Synthesis, resolution, and absolute stereochemistry of (-)-blestriarene C

Article abstract of DOI:10.1021/jo026747k

A naturally occurring 1,1′-biphenanthrene, blestriarene C (1), was prepared in 13 steps and 30% overall yield. The key steps are the ester-mediated nucleophilic aromatic substitution on 2,6-ditert-butyl-4-methoxyphenyl 5-isopropoxy-2-methoxybenzoate (4) b

Full text of DOI:10.1021/jo026747k

Syn th esis, Resolu tion , a n d Absolu te Ster eoch em istr y of
(-)-Blestr ia r en e C
Tetsutaro Hattori,*,† Yuhi Shimazumi,† Hitoshi Goto,‡ Osamu Yamabe,† Naoya Morohashi,†
Wataru Kawai,‡ and Sotaro Miyano*,†
Department of Biomolecular Engineering, Graduate School of Engineering, Tohoku University,
Aramaki-Aoba 07, Aoba-ku, Sendai 980-8579, J apan, and Department of Knowledge-based
Information Engineering, Toyohashi University of Technology, 1-1 Hibarigaoka, Tempaku-cho,
Toyohashi 441-8066, J apan
hattori@orgsynth.che.tohoku.ac.jp.
Received November 21, 2002
A naturally occurring 1,1′-biphenanthrene, blestriarene C (1), was prepared in 13 steps and 30%
overall yield. The key steps are the ester-mediated nucleophilic aromatic substitution on 2,6-di-
tert-butyl-4-methoxyphenyl 5-isopropoxy-2-methoxybenzoate (4) by 2-methoxy-4-methoxymethoxy-
6-methylphenylmagnesium bromide (5) and a novel intramolecular cyclization of the resulting
4-isopropoxy-2′-methoxy-4′-methoxymethoxy-6′-methylbiphenyl-2-carboxylic ester 14 to 7-isopro-
poxy-4-methoxy-2-(methoxymethoxy)phenanthren-9-ol (15). The racemic blestriarene C was optically
resolved by chiral HPLC on a preparative scale to give several 10-mg yields of both the enantiomers
in up to 95% ee. The absolute stereochemistry was determined to be Sa-(-) by the axial chirality
recognition method, which was based on the stereospecific formation of a 12-membered cyclic diester
containing two biaryl-o,o′-diyl unites joined by ester -CO2- linkages. The validity of the method
was confirmed by an X-ray crystallographic analysis and ab initio conformational analyses of such
12-membered cyclic diesters. It was found that blestriarene C and its 7,7′-diisopropyl ether 2
underwent rapid photoracemization even under ambient light exposure.
In tr od u ction
biphenanthrenes,3 although it is a well-known nonem-
pirical method often applied to biaryl compounds.4 Here,
we report a synthesis and optical resolutions of such a
biphenanthrene, (-)-blestriarene C (1),5,6 which was
There are a certain number of 1,1′-biphenanthrene
compounds, e.g. (-)-blestriarene C (cirrhopetalanthrin,
1),1 isolated from orchids along with analogues having
9,10-dihydro- and 9,9′,10,10′-tetrahydro-1,1′-biphenan-
threne frameworks.1a,c,d,2 These compounds generally
possess at least three hydroxy and/or methoxy groups in
total on each phenanthrene half, two being at the 2,2′-
positions. Therefore, they may exist as nonracemic
substances, as is often the case with the isolated ones.1a,d,2g
However, no studies have ever tried to determine their
absolute stereochemistries, not to mention their single-
enantiomer preparations. In this connection, we have
recently reported that the CD exciton chirality method
is not suitable for determining the axial chirality of 1,1′-
isolated from Bletilla striata by Yamaki and co-workers1a
and from Cirrhopetalum maculosum by Majumder et al.1b
The compound was reported to be active against gram-
positive bacteria, Staphylococcus aureus and Streptococ-
* To whom correspondence should be addressed. Fax: +81-22-217-
7293. Phone: +81-22-217-7263.
† Tohoku University.
‡ Toyohashi University.
(1) (a) Yamaki, M.; Bai, L.; Inoue, K.; Takagi, S. Phytochemistry
1989, 28, 3503. (b) Majumder, P. L.; Pal, A.; J oardar, M. Phytochem-
istry 1990, 29, 271. (c) Majumder, P. L.; Roychowdhury, M.; Chakraborty,
S. Phytochemistry 1998, 49, 2375. (d) Majumder, P. L.; Pal, S.;
Majumder, S. Phytochemistry 1999, 50, 891.
(2) (a) Majumder, P. L.; Banerjee, S. Tetrahedron 1988, 44, 7303.
(b) Tuchinda, P.; Udchachon, J .; Khumtaveeporn, K.; Taylor, W. C.;
Engelhardt, L. M.; White, A. H. Phytochemistry 1988, 27, 3267. (c)
Majumder, P. L.; Lahiri, S. Tetrahedron 1990, 46, 3621. (d) Majumder,
P. L.; Ghosal, S. Phytochemistry 1993, 32, 439. (e) Adam, K. P.; Becker,
H. Phytochemistry 1994, 35, 139. (f) Yamaki, M.; Honda, C. Phy-
tochemistry 1996, 43, 207. (g) Majumder, P. L.; Banerjee, S.; Lahiri,
S.; Mukhoti, N.; Sen, S. Phytochemistry 1998, 47, 855.
(3) Hattori, T.; Sakurai, K.; Koike, N.; Miyano, S.; Goto, H.; Ishiya,
F.; Harada, N. J . Am. Chem. Soc. 1998, 120, 9086.
(4) Harada, N.; Nakanishi, K. Circular Dichroic Spectroscopy:
Exciton Coupling in Organic Stereochemistry; University Science
Books: Mill Valley, CA, 1983.
(5) Preliminary communication: Hattori, T.; Shimazumi, Y.; Yam-
abe, O.; Koshiishi, E.; Miyano, S. Chem. Commun. 2002, 2234.
(6) Cirrhopetalanthrin is a racemate1b-d and its synthesis by oxida-
tive coupling of the naturally occurring phenanthrene half, flavan-
thrinin has been reported: Majumder, P. L.; Basak, M. Tetrahedron
1991, 47, 8601.
10.1021/jo026747k CCC: $25.00 © 2003 American Chemical Society
Published on Web 02/07/2003
J . Org. Chem. 2003, 68, 2099-2108
2099

Hattori et al.
SCHEME 1
SCHEME 2 a
cus mutans.1a During the study, we have found that
tetraol 1 undergoes rapid photoracemization even under
ambient light exposure and thus the compound isolated
from nature cannot be optically pure. Also reported is
its absolute stereochemistry determined by the axial
chirality recognition method, which is based on the
stereospecific formation of a 12-membered cyclic diester
containing two biaryl-o,o′-diyl unites joined by ester
-CO2- linkages, e.g. compound 21.7 The validity of the
method was confirmed by an X-ray crystallographic
analysis and ab initio conformational analyses of such
12-membered cyclic diesters.
a
Reagents: (a) K2CO3, TsCl, acetone; (b) MeI; (c) KOH, aq
EtOH; (d) K2CO3, MOMCl, acetone; (e) K2CO3, i-PrBr, KI, DMF;
(f) BHAOH, TFAA; (g) 5, PhH.
Resu lts a n d Discu ssion
Syn th esis of Ra cem ic Tetr a ol 1. Our synthetic
strategy for racemic tetraol 1 was focused on regioselec-
tive synthesis of properly protected phenanthrenetriol 3,
since 1 should be readily prepared from 3 by oxidative
phenol coupling reaction (Scheme 1). In previous papers,8
we reported that ester function substantially activates
an o-alkoxy group for nucleophilic aromatic substitution
(SNAr) reaction by various nucleophiles, which provides
a convenient substitute for the oxazoline-mediated o-
alkoxy displacement from aryloxazolines (the Meyers
reaction).9,10 We intended to employ the ester-mediated
SNAr protocol for the coupling reaction between ester 4
and Grignard reagent 5 to biphenyl 14, which was
expected to serve as a convenient precursor of phenan-
throl 3 (vide infra).
Prerequisite ester 4 and bromide 9 were prepared as
follows (Scheme 2). Regioselective tosylation of benzene-
diol 6 at the 1-position, followed by methylation of the
3-hydroxy group in a one-pot fashion, as demonstrated
by Wulff and co-workers for 4-bromobenzene-1,3-diol,11
gave methoxy sulfonate 7. It was hydrolyzed to phenol 8
and the hydroxy group was reprotected with MOMCl to
give bromide 9. On the other hand, regioselective func-
(7) (a) Miyano, S.; Tobita, M.; Nawa, M.; Sato, S.; Hashimoto, H. J .
Chem. Soc., Chem. Commun. 1980, 1233. (b) Miyano, S.; Tobita, M.;
Hashimoto, H. Bull. Chem. Soc. J pn. 1981, 54, 3522. (c) Miyano, S.;
Handa, S.; Shimizu, K.; Tagami, K.; Hashimoto, H. Bull. Chem. Soc.
J pn. 1984, 57, 1943. (d) Miyano, S.; Shimizu, K.; Sato, S.; Hashimoto,
H. Bull. Chem. Soc. J pn. 1985, 58, 1345. (e) Miyano, S.; Handa, S.;
Tobita, M.; Hashimoto, H. Bull. Chem. Soc. J pn. 1986, 59, 235. (f)
Miyano, S.; Fukushima, H.; Handa, S.; Ito, H.; Hashimoto, H. Bull.
Chem. Soc. J pn. 1988, 61, 3249. (g) Hattori, T.; Koike, N.; Miyano, S.
J . Chem. Soc., Perkin Trans. 1 1994, 2273. (h) Koike, N.; Hattori, T.;
Miyano, S. Tetrahedron: Asymmetry 1994, 5, 1899.
(8) For representative examples of the ester-mediated SNAr reaction,
see: (a) Hotta, H.; Suzuki, T.; Miyano, S. Chem. Lett. 1990, 143. (b)
Hattori, T.; Hotta, H.; Suzuki, T.; Miyano, S. Bull. Chem. Soc. J pn.
1993, 66, 613. (c) Hattori, T.; Suzuki, T.; Hayashizaka, N.; Koike, N.;
Miyano, S. Bull. Chem. Soc. J pn. 1993, 66, 3034. (d) Hattori, T.; Satoh,
S.; Miyano, S. Bull. Chem. Soc. J pn. 1993, 66, 3840. (e) Hattori, T.;
Hayashizaka, N.; Miyano, S. Synthesis 1995, 41. (f) Hattori, T.; Tanaka,
H.; Okaishi, Y.; Miyano, S. J . Chem. Soc., Perkin Trans. 1 1995, 235.
(g) Baker, R. W.; Hockless, D. C. R.; Pocock, G. R.; Sargent, M. V.;
Skelton, B. W.; Sobolev, A. N.; Twiss, E.; White, A. H. J . Chem. Soc.,
Perkin Trans. 1 1995, 2615. (h) Baker, R. W.; Hambley, T. W.; Turner,
P.; Wallace, B. J . J . Chem. Soc., Chem. Commun. 1996, 2571. (i)
Hattori, T.; Koike, N.; Okaishi, Y.; Miyano, S. Tetrahedron Lett. 1996,
37, 2057. (j) Kamikawa, K.; Uemura, M. Tetrahedron Lett. 1996, 37,
6359. (k) Wells, K. M.; Shi, Y.-J .; Lynch, J . E.; Humphrey, G. R.;
Volante, R. P.; Reider, P. J . Tetrahedron Lett. 1996, 37, 6439. (l)
Hattori, T.; Satoh, T.; Miyano, S. Synthesis 1996, 514. (m) Koike, N.;
Hattori, T.; Takeda, A.; Okaishi, Y.; Miyano, S. Chem. Lett. 1997, 641.
(n) Hattori, T.; Takeda, A.; Suzuki, K.; Koike, N.; Koshiishi, E.; Miyano,
S. J . Chem. Soc., Perkin Trans. 1 1998, 3661. (o) Aki, S.; Haraguchi,
Y.; Sakikawa, H.; Ishigami, M.; Fujioka, T.; Furuta, T.; Minamikawa,
J . Org. Proc. Res. Dev. 2001, 5, 535. (p) Kojima, T.; Ohishi, T.;
Yamamoto, I.; Matsuoka, T.; Kotsuki, H. Tetrahedron Lett. 2001, 42,
1709. (q) Koshiishi, E.; Hattori, T.; Ichihara, N.; Miyano, S. J . Chem.
Soc., Perkin Trans. 1 2002, 377.
(9) Review: (a) Reuman, M.; Meyers, A. I. Tetrahedron 1985, 41,
837. (b) Gant, T. G.; Meyers, A. I. Tetrahedron 1994, 50, 2297.
(10) Recent examples: (a) Denieul, M.-P.; Laursen, B.; Hazell, R.;
Skrydstrup, T. J . Org. Chem. 2000, 65, 6052. (b) Boisnard, S.; Neuville,
L.; Bois-Choussy, M.; Zhu, J . Org. Lett. 2000, 2, 2459. (c) Baker, R.
W.; Brkic, Z.; Sargent, M. V.; Skelton, B. W.; White, A. H. Aust. J .
Chem. 2000, 53, 925. (d) Baker, R. W.; Kyasnoor, R. V.; Sargent, M.
V.; Skelton, B. W.; White, A. H. Aust. J . Chem. 2000, 53, 487. (e) Baker,
R. W.; Kyasnoor, R. V.; Sargent, M. V. Tetrahedron Lett. 1999, 40, 3475.
(f) Imai, Y.; Zhang, W.; Kida, T.; Nakatsuji, Y.; Ikeda, I. Synlett 1999,
1319. (g) Meyers, A. I.; Willemsen, J . J . Tetrahedron 1998, 54, 10493.
(h) Baker, R. W.; Liu, S.; Sargent, M. V. Aust. J . Chem. 1998, 51, 255.
(i) Baker, R. W.; Liu, S.; Sargent, M. V.; Skelton, B. W.; White, A. H.
Chem. Commun. 1997, 451. (j) Chau, P.; Czuba, I. R.; Rizzacasa, M.
A.; Bringmann, G.; Gulden, K.-P.; Scha¨ffer, M. J . Org. Chem. 1996,
61, 7101. (k) Hutchings, R. H.; Meyers, A. I. J . Org. Chem. 1996, 61,
1004. (l) J ones, W. D., J r.; Ciske, F. L. J . Org. Chem. 1996, 61, 3920.
(m) Gable, R. W.; Martin, R. L.; Rizzacasa, M. A. Aust. J . Chem. 1995,
48, 2013. (n) Allen, J . V.; Coote, S. J .; Dawson, G. J .; Frost, C. G.;
Martin, C. J .; Williams, J . M. J . J . Chem. Soc., Perkin Trans. 1 1994,
2065.
(11) Bos, M. E.; Wulff, W. D.; Miller, R. A.; Chamberlin, S.;
Brandvold, T. A. J . Am. Chem. Soc. 1991, 113, 9293.
2100 J . Org. Chem., Vol. 68, No. 6, 2003

Synthesis and Absolute Stereochemistry of Blestriarene C
SCHEME 3
SCHEME 4 a
a
Reagents: (a) Tf2O, NEt3, CH2Cl2; (b) HCO2H, NEt3, Pd(OAc)2,
PPh3, DMF; (c) 1.5 M HCl, MeOH; (d) 1-phenylethylamine,
Cu(NO3)2‚3H2O, MeOH; (e) BCl3, CH2Cl2.
ature (0 °C) (Scheme 3). It is of interest to note that
lithium diethylamide was more effective than LDA as a
base, while butyllithium was less effective, giving uni-
dentified byproducts. A control reaction of ester 16 with
lithium diethylamide gave a substantial amount of acid
amide 17 (36%) (Scheme 3). Therefore, although direct
attack of the benzyl anion of ester 14 to the ester carbonyl
group should be the main path to phenanthrol 15, an
alternative path via the intermediary acid amide gener-
ated in situ from ester 14 with lithium diethylamide may
contribute to improving the product yield, to some extent,
in the case of the lithium amide (Scheme 3).
Reductive removal of the 9-hydroxy moiety of phenan-
throl 15 (Scheme 4),15 followed by deprotection of the
2-hydroxy moiety of the resulting phenanthrene 19, gave
the desired phenanthrol 3, which was oxidatively coupled
in the presence of a copper(II) complex to give biphenan-
throl 2.16 Deprotection of the 7,7′-dihydroxy groups of the
biphenanthrol gave racemic tetraol 1 in a total of 30%
yield based on the starting ester 10.
Op tica l Resolu tion of Tetr a ol 1 a n d Its P h otor a -
cem iza tion . It has been reported that optically pure 1,1′-
binaphthalene-2,2′-diol (BINOL) is obtained by the enan-
tioselective oxidative coupling of naphthalen-2-ol with the
aid of a complex of CuCl2 and (-)-sparteine.17 Deracem-
izations of BINOL by use of this complex17 and cyclohex-
ane-1,2-diamine18 are also fascinating procedures for the
single-enantiomer preparation. These methods were ap-
plied to biphenanthrol 2 and a little success was achieved
in the deracemization with the copper complex, recover-
ing (-)-2 of 30% ee from precipitate. Eventually, an
optical resolution method based on the formation of
diastereomeric thiophosphoramides was applied to 2
(Scheme 5).19,20 Thus, racemic 2 was converted into a
diastereomeric mixture of thiophosphoramides 20. Crys-
tallization of the mixture from hexane-benzene-aceto-
nitrile resulted in the formation of prismatic crystals,
which were composed of equimolar amounts of the dia-
stereomers. Several variations of the crystallization
tionalization of 2,5-dihydroxybenzoate 10 by the same
procedure as used for compound 6 gave methoxy sul-
fonate 11, which was hydrolyzed to give hydroxy acid 12.
The 5-hydroxy group was converted into an isopropoxy
group by treatment with 2-bromopropane in the presence
of K2CO3 and KI to ester 13, followed by its alkaline
hydrolysis. The resulting acid was esterified with 2,6-di-
tert-butyl-4-methoxyphenol (BHAOH) to give ester 4. The
SNAr reaction was first conducted by adding the Grignard
reagent 5, which had been prepared from bromide 9 and
magnesium turnings in THF, to a benzene solution of
ester 4 and then heating the mixture at reflux for 24 h
to give biphenyl 14 in 55% yield with recovery of the
starting ester (37%). However, the product yield was
improved to 91% by replacing the THF with benzene (see
Experimental Section), which may indicate the impor-
tance of the chelation between the substrate and the
Grignard reagent to further the SNAr reaction.8n,12
As the desired biphenyl was in hand, its transforma-
tion into phenanthrol 15 was investigated (Scheme 3).
Previously, Snieckus and co-workers reported that N,N-
diethyl-2′-methylbiphenyl-2-carboxamide on treatment
with LDA in THF gave the benzyl anion, which attacked
intramolecularly to the carbonyl carbon to afford phenan-
thren-9-ol after enolization of the resulting ketone.13,14
The method was extended to the cyclization of ester 14,
by conducting the cyclization in THF with 4.0 equiv of
LDA at room temperature according to the reported
procedure to give phenanthrol 15 in only 12% yield.
However, utilization of HMPA as a cosolvent significantly
increased the product yield (74%) even at lower temper-
(15) Cacchi, S.; Ciattini, P. G.; Morera, E.; Ortar, G. Tetrahedron
Lett. 1986, 27, 5541.
(16) Feringa, B.; Wynberg, H. Tetrahedron Lett. 1977, 18, 4447.
(17) (a) Smrcˇina, M.; Lorenc, M.; Hanusˇ, V.; Sedmera, P.; Kocˇovsky´,
P. J . Org. Chem. 1992, 57, 1917. (b) Smrcˇina, M.; Pola´kova´, J .; Vyskocˇil,
Sˇ.; Kocˇovsky´, P. J . Org. Chem. 1993, 58, 4534.
(18) Kawashima, M.; Hirata, R. Bull. Chem. Soc. J pn. 1993, 66,
2002.
(12) Hattori, T.; Takeda, A.; Yamabe, O.; Miyano, S. Tetrahedron
2002, 58, 233.
(13) Fu, J .-m.; Sharp, M. J .; Snieckus, V. Tetrahedron Lett. 1988,
29, 5459.
(14) For a related transformation, see: de Koning, C. B.; Michael,
J . P.; Rousseau, A. L. J . Chem. Soc., Perkin Trans. 1 2000, 787.
(19) Fabbri, D.; Delogu, G.; De Lucchi, O. J . Org. Chem. 1993, 58,
1748.
(20) See also: Gong, B.; Chen, W.; Hu, B. J . Org. Chem. 1991, 56,
423.
J . Org. Chem, Vol. 68, No. 6, 2003 2101

Hattori et al.
SCHEME 5 a
F IGURE 1. Racemization of (-)-blestriarene C (1) (left) and
its diether (-)-2 (right) under fluorescent lamp illumination
(circle) or dark (triangle).
racemization was completely suppressed under dark.
Diisopropyl ether 2 also had a tendency toward the
racemization (krac ) 1.07 × 10-6 s-1) (Figure 1), while 1,1′-
biphenanthrene-2,2′-diol did not in itself. There are
several precedents in which biaryl compounds racemized
under strong UV irradiation. For example, 1,1′-binaph-
thalene reportedly racemized through its triplet excited
state where the rotation barrier of the biaryl axis was
diminished compared to that in its ground state.21 6H-
Dibenzo[b,d]pyrans racemized through biaryl quinone
methides,22 1,1′-binaphthalene-2,2′-diol under the condi-
tions where a photoproduct was formed by intramolecular
addition of the 2′-hydroxy group to the C2-C3 bond,23 and
so on.24 However, these mechanisms seem not to explain
the marked tendency of the present compounds toward
racemization. Although the reaction mechanism is not
clear at present, a photoexcited quinone-type species
might mediate the reaction.25
Deter m in a tion of th e Absolu te Ster eoch em istr y
of (-)-Blestr ia r en e C. The axial chirality recognition
method predicts that two biaryl-o,o′-diyl units should
have the same axial twist to form a 12-membered cyclic
diester, e.g. compound 21, because of the steric require-
ments imposed by the bulky and rigid components.7,26
This provides a convenient method for recognizing axial
chirality of a biaryl half of unknown stereochemistry by
forming a cyclic diester with the other biaryl half of
known axial chirality. This method was applied to
determine the absolute stereochemistry of (-)-blestri-
arene C (Scheme 6). Thus, treatment of racemic bi-
a
Reagents: (a) (R)-(+)-1-phenylethylamine, PSCl3, pyridine; (b)
LiAlH4, THF; (c) BCl3, CH2Cl2.
conditions including change of the solvent, crystallization
temperature, and the like did not alter the diastereomeric
composition. However, it could be separated into diaste-
reomerically pure (-)-20 and (+)-enriched 20 by prepara-
tive scale HPLC on a silica gel column. The latter was
crystallized from hexane-benzene-ethanol to give (+)-
20 of 100% de. Reduction of (+)-20 with LiAlH4 gave
biphenanthrol (-)-2 with a slight loss of the axial
integrity (98% ee), which was ascribed to a tendency for
biphenanthrol 2 to racemize under ambient light expo-
sure (vide infra). To our surprise, tetraol 1 was found to
undergo far more rapid photoracemization. Thus, depro-
tection of biphenanthrol (-)-2 of 98% ee with BCl3 gave
the desired (-)-1 but its optical purity was only 42% ee
although considerable care was taken not to expose these
photosensitive compounds to light during the manipula-
tions. On the other hand, baseline resolution of racemic
1 could be achieved by HPLC on a preparative scale by
using a cellulose-derived chiral column (Daicel Chiralpak
AD), which gave several 10-mg yields of both the enan-
tiomers in up to 95% ee. It should be noted that a sample
of (-)-1 showed an [R]D value of -101.6° in methanol,
while its optical purity was estimated to be 95-92% ee
by HPLC analyses conducted before and after the rota-
tion measurement. Therefore, naturally occurring (-)-
blestriarene C, the specific rotation of which was reported
to be -16.7°,1a seems to have partially racemized during
the isolation from the plant.
(21) Irie, M.; Yoshida, K.; Hayashi, K. J . Phys. Chem. 1977, 81, 969.
(22) (a) Shi, Y.; Wan, P. Chem. Commun. 1997, 273. (b) Burnham,
K. S.; Schuster, G. B. J . Am. Chem. Soc. 1998, 120, 12619.
(23) Cavazza, M.; Zandomeneghi, M.; Ouchi, A.; Koga, Y. J . Am.
Chem. Soc. 1996, 118, 9990.
(24) (a) Zimmerman, H. E.; Crumrine, D. S. J . Am. Chem. Soc. 1972,
94, 498. (b) Te´treau, C.; Lavalette, D.; Cabaret, D.; Geraghty, N.;
Welvart, Z. Nouv. J . Chim. 1982, 6, 461. (c) Zhang, M.; Schuster, G.
B. J . Am. Chem. Soc. 1994, 116, 4852.
(25) Lantratova, O. B.; Kuz’min, V. A.; Prokof’ev, A. I.; Khudyakov,
I. V.; Pokrovskaya, I. E. Bull. Acad. Sci. USSR Div. Chem. Sci. 1981,
30, 1459.
(26) See also: (a) Yamamoto, K.; Kitsuki, T.; Okamoto, Y. Bull.
Chem. Soc. J pn. 1986, 59, 1269. (b) Yamamoto, K.; Yumioka, H.;
Okamoto, Y.; Chikamatsu, H. J . Chem. Soc., Chem. Commun. 1987,
168. (c) Nozaki, K.; Terakawa, T.; Takaya, H.; Hiyama, T. Angew.
Chem., Int. Ed. 1998, 37, 131.
Figure 1 shows a decrease in the optical purity of
tetraol 1 under fluorescent lamp illumination. The reac-
tion followed first-order kinetics, the apparent rate
constant krac under the conditions being 1.90 × 10-4 s-1
.
No side products were detected by HPLC and the
2102 J . Org. Chem., Vol. 68, No. 6, 2003

Synthesis and Absolute Stereochemistry of Blestriarene C
under kinetic control.29b-d,g,i In this respect, it is of
interest to note the diastereoselectivity in the cyclic
diester formation between a substituted diphenic acid
and the 2,3-dihydroxy groups of a properly protected R-D-
glucopyranose, which was studied in connection with the
synthesis of ellagitannins. Intramolecular Ullmann coup-
ling of two substituted benzoyl halves linked together
with the glucopyranose resulted in exclusive formation
of a cyclic diester of Sa chirality,29h while kinetic resolu-
tion of the racemic diphenic acid by esterification with
the glucopyranose gave the (Ra)-cyclic diester as a single
diastereomer.29g In our axial chirality recognition method,
both the intramolecular Ullmann coupling and the
kinetic esterification give a cyclic diester of the same
absolute stereochemistry,7,26 which qualifies the method
as a convenient and reliable way to determine the axial
chirality. Now that the X-ray crystal structure of such a
cyclic diester was obtained for the first time, conforma-
tional analyses of this kind of cyclic diesters 22-24 were
carried out by the ab initio molecular orbital method to
deduce the origin of the stereospecificity.
SCHEME 6 a
a
Reagents: (a) DMAP, NEt3, PhH; (b) LiAlH4, THF.
phenanthrol 2 with 1.0 equiv of (Ra)-1,1′-binaphthalene-
2,2′-dicarbonyl chloride in refluxing benzene-triethyl-
amine in the presence of DMAP picked up only one
enantiomer (Ra)-2 among the racemate to allow cycliza-
tion to give diastereomerically pure cyclic diester 21,
which should be Ra,Ra configuration. Reductive cleavage
of diester 21 with LiAlH4 gave dextrorotatory biphenan-
throl 2 of 95% ee. The incomplete preservation of enan-
tiomeric integrity should be ascribed to the photorace-
mization (vide supra). Thus, the absolute stereochemistry
of biphenanthrol 2 was unambiguously assigned to be
Ra-(+). This, combined with the fact that deprotection of
(-)-2 gave (-)-1 (vide supra), determined the absolute
stereochemistry of naturally occurring (-)-blestriarene
C to be Sa. This assignment was unambiguously con-
firmed by an X-ray crystallographic analysis of cyclic
diester 21. The ORTEP drawing of diester 21 clearly
showed the R chirality of the biphenanthrene axis,
referring to the R axis of the binaphthalene moiety (see
Figure S1 in Supporting Information).
The X-ray crystal structure of (Ra,Ra)-21 showed that
the two Aryl-CO2-Aryl moieties adopt a double-helix-
like conformation, a C2 symmetry axis passing through
the midpoints of the biaryl axes (Figure S1). Conforma-
tional analysis of diester (Ra,Ra)-22 at the HF/6-31G*
level by using Gaussian 9831 revealed that there are two
stable conformations in the same energy level (Figure 2).
Thus, one has a C2-symmetric structure similar to the
X-ray structure of (Ra,Ra)-21, except that the carbonyl
groups are a little more distorted out of the 12-membered
ring than those of (Ra,Ra)-21, as shown by comparison of
the dihedral angle η between the two (Table 1). The other
has an asymmetric structure, tilting the one carbonyl
Mech a n istic Con sid er a tion of th e Cyclic Diester
F or m a tion Meth od . The asymmetric intramolecular
coupling of two aryl halves held together by a chiral
tether is an efficient way to obtain nonracemic biaryl
compounds.27 An alternative method to this is the kinetic
resolution of racemic biaryls by cyclization with such a
bifunctional chiral tether molecule.28 These methods have
been employed for the synthesis of natural products,
taking advantage of an inherent chiral tether found in
the target molecule.29 Synthesis of biaryl-type chirality-
recognizing elements by using an artificial tether has also
been studied,30 since the axial chirality recognition
method had been developed in this laboratory.7,26 In these
reactions, it has often been claimed that the thermody-
namically less stable diastereomer preferentially forms
(29) (a) Damon, R. E.; Schlessinger, R. H.; Blount, J . F. J . Org.
Chem. 1976, 41, 3772. (b) Tomioka, K.; Ishiguro, T.; Iitaka, Y.; Koga,
K. Tetrahedron 1984, 40, 1303. (c) Tomioka, K.; Mizuguchi, H.;
Ishiguro, T.; Koga, K. Chem. Pharm. Bull. 1985, 33, 121. (d) Evans,
D. A.; Dinsmore, C. J .; Evrard, D. A.; DeVries, K. M. J . Am. Chem.
Soc. 1993, 115, 6426. (e) Feldman, K. S.; Sambandam, A. J . Org. Chem.
1995, 60, 8171. (f) Feldman, K. S.; Smith, R. S. J . Org. Chem. 1996,
61, 2606. (g) Itoh, T.; Chika, J .; Shirakami, S.; Ito, H.; Yoshida, T.;
Kubo, Y.; Uenishi, J . J . Org. Chem. 1996, 61, 3700. (h) Dai, D.; Martin,
O. R. J . Org. Chem. 1998, 63, 7628. (i) Carbonnelle, A.-C.; Zhu, J . Org.
Lett. 2000, 2, 3477.
(30) (a) Lipshutz, B. H.; Kayser, F.; Liu, Z.-P. Angew. Chem., Int.
Ed. Engl. 1994, 33, 1842. (b) Rawal, V. H.; Florjancic, A. S.; Singh, S.
P. Tetrahedron Lett. 1994, 35, 8985. (c) Mazaleyrat, J .-P.; Wakselman,
M. J . Org. Chem. 1996, 61, 2695. (d) Sugimura, T.; Yamada, H.; Inoue,
S.; Tai, A. Tetrahedron: Asymmetry 1997, 8, 649. (e) Harada, T.; Ueda,
S.; Tuyet, T. M. T.; Inoue, A.; Fujita, K.; Takeuchi, M.; Ogawa, N.;
Oku, A.; Shiro, M. Tetrahedron 1997, 53, 16663. (f) Lipshutz, B. H.;
Shin, Y.-J . Tetrahedron Lett. 1998, 39, 7017. (g) Rosini, C.; Superchi,
S.; Bianco, G.; Mecca, T. Chirality 2000, 12, 256. (h) Rajca, A.; Safronov,
A.; Rajca, S.; Wongsriratanakul, J . J . Am. Chem. Soc. 2000, 122, 3351.
(i) Spring, D. R.; Krishnan, S.; Schreiber, S. L. J . Am. Chem. Soc. 2000,
122, 5656. (j) Bandyopadhyaya, A. K.; Sangeetha, N. M.; Maitra, U. J .
Org. Chem. 2000, 65, 8239.
(27) Tomioka, K.; Ishiguro, T.; Koga, K. J . Chem. Soc., Chem.
Commun. 1979, 652.
(28) Itoh, T.; Chika, J . J . Org. Chem. 1995, 60, 4968.
J . Org. Chem, Vol. 68, No. 6, 2003 2103

Hattori et al.
TABLE 2. Tota l a n d Rela tive En er gies for Op tim ized
22-24a
conformation
Index
compd
E(Ra,Ra)
-1 386 347.11 -1 386 333.13 13.98
-1 386 349.51 16.38
-1 194 763.49 -1 194 749.57 13.92
E(Sa,Ra)
∆Eb
22
sym
asym
sym
asym
sym
asym
23
24
-1 194 765.79
-811 610.37
-811 613.31
16.22
-811 596.64 13.73
16.67
a
b
Units: kcal mol-1
.
Relative energy given by E(Sa,Ra) -
E(Ra,Ra).
and 16.38 kcal mol-1 lower in energy than the (Sa,Ra)-
counterpart, respectively (Table 2). The same tendency
was observed in the relative energies between two
diastereomers of diesters 23 and 24 estimated by the
same theoretical level calculations.32 Therefore, it will be
concluded that a thermodynamically stable diastereomer
preferentially forms in the axial chirality recognition
method.
F IGURE 2. Geometries of cyclic diesters (Ra,Ra)- and (Sa,Ra)-
22 optimized at the HF/6-31G* level. Hydrogen atoms are
omitted for clarity.
Con clu sion
Racemic blestriarene C (1) was synthesized and opti-
cally resolved by chiral HPLC or via diastereomeric
thiophosphoramides. Compound 1 and its 7,7′-diisopropyl
ether 2 were found to undergo unprecedentedly rapid
photoracemization even under ambient light exposure.
The axial chirality recognition method could be advan-
tageously utilized for the determination of the absolute
stereochemistries of these easily racemizing biaryls.
Further studies on the photoracemization mechanism are
in progress.
TABLE 1. Dih ed r a l An gles for Op tim ized 22-24
(Ra,Ra)-isomer
φb ηc
(Sa,Ra)-isomer
conformation
index
θa
(deg) (deg)
θa
φb
ηc
compd
(deg) (deg) (deg) (deg)
21d
22
sym
sym
asym
-76.8 -65.7 -43.1
-76.7 -70.5 -52.7 110.7 -86.1 -52.9
-68.3 -84.4 -44.5
-138.8
-76.3 -70.1 -51.7 112.3 -86.3 -52.7
-67.6 -84.3 -44.1
-140.6
-62.9 -57.9 -49.3 130.7 -97.4 -58.8
-57.3 -74.1 -42.9
-150.5
23
24
sym
asym
sym
asym
Exp er im en ta l Section
Gen er a l. Melting points were taken on a micro melting
point apparatus and are uncorrected. Specific rotations are
given in units of 10-1 deg cm2 g-1. Microanalyses were carried
out in the Microanalytical Laboratory of the Institute of
Multidisciplinary Research for Advanced Materials, Tohoku
University. 1H and 13C NMR spectra were measured with
tetramethylsilane as an internal standard and CDCl3 as a
solvent, unless otherwise noted. Silica gel (63-200 µm) was
used for analytical and preparative TLC (PLC) and for column
chromatography. Water- and air-sensitive reactions were
routinely carried out under nitrogen. Diethyl ether, THF, and
benzene were distilled from sodium diphenyl ketyl just before
use. Other solvents for experiments requiring anhydrous
conditions were purified by the usual methods. 4-Bromo-5-
methylbenzene-1,3-diol (6) was prepared according to the
literature procedure.34
a
b
Dihedral angle between C2-C3 and C4-C5 bonds. Dihedral
angle between C8-C9 and C10-C11 bonds. c Dihedral angle be-
tween C7dO (C12dO) and C8-C9 (C10-C11) bonds. X-ray data.
d
group toward the pseudoequatorial orientation of the 12-
membered ring. The preference of the symmetric struc-
ture in crystals may be attributed to some packing forces.
On the other hand, a similar calculation of the (Sa,Ra)-
counterpart gave a unique structure, where the two
aromatic planes of each Aryl-CO2-Aryl moiety bent to
form a v-shape and the two v-shape moieties were
arranged upside down as shown in Figure 2. A C2
symmetry axis passed through the midpoints of the biaryl
axes in the same way as the symmetric (Ra,Ra)-isomer.
The symmetric and asymmetric (Ra,Ra)-isomers lay 13.98
4-Br om o-3-m et h oxy-5-m et h ylp h en yl Tolu en e-p -su l-
fon a te (7). A mixture of dihydroxybenzene 6 (5.74 g, 28.3
mmol), K2CO3 (25.4 g, 184 mmol), and dry acetone (420 mL)
was stirred at room temperature for 30 min. To the mixture
was added TsCl (5.40 g, 28.3 mmol) and the mixture was
heated under reflux. After 23 h, iodomethane (10.9 g, 76.8
(31) Frisch, M. J .; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J . R.; Zakrzewski, V. G.; Montgomery, J . A.,
J r.; Stratmann, R. E.; Burant, J . C.; Dapprich, S.; Millam, J . M.;
Daniels, A. D.; Kudin, K. N.; Strain, M. C.; Farkas, O.; Tomasi, J .;
Barone, V.; Cossi, M.; Cammi, R.; Mennucci, B.; Pomelli, C.; Adamo,
C.; Clifford, S.; Ochterski, J .; Petersson, G. A.; Ayala, P. Y.; Cui, Q.;
Morokuma, K.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.;
Foresman, J . B.; Cioslowski, J .; Ortiz, J . V.; Stefanov, B. B.; Liu, G.;
Liashenko, A.; Piskorz, P.; Komaromi, I.; Gomperts, R.; Martin, R. L.;
Fox, D. J .; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.;
Gonzalez, C.; Challacombe, M.; Gill, P. M. W.; J ohnson, B. G.; Chen,
W.; Wong, M. W.; Andres, J . L.; Head-Gordon, M.; Replogle, E. S.;
Pople, J . A. Gaussian 98, revision A.10; Gaussian, Inc.: Pittsburgh,
PA, 1998.
(32) Conformational analyses of cyclic diesters 22-24 by
MOPAC2000 (ref 33) with use of AM1 and PM3 Hamiltonians gave
similar optimized geometries to those obtained by the ab initio cal-
culations. However, the relative energies between the two diastereo-
mers estimated by these Hamiltonians were opposite to each other in
every diester (see Supporting Information).
(33) Stewart, J . J . P. MOPAC2000; Fujitsu Ltd.: Tokyo, J apan,
1999.
(34) Kajigaeshi, S.; Kakinami, T.; Okamoto, T.; Nakamura, H.;
Fujikawa, M. Bull. Chem. Soc. J pn. 1987, 60, 4187.
2104 J . Org. Chem., Vol. 68, No. 6, 2003

Synthesis and Absolute Stereochemistry of Blestriarene C
mmol) was added and the mixture was refluxed for a further
28 h. After cooling, the resulting precipitate was filtered off
on a kieselguhr plug and the filtrate was evaporated. The
residue was chromatographed on silica gel with hexane-ethyl
acetate (30:1) as the eluent to give tosylate 7 (8.86 g, 84%) as
crystals, mp 72.9-74.6 °C; IR (KBr) 1604 cm-1; 1H NMR (500
MHz) δ 2.32 (3H, s), 2.46 (3H, s), 3.74 (3H, s), 6.37 (1H, d, J
) 2.5 Hz), 6.52 (1H, d, J ) 2.5 Hz), 7.33 (2H, d, J ) 8.3 Hz),
7.73 (2H, d, J ) 8.3 Hz); 13C NMR (125 MHz) δ 21.7, 23.3,
56.4, 103.9, 112.4, 116.2, 128.6, 129.7, 132.2, 140.4, 145.5,
148.8, 156.4. Anal. Calcd for C15H15BrO4S: C, 48.53; H, 4.07;
Br, 21.52; S, 8.64. Found: C, 48.26; H, 4.02; Br, 21.77; S, 8.78.
diethyl ether and then acidified with concentrated HCl. The
mixture was extracted with diethyl ether and the extract was
washed with brine, dried over MgSO4, and evaporated. The
residue was crystallized from ethyl acetate to give acid 12 (9.47
g, 82%) as crystals, mp 171-173 °C; IR (KBr) 3435, 1674 cm-1
;
1H NMR (400 MHz, acetone-d6) δ 3.99 (3H, s), 7.07 (1H, dd, J
) 8.9, 3.0 Hz), 7.11 (1H, d, J ) 8.9 Hz), 7.43 (1H, d, J ) 3.0
Hz), 8.41 (1H, s), 11.05 (1H, br); 13C NMR (100 MHz) δ 57.2,
115.0, 118.8, 121.0, 121.9, 152.2, 153.8, 169.2. Anal. Calcd for
C8H8O4: C, 57.14; H, 4.80. Found: C, 57.02; H, 4.91.
Isop r op yl 5-Isop r op oxy-2-m eth oxyben zoa te (13). A
mixture of acid 12 (6.21 g, 36.9 mmol), K2CO3 (20.4 g, 148
mmol), and dry DMF (175 mL) was stirred at room tempera-
ture for 15 min. To the mixture was added 2-bromopropane
(18.2 g, 148 mmol) and the resulting mixture was refluxed for
27 h. To the cooled mixture was added KI (610 mg, 3.67 mmol)
and the mixture was stirred at room temperature for 20 h to
complete the reaction. The mixture was cooled in an ice bath
and quenched with 2 M HCl. The resulting mixture was
extracted with diethyl ether and the extract was washed
successively with 2 M Na2CO3 and water, dried over MgSO4,
and evaporated. The residue was chromatographed on silica
gel with hexane-ethyl acetate (5:1) as the eluent to give
4-Br om o-3-m eth oxy-5-m eth ylp h en ol (8). Tosylate 7 (8.85
g, 23.8 mmol) was boiled with KOH (3.00 g) in a mixture of
ethanol (150 mL) and water (150 mL) for 2 h. After the ethanol
had been evaporated, the aqueous solution was neutralized
with acetic acid and the resulting mixture was extracted with
diethyl ether. The organic layer was washed with 1 M NaHCO3
and extracted with 5% aqueous KOH. The extract was acidified
with 6 M HCl and the liberated phenol was extracted with
diethyl ether. The extract was washed with brine, dried over
MgSO4, and evaporated. The residue was purified by column
chromatography on silica gel with hexane-ethyl acetate (4:1)
as the eluent to give phenol 8 (4.88 g, 94%) as crystals, mp
isopropyl ester 13 (9.14 g, 98%) as an oil, IR (neat) 1728 cm-1
;
1H NMR (250 MHz) δ 1.31 (6H, d, J ) 6.1 Hz), 1.35 (6H, d, J
) 6.3 Hz), 3.84 (3H, s), 4.46 (1H, sept, J ) 6.1 Hz), 5.24 (1H,
sept, J ) 6.3 Hz), 6.88 (1H, d, J ) 9.1 Hz), 6.99 (1H, dd, J )
9.1, 3.1 Hz), 7.31 (1H, d, J ) 3.1 Hz); 13C NMR (100 MHz) δ
21.9, 22.0, 56.8, 68.1, 71.0, 113.8, 119.0, 120.9, 121.7, 151.1,
153.4, 165.5. Anal. Calcd for C14H20O4: C, 66.65; H, 7.99.
Found: C, 66.37; H, 7.93.
119-121 °C; IR (KBr) 3288 cm-1 1H NMR (400 MHz) δ
;
2.34 (3H, s), 3.84 (3H, s), 4.97 (1H, s), 6.30 (1H, d, J ) 2.7
Hz), 6.36 (1H, d, J ) 2.7 Hz); 13C NMR (100 MHz) δ 23.2,
56.3, 97.8, 104.9, 109.7, 140.1, 155.1, 156.7. Anal. Calcd for
C8H9BrO2: C, 44.27; H, 4.18; Br, 36.81. Found: C, 44.11; H,
4.15; Br, 36.77.
2-Br om o-1-m eth oxy-5-m eth oxym eth oxy-3-m eth ylben -
zen e (9). A mixture of phenol 8 (8.68 g, 40.0 mmol), K2CO3
(13.8 g, 99.9 mmol), and dry acetone was stirred at room
temperature for 20 min. To the mixture was added chloro-
(methoxy)methane (6.44 g, 80.0 mmol) and the mixture was
refluxed for 17 h. The mixture was passed through a kiesel-
guhr plug and the solvent was evaporated. The residue was
dissolved by the addition of water and diethyl ether, and the
two layers were separated. The aqueous layer was extracted
with diethyl ether and the combined organic layer was washed
with water, dried over MgSO4, and evaporated. The residue
was chromatographed on silica gel with hexane-ethyl acetate
(12:1) as the eluent to give MOM ether 9 (8.64 g, 83%) as
crystals, mp 33.4-35.1 °C; 1H NMR (250 MHz) δ 2.38 (3H, s),
3.48, (3H, s), 3.86 (3H, s), 5.15 (2H, s), 6.48 (1H, d, J ) 2.7
Hz), 6.59 (1H, d, J ) 2.7 Hz); 13C NMR (100 MHz) δ 23.4, 56.0,
56.2, 94.5, 98.8, 106.3, 110.0, 139.9, 156.6, 156.9. Anal. Calcd
for C10H13BrO3: C, 46.00; H, 5.02; Br, 30.60. Found: C, 45.71;
H, 4.85; Br, 30.75.
2,6-Di-ter t-bu tyl-4-m eth oxyph en yl 5-Isopr opoxy-2-m eth -
oxyben zoa te (4). Ester 13 (9.05 g, 35.9 mmol) was hydrolyzed
by boiling with KOH (6.01 g) in a mixture of ethanol (100 mL)
and water (20 mL) for 3 h. After the ethanol had been
evaporated, the aqueous solution was washed with diethyl
ether and acidified with 2 M HCl to liberate the free acid,
which was extracted with diethyl ether. The extract was
washed with brine, dried over MgSO4, and evaporated to give
5-isopropoxy-2-methoxybenzoic acid35 as an oil (7.47 g), IR
(neat) 3261, 1734 cm-1; 1H NMR (400 MHz) δ 1.32 (6H, d, J )
6.0 Hz), 4.04 (3H, s), 4.53 (1H, sept, J ) 6.0 Hz), 6.99 (1H, d,
J ) 9.0 Hz), 7.10 (1H, dd, J ) 9.0, 3.2 Hz), 7.68 (1H, d, J )
3.2 Hz), 11.02 (1H, br); 13C NMR (100 MHz) δ 21.8, 57.1, 70.9,
113.1, 117.9, 118.9, 123.8, 152.1, 152.5, 165.4. The acid (1.03
g) was treated with BHAOH (1.17 g, 4.95 mmol) in TFAA (4.2
mL) at room temperature for 2 d. The mixture was cooled in
an ice bath, made basic with 2 M NaOH, and then extracted
with diethyl ether. The extract was washed successively with
2 M NaOH and water, dried over MgSO4, and evaporated. The
residue was purified by column chromatography on silica gel
with hexane-ethyl acetate (5:1 to 7:1) as the eluent to give
BHA ester 4 (1.61 g, 76%) as crystals, mp 121-123 °C; IR
(KBr) 1743 cm-1; 1H NMR (500 MHz) δ 1.33 (18H, s), 1.34 (6H,
d, J ) 6.1 Hz), 3.81 (3H, s), 3.86 (3H, s), 4.49 (1H, sept, J )
6.1 Hz), 6.89 (2H, s), 6.98 (1H, d, J ) 9.1 Hz), 7.11 (1H, dd, J
) 9.1, 3.2 Hz), 7.66 (1H, d, J ) 3.2 Hz); 13C NMR (125 MHz)
δ 22.0, 31.3, 35.6, 55.3, 56.5, 71.0, 111.5, 114.2, 119.7, 120.0,
123.0, 141.9, 143.7, 151.1, 154.6, 156.2, 166.1. Anal. Calcd for
Meth yl 2-Meth oxy-5-(tolu n en e-p-su lfon yloxy)ben zoa te
(11). A mixture of dihydroxybenzoate 10 (16.0 g, 95.2 mmol),
K2CO3 (79.8 g, 577 mmol), and dry acetone (1.0 L) was stirred
at room temperature for 30 min. To the mixture was added
TsCl (18.3 g, 96.0 mmol) portionwise over a period of 2 h and
the mixture was refluxed for 19 h. To this mixture was added
iodomethane (36.5 g, 257 mmol) and the resulting mixture was
refluxed for
a further 20 h. After cooling, the resulting
precipitate was filtered off on a kieselguhr plug and the filtrate
was evaporated. The residue was chromatographed on silica
gel with hexane-ethyl acetate (2:1) as the eluent to give ester
11 (25.6 g, 80%) as crystals, mp 80.9-82.1 °C; IR (KBr) 1722
C
26H36O5: C, 72.87; H, 8.47. Found: C, 72.63; H, 8.45.
2,6-Di-ter t-b u t yl-4-m et h oxyp h en yl 4-Isop r op oxy-2′-
cm-1 1H NMR (250 MHz) δ 2.45 (3H, s), 3.84 (3H, s), 3.87
;
m et h oxy-4′-m et h oxym et h oxy-6′-m et h ylb ip h en yl-2-ca r -
boxyla te (14). The Grignard reagent 5 was prepared from
bromide 9 (3.27 g, 12.5 mmol) and magnesium turnings (607
mg, 25.0 mmol) in THF (25 mL) as usual.8b The solvent was
removed under reduced pressure and the residue was dissolved
by addition of benzene (20 mL). The Grignard solution was
added dropwise to a solution of ester 4 (2.98 g, 6.95 mmol) in
benzene (25 mL) over a period of 30 min and the mixture was
(3H, s), 6.86 (1H, d, J ) 9.0 Hz), 7.10 (1H, dd, J ) 9.0, 3.0
Hz), 7.31 (2H, d, J ) 7.2 Hz), 7.39 (1H, d, J ) 3.0 Hz), 7.71
(2H, d, J ) 7.2 Hz); 13C NMR (125 MHz) δ 21.6, 52.1, 56.3,
112.7, 120.5, 125.5, 127.2, 128.4, 129.7, 131.8, 142.0, 145.5,
157.7, 165.0. Anal. Calcd for C16H16O6S: C, 57.13; H, 4.79; S,
9.53. Found: C, 57.10; H, 4.91; S, 9.48.
5-Hyd r oxy-2-m eth oxyben zoic Acid (12). Ester 11 (23.1
g, 68.7 mmol) was boiled with KOH (23.1 g) in a mixture of
ethanol (135 mL) and water (30 mL) for 4 h. After the ethanol
had been evaporated, the aqueous solution was washed with
(35) Hughes, A. B.; Sargent, M. V. J . Chem. Soc., Perkin Trans. 1
1989, 1787.
J . Org. Chem, Vol. 68, No. 6, 2003 2105

Hattori et al.
refluxed for 24 h. After cooling, the mixture was quenched with
saturated aqueous NH4Cl and the resulting mixture was
extracted with diethyl ether. The extract was washed with
water, dried over MgSO4, and evaporated. The residue was
chromatographed on silica gel with hexane-ethyl acetate
(6:1) as the eluent to give biphenyl 14 (3.65 g, 91%) as crystals,
Tf2O (1.90 g, 6.73 mmol) at -78 °C and the mixture was stirred
at this temperature for 1.5 h. The reaction was quenched by
successive addition of water and 1 M HCl and the mixture
was extracted with diethyl ether. The extract was washed with
water, dried over MgSO4, and evaporated. The residue was
chromatographed on silica gel with hexane-ethyl acetate
(6:1) as the eluent to give triflate 18 (2.04 g, 96%) as crystals,
1
mp 151-153 °C; IR (KBr) 1749 cm-1; H NMR (400 MHz) δ
1
mp 83.6-85.0 °C; IR (KBr) 1620 cm-1; H NMR (400 MHz) δ
1.28 (9H, s), 1.30 (9H, s), 1.43 (6H, d, J ) 6.1 Hz), 1.87 (3H,
s), 3.48 (3H, s), 3.54 (3H, s), 3.74 (3H, s), 4.65 (1H, sept, J )
6.1 Hz), 5.11-5.15 (2H, m), 6.36 (1H, d, J ) 2.2 Hz), 6.46 (1H,
d, J ) 2.2 Hz), 6.80-6.82 (2H, m), 7.09 (1H, d, J ) 8.4 Hz),
7.18 (1H, dd, J ) 8.4, 2.7 Hz), 8.00 (1H, d, J ) 2.7 Hz); 13C
NMR (100 MHz) δ 20.3, 22.0, 31.4, 31.5, 35.5, 35.6, 55.2, 55.2,
56.0, 70.1, 94.5, 96.9, 108.3, 111.5, 111.7, 117.6, 121.0, 124.0,
129.7, 133.4, 133.9, 137.3, 141.6, 143.5, 143.7, 156.2, 156.9,
157.1, 157.4, 164.9. Anal. Calcd for C35H46O7: C, 72.64; H, 8.01.
Found: C, 72.44; H, 8.06.
1.44 (6H, d, J ) 6.1 Hz), 3.55, (3H, s), 4.10 (3H, s), 4.76 (1H,
sept, J ) 6.1 Hz), 5.31 (2H, s), 6.88 (1H, d, J ) 2.4 Hz), 7.11
(1H, d, J ) 2.4 Hz), 7.29 (1H, dd, J ) 9.5, 2.8 Hz), 7.46 (1H,
d, J ) 2.8 Hz), 7.61 (1H, s), 9.50 (1H, d, J ) 9.5 Hz); 13C NMR
(100 MHz) δ 21.9, 55.8, 56.2, 70.1, 94.6, 101.2, 103.4, 105.1,
115.9, 117.1, 118.3, 119.0, 126.2, 126.3, 129.9, 132.4, 144.7,
155.6, 155.9, 159.0. Anal. Calcd for C21H21F3O7S: C, 53.16; H,
4.46; S, 6.76. Found: C, 53.04; H, 4.64; S, 6.59.
7-Isop r op oxy-4-m eth oxy-2-(m eth oxym eth oxy)p h en a n -
th r en e (19). A mixture of triflate 18 (2.07 g, 4.36 mmol),
triethylamine (1.37 g, 13.5 mmol), palladium acetate (19.6 mg,
87.3 µmol), triphenylphosphine (57.2 mg, 218 µmol), and dry
DMF (70 mL) was stirred at room temperature for 10 min. To
the mixture was added formic acid (385 mg, 8.36 mmol) and
the resulting mixture was heated at 65 °C for 16.5 h. After
being cooled in an ice bath, the mixture was quenched by
successive addition of water and 2 M HCl. The mixture was
extracted with diethyl ether and the extract was washed with
water, dried over MgSO4, and evaporated. The residue was
chromatographed on silica gel with hexane-ethyl acetate (10:
1) as the eluent to give phenanthrene 19 (1.36 g, 96%) as
crystals, mp 50.1-52.7 °C; 1H NMR (400 MHz) δ 1.42 (6H, d,
J ) 6.1 Hz), 3.55 (3H, s), 4.10 (3H, s), 4.73 (1H, sept, J ) 6.1
Hz), 5.31 (2H, s), 6.85 (1H, d, J ) 2.4 Hz), 7.09 (1H, d, J ) 2.4
Hz), 7.21 (1H, dd, J ) 9.2, 2.8 Hz), 7.24 (1H, d, J ) 2.8 Hz),
7.58 (1H, d, J ) 8.9 Hz), 7.61 (1H, d, J ) 8.9 Hz), 9.44 (1H, d,
J ) 9.2 Hz); 13C NMR (100 MHz) δ 22.1, 55.6, 56.1, 69.8, 94.6,
100.0, 104.9, 111.2, 116.5, 117.6, 124.6, 127.3, 127.9, 129.3,
133.5, 134.2, 154.9, 155.0, 159.2. Anal. Calcd for C20H22O4: C,
73.60; H, 6.79. Found: C, 73.63; H, 6.79.
7-Isop r op oxy-4-m eth oxy-2-(m eth oxym eth oxy)p h en a n -
th r en -9-ol (15). To an ice-cold solution of biphenyl 14 (3.00
g, 5.18 mmol) in a mixture of THF (20 mL) and dry HMPA
(20 mL) was added dropwise lithium diethylamide, which had
been prepared from diethylamine (1.70 g, 23.2 mmol) and
butyllithium (1.59 M in hexane; 13.4 mL, 21.3 mmol) in THF
(12 mL). After being stirred at 0 °C for 2 h, the mixture was
quenched by successive addition of water and 1 M HCl. The
resulting mixture was extracted with diethyl ether and the
extract was washed with water, dried over MgSO4, and
evaporated. The residue was chromatographed on silica gel
with hexane-ethyl acetate (3:1) as the eluent to give phenan-
throl 15 (1.56 g, 88%) as an amorphous solid, IR (KBr) 3332
cm-1 1H NMR (400 MHz) δ 1.42 (6H, d, J ) 6.1 Hz), 3.56,
;
(3H, s), 4.06 (3H, s), 4.79 (1H, sept, J ) 6.1 Hz), 5.29 (2H, s),
5.74 (1H, s), 6.70 (1H, d, J ) 2.4 Hz), 6.84 (1H, s), 6.90 (1H, d,
J ) 2.4 Hz), 7.24 (1H, dd, J ) 9.4, 2.9 Hz), 7.72 (1H, d, J )
2.9 Hz), 9.44 (1H, d, J ) 9.4 Hz); 13C NMR (125 MHz) δ 22.1,
55.6, 56.1, 70.0, 94.4, 97.9, 103.2, 105.2, 106.8, 112.7, 118.3,
126.0, 126.5, 129.4, 134.7, 149.9, 155.0, 155.1, 159.2.
2,6-Di-ter t-bu tyl-4-m eth oxyp h en yl Bip h en yl-2-ca r box-
yla te (16). This compound was prepared by the same proce-
dure as used for the preparation of similar biphenyls before.8c
2,6-Di-tert-butyl-4-methoxyphenyl 2-methoxybenzoate8l (372
mg, 1.00 mmol) was treated with 2.5 equiv of phenylmagne-
sium bromide in a mixture of diethyl ether (3.5 mL) and
benzene (7.0 mL) at room temperature for 24 h. After the usual
workup, the crude product was purified by PLC with hexane-
ethyl acetate (9:1) as the developer to give biphenyl 16 (414
7-Isop r op oxy-4-m eth oxyp h en a n th r en -2-ol (3). A mix-
ture of phenanthrene 19 (2.92 g, 8.95 mmol), 1.5 M HCl (5.97
mL, 8.96 mmol), and methanol (70 mL) was heated at 60 °C
for 7 h. After the methanol had been evaporated, the residue
was dissolved by the addition of water and diethyl ether. The
aqueous layer was extracted with diethyl ether and the
combined organic layer was washed with water, dried over
MgSO4, and evaporated. The residue was purified by column
chromatography on silica gel with hexane-ethyl acetate (2:1)
as the eluent to give phenanthrol 3 (2.36 g, 93%) as crystals,
mg, 99%) as crystals, mp 193-194 °C; IR (KBr) 1745 cm-1
;
1H NMR (400 MHz) δ 1.30 (18H, s), 3.75 (3H, s), 6.82 (2H, s),
7.21-7.31 (5H, m), 7.35 (1H, dd, J ) 7.6, 1.2 Hz), 7.56 (1H,
td, J ) 7.6, 1.2 Hz), 7.63 (1H, td, J ) 7.6, 1.2 Hz), 8.45 (1H,
dd, J ) 7.6, 1.2 Hz); 13C NMR (100 MHz) δ 31.5, 35.6, 55.2,
111.6, 119.6, 126.8, 127.3, 127.6, 128.6, 131.4, 132.2, 132.3,
141.6, 141.7, 143.6, 146.2, 156.2, 165.5. Anal. Calcd for
mp 112-114 °C; IR (KBr) 3350 cm-1 1H NMR (400 MHz,
;
CD2Cl2) δ 1.40 (6H, d, J ) 6.1 Hz), 4.08 (3H, s), 4.73 (1H, sept,
J ) 6.1 Hz), 5.17 (1H, s), 6.74 (1H, d, J ) 2.5 Hz), 6.86 (1H, d,
J ) 2.5 Hz), 7.18 (1H, dd, J ) 9.4, 2.8 Hz), 7.23 (1H, d, J )
2.8 Hz), 7.52 (1H, d, J ) 8.8 Hz), 7.60 (1H, d, J ) 8.8 Hz),
9.41 (1H, d, J ) 9.4 Hz); 13C NMR (100 MHz) δ 22.1, 55.6,
70.2, 99.0, 104.8, 111.7, 115.5, 117.7, 124.8, 126.8, 128.0, 129.2,
133.2, 134.4, 153.3, 154.7, 159.5. Anal. Calcd for C18H18O3: C,
76.57; H, 6.43. Found: C, 76.49; H, 6.52.
C
28H32O3: C, 80.73; H, 7.74. Found: C, 80.80; H, 7.68.
N,N-Dieth ylbip h en yl-2-ca r boxa m id e (17). This com-
pound was prepared by a similar procedure to that used for
the preparation of phenanthrol 15. Biphenyl 16 (212 mg, 509
µmol) was treated with 4.0 equiv of lithium diethylamide in a
mixture of THF (3.0 mL) and HMPA (1.5 mL) at 0 °C for 2 h.
After the workup, the crude product was chromatographed on
silica gel with hexane-ethyl acetate (5:1) as the eluent to give
7,7′-Diisop r op oxy-4,4′-d im eth oxy-1,1′-bip h en a n th r en e-
2,2′-d iol (2). A mixture of Cu(NO3)2‚3H2O (2.72 g, 11.3 mmol),
1-phenylethylamine (4.08 g, 33.7 mmol), and dry methanol (35
mL) was stirred at room temperature for 1 h. To the mixture
was added dropwise a solution of phenanthrol 3 (2.12 g, 7.51
mmol) in methanol (55 mL) over a period of 2 h and the
resulting mixture was stirred for a further 2 h. The mixture
was cooled in an ice bath and quenched with 2 M HCl. The
resulting mixture was extracted with ethyl acetate and the
extract was washed with water, dried over MgSO4, and
evaporated. The residue was crystallized from ethanol to give
biphenanthrol 2 (1.95 g, 92%) as crystals, mp 141-143 °C; IR
amide 17 (46.4 mg, 36%) as an oil, IR (neat) 1627 cm-1 1H
;
NMR (400 MHz) δ 0.73 (3H, t, J ) 7.2 Hz), 0.89 (3H, t, J )
7.2 Hz), 2.61-2.68 (1H, m), 2.91-3.02 (2H, m), 3.69-3.79 (1H,
m), 7.32-7.48 (9H, m); 13C NMR (100 MHz) δ 11.9, 13.3, 38.4,
42.2, 127.0, 127.5, 127.5, 128.2, 128.8, 128.9, 129.4, 136.4,
138.4, 139.8, 170.4. Anal. Calcd for C17H19NO: C, 80.60; H,
7.56; N, 5.53. Found: C, 80.33; H, 7.57; N, 5.38.
7-Isop r op oxy-4-m eth oxy-2-(m eth oxym eth oxy)p h en a n -
th r en -9-yl Tr iflu or om eth a n esu lfon a te (18). To a mixture
of phenanthrol 15 (1.54 g, 4.50 mmol), triethylamine (1.37 g,
13.5 mmol), and dichloromethane (15 mL) was added dropwise
1
(KBr) 3519 cm-1; H NMR (400 MHz) δ 1.39 (6H, d, J ) 6.1
Hz), 1.41 (6H, d, J ) 6.1 Hz), 4.22 (6H, s), 4.73 (2H, sept, J )
6.1 Hz), 5.08 (2H, s), 7.04 (2H, s), 7.09 (2H, d, J ) 9.1 Hz),
2106 J . Org. Chem., Vol. 68, No. 6, 2003

Synthesis and Absolute Stereochemistry of Blestriarene C
7.19 (2H, d, J ) 2.8 Hz), 7.27 (2H, dd, J ) 9.4, 2.8 Hz), 7.46
(2H, d, J ) 9.1 Hz), 9.55 (2H, d, J ) 9.4 Hz); 13C NMR (100
MHz) δ 22.1, 22.1, 55.9, 69.9, 98.5, 105.8, 111.3, 116.7, 118.3,
123.8, 124.9, 129.2, 129.5, 133.2, 133.8, 153.2, 155.2, 160.6.
Anal. Calcd for C36H34O6: C, 76.85; H, 6.09. Found: C, 76.57;
H, 6.10.
extracted with ethyl acetate. The extract was washed succes-
sively with 0.5 M HCl and water, dried over MgSO4, and
evaporated. The residue was purified by column chromatog-
raphy on silica gel with hexane-ethyl acetate (1:1) as the
eluent to give levorotatory biphenanthrol 2 (21.3 mg, 95%) as
crystals, [R]30 -5.22 (c 3.95, CHCl3). The spectral data of the
D
sample were identical with those of the racemate (vide supra).
The optical purity of the sample was determined to be 98% ee
by HPLC on a Daicel Chiralpak AD with hexane-ethanol (1:
1) as the eluent.
4,4′-Dim eth oxy-1,1′-biph en an th r en e-2,2′,7,7′-tetr aol (1).
To an ice-cold solution of biphenanthrol 2 (84.4 mg, 150 µmol)
in dichloromethane (10 mL) was added dropwise BCl3 (1.0 M
in pentane; 750 µL, 750 µmol) and the mixture was stirred at
0 °C for 2 h. The reaction was quenched with water and the
mixture was extracted with ethyl acetate. The extract was
washed with water, dried over MgSO4, and evaporated. The
residue was purified by column chromatography on silica gel
with hexane-ethyl acetate (1:2) as the eluent to give tetraol
1 (69.7 mg, 97%) as crystals. Spectral data of the sample were
identical with those of blestriarene C reported in the literature.1a
(Ra ,R)-(-)- a n d (Sa ,R)-(+)-N-(1-P h en yleth yl)-7,7′-d i-
isop r op oxy-4,4′-d im e t h oxy-1,1′-b ip h e n a n t h r e n e -2,2′-
d iylth iop h osp h or a m id e (20). To an ice-cold solution of
thiophosphoryl chloride (115 mg, 679 µmol) in dry pyridine
(6.0 mL) was added (R)-(+)-1-phenylethylamine (164 mg, 679
µmol) and the solution was allowed to warm to room temper-
ature. To the solution was added biphenanthrol 2 (322 mg,
572 µmol) and the mixture was refluxed for 6 h. The reaction
was quenched with 10% H2SO4 and the mixture was extracted
with ethyl acetate. The extract was washed successively with
10% H2SO4 and water, dried over MgSO4, and evaporated. The
residue was chromatographed on silica gel with hexane-ethyl
acetate (4:1) as the eluent to give diastereomeric phosphora-
(Sa )-(-)-4,4′-Dim et h oxy-1,1′-b ip h en a n t h r en e-2,2′,7,7′-
tetr a ol (1). Nonracemic tetraol (-)-1 was obtained from
biphenanthrol (-)-2 of 98% ee by the same procedure as used
for the preparation of racemic 1. Thus, biphenanthrol (-)-2
(25.1 mg, 44.6 µmol) was treated with BCl3 (1.0 M in pentane;
233 µL, 233 µmol) in dichloromethane (2.0 mL) at 0 °C for 2
h. After workup, the crude product was purified by PLC with
hexane-ethyl acetate (2:3) as the developer to give tetraol
(-)-1 (20.3 mg, 95%) as crystals, the spectral data of which
were identical with those of the racemate. The optical purity
of the sample was determined to be 42% ee by HPLC on a
Daicel Chiralpak AD with hexane-ethanol (1:1) as the eluent.
Ch ir a l HP LC Sep a r a tion of 1. Racemic tetraol 1 (151 mg)
was dissolved in ethanol (20 mL) and a 14th part each of the
solution was injected into the preparative HPLC apparatus
equipped with a Daicel Chiralpak AD column (250 mm × 20
mm i.d.) with hexane-ethanol (1:1) as the eluent. Because of
the rapid photoracemization, the optical purity of the sample
used for the optical rotation measurement was estimated by
HPLC analyses conducted before and after the rotation
measurement.
mides 20 (265 mg, 62%) as crystals. Anal. Calcd for C44H42
-
NO6PS: C, 71.05; H, 5.69; N, 1.88; S, 4.31. Found: C, 71.04;
H, 5.88; N, 1.88; S, 4.29. The diastereomeric mixture of 20 (190
mg) was separated into diastereomerically pure (-)-20 (37.9
mg, 20%) and (+)-enriched 20 (152 mg) by preparative HPLC
on a YMC silica gel column (S-5 120A SIL; 250 mm × 20 mm
i.d.) with hexane-ethyl acetate (9:1) as the eluent. The latter
was crystallized from a mixture of hexane (5.0 mL), benzene
(1.2 mL), and ethanol (1.2 mL) to give diastereomerically pure
(+)-20 (68.3 mg, 36%).
(Ra )-(+)-1: as the first-eluted fraction in total yield of 68.3
mg (94% ee), [R]29 +98.3 (c 0.565, MeOH) for the sample of
D
94-92% ee.
(Sa )-(-)-1: as the second-eluted fraction in total yield of 66.7
mg (95% ee), [R]28 -101.6 (c 0.525, MeOH) for the sample of
D
95-92% ee {lit.1a [R]20 -16.7}.
D
Mea su r em en t of P h otor a cem iza tion of Bip h en a n -
th r en es 1 a n d 2. A solution of a nonracemic biphenanthrene
(120 µM in ethanol) in a quartz cuvette (10 × 10 mm) was
placed 15 cm behind a 18 W fluorescent lamp (Hitachi, FL20SS
N/18-B) at 22 °C under air and a decrease in the enantiomeric
purity of the sample was monitored by HPLC.
(-)-20: mp 162-164 °C; [R]28 -192 (c 0.69, CHCl3); IR
D
(KBr) 3393, 1015 cm-1; 1H NMR (400 MHz) δ 1.40-1.43 (12H,
m), 1.50 (3H, d, J ) 6.8 Hz), 3.78 (1H, dd, J ) 11.7, 10.6 Hz),
3.81 (3H, s), 4.24 (3H, s), 4.36-4.47 (1H, m), 4.73 (1H, sept, J
) 6.2 Hz), 4.74 (1H, sept, J ) 6.2 Hz), 6.81 (1H, s), 7.06-7.30
(12H, m), 7.36 (1H, d, J ) 9.1 Hz), 7.42 (1H, d, J ) 9.1 Hz),
9.56 (1H, d, J ) 9.5 Hz), 9.61 (1H, d, J ) 9.5 Hz); 13C NMR
(100 MHz) δ 22.1, 22.2, 22.2, 26.2, 26.2, 53.2, 55.7, 56.3, 69.9,
69.9, 102.6, 103.3, 110.8, 115.8, 115.8, 118.1, 118.2, 119.3,
119.7, 119.9, 124.3, 124.5, 125.7, 125.9, 126.1, 127.3, 128.1,
128.3, 128.6, 130.2, 130.3, 132.7, 133.9, 133.9, 144.0, 144.0,
146.2, 146.3, 147.5, 147.7, 155.9, 156.0, 159.0, 159.4.
(Ra,Ra)-(+)-3,10-Diisop r op oxy-13,32-d im eth oxyd in a p h -
t h o [2 ,1 -h :1 ′,2 ′-j ]d i p h e n a n t h r o [2 ,1 -b :1 ′,2 ′-d ][1 ,6 ]-
d ioxa cyclod od ecin -16,29-d ion e (21). (Ra)-1,1′-Binaphtha-
lene-2,2′-dicarboxylic acid36 (343 mg, 1.00 mmol) was boiled
in thionyl dichloride (10 mL) for 4 h and then volatiles were
removed under reduced pressure to give the acid chloride,
which was dissolved in benzene (50 mL). Also prepared was a
solution of racemic biphenanthrol 2 (563 mg, 1.00 mmol) in
benzene (50 mL). The two solutions were added dropwise at
the same rate over a period of 3 h to a boiled mixture of DMAP
(244 mg, 2.00 mmol), triethylamine (5 mL), and benzene (150
mL). After the addition had been completed, the mixture was
refluxed for a further 3 h. After cooling, the mixture was
quenched with 2 M HCl and the resulting mixture was
extracted with diethyl ether. The extract was washed with
water, dried over MgSO4, and evaporated. The residue was
chromatographed on silica gel with benzene as the eluent to
give cyclic diester (Ra,Ra)-(+)-21 (89.0 mg, 10%) as crystals,
(+)-20: mp 166-170 °C; [R]28 +226 (c 0.89, CHCl3); IR
D
(KBr) 3366, 1015 cm-1; 1H NMR (400 MHz) δ 1.41 (6H, d, J )
6.1 Hz), 1.41 (6H, d, J ) 6.1 Hz), 1.55 (3H, d, J ) 6.9 Hz),
3.58 (1H, dd, J ) 10.3, 6.4 Hz), 3.85 (3H, s), 4.23 (3H, s), 4.72
(1H, sept, J ) 6.1 Hz), 4.73 (1H, sept, J ) 6.1 Hz), 4.88-4.99
(1H, m), 6.56 (1H, s), 7.14-7.18 (3H, m), 7.22-7.28 (4H, m),
7.30-7.42 (7H, m), 9.53 (1H, d, J ) 9.5 Hz), 9.59 (1H, d, J )
9.5 Hz); 13C NMR (100 MHz) δ 22.1, 22.1, 22.2, 24.2, 24.3, 52.7,
56.0, 56.2, 69.9, 70.0, 102.7, 103.3, 110.8, 110.9, 115.9, 116.4,
118.1, 118.2, 119.3, 119.8, 124.2, 124.5, 125.9, 126.0, 126.4,
127.6, 128.1, 128.3, 128.8, 130.1, 130.3, 132.7, 133.8, 133.9,
144.5, 144.5, 146.1, 146.1, 147.1, 147.2, 155.9, 155.9, 159.1,
159.4.
mp 267-270 °C; [R]32 +357 (c 1.12, CHCl3); IR (KBr) 1757
D
cm-1; 1H NMR (400 MHz) δ 1.39 (6H, d, J ) 6.1 Hz), 1.39 (6H,
d, J ) 6.1 Hz), 3.90 (6H, s), 4.71 (2H, sept, J ) 6.1 Hz), 6.87
(2H, s), 6.94 (2H, d, J ) 9.2 Hz), 7.13-7.17 (4H, m), 7.22 (2H,
dd, J ) 9.5, 2.7 Hz), 7.29-7.34 (4H, m), 7.51-7.55 (2H, m),
7.80 (2H, d, J ) 8.6 Hz), 7.89-7.92 (4H, m), 9.51 (2H, d, J )
9.5 Hz); 13C NMR (100 MHz) δ 22.0, 22.1, 55.6, 69.8, 103.4,
(Sa)-(-)-7,7′-Diisopr opoxy-4,4′-dim eth oxy-1,1′-biph en an -
th r en e-2,2′-d iol (2). To an ice-cold solution of (+)-20 (29.7
mg, 39.9 µmol) in THF (3.0 mL) was added LiAlH4 (15.2 mg,
400 µmol) and the mixture was stirred at 0 °C for 10 min. The
mixture was allowed to warm to room temperature and stirred
for a further 3 h. The reaction was quenched by successive
addition of water and 2 M HCl at 0 °C, and the mixture was
(36) (a) Oi, S.; Matsunaga, K.; Hattori, T.; Miyano, S. Synthesis 1993,
895. (b) Oi, S.; Matsuzaka, Y.; Yamashita, J .; Miyano, S. Bull. Chem.
Soc. J pn. 1989, 62, 956.
J . Org. Chem, Vol. 68, No. 6, 2003 2107

Hattori et al.
110.8, 115.7, 117.9, 119.3, 124.3, 124.7, 125.7, 127.2, 127.5,
127.6, 127.9, 128.1, 128.6, 130.1, 130.1, 133.0, 133.7, 133.9,
134.3, 137.1, 147.0, 155.7, 158.0, 167.2. Anal. Calcd for
(c 3.75, CHCl3). Spectral data of the sample were identical with
those of racemic 2. The optical purity was determined to be
95% ee by HPLC on a Daicel Chiralpak AD with hexane-
ethanol (1:1) as the eluent.
C
58H44O8: C, 80.17; H, 5.10. Found: C, 79.85; H, 5.34.
X-r a y Cr yst a llogr a p h ic An a lysis of Cyclic Diest er
The positive sign of the specific rotation indicated that the
absolute stereochemistry of diol 2 is Ra-(+). This, combined
with the fact that (-)-2 gave (-)-1 (vide supra), determined
the axial chirality of naturally occurring (-)-blestriarene C to
be S.
Com p u ta tion a l Meth od . Gaussian9831 and MOPAC200033
were used for Hatree-Fock level calculations of cyclic diesters
22-24, using AM1/PM3 Hamiltonians and 6-31G* basis set,
respectively. Standard default criteria of each package were
applied for the SCF convergence and the gradient geometry
optimization. In both the MOPAC and Gaussian calculations,
vibrational analyses and the imaginary frequency criterion
were used to identify energy minima.
(Ra ,Ra )-(+)-21. Vapor diffusion of hexane into a solution of
diester 21 in acetone at room temperature gave prismatic
crystals, one of which was subjected to X-ray crystallographic
analysis. Data were collected on a CCD diffractometer with
graphite-monochromated Mo KR radiation. The structure was
solved by direct methods (SIR9237) and expanded by using
Fourier techniques (DIRDIF9438). A total of 21216 reflections
were measured and 2876 were unique (Rint ) 0.028). Crystal
data and refinement statistics are as follows: C58H44O8, M )
868.98, orthorhombic, a ) 14.090(2) Å, b ) 28.820(4) Å, c )
11.160(2) Å, V ) 4531(1) Å3, T ) 173 K, space group C2221
(no. 20), Z ) 4, µ(Mo KR) ) 0.84 cm-1, R(F) ) 0.047, wR(F) )
0.048, GOF ) 1.42. The absolute stereochemistry of the
biphenanthrene moiety was assigned to be Ra by using the
R-binaphthalene axis as an internal reference. See Figure S1
for the ORTEP drawing.
Ack n ow led gm en t. This work was partly supported
by a Grant-in-Aid for Scientific Research from the
Ministry of Education, Culture, Sports, Science and
Technology, J apan (No. 13450361).
(Ra)-(+)-7,7′-Diisopr opoxy-4,4′-dim eth oxy-1,1′-biph en an -
th r en e-2,2′-d iol (2). To an ice-cold solution of diester (Ra,Ra)-
(+)-21 (43.6 mg, 50.2 µmol) in THF (5.0 mL) was added LiAlH4
(47.4 mg, 1.25 mmol) portionwise and the mixture was stirred
at 0 °C for 15 min. The resulting mixture was allowed to warm
to room temperature and stirred for a further 3 h. After being
cooled in an ice bath, the mixture was quenched by successive
addition of water and 2 M HCl. The mixture was extracted
with ethyl acetate and the extract was washed with water,
dried over MgSO4, and evaporated. The residue was purified
by PLC with hexane-ethyl acetate as the developer to give
Su p p or tin g In for m a tion Ava ila ble: ORTEP drawing
and detailed X-ray data for (Ra,Ra)-21, tables of dihedral angles
and heats of formation for AM1 and PM3 geometries of 22-
24, Cartesian coordinates for calculated structures of 22-24,
1
and a H NMR spectrum of 15. This material is available free
of charge via the Internet at http://pubs.acs.org.
J O026747K
biphenanthrol (Ra)-2 (26.6 mg, 94%) as crystals, [R]29 +0.72
D
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