Synthesis and inclusion properties of 6,6′-Bi(benzo[b]fluoren-5-ol) derivative by cycloaromatization

Article abstract of DOI:10.1246/cl.2006.58

Aromatic non-conjugated tetraynes underwent step-by-step cycloaromatization to yield 6,6′-bi(benzo[b]fluoren-5-ol) derivative 1 via benzo[b]fluoren-5-ol derivatives. Treatment of compound 1 with a kind of organic guest compounds afforded crystalline inclusion compounds (clathrates). Copyright

Full text of DOI:10.1246/cl.2006.58

58
Chemistry Letters Vol.35, No.1 (2006)
Synthesis and Inclusion Properties of 6,60-Bi(benzo[b]fluoren-5-ol) Derivative
by Cycloaromatization
Tomikazu Kawano,ꢀ Masako Suehiro, and Ikuo Ueda
The Institute of Scientific and Industrial Research, Osaka University, 8-1 Mihogaoka, Ibaraki, Osaka 567-0047
(Received October 17, 2005; CL-051313; E-mail: kawano@sanken.osaka-u.ac.jp)
Aromatic non-conjugated tetraynes underwent step-by-step
OH
HO
cycloaromatization to yield 6,60-bi(benzo[b]fluoren-5-ol) deriv-
ative 1 via benzo[b]fluoren-5-ol derivatives. Treatment of com-
pound 1 with a kind of organic guest compounds afforded crys-
talline inclusion compounds (clathrates).
CHO
Ph
TMS
Ph
a
b
Ph
Ph
2
3
4
Benzo[b]fluorenes (BFs) have received considerable atten-
tion in the field of organic chemistry and medicinal chemistry.
They are among the most fundamental intermediates for the
synthesis of natural products possessing a tetracycline core such
as kinobscurinone, stealthin C, kinamycin, and cysfluoretin.1
A number of these natural products show Gram-positive and
-negative antibacterial properties, and antitumor activity.2
Recently, preparations of BFs as estrogen receptor antagonists
have also been reported.3 We have reported the synthesis of a
series of polycyclic aromatic compounds, including BFs, by
cycloaromatization of non-conjugated polyyne derivatives
since 1997.4 Two research groups reported the preparation of a
benzo[b]fluorene core by cycloaromatization of non-conjugated
benzodiynes5 and benzotriynes6 using our cyclization procedure.
In the hope of further developing our procedure and discovering
a new class of BFs, we newly designed 6,60-bi(5-phenylbenzo-
[b]fluoren-5-ol) derivative 1 in this study. Compound 1 was
expected to possess inclusion properties because it possesses a
double ‘‘diarylmethanol unit,’’ which is characteristic of a series
of wheel-and-axle-type host compounds with inclusion proper-
ties, such as A (Chart 1).7 We herein describe the first synthesis
of 1 by cycloaromatization of non-conjugated novel tetraynes,
along with the inclusion properties.
In the first place, we planned to synthesize the target
compound 1 by double cycloaromatization of tetrayne 5
(Scheme 1). Reaction of aldehyde 28 with lithium salt of (tri-
methylsilyl)acetylene, obtained by treatment of (trimethylsilyl)-
acetylene with n-butyllithium, gave alcohol 3 in a quantitative
yield. o-Iodoxybenzoic acid (IBX) oxidation of 3 led to the
formation of ketone derivative, followed by Grignard reaction
of the resulting ketone with phenylmagnesium bromide
(PhMgBr), and subsequent deprotection of the trimethylsilyl
group gave non-conjugated diyne 4 in 98% yield in three steps.
Dimerization of 4 for the synthesis of tetrayne 5, which is a
Ph
OH
c
Ph
Ph
HO
Ph
5
Ph
HO
5'
Ph
OH
6
HO
OH
Ph
Ph
Ph
5
(5S*, 5'S*, 6R*)-1
( )-6
Scheme 1. Cycloaromatization of non-conjugated tetraynes.
Reagents and conditions: (a) n-BuLi, (trimethylsilyl)acetylene,
THF, ꢁ78 ꢂC. (b) (1) IBX, DMSO, rt; (2) PhMgBr, THF, 0 ꢂC;
(3) K2CO3, MeOH, 0 ꢂC. (c) TMEDA, CuI, O2, acetone, 45 ꢂC.
precursor of target compound 1, under Hay’s conditions yielded
interesting results. The Hay’s coupling9 of 4 in the presence of
tetramethylethylenediamine (TMEDA) and copper(I) iodide
(CuI) in acetone under an oxygen atmosphere gave 6,60-bi-
(5-phenylbenzo[b]fluoren-5-ol) derivative 1 directly and mono-
cycloaromatized product 6 in 23 and 18% yields, respectively,
along with unchanged 4 in a recovery yield of 45%, without
isolating tetrayne 5. It is noteworthy that cycloaromatization of
6 gave a diastereomer of 1, (5Sꢀ, 50Rꢀ, 6Rꢀ)-1, in 30% yield.
We then examined the synthesis of 1 by the step-by-step cy-
cloaromatization approach as shown in Scheme 2. Treatment of
3 with K2CO3 gave 8 in a quantitative yield. Protection of alco-
hol group of 8 with dihydropyran and subsequent iodonation of
the acetylene terminus, followed by deprotection of tetrahydro-
pyranyl group afforded 9 in 88% yield by three steps. Cross cou-
pling reaction of 4 with 9 in the presence of CuI in pyrrolidine
gave asymmetrical tetrayne 10 in 85% yield, along with 3%
yield of the homo-coupling product of 4. Cycloaromatization
of 10 in acetone gave mono-benzo[b]fluoren-5-ol 11 in 55%
yield as a mixture of diastereomers. IBX oxidation of 11 afford-
ed ketone 12 in 88% yield. Grignard reaction of 12 with PhMgBr
gave selectively alcohol 13 in 47% yield, which was found to be
5'
Ph
Ph
Ph
OH
HO
Ph
Ph
Ph
6
5
OH
OH
(5S*, 5'S*, 6R*)-1
Chart 1.
A
1
a diastereomer of 6 on the basis of H NMR. This selectivity
Copyright Ó 2006 The Chemical Society of Japan

Chemistry Letters Vol.35, No.1 (2006)
59
thesis of a series of BFs and their detailed inclusion properties,
including determination of crystal structure, are now in progress.
HO
HO
R
I
c
b
Ph
Ph
We thank the Materials Analysis Center of ISIR-Sanken,
Osaka University for assisting us with elemental analysis.
3 (R = TMS)
8 (R = H)
9
a
References and Notes
1
HO
For examples, see: a) S. J. Gould, S.-T. Hong, J. R. Carney, J.
Antibiot. 1998, 51, 50. b) H. Koyama, T. Kamikawa, J. Chem.
Soc., Perkin Trans. 1 1998, 203. c) S.-I. Mohri, M. Stefinovic,
V. Snieckus, J. Org. Chem. 1997, 62, 7072. d) S. J. Gould, C. R.
Melville, M. C. Cone, J. Chen, J. R. Carney, J. Org. Chem.
1997, 62, 320. e) T. Aoyama, W. Zhao, F. Kojima, Y. Muraoka,
H. Naganawa, T. Takeuchi, T. Aoyagi, J. Antibiot. 1993, 46, 1471.
S. J. Gould, C. R. Melville, Bioorg. Med. Chem. Lett. 1995, 5, 51.
a) H. J. J. Loozen, M. Wagener, G. H. Veeneman, E. W. De Zwart,
PCT Int. Appl. WO 2003070675, 2003. b) G. H. Veeneman,
H. J. J. Loozen, J. Mestres, E. W. De Zwart, PCT Int. Appl. WO
2002016316, 2002.
a) T. Kawano, H. Inai, K. Miyawaki, I. Ueda, Tetrahedron Lett.
2005, 46, 1233. b) K. Miyawaki, T. Kawano, I. Ueda, Tetrahedron
Lett. 2000, 41, 1447. c) T. Kawano, C. Ikemoto, I. Ueda, Tetra-
hedron Lett. 1998, 39, 6491. d) K. Miyawaki, R. Suzuki, T.
Kawano, I. Ueda, Tetrahedron Lett. 1997, 38, 3943.
Ph
OH
e
d
Ph
OH
Ph
Ph
OH
Ph
10
11
2
3
HO
Ph
O
g
f
(5S*, 5'S*, 6R*)-1
OH
Ph
OH
Ph
4
Ph
Ph
( )-12
( )-13
Scheme 2. Step-by-step cycloaromatization of non-conjugated
tetrayne. Reagents and conditions: (a) K2CO3, MeOH, 0 ꢂC.
(b) (1) DHP, PPTS, CH2Cl2, rt; (2) MeLi, I2, THF, ꢁ23 ꢂC;
(3) PPTS, MeOH, 55 ꢂC. (c) 4, CuI, O2, pyrrolidine, ꢁ23 ꢂC.
(d) Acetone, ꢁ45 ꢂC. (e) IBX, DMSO, rt. (f) PhMgBr, THF,
0 ꢂC. (g) Benzene, 80 ꢂC.
5
6
M. Schmittel, M. Strittmatter, W. A. Schenk, M. Hagel, Z.
Naturforsch. 1998, 53b, 1015.
´
a) D. Rodrıguez, L. Castedo, D. Domınguez, C. Saa, Tetrahedron
Lett. 1999, 40, 7701. b) G. Rodrıguez, D. Rodrıguez, M. Lopez,
´
´
´
´
´
´
´
L. Castedo, D. Domınguez, C. Saa, Synlett 1998, 1282.
For examples, see: a) F. Toda, K. Akagi, Tetrahedron Lett. 1968,
9, 3695. b) K. Kobayashi, Bull. Chem. Soc. Jpn. 2003, 76, 247, and
references cited therein.
7
would be caused by chelation-control in the Grignard reaction of
12. Finally, cycloaromatization of 13 in benzene led to the for-
mation of 1 in 67% yield. All compounds obtained in this study
were characterized by spectroscopy (NMR, IR, and FABMS)
and elemental analysis.10
Among the many species of wheel-and-axle-type host com-
pounds, molecules containing the hydroxyl group, especially the
‘‘diarylmethanol unit,’’ are known to be effective for the forma-
tion of crystalline inclusion compounds (clathrates).11 The inclu-
sion behavior of compound 1 bearing a double diarylmethanol
unit was estimated using a broad variety of guest compounds
(Table 1). The results showed that compound 1 mainly favored
clathrates in the 1:2 host/guest stoichiometric ratio, though a
few examples of the formation of clathrates in the 1:1 ratio or
2:1 ratio were observed.12
8
9
P. Sagar, R. Frohlich, E.-U. Wurthwein, Angew. Chem., Int. Ed.
¨
¨
2004, 43, 5694.
A. S. Hay, J. Org. Chem. 1962, 27, 3320.
10 Selected physical data are as follows. Compound 1: Colorless
prisms, mp 302.5–303.0 ꢂC (from benzene–hexane).1H NMR
(400 MHz, CDCl3) ꢀ 4.86 (s, 2H), 6.10 (d, 2H, J ¼ 8:3 Hz),
6.44–6.52 (m, 10H), 6.59–6.62 (m, 2H), 7.04 (d, 2H, J ¼ 7:6
Hz), 7.11–7.14 (m, 2H), 7.22–7.26 (m, 2H), 7.46 (d, 2H, J ¼
7:6 Hz), 7.71 (d, 2H, J ¼ 8:3 Hz), 7.97 (d, 2H, J ¼ 7:6 Hz), 8.24
(s, 2H) ppm. IR (KBr) ꢁ 3270, 3045, 3020 cmꢁ1. FABMS
(NBA) m=z 615 ½M þ Hꢃþ. Anal. Calcd for C46H30O2: C, 89.88;
H, 4.92%. Found: C, 89.64; H, 5.11%. Compound 6: Colorless
powder, mp 153.5–154.5 ꢂC. 1H NMR (400 MHz, CDCl3) ꢀ 3.03
(s, 1H), 3.51 (s, 1H), 7.11–7.29 (m, 15H), 7.33–7.51 (m, 7H),
7.64 (d, 1H, J ¼ 7:3 Hz), 7.81 (d, 1H, J ¼ 7:6 Hz), 7.89–7.94
(m, 2H), 8.14 (s, 1H), 8.29 (d, 1H, J ¼ 8:3 Hz) ppm. IR (KBr) ꢁ
3545, 3470, 3060, 3035, 2235, 2195 cmꢁ1. FABMS (NBA) m=z
In conclusion, we have demonstrated that step-by-step
cycloaromatization of non-conjugated tetraynes proceeded
smoothly to produce 6,60-bi(5-phenylbenzo[b]fluoren-5-ol)
derivative with inclusion properties. Further studies for the syn-
615 ½M þ Hꢃþ. Anal. Calcd for C46H30O2 1/2H2O: C, 88.58; H,
.
5.01%. Found: C, 88.77; H, 4.78%.
11 a) E. Waber, T. Hens, Q. Li, T. C. W. Mak, Eur. J. Org. Chem.
1999, 1115. b) Inclusion Compounds, ed. by J. L. Atwood, J. E.
D. Davies, D. D. MacNicol, Academic Press, London, 1984.
12 A typical method for the formation of clathrates: (Method A)
A mixture of 1 and an excess amount of guest compound in ether
was stirred at room temperature for 24 h. After addition of
petroleum ether, the precipitates were collected and dried in
vacuo. (Method B) Compound 1 was dissolved under heating in
a minimum amount of guest compound. The resulting solution
was allowed to stand overnight at room temperature, the precipi-
tates which formed were collected and dried in vacuo. Selected
Table 1. Crystalline inclusion compounds of 1a
CH2Cl2 DMSO DMF Et3N
Pyridine
1:2
PhCHO
1:2
1:1
1:2
1:2
1:1
Acetone
1:2
Butan-2-one
NTd
CPb Acetophenone
NT
1:2e
BPc
2:1e
aHost/guest stoichiometric ratios, which were determined by
b
c
d
1H NMR. Cyclopentanone. Benzophenone. Not detected.
eBinding constants of acetophenone and BP were 3:64 ꢄ
103 and 4:29 ꢄ 103 Mꢁ1, respectively.
.
physical data are as follows. Clathrate 1 2DMSO: Colorless
prisms. mp 300.0–301.0 ꢂC (from DMSO). Anal. Calcd for
C50H42O4S2: C, 77.89; H, 5.49%. Found: C, 77.88; H, 5.41%.
Published on the web (Advance View) December 3, 2005; DOI 10.1246/cl.2006.58