Synthesis and characteristic stereostructure of a biphenanthryl ether

Article abstract of DOI:10.1016/j.tetasy.2008.05.001

A biphenanthryl ether with substituents in the bay regions was efficiently synthesized for the first time. The unique stereostructure of 1 was clarified. Its twisted conformation and optical behavior as well as its characteristic supramolecular helical structure, which is constructed through a C-H...F hydrogen bonding network in the solid state, are discussed.

Full text of DOI:10.1016/j.tetasy.2008.05.001

Tetrahedron: Asymmetry 19 (2008) 1407–1410
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Synthesis and characteristic stereostructure of a biphenanthryl ether
Yasuaki Koizumi a, Shinya Suzuki a, Kyo Takeda a, Ken Murahashi a, Manabu Horikawa b, Kosuke Katagiri c,
a
Hyuma Masu c, Takako Kato c, Isao Azumaya c, Satoshi Fujii a, Takumi Furuta a, , Kiyoshi Tanaka ,
*
Toshiyuki Kan a,
*
a School of Pharmaceutical Sciences, University of Shizuoka and Global COE Program, 52-1 Yada, Shizuoka 422-8526, Japan
b Suntry Institute for Bioorganic Research, Mishima-gun, Osaka 618-8503, Japan
c Faculty of Pharmaceutical Sciences at Kagawa Campus, Tokushima Bunri University, 1314-1 Shido, Sanuki, Kagawa 769-2193, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 4 April 2008
Accepted 1 May 2008
A biphenanthryl ether with substituents in the bay regions was efficiently synthesized for the first time.
The unique stereostructure of 1 was clarified. Its twisted conformation and optical behavior as well as its
characteristic supramolecular helical structure, which is constructed through a C–Hꢀ ꢀ ꢀF hydrogen bond-
ing network in the solid state, are discussed.
Ó 2008 Elsevier Ltd. All rights reserved.
This paper is dedicated to the late Professor
Kiyoshi Tanaka, who passed away December
8, 2004
1. Introduction
CO2Me
Axially chiral compounds are promising resources for asymmet-
ric synthesis and chiral recognition studies in host–guest chemis-
try. Among such compounds, chiral biaryls such as BINAP and
BINOL are recognized as exceptionally powerful chiral inducers.1
For these atropisomeric compounds, the chirality is generated by
preventing bond rotation around the sp2 carbon–sp2 carbon single
bond, which connects both naphthyl rings. On the other hand, biar-
yl compounds, which have two aromatic rings connected via a het-
eroatom, have not been well documented as axially chiral
compounds. However, Fuji2 and Clayden3 have recently reported
chiral binaphthyl and biphenyl ethers, respectively, in which an
oxygen atom is present within the aryl rings. The restricted rota-
tion of the sp3 oxygen–sp2 carbon single bond induces axial chiral-
ity in both these molecules.
CO2Me
bay
R
R
R
R
O
R
O
R
R
R
CO2Me
CO2Me
2: R = F
1: R = F
CO2Me
CHO
During the course of our continuing studies on axially chiral
molecules,4 we have focused on using biaryl ether-type atropisom-
ers to develop novel axially chiral compounds. For example, we
have designed biphenanthryl ether 1, a unique axially chiral mole-
CO2Me
PPh3+Br-
O
OBn
+
cule, by considering the
p-face of the phenanthrene ring, which
R
R
may construct a wide and relatively rigid chiral environment
(Scheme 1). Moreover, we envisioned that the substituents (R) in
the bay regions of both phenanthrene rings of 1 may enhance
the rotational barrier around the C–O single bond. Among these
derivatives,5 1 containing fluorine atoms gave crystals suitable
for X-ray analysis. The analysis clearly demonstrates the unique
OH
OHC
CO2Me
3: R = F
5
4
Scheme 1. Retrosynthetic analysis of biphenanthryl ether 1.
chiral stereostructure, which includes both axial and helical chiral-
ities. Herein, we report the synthesis and characteristic stereo-
structure of novel biphenanthryl ethers, which are promising
candidates for unique axially chiral molecules.
* Corresponding authors. Tel.: +81 54 264 5742; fax: +81 54 264 5745 (T.F.); tel.:
+81 54 264 5746; fax: +81 54 264 5745 (T.K.).
E-mail addresses: furuta@u-shizuoka-ken.ac.jp (T. Furuta), kant@u-shizuoka-
ken.ac.jp (T. Kan).
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.05.001

1408
Y. Koizumi et al. / Tetrahedron: Asymmetry 19 (2008) 1407–1410
2. Results and discussion
CO2Me
OBn
1) H2, Pd-C
Scheme 1 illustrates the heart of our synthetic plan. Because di-
rect coupling of phenanthrol derivatives is difficult, the phenan-
threne skeleton is constructed after preparing the bis-phenol
ether. Moreover, because a photocyclization reaction6 is a suitable
method for preparing the phenanthrene ring, stilbene derivative 2
is an ideal intermediate. The double bond of stilbene 2 could be
constructed by a Wittig reaction of 3 and 4. The advantage of this
method is that it easily provides diverse derivatives due to the
ready availability of substituted benzyl halides, precursors of phos-
phonium salt 3. Because the biphenyl ether 4 can be constructed
according to Buchwald’s protocol,7 3,4-disubstituted phenol 5 is a
suitable starting material.
Pd(OAc)2, 9
K2CO3
AcOEt
96%
5 + 8
9 =
O
toluene, 95 °C
71%
2) Swern oxid.
71%
BnO
CO2Me
10
P(t-Bu)2
CO2Me
CHO
CO2Me
Disubstituted phenol 5 was prepared using an intermolecular
Diels–Alder reaction (Scheme 2). Upon treatment of alkyne 6 and
Danishefsky’s diene 7, the cycloadditon reaction proceeded
smoothly in a regioselective manner. After an acidic work-up pro-
vided 3,4-disubstituted phenol 5 in good yield, the other coupling
partner triflate 8 was prepared by treatment of 5 with trifluoro-
methanesulfonic anhydride in pyridine.
n-BuLi, 3
F
F
O
O
THF, 0 °C
F
F
98%
OHC
CO2Me
CO2Me
4
2
CO2Me
MeO2C
MeO
CO2Me
OBn
neat, 190 °C;
6
7
OBn
I2, hν,
HCl:THF (1:5)
84%
F
F
O
F
F
OR
cyclohexane
72%
OTMS
5 (R = H)
8 (R = Tf)
Tf2O
DMAP
pyridine
98%
CO2Me
1
Scheme 2. Preparation of 2-substituted phenol 5 and triflate 8.
Scheme 3. Preparation of biphenanthryl ether 1.
The coupling reaction of phenol 5 and aryl triflate 8 was accom-
plished by Buchwald’s protocol.7 Upon treatment of 5 and 8 in the
presence of a combination of Pd(OAc)2 and ligand 9 catalyst with
K2CO3 in toluene, the coupling reaction proceeded smoothly to pro-
vide desired symmetrical biphenyl ether 10 in 71% yield (Scheme 3).
After removing the Bn ether of 10 under hydrogenolysis condi-
tions, Swern oxidation of the corresponding diol gave aldehyde 4 in
good yield. A benzyl-type ylide was generated by treatment with
n-BuLi and phosphonium salt 3, and subsequent subjection to alde-
hyde 4. The Wittig reaction proceeded smoothly to provide stil-
bene derivative 2 as an E/Z mixture. The phenanthrene skeleton
was efficiently constructed by photoirradiation of 2 in the presence
of I2, and a double cyclization–aromatization reaction proceeded
smoothly to give desired biphenanthryl ether 1.8 To our surprise,
the crystals of 1 exhibited an optically active form and a detailed
analysis is discussed in the following paragraph.
The crystal structure clearly shows the positively twisted con-
formation of 19 where the dihedral angle of both phenanthrene
rings (C4,C8–C40,C80) is 64° (Fig. 1a and b). This observation indi-
cates that the biphenanthryl ether can be an atropisomer if the
C–O bond possesses a substantial rotational barrier. The bond an-
gle of C4–O–C40 in the biaryl ether moiety is 123° (Fig. 1a). More-
over, the phenanthrene rings themselves have helical chiralities
due to the repulsion between the oxygen atom of the ether linkage
and the substituent (F atom) in the bay positions (the torsion angle
of C40,C4a0–C4b0,C50: 25°) (Fig. 1c). Therefore, each molecule has
three chiral twists. These structural features might be promising
for further applications of 1 as a chiral source for chiral recognition
as well as in asymmetric synthesis.
The space group (C2) indicates that the crystals are themselves
chiral. Indeed, crystal packing clearly shows that the homo-chiral
Figure 1. Stereostructure of (P)-1.

Y. Koizumi et al. / Tetrahedron: Asymmetry 19 (2008) 1407–1410
1409
Figure 2. Packing diagram of (P)-1.
molecules are self-assembled into optically active crystals (Fig. 2a).
The hydrogen bonding network (red dotted line) between the
acidic C–H by virtue of the neighboring F functional groups and
the F atom in the bay region might play an important role in
homo-chiral crystallization (Fig. 2a). Interestingly, the molecules,
which are connected by C–Hꢀ ꢀ ꢀF hydrogen bonding (Hꢀ ꢀ ꢀF:
2.526 Å), form the supramolecular helical structure as shown in
Figure 2b.
color) and negative Cotton effects randomly appear with the crystals
obtained from distinct trials of crystallization. This suggests that 1
asymmetrically crystallizes to give optically active crystals.12
Next, we investigated the activation energy of racemization of
1. Due to the lack of apparent CD of 1 in solution, a dynamic
NMR study of benzyl protected derivative 11,13 which was pre-
pared by an ester exchange reaction of 1 with benzyl alcohol,
To clarify the optical behavior of 1, CD was measured after dis-
solving the crystals in MeOH. However, the Cotton effect was not
detected even at ꢁ100 °C.
On the other hand, obvious Cotton effects were observed in the
solid state (Fig. 3).10 The relationship between the sign of the Cotton
effect and the stereostructure of 19 affords a correlation of a negative
Cotton effect (green color) and the positively twisted conformation
of (P)-1 as depicted in Figure 1.11 Interestingly, both positive (blue
coalescence
point
B
A
O
CO2Bn
O
H
A
F
F
F
F
H
B
Ph
11 kcal/mol
F
F
O
O
F
F
CO2Bn
CO2Bn
11
Figure 3. Solid-state CD spectra of the crystals of 1.
Figure 4. Dynamic NMR of 11.

1410
Y. Koizumi et al. / Tetrahedron: Asymmetry 19 (2008) 1407–1410
2. Fuji, K.; Oka, T.; Kawabata, T.; Kinoshita, T. Tetrahedron Lett. 1998, 39, 1373–
1376.
3. (a) Betson, M. S.; Clayden, J.; Worrall, C. P.; Peace, S. Angew. Chem., Int. Ed. 2006,
45, 5803–5807; (b) Clayden, J.; Worrall, C. P.; Moran, W. J.; Helliwell, M. Angew.
Chem., Int. Ed. 2008, 47, 3234–3237.
4. Yoshikawa, S.; Odaira, J.; Kitamura, Y.; Bedekar, A. V.; Furuta, T.; Tanaka, K.
Tetrahedron. 2004, 60, 2225–2234.
5. We synthesized several biphenanthryl ether derivatives where the methyl
groups in the bay positions were substituted. Detailed synthetic procedures
will be described in due course.
6. For a review see: Mallory, F. B.; Mallory, C. W. Org. React. 1984, 30, 1–39.
7. Aranyos, A.; Old, D. W.; Kiyomori, A.; Wolfe, J. P.; Sadighi, J. P.; Buchwald, S. L. J.
Am. Chem. Soc. 1999, 121, 4369–4378.
8. The CO2Me groups of cyclization precursor 2 are essential for regioselective
cyclization.
was carried out as shown in Figure 4. The calculated racemization
barrier using a coalescence temperature of the prochiral benzyl
protons (HA and HB) of ꢁ55 °C was 11 kcal/mol (Fig. 4).14 This
means that the C–O bond of 1 almost rotates freely, and the helical
twist of the phenanthrene rings is rapidly inverting, which gives a
smooth racemization in solution at ambient temperature. On the
other hand, in solid state, the chirality is completely fixed to give
optically active crystals.
The stereostructure of 1 is quite informative for designing novel
stable atropisomeric derivatives. Moreover, 1 has appropriate func-
tional groups such as methyl ester moieties as well as fluorine
atoms for further chemical modifications. From these aspects, 1
should be a potential scaffold for developing chiral biphenanthryl
ether derivatives.
9. Crystallographic data for 1: C32H18F4O5, M = 558.48, monoclinic, space group
C2, T = 298 K, a = 14.425(2) Å, b = 6.5297(12) Å, c = 12.973(3) Å,
a
k
= 90°,
(Cu
b = 94.773(14)°,
c
= 90°, V = 1217.7(4) Å3, Z = 2, D = 1.259 g/cm3,
Ka
) = 1.54178 Å, R = 0.0434, wR2[F2] = 0.1204 for 2195 unique reflections. The
absolute structure of 1 was determined by the Flack parameter method.
10. The KBr tablet (13
measurement.
lg of 1 per 40 mg of KBr) was prepared for solid-state CD
3. Conclusions
11. This suggests that the exciton chirality method cannot simply be applied to
biphenanthryl ether derivatives. Further investigation of this optical behavior
are currently under way.
In conclusion, novel chiral biphenanthryl ether derivatives were
developed, and their unique stereostructure was clarified. The ste-
reostructure presented here may be a useful structural basis to fur-
ther develop chiral inducers and/or ligands using biphenanthryl
ether frameworks. Further chemical modifications of 1 toward sta-
ble atropisomers are currently underway.
12. For examples of asymmetric crystallization (chiral transformation), see the
following references and references cited therein: (a) Matsuura, T.; Koshima, H.
J. Photochem. Photobiol. C: Photochem. Rev. 2005, 6, 7–24; (b) Sakamoto, M. J.
Photochem. Photobiol. C: Photochem. Rev. 2006, 7, 183–196; (c) Azumaya, I.;
Uchida, D.; Kato, T.; Yokoyama, A.; Tanatani, A.; Takayanagi, H.; Yokozawa, T.
Angew. Chem., Int. Ed. 2004, 43, 1360–1363; (d) Kato, T.; Okamoto, I.; Tanatani,
A.; Hatano, T.; Uchiyama, M.; Kagechika, H.; Masu, H.; Katagiri, K.; Tominaga,
M.; Yamaguchi, K.; Azumaya, I. Org. Lett. 2006, 8, 5017–5020.
Acknowledgments
13. Experimental procedure for 11: To a stirred solution of 1 (50 mg, 0.0895 mmol)
in toluene (6 ml) were added Ti(OiPr)4 (79 mg, 0.269 mmol) and BnOH
This work was financially supported by the SUNBOR Founda-
tion, the Uehara Memorial Foundation, the 21st Century COE Pro-
gram, and a Grant-in-Aid for Scientific Research on Priority Areas
17025011 from the Ministry of Education, Culture, Sports, Science
and Technology (MEXT) of Japan.
(120 mg, 1.07 mmol). The reaction mixture was refluxed for 3 h using
a
Dean–Stark trap. The reaction was quenched with saturated aqueous NaHCO3.
The organic layer was separated and the aqueous layer was extracted with
EtOAc. The combined organic layers were washed with brine, dried over
anhydrous MgSO4, and concentrated in vacuo. The residue was purified by
column chromatography on silica gel (hexanes/EtOAc = 9:1) to give 11
(29.2 mg, 46%) as a pale yellow oil.
14. Dynamic NMR of methyl-substituted derivatives have been measured.
However, the complexity of the spectra due to the presence of two different
conformers at low temperature makes the calculation of the racemization
barrier difficult.
References
1. For reviews see: (a) Brunel, J. M. Chem. Rev. 2005, 105, 857–897; (b) Berthod,
M.; Mignani, G.; Woodward, G.; Lemaire, M. Chem. Rev. 2005, 105, 1801–1836.