First determination of the absolute stereochemistry of a naturally occurring 1,1'-biphenanthrene, (--)-blestriarene C, and its unexpected photoracemization.

Article abstract of DOI:10.1039/b207517b

A naturally occurring 1,1'-biphenanthrene, blestriarene C, was prepared and its absolute stereochemistry was determined to be Sa-(-) by an empirical method, during which the compound was found to undergo rapid photoracemization even under ambient light ex

Full text of DOI:10.1039/b207517b

First determination of the absolute stereochemistry of a naturally
occurring 1,1A-biphenanthrene, (2)-blestriarene C, and its unexpected
photoracemization†
Tetsutaro Hattori,* Yuhi Shimazumi, Osamu Yamabe, Eiji Koshiishi and Sotaro Miyano*
Department of Biomolecular Engineering, Graduate School of Engineering, Tohoku University,
Aramaki-Aoba 07, Aoba-ku, Sendai 980-8579, Japan. E-mail: hattori@orgsynth.che.tohoku.ac.jp;
Fax: +81-22-217-7293; Tel: +81-22-217-7263
Received (in Cambridge, UK) 1st August 2002, Accepted 23rd August 2002
First published as an Advance Article on the web 6th September 2002
A naturally occurring 1,1A-biphenanthrene, blestriarene C,
was prepared and its absolute stereochemistry was deter-
mined to be Sa-(2) by an empirical method, during which
the compound was found to undergo rapid photoracemiza-
tion even under ambient light exposure.
5-isopropyl-2-methoxybenzoic acid,9 ester 3, with a Grignard
reagent 4 to give biphenyl 5 in excellent yield. It was reported
that N,N-diethyl-2A-methylbiphenyl-2-carboxamide on treat-
ment with LDA in THF gave the benzyl anion, which attacked
intramolecularly to the carbonyl carbon to afford phenanthren-
9-ol after spontaneous enolization of the resulting ketone.10 The
method was extended to the cyclization of ester 5, by
conducting in THF using 4.0 equiv. of LDA at room
temperature according to the reported procedure to give
phenanthrol 6 only in 12% yield. It was found, however, that
utilization of HMPA as a cosolvent, in combination with lithium
diethylamide as a base, significantly increased the product yield
(88%) even at lower temperature. Reductive removal of the
9-hydroxy group of phenanthrol 6, followed by deprotection of
the 2-hydroxy moiety of the resulting phenanthrene 8, gave
phenanthrol 9, which was oxidatively coupled in the presence of
a copper(II) complex to give biphenanthrol 2.11
The axial chirality recognition method predicts that two
biaryl-o,oA-diyl units should have the same axial twist to form a
12-membered cyclic diester, e.g. compound 10, because of the
steric requirements imposed by the bulky and rigid compo-
nents.6 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 (2)-blestriarene C (Scheme 2). Thus,
treatment of racemic biphenanthrol 2 with 1.0 equiv. of (Ra)-
1,1A-binaphtharene-2,2A-dicarbonyl chloride in refluxing ben-
zene–triethylamine in the presence of DMAP picked up only
one enantiomer (Ra)-2 among the racemate to allow cyclization
There are a certain number of 1,1A-biphenanthrene compounds,
e.g. (2)-blestriarene C (cirrhopetalanthrin, 1), isolated from
orchids along with analogues having 9,10-dihydro- and
9,9A,10,10A-tetrahydro-1,1A-biphenanthrene
frameworks.1,2
These compounds generally possess at least three hydroxy and/
or methoxy groups in total on each phenanthrene half, two being
at the 2,2A-positions. Therefore, they may exist as nonracemic
atropisomeric substances, as is the case for some of 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 1,1A-biphenanthrenes,3 al-
though it is a well-known nonempirical method often applied to
biaryl compounds.4 We have set out to prepare such a
biphenanthrene, (2)-blestriarene C (1),1,5 which is reported to
be active against gram-positive bacteria,1a and to determine its
absolute stereochemistry by the axial chirality recognition
method developed in this laboratory (vide infra).6 During this
study, we have found that blestriarene C undergoes rapid
photoracemization even under ambient light exposure and thus
the compound isolated from nature cannot be optically pure.
Racemic diisopropyl ether (2) of tetraol 1 was readily
prepared as shown in Scheme 1. In previous papers,7 we
reported that ester function substantially activates an ortho-
alkoxy group for nucleophilic aromatic substitution (SNAr)
reaction by various nucleophiles, which provides a convenient
substitute for the oxazoline-mediated ortho-alkoxy displace-
ment from aryloxazolines (the Meyers reaction).8 The ester-
mediated SNAr protocol was applied to the reaction of 2,6-di-
tert-butyl-4-methoxyphenyl
(BHA)
ester
of
Scheme 1 Reagents and conditions: i, benzene, reflux, 24 h, 91%; ii,
LiNEt2, THF–HMPA (3:2), 0 °C, 2 h, 88%; iii, Tf2O, NEt3, CH2Cl2, 278
°C, 1.5 h, 96%; iv, HCO2H, NEt3, Pd(OAc)2, PPh3, DMF, 65 °C, 16.5 h,
96%; v, 1.5 mol dm23 HCl, MeOH, 60 °C, 7 h, 93%; vi, 1-phenyl-
ethylamine, Cu(NO3)2·3H2O, MeOH, rt, 4 h, 92%.
† Electronic supplementary information (ESI) available: Spectral and
physical data of compounds 2 and 5–10. See http://www.rsc.org/suppdata/
cc/b2/b207517b/
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CHEM. COMMUN., 2002, 2234–2235
This journal is © The Royal Society of Chemistry 2002

intermediate formed by intramolecular addition of 2A-hydroxy
group to the C2–C3 bond,14 and so on. However, these
mechanisms seem not to explain the marked tendency of the
present compounds toward racemization. The importance of the
presence of a 7-hydroxy or alkoxy substituent may suggest that
the reaction proceeds via quinone-like intermediates.
It should be noted that a sample of tetraol (2)-1 showed an
[a]D28 value of 2101.6 in methanol (c 0.525), while its optical
purity was estimated to be 95–92% ee by HPLC analyses
conducted before and after the rotation measurement. There-
fore, naturally occurring (2)-blestriarene C, the specific
rotation of which was reported to be 216.7,1a seems to have
partially racemized during isolation from the plant. Further
studies on the photoracemization mechanism are in progress.
Scheme 2 Reagents and conditions: i, (Ra)-1,1A-binaphthalene-2,2A-dicarbo-
nyl chloride, DMAP, NEt3, benzene, reflux, 6 h, 10%; ii, LiAlH4, THF, 0
°C, 15 min then rt, 3 h, 94%, 95% ee; iii, BCl3, CH2Cl2, 0 °C, 2 h, 97%, 14%
ee.
Notes and references
‡ A solution of a nonracemic biphenanthrene (120 mmol dm23 in ethanol)
in a quartz cuvette (10 3 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.
to give diastereomerically pure cyclic diester 10, which should
be Ra,Ra configuration. Reductive cleavage of diester 10 with
LiAlH4 gave dextrorotatory biphenanthrol 2 of 95% ee, which
was then treated with BCl3 to give tetraol 1 of the same sign.
Thus, the absolute stereochemistry of tetraol 1, as well as
biphenanthrol 2, was assigned to be Ra-(+). Therefore, naturally
occurring (2)-blestriarene C should have Sa configuration.
To our surprise, the optical purity of tetraol 1 thus obtained
was found to be only 14% ee as judged by a chiral HPLC
analysis, which was ascribed to photoracemization (vide infra).
Optical resolution of racemic tetraol 1 could be achieved by
HPLC on a preparative scale using a cellulose-derived chiral
column (Daicel Chiralpak AD, 250 mm 3 20 mm i.d.) with
hexane–ethanol (1+1) as the eluent, which gave several ten
milligram yields of both of the enantiomers in up to 95% ee.
Fig. 1 shows a decrease in the optical purity of tetraol 1 under
fluorescent lamp illumination.‡ The reaction followed first-
order kinetics, the apparent rate constant krac under the
conditions being 1.90 3 1024 s21. No side products were
detected by HPLC and the racemization was completely
suppressed under dark. Diisopropyl ether 2 also had a tendency
toward the racemization (krac = 1.07 31026 s21) (Fig. 1), while
1,1A-biphenanthrene-2,2A-diol did not. Biaryl compounds have
been reported to racemize under strong UV irradiation by
several reaction mechanisms. For example, 1,1A-binaphthalene
reportedly racemizes through its triplet excited state where the
rotation barrier of the biaryl axis is diminished compared to that
in its ground state,12 5H-dibenzo[b,d]pyrans through biaryl
quinone methides,13 1,1A-binaphthalene-2,2A-diol through an
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Fig. 1 Racemization of (2)-blestriarene C (left) and its diether (2)-2 (right)
under fluorescent lamp illumination (5) or dark (:).
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