectra of (M,M)-2 (1.0×10−5 M,
25°C) in CH3OH (black line) and in H2O (red line) with
excitation at 350 nm.
Figure 1. 1H NMR (23°C, 1.0 mM) spectra of (M,M)-2 in
CD3OD (a) or D2O (b).

S. Honzawa et al. / Tetrahedron: Asymmetry 13 (2002) 1043–1052
1045
layered structures8,9 of (M,M)-2 in water, while the
compound is not folded in organic solvents. Such solvent
1
effects were also observed in the H NMR, UV, and
fluorescence spectra of the diastereomer (P,M)-2 (Figs.
1
4–6). The H NMR spectra of this compound exhibited
high field shift of not only 6-H and 7-H but also 2-H and
11-H, when the solvent was changed from CD3OD to D2O
(Fig. 4).
In contrast to the chiral compounds 2, the 1H NMR and
UVspectraoftheachiral3weresimilarinorganicsolvents
and in water. The folding of 2 in water is therefore due
to stronger intramolecular interactions, not only hydro-
phobic effects but also p-p interactions. The difference
Figure 6. Fluorescence spectra of (P,M)-2 (1.0×10−5 M, 25°C)
in CH3OH (black line) and in H2O (red line) with excitation
at 350 nm.
in the number of benzene rings at the aromatic moiety,
four for compound 2 and two for compound 3, or the
chirality of the p-electron system is playing an important
role. At present, we prefer the latter interpretation, since
some indications were obtained for the strong affinity of
the helical p-electron system with the same absolute
configuration.3 In addition, different folding behaviors
observed between the isomeric (M,M)-2 and (P,M)-2
support the interpretation. When the UV absorption
coefficients m at 290 nm of the isomeric 2 were plotted
against the solvent composition of methanol and water,
sigmoidal curves were obtained (Fig. 7). The ratio of the
folded and unfolded structures in solution were obtained
at each solvent composition, and the free energy differ-
ences DG between the two states could be calculated (Fig.
8). Linear extrapolation of these data to 100% water gave
the values DGM,M(H2O)=–1.8 kcal/mol and DGP,M(H2O)
=–1.5 kcal/mol, which are the free energy differences in
water between the folded and unfolded structures for each
isomer.10 The results indicate that (M,M)-2, with match-
ing configuration of helicenes, forms more stable folded
structure(s) than (P,M)-2 with enantiomeric helicene
moieties.
Figure 4. 1H NMR (23°C, 1.0 mM) spectra of (P,M)-2 in
CD3OD (a) or D2O (b).
Figure 7. Plots of the UV absorption coefficient m at 290 nm
versus the volume percent of H2O in CH3OH for (M,M)-2 (ꢀ)
and (P,M)-2 (ꢁ) (25°C, 1.1×10−5 to 1.5×10−5 M).
Figure 5. UV spectra of (P,M)-2 (1.0×10−5 M, 25°C) in CH3OH
(black line) and in H2O (red line).

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S. Honzawa et al. / Tetrahedron: Asymmetry 13 (2002) 1043–1052
Figure 8. Plots of DG versus the volume percent of CH3OH in
H2O for (M,M)-2 (ꢀ,ꢂ) and (P,M)-2 (ꢃ,ꢁ) (25°C, 1.0×
10−5 to 1.5×10−5 M). Linear extrapolation of these data to
100% H2O gives the values: DGM,M(H2O)=−1.8 0.6 (ꢀ) and
−1.7 0.4 (ꢂ) kcal/mol; DGP,M(H2O)=−1.5 0.3 (ꢃ) and
−1.5 0.3 (ꢁ) kcal/mol. The same experiments were con-
ducted twice.
The most stable conformations of (M,M)-2 and (P,M)-
2 in water were obtained by the Monte Carlo method
with Amber force field (Fig. 9). Both isomers of 2 stack
at the B ring of the helicene moiety, and the structures
are consistent with the high field shifts of 2 at 6-H and
7-H on folding. Reflecting the helicity, however, the
,
distances between the two D-rings of (M,M)-2 (7.1 A)
,
is substantially longer than that of (P,M)-2 (5.8 A),
which reasonably explains the high field shifts at 2-H
and 11-H for the latter compound (Fig. 9b). The calcu-
lations also indicated the higher stability of the folded
structure of (M,M)-2 over (P,M)-2 by 1.7 kcal/mol,
which is in fair agreement with 0.3 kcal/mol obtained
by the above experiments (Fig. 8).
Figure 9. The calculated structures of (M,M)-2 (a) and
(P,M)-2 (b) in water obtained by the Monte Carlo method
with Amber force field using Macromodel.
4. Experimental
X-Ray crystallographic analyses of (M)-1 and ( )-1
provided additional information on the folded structure
of 2 (Fig. 10a and b).11 Both crystals contained colum-
nar structures of the helicene, in which the B-rings
stack with each other. The calculated structures of 2
(Fig. 9) are therefore probable. It may also be interest-
ing to note that, in the crystal of ( )-1, (M)-1 and (P)-1
formed different columns (Fig. 10c). Thus, the helicene
favors the same configuration of the compound via p-p
stacking in the crystallization process.
4.1. (M)-1,12-Dimethyl-5,8-bis(aminomethyl)benzo[c]-
phenanthrene dihydrochloride, (M)-1
Under a hydrogen atmosphere, a mixture of (M)-41
(200 mg, 0.65 mmol), palladium on carbon (5%, 200
mg), ethyl acetate (20 mL), methanol (20 mL) and 2 M
hydrochloric acid (2 mL) was vigorously stirred at 40°C
for 36 h. The insoluble materials were removed by
filtration and the solution was concentrated in vacuo.
Recrystallization from ethanol gave (M)-1 (180 mg,
71%). Mp 240°C dec. (ethanol). [h]3D1 +102 (c 0.49,
methanol). Anal calcd for C22H22N2Cl2·H2O: C, 65.19;
H, 6.46; N, 6.91; Cl, 17.49. Found: C, 64.59; H, 6.61;
N, 7.06; Cl, 17.73%. LRMS (EI, 70 eV) m/z 314
(M+−2HCl, 100%), 282 (M+−2NH3Cl, 49%). HRMS
(EI, 70 eV) calcd for C22H22N2: 314.1783. Found:
314.1768. IR (KBr) 3700–3300 cm−1. 1H NMR
(DMSO-d6) l 1.85 (6H, s), 4.67 (2H, d, J=15 Hz), 4.73
(2H, d, J=15 Hz), 7.55 (2H, d, J=7 Hz), 7.73 (2H, dd,
J=7, 8 Hz), 8.02 (2H, s), 8.18 (2H, d, J=8 Hz). 13C
3. Conclusion
To summarize, dihelicenetriamines form folded struc-
tures in the water and unfolded structures in organic
solvents, and the folding behaviors of these structures
were affected by the chirality at the helicene moiety.
Studies on the synthesis and folding behavior of higher
oligoamines are now underway.

S. Honzawa et al. / Tetrahedron: Asymmetry 13 (2002) 1043–1052
1047
C, 85.41; H, 4.89; N, 4.53. Found: C, 84.85; H, 5.20; N,
4.63%. LRMS (EI, 70 eV) m/z 309 (M+, 100%), 294
(M+−Me, 20%), 281 (M+−CHO, 7%). HRMS (EI, 70
eV) calcd for C22H15NO: 309.1154. Found: 309.1172.
1
IR (KBr) 2730, 2221, 1685 cm−1. H NMR (CDCl3) l
1.90 (3H, s), 1.92 (3H, s), 7.53 (1H, d, J=7 Hz), 7.57
(1H, d, J=7 Hz), 7.79 (1H, dd, J=7, 8 Hz), 7.81 (1H,
dd, J=7, 8 Hz), 8.29 (1H, s), 8.33 (1H, d, J=8 Hz),
8.38 (1H, d, J=8 Hz), 9.25 (1H, d, J=8 Hz), 10.51
(1H, s). 13C NMR (CDCl3) l 23.2, 23.5, 110.1, 117.5,
122.4, 122.9, 129.0, 129.0, 129.3, 129.8, 129.9, 130.3,
130.5, 131.1, 131.3, 131.5, 132.6, 132.6, 136.1, 136.9,
137.9, 192.1. (P)-6: [h]2D2 +195 (c 0.53, CHCl3).
4.3. (M)-8-Benzyloxycarbonylaminomethyl-5-(t-butoxy-
carbonylaminomethyl)-1,12-dimethylbenzo[c]phen-
anthrene, (M)-5
To
a mixture of (M)-1 (390 mg, 1.0 mmol),
dichloromethane (10 mL), water (5 mL) and 10%
aqueous sodium hydroxide (5 mL) was added di(t-
butyl) dicarbonate (220 mg, 1 mmol) at 0°C. After
being stirred for 30 min at the temperature, benzyloxy-
carbonyl chloride (0.28 mL, 2 mmol) was added, and
the mixture was stirred for another 30 min. The reac-
tion was quenched by adding saturated aqueous ammo-
nium chloride, and the organic materials were extracted
with ethyl acetate three times. The combined organic
layers were washed with water and brine, dried over
magnesium sulfate and concentrated in vacuo. Purifica-
tion by silica gel chromatography (ethyl acetate/hex-
ane=1/2) gave (M)-5 (180 mg, 35%). Mp 124–125°C
(toluene). [h]2D7 +70 (c 0.9, CHCl3). Anal. calcd for
C35H36N2O4: C, 76.62; H, 6.61; N, 5.11. Found: C,
76.38; H, 6.90; N, 4.86%. LRMS (EI, 70 eV) m/z 548
(M+, 9%), 448 (M+−Boc, 100%). HRMS (EI, 70 eV)
calcd for C35H36N2O4: 548.2675. Found: 548.2699. IR
1
(KBr) 3500–3300, 1698 cm−1. H NMR (CDCl3) l 1.50
(9H, s), 1.91 (3H, s), 1.92 (3H, s), 4.80–5.10 (2H, m),
5.18 (2H, s), 5.21 (2H, br), 7.28–7.40 (5H, m), 7.40 (2H,
d, J=7 Hz), 7.60 (1H, t, J=8 Hz), 7.60 (1H, t, J=8
Hz), 7.68 (1H, s), 7.69 (1H, s), 8.02 (1H, d, J=7 Hz),
8.04 (1H, d, J=8 Hz). 13C NMR (CDCl3) l 23.4, 23.4,
28.4, 42.7, 43.1, 66.7, 79.4, 120.3, 120.4, 124.6, 124.7,
125.1, 125.8, 127.8, 127.8, 128.0, 128.2, 130.0, 130.2,
131.0, 131.4, 132.5, 133.0, 136.2, 136.5, 136.5, 155.5,
156.0. (P)-5:[h]2D6 −70 (c 0.6, CHCl3).
Figure 10. X-Ray structures of (M)-1 (a) and ( )-1 (b,c).
Protons are omitted for clarity.
NMR (DMSO-d6) l 23.2, 48.8, 121.0, 125.3, 125.9,
126.8, 128.8, 129.7, 129.8, 130.3, 130.6, 136.2. (P)-1:
[h]3D1 −97 (c 0.23, methanol).
4.2. (M)-1,12-Dimethyl-5-formyl-benzo[c]phenanthrene-
8-carbonitrile, (M)-6
4.4. (M)-5-Aminomethyl-8-(t-butoxycarbonylamino-
methyl)-1,12-dimethylbenzo[c]phenanthrene
Under an argon atmosphere, to a solution of (M)-4
(770 mg, 2.50 mmol) in dichloromethane (20 mL) was
added diisobutylaluminum hydride in hexane (1.0 M,
3.0 mL, 3.0 mmol) at −90°C. After stirring the mixture
for 10 min at the temperature, 1 M hydrochloric acid
(20 mL) was added, and the mixture was warmed to
room temperature. The organic materials were
extracted with chloroform three times. The combined
organic extracts were washed with brine, dried over
sodium sulfate, and concentrated in vacuo. Purification
by silica gel chromatography gave (M)-6 (330 mg,
42%). An analytical sample was obtained by recrystal-
lization from toluene/hexane. Mp 240°C sublimation.
[h]2D9 −182 (c 0.38, CHCl3). Anal. calcd for C22H15NO:
Under a hydrogen atmosphere, a mixture of (M)-5 (250
mg, 0.5 mmol), 5% palladium on carbon (350 mg),
ethyl acetate (5 mL) and methanol (5 mL) was vigor-
ously stirred for 1 h at room temperature. Insoluble
materials were removed by filtration, and the solution
was concentrated in vacuo. Purification by silica gel
chromatography (ethyl acetate/methanol=1/1) gave the
title compound (150 mg, 72%). [h]2D7 +88 (c 1.1, CHCl3).
Anal. calcd for C27H30N2O2: C, 78.23; H, 7.29; N, 6.76.
Found: C, 77.96; H, 7.25; N, 6.74%. LRMS (EI, 70 eV)
m/z 415 (M++1, 30%), 414 (M+, 90%), 357 (M+−tBu,
100%). HRMS (EI, 70 eV) calcd for C27H30N2O2:

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S. Honzawa et al. / Tetrahedron: Asymmetry 13 (2002) 1043–1052
414.2307. Found: 414.2307. IR (KBr) 3500–3200, 1702
J=8 Hz), 7.72 (1H, s), 7.84 (1H, s), 7.87 (1H, s), 8.04
(1H, d, J=8 Hz), 8.15 (2H, d, J=8 Hz), 8.24 (1H, s),
8.28 (1H, d, J=8 Hz). 13C NMR (CDCl3) l 23.3, 23.5,
23.6, 23.6, 28.6, 43.0, 51.4, 51.8, 79.6, 108.9, 118.1,
120.5, 120.9, 121.2, 122.6, 124.3, 124.9, 125.1, 125.2,
125.7, 125.9, 127.2, 127.3, 128.0, 128.1, 128.2, 128.6,
129.7, 129.8, 130.1, 130.2, 130.6, 130.9, 131.1, 131.2,
131.7, 132.3, 132.7, 133.0, 134.5, 136.1, 136.7, 136.9,
137.3, 155.5.
1
cm−1. H NMR (CDCl3) l 1.50 (9H, s), 1.93 (6H, s),
4.42 (1H, d, J=15 Hz), 4.50 (1H, d, J=14 Hz), 4.85
(1H, dd, J=5,14 Hz), 4.97 (1H, dd, J=6,14 Hz), 5.03
(1H, br), 7.39 (2H, d, J=7 Hz), 7.59 (1H, t, J=8 Hz),
7.59 (1H, t, J=8 Hz), 7.71 (1H, s), 7.74 (1H, s), 8.04
(1H, d, J=8 Hz), 8.06 (1H, d, J=8 Hz). 13C NMR
(CDCl3) l 23.6, 23.6, 28.6, 43.0, 44.1, 79.5, 120.2, 120.5,
123.1, 124.8, 125.0, 125.8, 128.0, 128.1, 130.2, 130.3,
131.5, 131.6, 131.7, 133.0, 136.7, 136.8, 137.8, 155.6.
(P)-isomer: [h]2D6 −90 (c 1.0, CHCl3).
4.6. (M,M)-5-{8-(t-Butoxycarbonylaminomethyl)-1,12-
dimethylbenzo[c]phenanthrene-5-yl}methylaminomethyl-
8-(t-butoxycarbonylaminomethyl)-1,12-dimethylbenzo[c]-
phenanthrene, (M,M)-8
4.5. (M,M)-5-{8-(t-Butoxycarbonylaminomethyl)-1,12-
dimethylbenzo[c]phenanthrene-5-yl}methylaminomethyl-
8-cyano-1,12-dimethylbenzo[c]phenanthrene, (M,M)-7
Under an argon atmosphere, to a solution of (M,M)-7
(90 mg, 0.13 mmol) in dichloromethane (20 mL) was
added 1.0 M diisobutylaluminum hydride in hexane
(1.0 mL, 1.0 mmol) at 0°C and the mixture was stirred
for 30 min at the temperature. Then the mixture was
added to a suspension of sodium borohydride (200 mg,
5.4 mmol) in tetrahydrofuran (10 mL) and methanol
(20 mL) at 0°C. The ice bath was removed and stirring
was continued at room temperature for 30 min, when
saturated aqueous ammonium chloride was added.
After being stirred for 30 min at room temperature,
aqueous 10% sodium hydroxide was added. The
organic materials were extracted with dichloromethane
three times. The combined organic layers were washed
with water and brine, dried over potassium carbonate,
and concentrated in vacuo. The resulted amorphous
solid was diluted with dichloromethane (10 mL), to
which di(t-butyl) dicarbonate (2 g, 10 mmol), water (5
mL), and aqueous 10% sodium hydroxide (5 mL) were
added successively. The mixture was stirred for 30 min
at room temperature, and the reaction was quenched by
adding saturated aqueous ammonium chloride. The
organic materials were extracted with ethyl acetate
three times. The combined organic layers were washed
with water and brine, dried over magnesium sulfate,
and concentrated in vacuo. Purification by silica gel
chromatography (ethyl acetate/hexane=1/2) gave
(M,M)-8 (80 mg, 70%). Mp 180°C dec. (ethyl acetate/
hexane). [h]2D7 −8.2 (c 2.0, CHCl3). Anal. calcd for
C59H65N3O6: C, 77.69; H, 7.18; N, 4.61. Found: C,
78.06; H, 7.12; N, 4.25%. MS (FAB, NBA) m/z 911
(M+). IR (KBr) 3500–3300, 1696 cm−1. 1H NMR
(CDCl3 at 50°C) l 1.48 (18H, s), 1.60 (9H, s), 1.87 (6H,
s), 1.91 (6H, s), 4.57 (2H, d, J=14 Hz), 4.65 (2H, brs),
4.79 (2H, dd, J=5, 14 Hz), 4.85 (2H, d, J=14 Hz), 5.33
(2H, brs), 7.09 (2H, s), 7.14 (2H, s), 7.35 (2H, d, J=7
Hz), 7.40 (2H, d, J=7 Hz), 7.49 (2H, t, J=7 Hz), 7.59
(2H, t, J=8 Hz), 7.98 (2H, d, J=8 Hz), 8.00 (2H, brs).
13C NMR (CDCl3 at 50°C) l 23.5, 23.5, 28.6, 28.7,
42.8, 48.1, 79.5, 80.5, 120.4, 124.0, 124.9, 125.8, 127.4,
127.7, 127.9, 128.0, 128.1, 130.3, 130.5, 131.1, 131.6,
131.7, 132.1, 132.9, 136.6, 136.7, 155.5, 155.8. (P,P)-8:
[h]2D8 +8.3 (c 1.6, CHCl3). (P,M)-8: Mp 180°C dec.
A solution of (M)-monoamine obtained as above (150
mg, 0.36 mmol) and (M)-6 (120 mg, 0.4 mmol) in
toluene (10 mL) was heated under reflux for 24 h. The
mixture was added to a suspension of sodium borohy-
dride (300 mg, 8 mmol) in methanol (20 mL) and
tetrahydrofuran (10 mL) at 0°C. The mixture was
stirred at the temperature for 10 min, and the reaction
was quenched by adding saturated aqueous ammonium
chloride. The organic materials were extracted with
ethyl acetate three times. The combined organic layers
were washed with water and brine, dried over magne-
sium sulfate, and concentrated in vacuo. Purification by
silica gel chromatography (ethyl acetate/hexane=1/2)
gave (M,M)-7 (180 mg, 70%). Mp 150°C dec. (ethyl
acetate/hexane). [h]D27 −14 (c 1.2, CHCl3). Anal. calcd
for C49H45N3O2: C, 83.14; H, 6.41; N, 5.94. Found: C,
82.98; H, 6.09; N, 5.57%. LRMS (EI, 70 eV) m/z 707
(M+, 1%), 607 (M+−Boc, 5%), 299 (MeAr*CH2NH2,
100%). IR (KBr) 3500–3300, 2222, 1704 cm−1. 1H NMR
(CDCl3) l 1.50 (9H, s), 1.89 (3H, s), 1.92 (3H, s), 1.93
(6H, s), 4.49 (1H, d, J=14 Hz), 4.49 (1H, d, J=14 Hz),
4.59 (1H, d, J=15 Hz), 4.63 (1H, d, J=13 Hz), 4.81–
5.00 (3H, m), 7.39 (1H, d, J=7 Hz), 7.41 (1H, d, J=7
Hz), 7.42 (1H, d, J=8 Hz), 7.49 (1H, d, J=7 Hz), 7.53
(1H, dd, J=7, 8 Hz), 7.59 (1H, dd, J=7, 8 Hz), 7.60
(1H, dd, J=7, 8 Hz), 7.70 (1H, t, J=8 Hz), 7.71 (1H,
s), 7.83 (1H, s), 7.86 (1H, s), 8.04 (1H, d, J=8 Hz), 8.14
(2H, d, J=8 Hz), 8.23 (1H, s), 8.28 (1H, d, J=8 Hz).
13C NMR (CDCl3) l 23.3, 23.5, 23.6, 23.6, 28.6, 43.0,
51.4, 51.8, 79.6, 109.0, 118.1, 120.6, 120.9, 121.2, 122.6,
124.3, 124.9, 125.2, 125.3, 125.7, 125.9, 127.2, 127.3,
128.0, 128.1, 128.2, 128.6, 129.7, 129.8, 130.1, 130.3,
130.6, 130.9, 131.1, 131.2, 131.7, 132.3, 132.7, 133.0,
134.6, 136.2, 136.7, 136.9, 137.3, 155.5. (P,P)-7: [h]D26
+13 (c 1.0, CHCl3). (P,M)-7 was obtained from (P)-5
and (M)-6 in 82% yield. Mp 150°C dec. (ethyl acetate/
hexane). [h]2D6 −52 (c 0.6, CHCl3). Anal. calcd for
C49H45N3O2: C, 83.14; H, 6.41; N, 5.94. Found: C,
83.41; H, 5.89; N, 6.07%. LRMS (EI, 70 eV) m/z 707
(M+, 3%), 607 (M+−Boc, 19%), 310 (NC-Ar*CH2NH2,
100%). IR (KBr) 3500–3300, 2222, 1705 cm−1. 1H NMR
(CDCl3) l 1.50 (9H, s), 1.90 (3H, s), 1.91 (3H, s), 1.93
(6H, s), 4.48 (1H, d, J=14 Hz), 4.49 (1H, d, J=14 Hz),
4.61 (1H, d, J=15 Hz), 4.65 (1H, d, J=14 Hz), 4.80–
5.00 (3H, m), 7.39 (1H, d, J=7 Hz), 7.41 (1H, d, J=7
Hz), 7.43 (1H, d, J=8 Hz), 7.49 (1H, d, J=7 Hz), 7.54
(1H, t, J=8 Hz), 7.60 (2H, t, J=8 Hz), 7.70 (1H, t,
(ethyl
acetate/hexane).
Anal.
calcd
for
C59H65N3O6·H2O: C, 76.18; H, 7.26; N, 4.52. Found: C,
76.41; H, 7.02; N, 4.18%. MS (FAB, NBA) m/z 911
(M+). IR (KBr) 3500–3300, 1697 cm−1. 1H NMR

S. Honzawa et al. / Tetrahedron: Asymmetry 13 (2002) 1043–1052
1049
(CDCl3 at 45°C) l 1.51 (18H, s), 1.55 (9H, s), 1.79 (6H,
s), 1.81 (6H, s), 4.81 (2H, dd, J=6, 16 Hz), 4.89 (2H,
dd, J=6, 16 Hz), 5.13 (2H, brs), 5.16 (2H, brs), 7.31
(2H, d, J=7 Hz), 7.33 (2H, d, J=7 Hz), 7.48 (2H, brs),
7.49 (2H, brs), 7.55 (4H, t, J=8 Hz), 8.01 (4H, d, J=8
Hz). 13C NMR (CDCl3) l 23.4, 23.4, 28.4, 28.6, 43.0,
48.0, 79.6, 80.5, 120.4, 124.8, 125.2, 125.7, 125.8, 128.0,
128.1, 128.9, 130.3, 131.1, 131.5, 131.7, 132.1, 133.0,
136.6, 136.7, 155.6, 155.9. When the imine derived from
(M,M)-7 was reduced with NaBD4, (M,M)-8-d was
trifluoroacetic acid (3 mL) at 0°C, and the mixture was
stirred for 1 h at the temperature. Then, 2 M hydro-
chloric acid (3 mL) was added, and the solvents were
removed in vacuo. The resulted solid was diluted with a
small amount of methanol, to which was added 10%
lithium perchlorate in methanol (2 mL). The solid was
collected, and recrystallization from water/methanol
gave the title compound (80 mg, 73%). Mp 200°C dec.
(H2O/methanol). [h]2D8 +19 (c 0.3, methanol). Anal.
calcd for C44H44N3Cl3O12: C, 57.87; H, 4.86; N, 4.60;
Cl, 11.65. Found: C, 57.90; H, 5.06; N, 4.31; Cl,
11.38%. LRMS (EI, 70 eV) m/z 611 (M+, 7%), 579
(M+−CH2NH2, 66%), 298 (CH2ArCH2NH2, 100%).
HRMS (EI, 70 eV) calcd for C44H41N3: 611.3300.
1
obtained. H NMR (CDCl3 at 45°C) l 1.50 (18H, s),
1.57 (9H, s), 1.87 (6H, s), 1.92 (6H, s), 4.55 (2H, d,
J=14 Hz), 4.60 (1H, brs), 4.79 (2H, dd, J=5, 14 Hz),
4.84 (2H, d, J=14 Hz), 5.34 (2H, brs), 7.09 (2H, s),
7.15 (2H, s), 7.33 (2H, d, J=7 Hz), 7.40 (2H, d, J=7
Hz), 7.49 (2H, t, J=7 Hz), 7.60 (2H, t, J=8 Hz), 7.99
(2H, d, J=8 Hz), 8.01 (2H, brs).
1
Found: 611.3322. IR (KBr) 3500–2500 cm−1. H NMR
(D2O at 50°C) l 1.78 (12H, s), 4.06 (2H, d, J=14 Hz),
4.53 (2H, d, J=14 Hz), 4.99 (2H, d, J=14 Hz), 5.49
(2H, d, J=14 Hz), 7.10 (2H, s), 7.40 (2H, s), 7.60 (2H,
d, J=6 Hz), 7.69 (2H, d, J=7 Hz), 7.82 (2H, t, J=8
Hz), 7.93 (2H, t, J=8 Hz), 8.02 (2H, d, J=8 Hz), 8.17
(2H, d, J=8 Hz). 13C NMR (CDCl3) l 23.4, 24.0, 41.3,
48.9, 120.5, 120.9, 127.0, 127.5, 127.5, 128.2, 128.3,
128.4, 128.9, 130.0, 130.3, 130.4, 130.4, 130.5, 131.6,
131.7, 138.1, 138.4. Triperchlorate derivative of (P,P)-
2:[h]2D6 −20 (c 0.2, methanol). Triperchlorate derivative
of (P,M)-2: Mp 200°C dec. (H2O/methanol). Anal.
calcd for C44H44N3Cl3O12·H2O: C, 56.75; H, 4.98; N,
4.51; Cl, 11.42. Found: C, 56.37; H, 5.38; N, 4.32; Cl,
11.70%. LRMS (EI, 70 eV) m/z 611 (M+, 2%), 579
(M+−CH2NH2, 15%), 299 (MeArCH2NH2, 100%).
HRMS (EI, 70 eV) calcd for C44H41N3: 611.3300.
4.7. (M,M)-5-{8-(Aminomethyl)-1,12-dimethylbenzo[c]-
phenanthrene-5-yl}methylaminomethyl-8-
aminomethyl-1,12-dimethylbenzo[c]phenanthrene
trihydrochloride, (M,M)-2
To a solution of (M,M)-8 (64 mg, 0.07 mmol) in
dichloromethane (2 mL) was added trifluoroacetic acid
(0.5 mL) at 0°C, and the mixture was stirred for 1 h at
the temperature. Then, 2 M hydrochloric acid (3 mL)
was added and the solvents were removed in vacuo.
Recrystallization from toluene/methanol gave (M,M)-2
(45 mg, 89%). Mp 275°C dec. (toluene/methanol). [h]D25
1
+11
(c
0.12,
methanol).
Anal.
calcd
for
Found: 611.3301. IR (KBr) 3500–2600 (br) cm−1. H
C44H44N3Cl3·3H2O: C, 68.17; H, 6.50; N, 5.42. Found:
C, 68.03; H, 6.32; N, 4.96%. LRMS (EI, 70 eV) m/z 611
NMR (CD3OD) l 1.81 (6H, s), 1.85 (6H, s), 4.69 (2H,
d, J=14 Hz), 4.86 (2H, d, J=14 Hz), 5.03 (2H, d,
J=14 Hz), 5.24 (2H, d, J=14 Hz), 7.49 (2H, d, J=7
Hz), 7.51 (2H, d, J=7 Hz), 7.61 (2H, t, J=8 Hz), 7.77
(2H, t, J=8 Hz), 8.01 (2H, s), 8.07 (2H, d, J=8 Hz),
8.16 (2H, d, J=8 Hz), 8.23 (2H, s). 13C NMR
(CD3OD) l 23.6, 23.6, 41.6, 121.2, 127.7, 127.7, 128.2,
128.3, 128.4, 129.9, 130.1, 130.1, 130.2, 131.3, 131.6,
131.6, 132.4, 132.4, 138.3.
(M+,
7%),
579
(M+−CH2NH2,
66%),
298
(CH2ArCH2NH2, 100%). HRMS (EI, 70 eV) calcd for
C44H41N3: 611.3300. Found: 611.3289. IR (KBr) 3500–
1
2500 (br) cm−1. H NMR (CD3OD) l 1.87 (6H, s), 1.89
(6H, s), 4.70 (2H, d, J=14 Hz), 4.87 (2H, d, J=14 Hz),
5.02 (2H, d, J=14 Hz), 5.23 (2H, d, J=14 Hz), 7.49
(2H, d, J=8 Hz), 7.55 (2H, d, J=8 Hz), 7.60 (2H, t,
J=8 Hz), 7.78 (2H, t, J=8 Hz), 8.03 (2H, d, J=8 Hz),
8.04 (2H, s), 8.17 (2H, d, J=8 Hz), 8.24 (2H, s). 13C
NMR (CD3OD) l 23.6, 23.7, 41.6, 49.3, 121.2, 121.2,
127.7, 128.2, 128.4, 128.4, 129.9, 130.0, 130.2, 130.2,
131.4, 131.5, 131.7, 132.4, 132.4, 138.3, 138.3. (P,P)-2:
[h]2D5 –12 (c 0.44, methanol). (P,M)-2: Mp 270°C dec.
(toluene/methanol). Anal. calcd for C44H44N3Cl3·4H2O:
C, 66.62; H, 6.61; N, 5.30; Cl, 13.41. Found: C, 66.53;
H, 6.43; N, 5.10; Cl, 12.80%. LRMS (EI, 70 eV) m/z
611 (M+, 2%), 579 (M+−CH2NH2, 15%), 299
4.8. 2,7-Dicyanonaphthalene
A mixture of 2,7-naphthalenedicarboxylic acid7 (130
mg, 0.62 mmol) and thionyl chloride (5 mL) was heated
at reflux for 3 h. After removing the excess thionyl
chloride under reduced pressure, the resulted solid was
dissolved in dichloromethane (10 mL) and the solution
was added to excess ammonia at −78°C. The cooling
bath was removed, and the reaction mixture was
warmed to room temperature. After being stirred for 1
h water was added. The resulted crude diamide was
collected by filtration, washed with water, and dried in
vacuo. The residue was dissolved in thionyl chloride (6
mL) and the mixture was heated at reflux for 18 h
under an argon atmosphere. Then excess thionyl chlo-
ride was removed under reduced pressure, and purifica-
1
(MeArCH2NH2, 100%). IR (KBr) 3500–2600 cm−1. H
NMR (CD3OD) l 1.81 (6H, s), 1.85 (6H, s), 4.68 (2H,
d, J=14 Hz), 4.85 (2H, d, J=14 Hz), 5.02 (2H, d,
J=14 Hz), 5.23 (2H, d, J=14 Hz), 7.49 (2H, d, J=8
Hz), 7.52 (2H, d, J=8 Hz), 7.61 (2H, t, J=8 Hz), 7.77
(2H, t, J=8 Hz), 8.02 (2H, s), 8.06 (2H, d, J=8 Hz),
8.17 (2H, d, J=8 Hz), 8.22 (2H, s). 13C NMR
(CD3OD) l 23.6, 23.6, 41.6, 49.5, 121.2, 121.2, 127.7,
128.2, 128.4, 128.5, 129.9, 130.1, 130.2, 130.2, 131.4,
131.6, 131.6, 132.4, 132.4, 138.3, 138.3. Triperchlorate
derivative of (M,M)-2. To a solution of (M,M)-8 (110
mg, 0.12 mmol) in dichloromethane (5 mL) was added
tion
by
silica
gel
chromatography
(ethyl
acetate/hexane=1/2) gave the title compound (50 mg,
45%). An analytical sample was obtained by sublima-
tion at 1 mmHg. Mp 180°C sublimation. Anal calcd for
C12H6N2: C, 80.89; H, 3.39; N, 15.72. Found: C, 80.94;

1050
S. Honzawa et al. / Tetrahedron: Asymmetry 13 (2002) 1043–1052
H, 3.48; N, 15.42%. LRMS (EI, 70 eV) m/z 179 (M++1,
16%), 178 (M+, 100%), 151 (M+−HCN, 19%). HRMS
(EI, 70 eV) calcd for C12H6N2: 178.0531. Found:
4.11. 2-(Benzyloxycarbonyl)aminomethyl-7-(t-butoxy-
carbonylaminomethyl)naphthalene
1
178.0544. IR (KBr) 2227 cm−1. H NMR (CDCl3) l
To a mixture of 2,7-bis(aminomethyl)naphthalene (83
mg, 0.44 mmol), dichloromethane (20 mL) and 1 M
sodium hydroxide (20 mL) was added di(t-butyl) dicar-
bonate (89 mg, 0.41 mmol) in dichloromethane (1 mL)
at room temperature. After being stirred for 30 min,
benzyloxycarbonyl chloride (0.076 mL, 0.53 mmol) was
added, and the mixture was stirred for 30 min. The
reaction was quenched by adding saturated aqueous
ammonium chloride, and the organic materials were
extracted three times with ethyl acetate. The combined
organic layers were washed with water and brine, dried
over magnesium sulfate and concentrated in vacuo.
Purification by silica gel chromatography (ethyl acetate/
hexane=1/5) gave the title compound (54 mg, 29%).
Mp 154–156°C (ethanol). LRMS (EI, 70 eV) m/z 420
(M+, 6%), 363 (M+−t-Bu, 18%), 319 (M+−Boc, 27%),
273 (M+−C4H8−PhCH2, 33%), 156 (CH3-Np-CH3,
7.79 (2H, dd, J=2, 8 Hz), 8.01 (2H, d, J=8 Hz), 8.31
(2H, t, J=2 Hz). 13C NMR (CDCl3) l 111.6, 118.0,
129.3, 129.3, 131.1, 134.1, 135.5.
4.9. 2-Cyano-7-naphthalenecarbaldehyde
Under an argon atmosphere to a solution of 2,7-
dicyanonaphthalene (15 mg, 0.084 mmol) in
dichloromethane (15 mL) was added 1.0 M diisobutyl-
aluminum hydride in hexane (0.090 mL, 0.090 mmol) at
−78°C. After stirring the mixture for 15 min at the
temperature, 2 M hydrochloric acid (10 mL) was
added, and the mixture was warmed to room tempera-
ture. The organic materials were extracted with chloro-
form three times. The combined organic layers were
washed with brine, dried over magnesium sulfate, and
concentrated in vacuo. Purification by silica gel chro-
matography (toluene/ethyl acetate=20/1) gave the title
compound (5.2 mg, 34%). Mp 140–141°C (toluene/hex-
ane). Anal calcd for C12H7NO: C, 79.55; H, 3.89; N,
7.73. Found: C, 79.58; H, 4.17; N, 7.56%. LRMS (EI,
70 eV) m/z 181 (M+, 98%), 180 (M+−H, 100%), 152
(M+−HCN, 76%). HRMS (EI, 70 eV) calcd for
C12H7NO: 181.0528. Found: 181.0513. IR (KBr) 2226,
+
87%), 91(PhCH2 , 100%). HRMS (EI, 70 eV) calcd for
C25H28N2O4: 420.2049. Found: 420.2403. IR (KBr)
1
3500–3300, 1687 cm−1. H NMR (CDCl3) l 1.48 (9H,
s), 4.46 (2H, d, J=5.2 Hz), 4.53 (2H, d, J=6.0 Hz),
4.93 (1H, brs), 5.16 (2H, s), 5.17 (1H, brs), 7.20–7.42
(7H, m), 7.65 (1H, brs), 7.66 (1H, brs), 7.78 (2H, d,
J=8.4 Hz). 13C NMR (CDCl3) l 28.4, 44.7, 45.2, 66.8,
79.4, 125.3, 125.5, 125.6, 127.9, 128.0, 128.2, 131.8,
133.0, 135.9, 136.1, 136.6, 155.5, 156.1
1
1695 cm−1. H NMR (CDCl3) l 7.77 (1H, dd, J=2, 8
Hz), 8.01 (2H, d, J=8 Hz), 8.12 (1H, dd, J=2, 8 Hz),
8.40 (2H, s), 10.21 (1H, s). 13C NMR (CDCl3) l 110.8,
118.3, 125.8, 129.1, 129.2, 129.3, 131.5, 133.9, 135.1,
135.2, 137.3, 190.9.
4.12. 7-{7-(t-Butoxycarbonyl)aminomethyl-2-
naphthylmethylaminomethyl}naphthalene-2-carbonitrile
Under a hydrogen atmosphere, a mixture of the above
compound (25 mg, 0.060 mmol), 10% palladium on
carbon (10 mg), ethyl acetate (2 mL), and methanol (2
mL) was vigorously stirred for 1 h at room tempera-
ture. The insoluble materials were removed by filtration
and the filtrate was concentrated in vacuo. The residue
was dissolved in toluene (2 mL), to which was added
2-cyano-7-naphthalenecarbaldehyde (9 mg, 0.05 mmol).
The mixture was heated under reflux for 4 h. After
being cooled to room temperature the mixture was
added to a suspension of sodium borohydride (21 mg,
0.57 mmol) in methanol (1.5 mL) and tetrahydrofuran
(1.5 mL) at 0°C. The mixture was stirred at the temper-
ature for 10 min, and water was added. The mixture
was extracted three times with ethyl acetate. The com-
bined organic layers were washed with water and brine,
dried over sodium sulfate and concentrated in vacuo.
Purification by silica gel chromatography (ethyl acetate/
hexane=1/1) gave the title compound (11 mg, 47%).
LRMS (EI, 70 eV) m/z 451 (M+, 4%), 395 (M+−C4H8,
22%), 350 (M+−Boc, 74%), 215 (100%). HRMS (EI, 70
eV) calcd for C29H29N3O4: 451.2260. Found: 451.2251.
IR (KBr) 3500–3300, 2226, 1709 cm−1. 1H NMR
(CDCl3) l 1.48 (9H, s), 4.01 (2H, s), 4.03 (2H, s), 4.48
(2H, d, J=5.2 Hz), 4.92 (1H, brs), 7.39 (1H, d, J=8.4
Hz), 7.48 (1H, dd, J=1.4, 8.4 Hz), 7.58 (1H, dd,
J=1.6, 8.4 Hz), 7.67 (1H, m), 7.69 (1H, s), 7.75 (1H, s),
7.80 (1H, d, J=8.4 Hz), 7.81 (1H, d, J=8.4 Hz), 7.86
(1H, s), 7.86 (1H, d), 7.90 (1H, d, J=8.4 Hz), 8.20 (1H,
s). 13C NMR (CDCl3) l 28.4, 44.8, 52.7, 53.2, 79.5,
4.10. 2,7-Bis(aminomethyl)naphthalene
Under an argon atmosphere, to a solution of 2,7-
dicyanonaphthalene (50 mg, 0.28 mmol) in
dichloromethane (7 mL) was added 1.0 M diisobutyl-
aluminum hydride in hexane (1.0 mL, 1.0 mmol) at
0°C, and the mixture was stirred for 30 min at the
temperature. Then the mixture was added to a suspen-
sion of sodium borohydride (200 mg, 5.4 mmol) in
tetrahydrofuran (7 mL) and methanol (14 mL) at 0°C.
Ice bath was removed, and stirring was continued at
room temperature for 30 min, when the reaction was
quenched by adding 2 M hydrochloric acid. After being
stirring for 30 min, aqueous 10% sodium hydroxide was
added, and the organic materials were extracted with
dichloromethane three times. The combined organic
layers were washed with water and brine, dried over
potassium carbonate, and concentrated in vacuo. The
resulted solid was recrystallized from toluene/hexane
giving the title compound (12 mg, 23%). Mp 158–160°C
(toluene/hexane). LRMS (EI, 70 eV) m/z 186 (M+,
100%), 169 (M+−NH3, 90%). HRMS (EI, 70 eV) calcd
for C12H14N2: 186.1157. Found: 186.1139. IR (KBr)
1
3500–3200 cm−1. H NMR (CDCl3) l 4.03 (4H, s), 7.41
(2H, dd, J=2, 8 Hz), 7.72 (2H, s), 7.80 (2H, d, J=8
Hz). 13C NMR (CDCl3) l 46.7, 124.8, 125.4, 127.9,
128.1, 128.9, 140.9.

S. Honzawa et al. / Tetrahedron: Asymmetry 13 (2002) 1043–1052
1051
(CD3OD) l 44.4, 52.3, 128.1, 128.7, 129.7, 129.9, 129.9,
130.6, 131.2, 132.7, 134.3, 134.7.
109.3, 119.0, 125.3, 125.8, 126.1, 126.2, 126.5, 127.7,
127.9, 128.6, 129.5, 131.7, 132.0, 133.6, 133.6, 136.4,
137.5, 139.7, 155.6.
4.14. Free energy differences between the folded and
unfolded conformers of 210
4.13. 1,1-Bis(7-aminomethyl-2-naphthylmethyl)amine
trihydrochloride, 3
UV absorption coefficients m of 2 at 290 nm were
measured at various ratios of CH3OH and H2O. At
each solvent ratio, the folded and unfolded conformers
are considered to be in equilibrium. At higher composi-
tions of CH3OH in solution, 2 should have an unfolded
conformer, and at lower compositions of CH3OH a
folded conformer. At each solvent composition, the
mole fraction x of 2 in the unfolded state can be
expressed as follows:
Under an argon atmosphere, to a solution of the above
compound (3 mg, 0.006 mmol) in dichloromethane (0.5
mL) was added diisobutylaluminum hydride in hexane
(1.0 M, 0.064 mL, 0.064 mmol) at 0°C. The mixture
was stirred for 10 min at the temperature and then
added to a suspension of sodium borohydride (2.5 mg,
0.066 mmol) in tetrahydrofuran (0.5 mL) and methanol
(0.5 mL) at 0°C. Stirring was continued at 0°C for 1 h,
when the reaction was quenched by adding water. The
organic materials were extracted three times with
dichloromethane. The combined organic layers were
washed with water and brine, dried over potassium
carbonate and concentrated in vacuo. The residue was
dissolved in dichloromethane (0.7 mL), to which 1 M
sodium hydroxide (0.5 mL) was added. Then, di(t-
butyl) dicarbonate (9 mg, 0.041 mmol) was added, and
the mixture was stirred at room temperature overnight.
The organic layer was separated, and the aqueous layer
was extracted three times with dichloromethane. The
combined organic layers were washed with water and
brine, dried over sodium sulfate and concentrated in
vacuo. Silica gel chromatography (ethyl acetate/hex-
ane=3/2) gave tri(t-butoxycarbonyl) derivative of 3 (3
mg, 71%). LRMS (FAB, NBA) m/z 656 (M++H), 598
(M++H−t-Bu), 554 (M+−Boc), 500 (M+−2C4H8−CO2),
498 (M+−Boc−t-Bu). IR (neat) 3500–3000, 1693 cm−1.
1H NMR (DMSO-d6 at 90°C) l 1.11 (18H, s), 1.13 (9H,
s), 3.99 (4H, d, J=6.4 Hz), 4.27 (4H, s), 6.74 (2H, brs),
7.05 (2H, dd, J=1.6, 8.4 Hz), 7.09 (2H, dd, J=1.6, 8.4
Hz), 7.34 (4H, s), 7.51 (2H, d, J=8.4 Hz), 7.52 (2H, d,
J=8.4 Hz). 13C NMR (DMSO-d6 at 90°C) l 27.9, 28.0,
43.8, 49.7, 77.6, 79.0, 124.5, 124.9, 125.1, 125.2, 127.0,
127.3, 130.9, 132.4, 135.5, 137.6, 154.8, 155.2.
x=(mfold−m)/(mfold−munfold
)
where mfold corresponds to a UV absorption coefficient
at lower composition of CH3OH, munfold an UV absorp-
tion coefficient at higher composition of CH3OH, and m
an UV absorption coefficient at a given composition of
CH3OH. The values mfold and munfold can be determined
from the plateau of titration curves at a higher and
lower CH3OH compositions in the plots of m verses
solvent compositions. Equilibrium constants Keq and
corresponding free energy changes DG for the confor-
mational transition at any point along the titration
curve were obtained by the standard relationships
Keq=x/(1−x) and DG=−RT lnKeq. The free energy
change between these conformational states was
assumed to depend linearly on solvent composition.
DG=DG(H2O)−m[CH3OH]
DG(H2O) represents the free energy difference between
the folded and unfolded conformations in water, and
the value of m describes how rapidly the free energy of
the transition changes with solvent composition, and
[CH3OH] means the percent concentration of CH3OH
in water. The intercept of a plot of DG verses composi-
tion thus provides DG(H2O).
Under an argon atmosphere, to a solution of the above
compound (3 mg, 0.004 mmol) in dichloromethane (0.5
mL) was added trifluoroacetic acid (0.3 mL) in
dichloromethane (0.5 mL) at 0°C, and the mixture was
stirred for 1 h at the temperature. The solvents were
removed under reduced pressure, to which was added 1
M hydrochloric acid (1 mL) and methanol (5 mL).
After being stirred at room temperature for 10 min, the
solvents were removed under reduced pressure to give 3
(2 mg, quant.). Mp 265°C dec. (methanol/ethanol).
Anal. calcd for C24H28N3Cl3·H2O: C, 59.70; H, 6.26; N,
8.70; Cl, 22.03. Found: C, 60.31; H, 6.07; N, 8.65; Cl,
21.96%. IR (KBr) 2924, 2853, 1613 cm−1. LRMS (EI,
70 eV) m/z 355 (free base, M+, 19%), 338 (free base,
M+−NH2−H, 15%), 185 (H2NCH2-Np-CH2NH, 57%),
183 (HNꢀCH-Np-CH2NH, 56%), 170 (H2NCH2-Np-
CH3, 100%). HRMS (EI, 70 eV) calcd for C24H25N3:
4.15. X-Ray crystallography
Details of crystal data, data collection, and refinement
for (M)-1 and ( )-1 are summarized in Table 1. The cell
and intensity data were collected using Rigaku/MSC
Mercury CCD diffractometer with graphite monochro-
mated Mo-Ka radiation. The data for (M)-1 were
measured at a temperature of −50°C, and those for
( )-1 at −100°C. All the calculations were carried out
using the teXsan software package (Crystal Structure
Analysis Package, Molecular Structure Corporation).
Acknowledgements
This work was supported by grants from the Japan
Society for the Promotion of Science. The authors
thank Professor J. Anzai (Tohoku University, Gradu-
ate School of Pharmaceutical Sciences) for allowing us
to use a fluorescence spectrometer.
1
355.2048. Found: 355.2033. H NMR (CD3OD) l 4.31
(4H, s), 4.52 (4H, s), 7.63 (2H, dd, J=1.6, 8.5 Hz), 7.69
(2H, dd, J=1.6, 8.7 Hz), 8.02 (2H, d, J=8.5 Hz), 8.03
(2H, d, J=8.7 Hz), 8.07 (2H, s), 8.16 (2H, s). 13C NMR

1052
S. Honzawa et al. / Tetrahedron: Asymmetry 13 (2002) 1043–1052
Table 1. Summary of crystal data, data collection, and
refinement details
Kitae, T.; Yamaguchi, M.; Okubo, H.; Hirama, M.
Chem. Lett. 1997, 715; (e) Kano, K.; Negi, S.; Kamo, H.;
Kitae, T.; Yamaguchi, M.; Okubo, H.; Hirama, M.
Chem. Lett. 1998, 151; (f) Kano, K.; Kamo, H.; Negi, S.;
Kitae, T.; Takaoka, R.; Yamaguchi, M.; Okubo, H.;
Hirama, M. J. Chem. Soc., Perkin Trans. 2 1999, 15; (g)
Feng, F.; Miyashita, T.; Okubo, H.; Yamaguchi, M. J.
Am. Chem. Soc. 1998, 120, 10166; (h) Okubo, H.; Feng,
F.; Nakano, D.; Hirata, T.; Yamaguchi, M.; Miyashita,
T. Tetrahedron 1999, 55, 14855; (i) Okubo, H.;
Yamaguchi, M. J. Org. Chem. 2001, 66, 824.
Compound
(M)-1
(9)-1
Formula
C22H24N2Cl2·CH3OH C22H24N2Cl2·CH3OH
Mr
418.16
418.16
Crystal size (mm)
Space group
Crystal system
Temp. (K)
0.07×0.1×0.35
P212121 (c19)
Orthorhombic
223
0.07×0.1×0.3
P21/c (c14)
Monoclinic
173
,
a (A)
5.147 (2)
13.329 (4)
29.895 (10)
15.572 (5)
5.320 (2)
25.693 (8)
100.010 (7)
2096 (1)
4
,
b (A)
5. The absolute configuration of the helicenes turned out to
be erroneous in our previous publications. All of the
absolute structures in Refs. 1, 2, 3 and 4 should be
corrected.
6. For other derivatives of 1, see: Honzawa, S.; Chiba, S.;
Okubo, H.; Yamaguchi, M. Heterocycles, 2002, 57, in
press.
7. Synthesized from 2,7-naphthalenediol by (i) (CF3SO2)2O,
pyridine, (ii) Pd cat., CO, MeOH, (iii) NaOH. Cf.: Katz,
T. J.; Liu, L.; Willmore, N. D.; Fox, J. M.; Rheingold, A.
L.; Shi, S.; Nuckolls, C.; Rickman, B. H. J. Am. Chem.
Soc. 1997, 119, 10054.
8. Formation of layered structures from achiral oligoarenes
possessing flexible linkers. Lockey, R. S.; Iverson, B. L.
Nature 1995, 375, 303. Tanatani, A.; Kagechika, H.;
Azumaya, I.; Fukutomi, R.; Ito, Y.; Yamaguchi, K.;
Shudo, K. Tetrahedron Lett. 1997, 38, 4425. Tanatani,
A.; Yamaguchi, K.; Azumaya, I.; Fukutomi, R.; Shudo,
K.; Kagechika, H. J. Am. Chem. Soc. 1998, 120, 6433.
9. Trimethylene bridge to form layered structures: Leonard,
N. J. Acc. Chem. Res. 1979, 12, 423.
,
c (A)
i (°)
V (A )
3
,
2050 (1)
4
1.358
3.33
Z
Dcalcd (g/cm3)
1.329
3.26
v (cm−1
)
Radiation
Mo-Ka
0.71070
53295
8676
Mo-Ka
0.71070
9190
,
u (A)
Measured data
Unique
4355
Rint
Observed data
0.049
2631
0.033
1990
[Io\3|(Io)]
254
[Io\3|(Io)]
251
No. of variables
R
Rw
0.069
0.075
0.40
0.068
0.075
0.52
−3
,
(Dz)max (e A
Flack parameter
)
0.01(2)
References
10. (a) Jasanoff, A.; Fersht, A. R. Biochemistry 1994, 33,
2129; (b) Prince, R. B.; Saven, J. G.; Wolynes, P. G.;
Moore, J. S. J. Am. Chem. Soc. 1999, 121, 3114.
11. Crystallographic data (excluding structure factors) for
(M)-1 and ( )-1 in this paper have been deposited with
the Cambridge Crystallographic Data Centre as supple-
mentary publication numbers CCDC 184943 and CCDC
184944, respectively. Copies of the data can be obtained,
free of charge, on application to CCDC, 12 Union Road,
Cambridge, CB2 1EZ, UK [fax: +44(0)-1223-336033 or
e-mail: deposit@ccdc.cam.ac.uk].
1. Okubo, H.; Nakano, D.; Anzai, S.; Yamaguchi, M. J.
Org. Chem. 2001, 66, 557.
2. Okubo, H.; Nakano, D.; Yamaguchi, M.; Kabuto, C.
Chem. Lett. 2000, 1316.
3. Nakamura, K.; Okubo, H.; Yamaguchi, M. Org. Lett.
2001, 3, 1097.
4. (a) Yamaguchi, M.; Okubo, H.; Hirama, M. J. Chem.
Soc., Chem. Commun. 1996, 1771; (b) Okubo, H.;
Yamaguchi, M.; Kabuto, C. J. Org. Chem. 1998, 63,
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