Bottom-up synthesis of optically active oligonaphthalenes: Three different pathways for controlling axial chirality

Article abstract of DOI:10.1021/jo060974v

The oxidative homocoupling of optically active binaphthalenes 1a-d with a stoichiometric amount of CuCl₂ and amines afforded quaternaphthalenes 2a-d in up to 93% de. The high diastereoselectivities were achieved through three different pathways

Full text of DOI:10.1021/jo060974v

Bottom-Up Synthesis of Optically Active Oligonaphthalenes: Three
Different Pathways for Controlling Axial Chirality1
Kazunori Tsubaki,*,† Hiroyuki Tanaka,† Kazuto Takaishi,† Masaya Miura,†
Hiroshi Morikawa,† Takumi Furuta,‡ Kiyoshi Tanaka,‡ Kaoru Fuji,§ Takahiro Sasamori,†
Norihiro Tokitoh,† and Takeo Kawabata†
Institute for Chemical Research, Kyoto UniVersity, Gokasho, Uji, Kyoto, 611-0011, Japan, School of
Pharmaceutical Sciences, UniVersity of Shizuoka, Yada, Shizuoka, 422-8002, Japan, and Faculty of
Pharmaceutical Sciences, Hiroshima International UniVersity, 5-1-1 Hirokoshingai, Kure, Hiroshima,
737-0112, Japan
tsubaki@fos.kuicr.kyoto-u.ac.jp
ReceiVed May 10, 2006
The oxidative homocoupling of optically active binaphthalenes 1a-d with a stoichiometric amount of
CuCl2 and amines afforded quaternaphthalenes 2a-d in up to 93% de. The high diastereoselectivities
were achieved through three different pathways (epimerization of the axis together with diastereoselective
crystallization, thermodynamic, and kinetic control pathways). The type of side chains on the naphthalene
influenced which pathway dominates. Three pathways were applicable to octinaphthalenes (8a-d) and
hexadecanaphthalene 10a with 46-99% de. The absolute configuration of the newly formed axial bond
was determined by (1) X-ray crystallographic analysis, (2) transformation to known compounds 15 and
16, (3) CD spectra of oligonaphthalenes with two pyrene rings as exciton parts, and (4) the shift values
in 13C NMR spectra of 13C-enriched derivatives 29-31 toward chiral shift reagent Eu(+tfc)3.
Introduction
are constructed by the addition of promoter molecules such as
metal cations,4 optically active small molecules,5 and gelators.6
However, the former group has inherent synthetic difficulties
against the selective introduction of functional groups on their
periphery, while the latter only maintains the helical structure
under limited conditions.
Meanwhile, the precise, bottom-up construction of molecules
from a nano to several tens of nanometer scale is one of most
challenging fields in chemistry. Although several molecules have
Helical motifs such as DNA double helices and various
helices in peptide secondary structures are among the most
ordered structures found in nature. These natural helical motifs
have inspired supramolecular chemists to construct various types
of artificial helical molecules.2 These artificial helical molecules
can be broadly classified into two groups. One is static and/or
stable helical molecules,3 which are represented by helicene
derivatives, and the other is dynamic helical molecules, which
† Kyoto University.
(3) (a) Kiupel, B.; Niederalt, C.; Nieger, M.; Grimme, S.; Vo¨gtle, F.
Angew. Chem., Int. Ed. 1998, 37, 3031-3034. (b) Takata, T.; Furusho, Y.;
Murakawa, K.; Endo, T.; Matsuoka, H.; Hirasa, T.; Matsuo, J.; Sisido, M.
J. Am. Chem. Soc. 1998, 120, 4530-4531. (c) Jiang, H.; Le´ger, J.-M.; Huc,
I. J. Am. Chem. Soc. 2003, 125, 3448-3449. (d) Aoki, T.; Kaneko, T.;
Maruyama, N.; Sumi, A.; Takahashi, M.; Sato, T.; Teraguchi, M. J. Am.
Chem. Soc. 2003, 125, 6346-6347.
(4) (a) Hasenknopf, B.; Lehn, J.-M.; Baum, G.; Fenske, D. Proc. Natl.
Acad. Sci. U.S.A. 1996, 93, 1397-1400. (b) Albrecht, M. Chem. ReV. 2001,
101, 3457-3498. (c) Cui, Y.; Lee, S. J.; Lin, W. J. Am. Chem. Soc. 2003,
125, 6014-6015.
(5) Nonokawa, R.; Yashima, E. J. Am. Chem. Soc. 2003, 125, 1278-
1283.
‡ University of Shizuoka.
§ Hiroshima International University.
(1) A preliminary communication of part of this work has been
published: Tsubaki, K.; Miura, M.; Morikawa, H.; Tanaka, H.; Kawabata,
T.; Furuta, T.; Tanaka, K.; Fuji, K. J. Am. Chem. Soc. 2003, 125, 16200-
16201.
(2) For recent reviews: (a) Nakano, T.; Okamoto, Y. Chem. ReV. 2001,
101, 4013-4038. (b) Schmuck, C. Angew. Chem., Int. Ed. 2003, 42, 2448-
2452. (c) Chow, H.-F.; Wan, C.-W. J. Org. Chem. 2001, 66, 5042-5047.
(d) Sugimura, T.; Kurita, S.; Inoue, S.; Fujita, M.; Okuyama, T.; Tai, A.
Enantiomer 2001, 6, 35-42. (e) Ma, L.; White, P. S.; Lin, W. J. Org. Chem.
2002, 67, 7577-7586. (f) Hattori, T.; Iwato, H.; Natori, K.; Miyano, S.
Tetrahedron: Asymmetry 2004, 15, 881-887. (g) Shibata, T.; Tsuchikama,
K. Chem. Commun. 2005, 6017-6019.
(6) Goto, H.; Zhang, H. Q.; Yashima, E. J. Am. Chem. Soc. 2003, 125,
2516-2523.
10.1021/jo060974v CCC: $33.50 © 2006 American Chemical Society
Published on Web 07/26/2006
J. Org. Chem. 2006, 71, 6579-6587
6579

Tsubaki et al.
SCHEME 1. Oxidative Coupling of Binaphthalenes 1a-d
been recently reported, each is comprised of aryl rings that are
directly connected to each other.7 Hence, completely controlling
the number of aryl rings, axial chirality, and the type and/or
arrangement of the functional groups on the aryl rings are
difficult tasks. We have investigated optically active rod-shaped
oligo(2,3-dioxyfunctionalized)naphthalenes, which are connected
at the 1,4-positions in a copper-promoted oxidative homocou-
pling reaction.8 Important characteristics of these oligonaph-
thalenes are: (1) a rigid framework in the rod direction, (2)
around the axes, they have chirality and some degree of
flexibility, and (3) functional groups can be introduced into
scaffolding 2,3-dioxy groups. In constructing optically active
oligonaphthalenes, the toughest synthetic difficulty is forming
axial bonds with high optical purity. Although optically active
naphthalene derivatives have been used as substrates, previous
papers have reported that in a homocoupling reaction, the
corresponding dimers were obtained with low diastereoselec-
tivities (∼10% de).8b,d,9a Thus, effective chirality induction from
the optically active axis to the newly formed axis did not occur.
To overcome this low diastereoselectivity, Okamoto and Habaue
applied a catalytic amount of copper(I) and a chiral diamine
combination, which gave an excellent enantiomeric excess of
the coupling of 2-naphthols toward polymerization of the chiral
binaphthalene as a monomer unit.9 They obtained quaternaph-
thalene with a 64% de in the dimerization of a chiral binaph-
thalene derivative.9a We have also been investigating the
synthesis of optically active oligonaphthalenes. In this paper,
we report the asymmetric synthesis of optically active oligo-
naphthalenes through three different pathways, which depend
on the variations of the naphthalene side chains.
TABLE 1. Oxidative Coupling of Binaphthalenes 1a-d
entry substrate amine major isomera isolationb yield (%)c de (%)d
1
2
3
4
5
6
7
8e
9
(S)-1a (RS)-3
(S,S,S)-2a
-
-
PF
P
73
69
87
58
15
77
54
75
55
96
81
89
94
77
77
12
26
75
93
17
82
79
19
62
75
75
70
81
62
65
(R)-3
(S)-3
(S)-3
(S)-3
F
(S)-1b (R)-3
(R)-1b (RS)-3
(R)-3
(S,S,S)-2b
(R,R,R)-2b
-
-
-
-
-
-
-
-
-
-
4
10
(S)-1c (RS)-3
(R)-3
(S)-3
4
(S)-1d (S)-3
(RS)-3
(S,S,S)-2c
11
12
13
14
15
(S,S,S)-2d
a Absolute configuration of major isomer was determined by transforma-
tion to the known compound or an X-ray analysis. See text. b - ) no
precipitation; PF ) without separation of precipitate and filtrate; P ) from
precipitate; F ) from filtrate. c Isolated yield. d Based on the isolated yields
of corresponding diastereomers. e Reaction temperature ) 0 °C to rt.
Results and Discussion
Synthesis of the Quaternaphthalenes from Homocoupling
of Optically Active Binaphthalenes. Diastereoselectivities were
investigated using optically active binaphthalenes 1a-d,10 which
possessed several types of side chains, under copper(II)-
promoted oxidative coupling conditions (Scheme 1 and Table
1).
of substrate and amine. In the early stage of our studies, we
tried to explain these diastereoselectivities by a single pathway.
However, we noticed that a large amount of brown precipitate
was generated only when (S)-1-phenylethylamine (3) and (S)-
1a, which have a methoxy group on naphthalene (Table 1, entry
3), were combined. This led us to consider that there was more
than one pathway triggering these diastereoselectivities.
For (S)-1a (entries 1-5), diastereoselectivity (12% de) was
barely observed using (RS)- or (R)-1-phenylethylamine (3),
whereas (S)-3 gave a high selectivity (75% de) and a brown
precipitate (entries 1, 2 vs 3). Brussee,11 Kocˇovsky´,12 and
Wulff13 have reported that copper- and amine-mediated dera-
cemization of binol derivatives together with diastereoselective
crystallization afforded chiral binol in a high enantio excess.
To confirm the mechanism of the high de for (S)-1a and (S)-3,
the brown precipitate was removed by filtration. Next, the
precipitate and the filtrate were separately purified (entries 4
and 5). An extremely high diastereoselectivity was observed
from the precipitate (93% de, 58% yield), but the filtrate gave
a low selectivity (17% de, 15% yield). Furthermore, the same
Table 1 overviews the results. Moderate to good diastereo-
selectivities were observed under the appropriate combination
(7) (a) Pu, L. Chem. ReV. 1998, 98, 2405-2494. (b) Inoue, S.; Nakanishi,
H.; Takimiya, K.; Aso, Y.; Otsubo, T. Synth. Met. 1997, 84, 341-342. (c)
Yamaguchi, S.; Goto, T.; Tamao, K. Angew. Chem., Int. Ed. 2000, 39,
1695-1697. (d) Meier, H.; Hormaza, A. Eur. J. Org. Chem. 2003, 3372-
3377. (e) Izumi, T.; Kobashi, S.; Takimiya, K.; Aso, Y.; Otsubo, T. J. Am.
Chem. Soc. 2003, 125, 5286-5287. (f) Miyata, Y.; Nishinaga, T.; Komatsu,
K. J. Org. Chem. 2005, 70, 1147-1153.
(8) (a) Tanaka, K.; Furuta, T.; Fuji, K.; Miwa, Y.; Taga, T. Tetrahe-
dron: Asymmetry 1996, 7, 2199-2202. (b) Fuji, K.; Furuta, T.; Tanaka,
K. Org. Lett. 2001, 3, 169-171. (c) Tsubaki, K.; Tanaka, H.; Furuta, T.;
Tanaka, K.; Kinoshita, T.; Fuji, K. Tetrahedron 2002, 58, 5611-5617. (d)
Furuta, T.; Tanaka, K.; Tsubaki, K.; Fuji, K. Tetrahedron 2004, 60, 4431-
4441. (e) Pieraccini, S.; Ferrarini, A.; Fuji, K.; Gottarelli, G.; Lena, S.;
Tsubaki, K.; Spada, G. P. Chem.-Eur. J. 2006, 12, 1121-1126. (f) Tsubaki,
K.; Miura, M.; Nakamura, A.; Kawabata, T. Tetrahedron Lett. 2006, 47,
1241-1244. (g) Tsubaki, K.; Takaishi, K.; Tanaka, H.; Miura, M.;
Kawabata, T. Org. Lett. 2006, 8, 2587-2590.
(9) (a) Habaue, S.; Seko, T.; Okamoto, Y. Macromolecules 2002, 35,
2437-2439. (b) Habaue, S.; Seko, T.; Okamoto, Y. Macromolecules 2003,
36, 2604-2608. (c) Habaue, S.; Seko, T.; Isonaga, M.; Ajiro, H.; Okamoto,
Y. Polym. J. 2003, 35, 592-597. (d) Habaue, S.; Ajiro, H.; Yoshii, Y.;
Hirasa, T. J. Polym. Sci., Part A: Polym. Chem. 2004, 42, 4528-4534. (e)
Habaue, S.; Muraoka, R.; Aikawa, A.; Murakami, S.; Higashimura, H. J.
Polym. Sci., Part A: Polym. Chem. 2005, 43, 1635-1640. (f) Temma, T.;
Habaue, S. Tetrahedron Lett. 2005, 46, 5655-5657. (g) Habaue, S.;
Ishikawa, K. Polym. Bull. 2005, 55, 243-250.
(11) (a) Brussee, J.; Jansen, A. C. A. Tetrahedron Lett. 1983, 24, 3261-
3262. (b) Brussee, J.; Groenendijk, J. L. G.; te Koppele, J. M.; Jansen, A.
C. A. Tetrahedron 1985, 41, 3313-3319.
(12) (a) Smrcˇina, M.; Lorenc, M.; Hanusˇ, V.; Sedmera, P.; Kocˇovsky´,
P. J. Org. Chem. 1992, 57, 1917-1920. (b) Smrcˇina, M.; Pola´kova´, J.;
Vyskocˇil, S.; Kocˇovsky´, P. J. Org. Chem. 1993, 58, 4534-4538.
(13) Zhang, Y.; Yeung, S.-M.; Wu, H.; Heller, D. P.; Wu, C.; Wulff,
W. D. Org. Lett. 2003, 5, 1813-1816.
(10) The optically active binaphthalenes 1a-d were synthesized from
the corresponding dibenzyl derivatives (Supporting Information).
6580 J. Org. Chem., Vol. 71, No. 17, 2006

Synthesis of Optically ActiVe Oligonaphthalenes
diastereomer (S,S,S)-2a was preferentially obtained from both
the precipitate and the filtrate. These results indicate that the
origin for the axial chirality control should be epimerization of
the axis together with diastereoselective crystallization.14
For other substrates 1b-d (entries 6-15), a precipitate was
not observed and homochiral quaternaphthalenes were predomi-
nantly formed over heterochiral quaternaphthalenes with a 19-
82% de. Thus, axial chirality was not induced via epimerization
together with diastereoselective crystallization. When 1b, which
had two tert-butoxycarbonyl methyl groups, was used as starting
material, 2b was obtained with a high selectivity (ca. 80% de)
regardless of the chirality of 1-phenylethylamine (3) (entries 6
and 7). This chirality induction was sensitive to the reaction
temperature; the diastereoselectivity drastically decreased from
about 80% to 19% de as the temperature increased (entries 6,
7 vs 8). Moreover, it should be emphasized that a moderate
selectivity (62% de) was observed in the presence of achiral
isopropylamine (4) (entry 9). Because the axial chirality of 1b
was the sole chiral source in the reactions, the origin of chirality
induction was a chirality transfer from the optically active axis
to the newly formed axis. The effects of tert-butoxycarbonyl
methyl on the side chain were similar to the case for homo-
coupling of 3-hydroxy-2-naphthoates reported by Nakajima15
and Kozlowski.16 They noted that the coordination of the
carbonyl to copper was crucial for a high enantioselectivity.
However, substrates with an amide group 1c, which might
generate a tight coordination to copper, showed slightly lower
selectivities than those of 1b (entries 10-12). To our surprise,
1d gave a relatively high selectivity (62-65% de) by appending
to the noncoordinating n-butyl group (entries 14 and 15).
To elucidate the reasons for the diastereoselectivities, the time
course for the conversion and diastereoselectivities of the
corresponding coupling reactions of 1b-d (Figure 1a, c, and
e) as well as epimerization between the homochiral and
heterochiral products 2b-d under the coupling reaction condi-
tions (Figure 1b, d, and f) were monitored. The data revealed
that chirality was induced by two or more pathways, which
depend on the side chains.
FIGURE 1. Time course of the diastereoselectivities with the coupling
reaction (a, c, and e) and with epimerization (b, d, and f). Reaction
conditions: For the homocoupling reaction, 1b-d (0.2 mmol), CuCl2
(0.4 mmol), (R,S)-3 (0.5 mmol), MeOH/CH2Cl2 ) 1 mL/1 mL, 0 °C.
For epimerization, 2b-d (0.1 mmol), CuCl2 (0.4 mmol), (R,S)-3 (0.5
mmol), MeOH/CH2Cl2 ) 1 mL/1 mL, 0 °C. Conversion and de were
monitored and determined by HPLC (cosmosil-packed column 5SL-2,
(nacalai), hexane/chloroform/ethyl acetate ) 92/6/2, 2.0 mL/min for
2d, hexane/chloroform/ethyl acetate ) 90/5/5, 1.2 mL/min for 2b,
hexane/ethanol ) 90/10, 1.0 mL/min for 2c).
axial chirality should be controlled by the difference in the
thermodynamic stabilities of the diastereomeric product/copper
adducts. On the other hand, the pathway of coupling reactions
of (S)-1c and the epimerization of 2c were completely different
from those of the former two cases. The initial diastereoselec-
tivity of the coupling reaction of (S)-1c was about 75% de,
which remained around 75% de for 12 h. The diastereoselec-
tivity then gradually decreased and plateaued at -20% de after
72 h. Both diastereomers slowly underwent epimerization and
achieved equilibrium at -20% de after 36 h (Figure 1e and f).
Thus, the rapid coupling reaction with a high diastereoselectivity
and a slow epimerization of the newly formed axial bond led
to a product under kinetic control.
Epimerization was due to either a rotation around the axial
bond or cleavage and regeneration of the axial bond. Thus, a
crossover experiment was conducted to determine the cause of
epimerization (Scheme 2).
A 1:1 mixture of (S,S,S)-2c and (S,S,S)-2c-d14 with two
deuterated benzyl groups on the top and bottom naphthalenes
was treated under coupling conditions, and the degree of
epimerization of the central axial bond was monitored by HPLC.
After the epimerization reached equilibrium (-20% de, see
Figure 1f), the mass distribution was measured by FAB mass
spectrometry (Figure 2). Because scrambled mass ion peaks
derived from 2c-d7 were not observed, epimerization occurs by
axial bond rotation. On the basis of these results, we propose
In the coupling reaction of (S)-1d, the diastereoselectivity of
(S,S,S)-2d increased from 54% de (5 min) and plateaued at 68%
de after 4 h (Figure 1a). Furthermore, the epimerization
reactions, which began from (S,S,S)- and (S,R,S)-2d, also
reached equilibrium at 70% de (Figure 1b). A similar tendency
was observed in the coupling reaction of (R)-1b and epimer-
ization of 2b (Figure 1c and d).17 The data indicated that the
(14) Neither precipitation nor enantioselectivity was observed for self-
coupling of 3-benzyloxy-naphthalen-2-ol under CuCl2 and (S)-1-phenyl-
ethylamine.
(15) (a) Noji, M.; Nakajima, M.; Koga, K. Tetrahedron Lett. 1994, 35,
7983-7984. (b) Nakajima, M.; Kanayama, K.; Miyoshi, I.; Hashimoto, S.
Tetrahedron Lett. 1995, 36, 9519-9520. (c) Nakajima, M.; Miyoshi, I.;
Kanayama, K.; Hashimoto, S.; Noji, M.; Koga, K. J. Org. Chem. 1999, 64,
2264-2271.
(16) (a) Li, X.; Yang, J.; Kozlowski, M. C. Org. Lett. 2001, 3, 1137-
1140. (b) Li, X.; Hewgley, J. B.; Mulrooney, C. A.; Yang, J.; Kozlowski,
M. C. J. Org. Chem. 2003, 68, 5500-5511. (c) Xie, X.; Phuan, P.-W.;
Kozlowski, M. C. Angew. Chem., Int. Ed. 2003, 42, 2168-2170. (d)
Mulrooney, C. A.; Li, X.; DiVirgilio, E. S.; Kozlowski, M. C. J. Am. Chem.
Soc. 2003, 125, 6856-6857.
(17) In Figure 4, we proposed homo-dimerization of the radical 5.
However, the actual reaction mechanisms will consist of the homo-
dimerization of the radical 5, hetero-dimerization of radical 5, and starting
material. In Figure 1c, the initial diastereoselectivity of the coupling reaction
of (R)-2b was about 72% de, and the de temporarily increased to 82% after
5 h, and then plateaued at 70% de. These phenomena should be reflected
in the balance between the homo- and hetero-dimerization.
J. Org. Chem, Vol. 71, No. 17, 2006 6581

Tsubaki et al.
SCHEME 2 a
With respect to the diastereoselectivity of the coupling
reaction, the following model is proposed (Figure 4).17 A one-
electron oxidation with Cu(II) generates an organic radical,
which has the shape speculated as 5. Thus, to avoid steric
repulsion, the OR group on the top naphthalene is oriented in
the opposite direction of the OBn group. This OR group controls
the direction of the other OR group on the bottom naphthalene
through steric repulsion, and the second OR group influences
the direction of Cu(I) coordinated to oxygen (as well as the
draping amine molecules and/or solvents as ligands).18 At last,
the homocoupling reaction occurs from their opposite face of
the Cu(I) site to afford intermediate 6. Finally, stereochemistry
is established through keto-enol tautomerization where the
direction of rotation is with the hydrogens on peri position
passing each other.
a Conditions: (S,S,S)-2c (0.5 equiv), (S,S,S)-2c-d14 (0.5 equiv), CuCl2
(4.0 equiv), (RS)-3 (5.0 equiv), MeOH/CH2Cl2, 0 °C.
Synthesis of High-Order Naphthalenes. Next, we investi-
gated the applicability of the three pathways (epimerization of
the axis together with diastereoselective crystallization, and axial
chirality induction through thermodynamic and kinetic control)
to higher naphthalene derivatives 7a-d and 9a (Scheme 3).
Table 2 shows the results.
The epimerization with diastereoselective crystallization
pathway was applicable to the conversion of (S,S,S)-7a to
(S,S,S,S,S,S,S)-8a (86% yield, 99% de) and to the conversion
of (S,S,S,S,S,S,S)-9a to all-(S)-10a (78% yield, 79% de). Because
of low solubility, higher oligonaphthalenes were not investi-
gated. The coupling reaction of quaternaphthalenes (S,S,S)-7b-d
through other pathways afforded octinaphthalenes 8b-d, which
have different substituents on naphthalenes with a relatively high
diastereoselectivity (46-83% de).19 Because these products have
sufficient solubility in organic solvents, they could be used as
precursors for starting materials of higher oligonaphthalenes.
Determination of the Absolute Configuration of Newly
Formed Axial Bond. During these studies, three empirical rules
were found. (1) The Rf value on silica gel TLC of the homochiral
isomer is larger than that of the opposite chirality-containing
isomer. This is probably because the dipole moments of the
first and third naphthalenes are parallel to the major axis of the
corresponding naphthalene and negate each other in the homo-
chiral isomer. (2) The absolute value of the specific rotation of
the homochiral isomer is larger than that of the opposite
chirality-containing isomer. (3) The amplitude of the CD
spectrum of the homochiral isomer is larger than that of the
opposite chirality-containing isomer (see Supporting Informa-
tion).8d Rule no. 3 seems to be widely applicable to these
oligonaphthalenes, but the difference of the amplitude between
corresponding diastereomers becomes smaller as the number
FIGURE 2. Mass spectrum of crossover experiment. NBA matrix;
ion mode, FAB+; inlet, direct.
FIGURE 3. Proposed mechanism of the epimerization of quaternaph-
thalenes 2.
(18) Ultra-remote stereocontrol by conformational communication was
reported. Clayden, J.; Lund, A.; Vallverdu´, L.; Hellwell, M. Nature 2004,
431, 966-971.
the following model for the thermodynamic stabilities of the
diastereomeric intermediates of quaternaphthalenes (Figure 3).
After the coupling reaction, an aryl radical intermediate was
generated in the presence of an excess amount of CuCl2, and
epimerization of the axial bond occurred through the intermedi-
ate. Considering the steric repulsions between the OR groups
on the top and bottom of naphthalene rings and Cu (draping
amine molecules and/or solvents as ligands) on third and second
of naphthalenes rings, a homochiral intermediate is more stable
than a heterochiral intermediate. In the case of 2c, two amide
carbonyls tightly coordinated to copper prevail over the steric
repulsions between them.
(19) Because we afforded starting (S)- and (R)-3,3-bis(benzyloxy)-1,1-
binaphthalene-2,2-diol by resolution of the racemic one21 and the examined
reaction conditions, there is disagreement on chiralities between the major
product in Table 1, entries 7-9, and the substrate in Table 2, entry 3.
(20) (a) Harada, N.; Nakanishi, K. Acc. Chem. Res. 1972, 5, 257-263.
(b) Harada, N.; Nakanishi, K. Circular Dichroic Spectroscopy - Exciton
Coupling in Organic Stereochemistry; University Science Books: Mill
Valley, CA, 1983. (c) Berova, N.; Nakanishi, K. In Circular Dichroism:
Principles and Applications, 2nd ed.; Berova, N., Nakanishi, K., Woody,
R. W., Eds.; Wiley-VCH: New York, 2000; pp 337-382. (d) Koslowski,
A.; Sreerama, N.; Woody, R. W. In Circular Dichroism: Principles and
Applications; Berova, N., Nakanishi, K., Harada, N., Eds.; Wiley-VCH:
New York, 2000; pp 55-95.
(21) Tsubaki, K.; Morikawa, H.; Tanaka, H.; Fuji, K. Tetrahedron:
Asymmetry 2003, 14, 1393-1396.
6582 J. Org. Chem., Vol. 71, No. 17, 2006

Synthesis of Optically ActiVe Oligonaphthalenes
FIGURE 4. Proposed mechanism of the dimerization of binaphthols. (i) Cu(II), one-electron oxidation; (ii) coupling; (iii) enolization; (iv) H+.
SCHEME 3. Oxidative Coupling of Higher Naphthalene
SCHEME 4 a
Derivatives 7a-d and 9a
a Reaction conditions: (i) CuCl2, (RS)-3, (ii) MeI, K2CO3.
TABLE 2. Oxidative Coupling of Higher Naphthalene Derivatives
7a-d and 9a
of homocoupling of quaternaphthalene (S,S,S)-11 and those of
heterocoupling of sexinaphthalene (S,S,S,S,S)-13 and binaph-
thalene (S)-14 (Scheme 4) were compared.
entry
substrate
amine major isomera yield (%)b de (%)c,d
1
2
3
4
5
(S,S,S)-7a
(S)-3 (S,S,S,S,S,S,S)-8a
86
78
50
69
55
99
79
80
46
83
(S,S,S,S,S,S,S)-9a (S)-3 all-(S)-10a
Although this comparison method is clear and conclusive for
determining the axial chirality, too many reaction steps,
especially for oligonaphthalenes with different functional groups
on the side chains, are required to determine one unknown axial
chirality. Therefore, we used compounds (S,S,S)-15 and
(S,S,S,S,S,S,S)-168b,d synthesized through the comparison method
as the standard materials (Figure 5) and transformed the chirality
of unknown compound to these standard materials.
(S,S,S)-7b19
(S,S,S)-7c
(S,S,S)-7d
(RS)-3 (S,S,S,S,S,S,S)-8b
(S,S,S,S,S,S,S)-8c
(RS)-3 (S,S,S,S,S,S,S)-8d
4
a The absolute configuration of the major isomer was determined by
transforming into a known compound and comparing the amplitude in the
CD spectrum of the corresponding diastereomers using the pyrene method
or 13C method. See text. b Isolated yield. c Based on the isolated yields of
corresponding diastereomers. d The reaction conditions were not optimized.
Determination of the Absolute Configuration of Quater-
naphthalenes 2d. An X-ray crystallographic analysis of major
product 2d derived from (S)-1d unequivocally defined the
structure as (S,S,S) (Figure 6). It is interesting to note that the
sum of the dihedral angles of the top and middle axes and the
sum of the middle and bottom axes were about 180°. Hence,
five naphthalene units are required for a 360° turn.
of naphthalene units increases. Therefore, we are trying to
construct a widely applicable determination method for oligo-
naphthalenes.
The absolute configurations of the newly formed axial bonds
were determined using several methods. In a previous paper,
we reported the synthesis and determination of the axial chirality
of quarter-, sexi-, and octinaphthalenes by comparing the
products.8b,d For example, for octinaphthalenes 12, the products
Determination of the Absolute Configuration of Quater-
naphthalenes 2a-c. Major diastereomers 2a and 2b were
J. Org. Chem, Vol. 71, No. 17, 2006 6583

Tsubaki et al.
SCHEME 5
Determination of the Absolute Configuration of Octi- and
Hexadecanaphthalenes 8a-c and 10a. Major diastereomer 8a,
which was derived from (S,S,S)-7a, was converted into octi-
naphthalene 16 via a route similar to those from 2a to 15, in a
31% overall yield in two steps, and the resulting product had
data identical to the standard (S,S,S,S,S,S,S)-16. There is not a
standard compound for hexadecanaphthalene 10a. Therefore,
we developed a new and efficient system based on a circular
dichroism (CD) exciton chirality method. We focused on the
two free hydroxy groups, which stride over the chirality of the
unknown axial bond, and chose pyrene as an exciter. Because
steric hindrance prohibits the introduction of 2-pyrene carboxylic
acid to the scaffolding hydroxy groups, 4-(2-pyreneyl)-butyric
acid was selected (Figure 7).
FIGURE 5.
First, the UV spectra and CD spectra of compounds 18-20
were carefully examined to determine whether the CD signals
derived from the two pyrene parts were separate from those of
the oligonaphthalene backbone and whether the CD signals
reflect the absolute configuration of the target axial chirality
using compounds 18, 19, and 21, which were synthesized from
chirality-clear oligonaphthalenes. Figure 8a-c shows the UV
and CD spectra. In Figure 8a, the UV-vis spectrum of 21 is
the simple sum of the spectrum of the main skeleton 22 and
the spectrum (twice as intense) of side chain 26. The absorption
bands at 279, 330, and 346 nm were assigned to the transitions
from the pyrene moiety. The mirror image CD spectra of (R)-
and (S)-21 indicate that the positive or negative sense near 280,
330, and 350 nm reflects the absolute configuration of the target
axial bond. Because of the large negative absorption from the
quaternaphthalene backbone, the absorption derived from the
pyrene groups around 280 nm was buried and that around 330
nm was influenced. However, the sense around 350 nm
demonstrated the absolute configuration of the central axial bond
(Figure 8b). As shown in Figure 8c, pyrene absorptions around
280 and 330 nm were engulfed by the deep absorption of the
octinaphthalene skeleton, and only the absorption at 350 nm
survived to indicate the absolute configuration. Considering
these results, the absorption around 350 nm on the CD spectra
of the major isomer from the homocoupling of (S,S,S,S,S,S,S)-
9a indicates a positive sense. Thus, the target axis is
(S,S,S,S,S,S,S,S,S,S,S,S,S,S,S).
FIGURE 6. Stereoview of the crystal structure of (S,S,S)-2d. Hydrogen
atoms have been omitted for clarity.
converted to standard compound 15 (Scheme 5). Thus, the major
diastereomer 2a derived from (S)-1a was debenzylated with
Pd/C and subsequently four hydroxy groups were methylated
to afford all-methoxy derivative 15, and all of the physical data
including the [R]D value agreed with those of standard (S,S,S)-
15. Thus, that absolute configuration was determined by the
comparison method. The side chains of major diastereomer 2b
derived from (R)-1b were exhaustively dealkylated by boron
tribromide and methylated to give compound 15, which showed
the opposite [R]D value. Thus, the absolute configuration of
major diastereomer 2b should be determined as (R,R,R).
Treatment of (R,R,R)-2b with (trimethylsilyl)diazomethane
afforded the methyl ether. Next, four tert-Bu groups were
removed, and diethylamino groups were introduced using BOP
to afford (R,R,R)-17. On the other hand, major isomer 2d from
(S)-1d was transformed to 17 and had the same physical data,
except an opposite [R]D. Thus, the absolute configuration of
the major isomer of 2d is (S,S,S).
This pyrene method is applicable for oligonaphthalenes with
butyl side chains 2d and 7d. Thus, quaternaphthalene 27 derived
6584 J. Org. Chem., Vol. 71, No. 17, 2006

Synthesis of Optically ActiVe Oligonaphthalenes
FIGURE 7.
from (S,S,S)- and (S,R,S)-2d, which have absolute configurations
that were determined by the comparison method, indicates a
positive sense for (S,S,S) and a negative sense for (S,R,S) near
the 350 nm region (Figures 9 and 10). These behaviors are the
same for quaternaphthalenes 18 with methoxy side chains.
Octinaphthalene 28, which was derived from the major dias-
tereomer of homocoupling of (S,S,S)-7d, shows a positive sense
in the 350 nm region. Thus, the target axial chirality should be
(S,S,S,S,S,S,S).
However, attempts to introduce two pyrenebutyryl groups into
the two central hydroxy groups of 2b, 2c, 8b, and 8c using an
acid chloride, an acid anhydride, and various types of condensa-
tion reagents (DCC, DIC, EEDQ, and cyanuric chloride) were
unfruitful due to the neighboring bulky side chains. Therefore,
the absolute configurations of the axial chirality of 8b and 8c
were determined by comparing the chemical shifts of carbon-
13-enriched methyl groups, which were introduced to a series
of oligonaphthalenes 29-31 after the stepwise addition of
europium tris[3-(trifluoromethylhydroxymethylene)-(+) cam-
phorate] [Eu(+tfc)3] (Figures 11 and 12).
When Eu(+tfc)3 was added to (S)- and (R)-29 without amide
side chains, the shifts of the signals that corresponded to the
13C-methyl group were negligible. For (R,R,R)- and (R,S,R)-
30, the absolute configuration was determined on the basis of
the comparison and derivation method, and, as the amount of
the chiral shift reagent increased relative to 30, the corresponding
13C-methyl groups shifted to a lower magnetic field and the
degree of the (R,S,R)-30 shift was larger than that of (R,R,R)-
30. A similar behavior was detected in octinaphthalenes 31.
Therefore, octinaphthalenes that show a larger lower magnetic
FIGURE 8. (a) UV-visible spectra of (S)-22 (dotted blue), 26 (gray),
and (S)-21 (blue), and CD spectra of (S)-21 (blue) and (R)-21 (red).
(b) UV-visible spectra of (S,S,S)-23 (dotted blue), (S,R,S)-23 (dotted
red), 26 (gray), (S,S,S)-18 (blue), and (S,R,S)-18 (red), and CD spectra
of (S,S,S)-18 (blue) and (S,R,S)-18 (red). (c) UV-visible spectra of
(S,S,S,S,S,S,S)-24 (dotted blue), 26 (gray), and (S,S,S,S,S,S,S)-19 (blue),
and CD spectra of (S,S,S,S,S,S,S)-19 (blue). (d) UV-visible spectra of
the major isomer of hexadecamer 20 (blue), 26 (gray), and hexadecamer
25 (major isomer of homocoupling of (S,S,S,S,S,S,S)-9a) (dotted blue),
and CD spectra of the hexadecamer 20 (blue). Conditions: for UV
spectra, chloroform, 2.0 × 10-6 M, light pass length ) 10 mm, 25 °C;
for CD spectra, chloroform, 1.0 × 10-4 M, light pass length ) 1 mm,
25 °C.
field shift should be (R,R,R,S,R,R,R,R)-31. This technique was
not applied to a series of oligonaphthalenes with ester side chains
due to the small magnitude of the lower magnetic shifts of the
13C-methyl groups. Currently, the absolute configuration of 8d
was determined solely on the basis of the deference of amplitude
in the CD spectrum of the homochiral isomer (major isomer,
J. Org. Chem, Vol. 71, No. 17, 2006 6585

Tsubaki et al.
FIGURE 9.
FIGURE 11.
FIGURE 12. Conditions: concentration 10 mg/mL, CDCl3, 20 °C,
50 MHz.
induction. To the best of our knowledge, they are the only
method for constructing oligonaphthalenes where all-axial
chirality, the types, and the alignments of the functional groups
on the side chains were controlled. These molecules can
contribute to the field of material chemistry because a versatile
method for oligonaphthalenes with any number of naphthalene
rings and any kind of side chains remains to be developed.
FIGURE 10. (a) UV-visible spectra of (S,S,S)-2d (dotted blue),
(S,R,S)-2d (dotted red), (S,S,S)-27 (blue), and (S,R,S)-27 (red), and CD
spectra of (S,S,S)-27 (blue) and (S,R,S)-27 (red). Conditions: for UV
spectra, chloroform, 1.0 × 10-5 M, light pass length ) 10 mm, 25 °C;
for CD spectra, chloroform, 1.0 × 10-4 M, light pass length ) 1 mm,
25 °C. (b) UV-visible spectra of (S,S,S,S,S,S,S)-8d (dotted blue),
(S,S,S,S,S,S,S)-28 (blue), and CD spectra of (S,S,S,S,S,S,S)-28 (blue).
Conditions: for UV spectra, chloroform, 1.0 × 10-5 M, light pass length
) 1 mm, 25 °C; for CD spectra, chloroform, 1.0 × 10-5 M, light pass
length ) 1 mm, 25 °C.
Experimental Section
General Procedure for the Synthesis of Compounds 2b-d.
The synthesis of (R,R,R)- and (R,S,R)-2b is typical. To a mixture
of CuCl2 (540 mg, 4.0 mmol) in methanol (10 mL) was added (DL)-
R-phenylethylamine (0.64 mL, 5.0 mmol) under argon atmosphere
under ice-bath cooling. After 30 min, a solution of (R)-1b (1.27 g,
2.0 mmol) in dichloromethane (10 mL) was added, and the reaction
mixture was stirred for 2 days at 0 °C. The reaction mixture was
poured into the mixed solvent of 1 M hydrochloric acid solution
and ethyl acetate. The organic layer was washed with water (three
times) and brine, dried over sodium sulfate, and evaporated to give
a residue. The residue was purified by column chromatography
(SiO2, n-hexane/chloroform/ethyl acetate ) 8/3/1) to afford (R,R,R)-
2b (605 mg, 48%) and (R,S,R)-2b (69 mg, 5.4%).
S,S,S,S,S,S,S) and the heterochiral isomer (minor isomer,
S,S,S,R,S,S,S).
Conclusion
In conclusion, the syntheses for a number of optically active
oligonaphthalene derivatives were developed through three
different pathways, which controlled the axial chirality. The side
chains on the naphthalene played crucial roles for chirality
(R,R,R)-2b. Colorless foam. [R]20D ) +51.0 (c ) 0.94, CHCl3).
1
IR (KBr): 3310, 2980, 1728, 1418, 1369, 1234 cm-1. H NMR
6586 J. Org. Chem., Vol. 71, No. 17, 2006

Synthesis of Optically ActiVe Oligonaphthalenes
(200 MHz, CDCl3): δ 1.28 (s, 18H), 1.39 (s, 18H), 4.03 (d, J )
16.6, 2H), 4.25 (d, J ) 16.6, 2H), 4.27 (d, J ) 15.8, 2H), 4.67 (d,
J ) 15.8, 2H), 5.37 (s, 4H), 7.0-7.6 (m, 26H), 7.80 (d, J ) 8.0,
2H), 8.82 (s, 2H). HRMS (FAB) calcd for C78H78O16: 1270.5290.
Found: 1270.5297. Anal. Calcd for C78H78O16‚1H2O: C, 72.65;
H, 6.25. Found: C, 72.58; H, 6.04.
ethyl acetate ) 3/1) to afford (S,S,S)-27 (34 mg, 92%). Mp 87 °C.
[R]21 ) -33.6 (c ) 0.80, CHCl3). IR (KBr): 3009, 1761, 1442,
D
1376 cm-1. H NMR (200 MHz, CDCl3): δ 0.38 (t, J ) 7.4 Hz,
1
6H), 0.72 (t, J ) 7.4 Hz, 6H), 0.6-1.6 (m, 16H), 1.9-2.2 (m,
4H), 2.4-2.6 (m, 4H), 2.9-3.3 (m, 4H), 3.4-3.6 (m, 2H), 3.7-
4.0 (m, 4H), 4.1-4.3 (m, 2H), 5.35 (s, 4H), 6.77 (t, J ) 7.0 Hz,
2H), 7.10-7.65 (m, 26H), 7.7-8.2 (m, 18H). HRMS (FAB) calcd
for C110H98O10: 1578.7160. Found: 1578.7177.
(R,S,R)-2b. Colorless foam. [R]20D ) +12.8 (c ) 1.00, CHCl3).
1
IR (KBr): 3454, 2979, 1750, 1726, 1439, 1369, 1234 cm-1. H
NMR (200 MHz, CDCl3): δ 1.28 (s, 18H), 1.38 (s, 18H), 4.21 (d,
J ) 16.6, 2H), 4.23 (d, J ) 15.2, 2H), 4.49 (d, J ) 16.6, 2H), 4.70
(d, J ) 15.2, 2H), 5.37 (s, 4H), 7.0-7.6 (m, 26H), 7.80 (d, J )
8.2, 2H), 8.71 (s, 2H). HRMS (FAB) calcd for C78H78O16:
1270.5290. Found: 1270.5302. Anal. Calcd for C78H78O16‚
0.5H2O: C, 73.16; H, 6.22. Found: C, 73.24; H, 6.29.
General Procedure for the Synthesis of Pyrene Compounds.
The synthesis of (S,S,S)-27 is typical. To a solution of (S,S,S)-2d
(25 mg, 0.024 mmol), 1-pyrenebutyric acid (21 mg, 0.072 mmol),
and DMAP (3 mg) in DMF (4.0 mL) was added WSC‚HCl (14
mg, 0.072 mmol), and the solution was stirred for 1 day at rt. The
reaction mixture was poured into chloroform and 0.1 M hydro-
chloric acid. The organic layer was separated, washed successively
with water (twice) and brine, dried over sodium sulfate, and
evaporated in vacuo. The residue was purified by PTLC (n-hexane/
Acknowledgment. This paper is dedicated to the memory
of the late Professor Kiyoshi Tanaka. This study was partly
supported by Grants-in-Aid for Scientific Research (17659004)
and the 21st Century COE Program on Kyoto University
Alliance for Chemistry from the Ministry of Education, Culture,
Sports, Science, and Technology, Japan.
Supporting Information Available: CD and UV spectra of 22-
25, full experimental details and characterization data of all new
compounds, and crystallographic information file (CIF) of (S,S,S)-
2d (CCDC 606842). This material is available free of charge via
the Internet at http://pubs.acs.org.
JO060974V
J. Org. Chem, Vol. 71, No. 17, 2006 6587