Isolation, structure determination and synthesis of a trichlorodihydroxybibenzyl from a terrestrial plant

Article abstract of DOI:10.1039/c3ra41325j

A new natural product isolated from the leaves of the plant Anthurium aripoense found in Trinidad is shown by spectroscopic analysis and total synthesis to be 2′,5,6′-trichloro-2,3′-dihydroxybibenzyl, a structure unprecedented in a higher plant. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3ra41325j

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Isolation, structure determination and synthesis of a
trichlorodihydroxybibenzyl from a terrestrial plant3
Cite this: RSC Advances, 2013, 3, 7230
R. Alan Aitken,*a Jaufret Bouquet,a Julia Frank,b Anna L. G. Gidlow,a Yomica
L. Powder,b Russel S. Ramsewak*b and William F. Reynoldsc
Received 31st January 2013,
Accepted 21st March 2013
DOI: 10.1039/c3ra41325j
www.rsc.org/advances
A new natural product isolated from the leaves of the plant
Anthurium aripoense found in Trinidad is shown by spectroscopic
analysis and total synthesis to be 29,5,69-trichloro-2,39-dihydrox-
ybibenzyl, a structure unprecedented in a higher plant.
quaternary carbons, and two aliphatic CH2 groups.{ Further
information derived from COSY, edited HSQC and HMBC, and
T-ROESY spectra was consistent with a 2,29,39,5,69-pentasubsti-
tuted bibenzyl, and consideration of the known pattern of
substituent effects on the chemical shifts of aromatic carbons
led to 29,5,69-trichloro-2,39-dihydroxybibenzyl 1 being identified as
the only structure consistent with all the observed data.
Although a large number of organohalogen compounds have now
been discovered in nature, many of which show interesting
chemical structures and biological activity,1,2 most of these are of
marine origin and the range of structures so far isolated from
terrestrial plants is much more limited.2,3 There is considerable
interest in such compounds as potential ‘‘natural pesticides’’ and,
for example, a variety of chlorinated orcinol derivatives formed in
bulbs of Lilium maximowiczii in response to Fusarium infection
have been suggested to act in this way.4 We now report the
isolation, structure determination and synthesis of a chlorinated
natural product of novel structure from the leaves of a shrub
growing in the northern highlands of Trinidad.
Exhaustive extraction of the dried leaves of Anthurium aripoense
(2 kg) with methanol followed by evaporation, suspension of the
residue in MeOH–H2O (9 : 1), and sequential extraction with
petroleum and ethyl acetate gave, upon evaporation of the ethyl
acetate extract, a fraction (18 g). This was subjected to column
chromatography (SiO2, petroleum–EtOAc, 3 : 1) and the third of
five fractions (37.6 mg) was then re-chromatographed (SiO2,
petroleum–CHCl3, 1 : 1) to give the product of interest (10.7 mg).
The molecular formula was shown by HRMS to be C14H11Cl3O2
and an IR absorption at 3355 cm21 indicated the presence of OH.
The 1H NMR spectrum showed the presence of five aromatic CH
signals and two non-equivalent CH2 groups, while the 13C NMR
spectrum showed five aromatic CH signals, seven aromatic
Such a structure appears to be unprecedented in a terrestrial
higher plant. The most closely similar natural products are the
mono- and bis(bibenzyls) bearing hydroxy and chlorine groups
such as 6,69,10,109,12,129-hexachloroisoperrottetin A isolated from
the liverwort Jamesoniella colorata5 and believed to be formed in
vivo by chlorination of 3,49-dihydroxybibenzyl (‘‘lunularin’’). More
recently similar chlorinated 3-hydroxybibenzyls have been isolated
from other liverwort species such as Riccardia marginata6 and
Riccardia polyclada.7 The occurrence of such compounds in
liverworts is the subject of a very recent review8 but, if they have
oxygen functionality of both aromatic rings, they are always
derived from 3,49-dihydroxybibenzyl, and not the 2,39-dihydroxy
isomer as is the case here.
In view of the unexpected structure of the natural product we
thought it wise to confirm it by unambiguous synthesis and
initially envisaged a Wittig approach involving reaction of the ylide
derived from an appropriately substituted benzyltriphenylpho-
sphonium salt with a substituted benzaldehyde. Such an approach
was successfully used by Speicher to prepare a range of
halogenated lunularins including 39,59,6-trichloro-3,49-dihydroxy-
bibenzyl, an isomer of 1.9 Chlorination of 2- and 3-hydroxyben-
zaldehyde using chlorine gas,10 followed by benzylation gave the
correctly substituted benzaldehydes 211 and 5, respectively, in
acceptable yield and free of unwanted isomers. These were readily
transformed, via the benzyl alcohols 312 and 6, into the benzyl
aEaStCHEM School of Chemistry, University of St Andrews, North Haugh, St
Andrews, Fife, KY16 9ST, UK. E-mail: raa@st-and.ac.uk; Fax: + 44 1334 463808;
Tel: + 44 1334 463865
bDepartment of Chemistry, University of the West Indies, St Augustine, Trinidad and
Tobago. E-mail: Russel.Ramsewak@sta.uwi.edu; Fax: + 1 868 645 3771;
Tel: + 1 868 662 2002
cDepartment of Chemistry, University of Toronto, Toronto, Ontario, M5S 3H6,
Canada
Electronic supplementary information (ESI) available: Full experimental details for
3
isolation, structure determination and synthesis of 1. See DOI: 10.1039/c3ra41325j
7230 | RSC Adv., 2013, 3, 7230–7232
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Scheme 1 Reagents and conditions: i, Cl2, AcOH, rt, 1.5 h; ii, BnBr, KOH, EtOH, reflux, 2 h; iii, NaBH4, aq MeOH, rt, 2 h; iv, PBr3, toluene, rt, 12 h; v, 3 eq. MeMgI, Et2O, reflux, 1
h; vi, Raney1 Ni, EtOH–THF (1 : 1), reflux, 5 h, 55% (10), 48% (1).
bromides 412 and 7 by treatment first with sodium borohydride
and then with phosphorus tribromide (Scheme 1). These were
readily converted into the corresponding phosphonium salts with
triphenylphosphine but all attempts to achieve coupling by a
Wittig reaction of the ylide derived from 7 with 2, or the ylide
derived from 4 with 5, met with failure. Attempted coupling of the
Grignard reagents derived from 7 or 4 with aldehydes 2 and 5
respectively was likewise unsuccessful. In both cases the highly
hindered nature of the bibenzyl products seems likely to be the
source of the problem. We were therefore attracted by an early
report of the formation of 2,29,4,49,6,69-hexabromobibenzyl in 62%
yield by treatment of 2,4,6-tribromobenzyl bromide with methyl-
magnesium iodide.13 The method was developed by Fuson and
coworkers for synthesis of bibenzyls,14 including 2,29,6,69-tetra-
substituted examples,15 but does not seem to have been applied to
mixed couplings so far. When equimolar amounts of benzyl
bromides 4 and 7 were reacted with MeMgI (3 eq.) in boiling
diethyl ether, two coupling products, 8 and 9, were formed in
moderate yield together with a small amount of 2-benzyloxy-5-
chloroethylbenzene. None of the more hindered product expected
from coupling of two molecules of 7 was apparently present.
Separation of the very similar compounds 8 and 9 by chromato-
graphy proved difficult and, although 8 could be obtained in pure
form, 9 was always contaminated with a little 8. A trial of the final
deprotection step on 8 using catalytic hydrogenation over Pd/C
showed this to be ineffective. However, following previous reports,
use of an excess of Raney1 nickel16 in THF–ethanol (1 : 1)17
proved to be effective and gave the symmetrical bibenzyl 10,
already a known compound,18 in moderate yield. When this
method was applied to a sample of 9, the target compound 1 was
formed and was found to be spectroscopically identical to the
natural product, although the repeated chromatographic purifica-
tion required to remove residual traces of 10 and produce an
analytically pure sample meant that the final yield was rather low.
Careful examination of the other fractions isolated from the
leaves of this plant has so far shown the complete absence of any
related chlorine-containing natural products. Compound
1
appears to be the first such natural product from a higher plant
and further investigations into its biosynthesis and biological
function are in progress.
Notes and references
{ Selected data for 1: mp 157–159 uC (Found: C, 52.97; H, 3.23.
C14H11Cl3O2 requires C, 52.94; H, 3.49%); dH 7.22 (1 H, d, J 8.7), 7.13 (1
H, d, J 2.7), 7.08 (1 H, dd, J 8.4, 2.7), 6.89 (1 H, d, J 8.7), 6.72 (1 H, d, J 8.4),
5.59 (1 H, s, OH), 4.84 (1 H, s, OH), 3.16 (2 H, m) and 2.80 (2 H, m); dC
152.3 (C), 150.5 (C), 137.0 (C), 130.0 (CH), 128.7 (CH), 128.6 (C), 127.4 (CH),
125.9 (C), 125.5 (C), 121.1 (C), 116.6 (CH), 114.7 (CH), 31.9 (CH2) and 28.4
(CH2).
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