Demethylation of 2,4-dimethoxyquinolines: the synthesis of atanine.

Article abstract of DOI:10.1039/b311281k

The synthesis of the quinoline alkaloid atanine 6, by selective demethylation of the 2,4-dimethoxyquinoline 11 is presented. An alternative demethylation utilising a thiolate anion leads to the regioisomeric 4-hydroxyquinoline 13.

Full text of DOI:10.1039/b311281k

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Demethylation of 2,4-dimethoxyquinolines: the synthesis of atanine
Keith Jones,*†a Xavier Roset,a Sharon Rossitera and Philip Whitfieldb
a Department of Chemistry, King’s College London, Strand, London, UK WC2R 2LS
b School of Life Sciences, King’s College London, Franklin-Wilkins Building, 150 Stamford St,
London, UK SE1 9NN
Received 17th September 2003, Accepted 20th October 2003
First published as an Advance Article on the web 6th November 2003
The synthesis of the quinoline alkaloid atanine 6, by selective demethylation of the 2,4-dimethoxyquinoline 11 is
presented. An alternative demethylation utilising a thiolate anion leads to the regioisomeric 4-hydroxyquinoline 13.
rutaecarpa and the demonstration of its anthelmintic activity
Introduction
particularly against Schistosoma mansoni.9 As a consequence,
we required quantities of atanine and structurally related
compounds for testing against a range of parasites. The first
synthesis of atanine was reported by Grundon in 1966 and
involved treatment of 4-hydroxyquinoline 7 with diazomethane
to give atanine 6 in 80% yield (Scheme 1).10 This approach has
recently been used by Boyd et al. in an investigation into the
absolute configuration of several of the alkaloids referred to
above.11 In 1973, Grundon et al. published an alternative
synthesis of atanine which avoided diazomethane and involved
ortholithiation of 2,4-dimethoxyquinoline 8, alkylation with
prenyl bromide and selective demethylation at the 4-position
using dry HCl gas in di-isopropyl ether (Scheme 2).12 This latter
approach appeared ideal for our purposes.
The Rutaceae family of plants is the source of over 500 alkaloids
containing the quinoline ring system.1,2 The pharmacological
properties of this class of compound have received only limited
investigation. Nevertheless, a wide range of medicinal prop-
erties have already been identified including anti-protozoal,3
anti-bacterial,4 anti-fungal5 and anti-viral6 activities. Among
the compounds isolated from Rutaceae, a range of structural
types is identifiable. These include the furanoquinolines such as
dictamine 1, the dihydrofuranoquinolines such as platydesmine
2, the isomeric dihydrofuranoquinolines such as araliopsine 3,
the dihydropyranoquinolines such as geibalansine 4, the
isomeric dihydropyranoquinolines such as ψ-ribalinine 5 and
the simple 2,4-dioxygenated quinolines such as atanine 6
(Fig. 1). Atanine was first isolated in 19687 although it had been
postulated to be a plausible biosynthetic intermediate of the
quinoline alkaloids prior to its isolation. Since 1968, it has been
found in many members of the Rutaceae family and its bio-
synthetic involvement has been demonstrated.8 Our interest
in this area was triggered by the discovery of atanine in Evodia
Scheme 1
Scheme 2
Results and discussion
Reaction of aniline with malonic acid in an excess of phos-
phorus oxychloride at reflux to give 2,4-dichloroquinoline 9
was first reported by Ziegler and Gelfert.13 Although a reaction
time of 24 to 40 hours has been reported, we found that the
best yield of 9 (48%) was obtained after only 5 hours at reflux
(Scheme 3). Reaction of 2,4-dichloroquinoline 9 with sodium
methoxide at reflux for 24 hours gave 2,4-dimethoxyquinoline
8 in 70% yield along with some 12% of 4-chloro-2-methoxy-
quinoline 10. Substitution at C-2 is known to be favoured
kinetically and the second substitution is slowed considerably
by the methoxy group at C-2 making bis-substitution difficult
to drive to completion.14 Ortho-lithiation of 8 using n-butyl-
lithium at 0 ЊC and addition of excess prenyl bromide gave
the desired 3-alkylated quinoline 11 in 88% yield. However,
reaction with dry HCl in di-isopropyl ether failed to give any
Fig. 1 Representative quinoline alkaloids.
† Present address: School of Chemical and Pharmaceutical Sciences,
Kingston University, Penrhyn Road, Kingston-upon-Thames, Surrey,
UK KT1 2EE. Email: keith.jones@kingston.ac.uk
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 3 8 0 – 4 3 8 3
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 3
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Scheme 3
atanine 6. A range of conditions was investigated without
isopropyl thiolate in DMF at reflux, gave 13 in 38% yield after
success. The reaction was repeated (in CDCl3) in an NMR tube.
After a very short period, the alkene proton at δ5.22
disappeared strongly suggesting that the fastest reaction was
addition of HCl to the double bond of the sidechain. Reaction
with various dilute mineral acids gave complex mixtures of
products from which no atanine could be isolated.
chromatography (Scheme 3). The structure of 13 was assigned
on the basis that the spectral data differed from the published
data for atanine and that a correlation between the O–H proton
at δ11.5 and the C-5 proton at δ7.98 was observed in the
NOESY spectrum. Presumably, this reaction proceeds via an
S2 process and favours 4-demethylation as the leaving group
from this site of attack is more stable owing to greater charge
delocalisation. On the basis of this result, trimethylsilyl iodide
(TMSI) was explored as we felt the first step in the reaction of
TMSI with quinoline 11 would be silylation of the nitrogen in a
manner similar to protonation. In order to prevent addition of
a proton (from any HI either in the reagent or generated in the
reaction) to the double bond, one equivalent of pyridine was
added along with the TMSI. To our delight stirring 11 with
TMSI and pyridine in dry dichloromethane at Ϫ78 ЊC to room
temperature gave a 2 : 1 mixture (as determined by 1H NMR) of
atanine 6 and pyranoquinoline 1416 formed by protonation of
the sidechain double bond and subsequent cyclisation onto the
2-quinolone oxygen. The reaction was repeated using the
stronger base 4-(dimethylamino)pyridine (DMAP) and atanine
6 was obtained in 62% yield after recrystallisation. The spectro-
scopic data of the synthetic material matched that of the
material isolated from Evodia fruits.9
At this point we chose to explore an alternative strategy in
which 2,4-dimethoxyquinoline 8 was selectively demethylated
to give 12 followed by ortholithiation and alkylation to give
atanine 6 (Scheme 3). Treatment of 8 with dry HCl in di-
isopropyl ether at reflux for 4 hours led to no reaction and
starting material was isolated. The lack of nucleophilicity of
the chloride ion was felt to be the problem and so we used HBr
instead. Treatment of 8 with 48% HBr led to double demethyl-
ation but reaction with 3% HBr in a 1 : 1 mixture of THF and
water at reflux for 3 hours gave 54% of 12 along with some
40% of starting material 8. Reaction of 12 with 2 equivalents of
n-butyllithium at Ϫ78 ЊC followed by addition of prenyl brom-
ide gave atanine 6 but in only 3% yield along with starting
material and decomposition products. The use of prenyl triflate
in place of prenyl bromide led to similar results. Clearly this was
not a viable method for the synthesis of atanine and analogues
and so we turned our attention back to the selective demethyl-
ation of 11.
Boron tribromide is well known to demethylate aromatic
methyl ethers and being a Lewis acid should avoid problems of
addition to the double bond in the sidechain. Treatment of 11
with boron tribromide gave an intractable red solid that could
not be characterised. This appeared to confirm the sensitivity
of the side chain to acid. A non-acidic approach was investi-
gated using thiolate ion, which is known to cleave aryl methyl
ethers in solvents such as DMF.15 Treatment of 11 with sodium
Conclusions
In summary, we have clarified the synthesis of atanine 6 via
ortholithiation–demethylation and have developed the TMSI–
DMAP reagent system for the demethylation of such acid-sen-
sitive aryl methyl ethers. We have also been able to synthesise
selectively via thiolate promoted demethylation the regioisomer
13 of atanine.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 3 8 0 – 4 3 8 3
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Experimental17
(1H, ddd, J 8.5, 6.9, 1.5, H-7), 7.35 (1H, ddd, J 8.2, 6.9, 1.2,
H-6), 5.22 (1H, br t, J 6.9, C᎐CH ), 4.08 (3H, s, 2-OMe), 3.95
᎐
2,4-Dichloroquinoline 9
(3H, s, 4-OMe), 3.45 (2H, d, J 6.9, CH2), 1.81 (3H, d, J 0.7,
᎐CCH ), 1.69 (3H, d, J 1.2, ᎐CCH ); δ 162.5 (C-4), 161.6 (C-2),
᎐
᎐
3
3
C
Aniline (6.7 g, 72 mmol) and malonic acid (11.7 g, 112 mmol)
were heated under reflux in phosphorus oxychloride (60 ml),
with stirring, for 5 hours. The mixture was cooled, poured into
crushed ice with vigorous stirring and then made alkaline with
5 M sodium hydroxide. Filtration gave the crude product as a
brown solid. A four hour continuous (Soxhlet) extraction with
hexane followed by evaporation of solvent under reduced
pressure yielded a pale yellow powder. Column chromato-
graphy (95 : 5 hexane : EtOAc) yielded the pure dichloro-
quinoline as off-white needles (6.8 g, 48%), mp 66–67 ЊC(lit.18
66 ЊC); Rf (95 : 5 hexane : EtOAc) 0.51; νmax/cmϪ1: 1580 (s,
146.1 (C-8a), 132.3 (᎐CMe ), 128.9, 127.3, (C-7, C-8) 123.6,
᎐
2
121.9, 121.8, (C-5, C-6 and ᎐CH), 121.2 (C-3), 116.9 (C-4a),
᎐
62.3 (OMe), 53.8 (OMe), 25.8 (CH3), 23.3 (CH2), 18.0 (CH3);
m/z 257 (100%, Mϩ), 242 (82, Mϩ Ϫ Me), 202 (52, Mϩ Ϫ Me C᎐
᎐
2
CH) (Found: Mϩ 257.1417. C16H19NO2 requires 257.1416).
4-Methoxy-1H-quinolin-2-one 12
2,4-Dimethoxyquinoline (2.0 g, 11 mmol) was dissolved in 3%
HBr in a 1 : 1 mixture of H2O–THF (100 ml). The solution was
heated under reflux for 3 hours, then cooled and neutralised
with aqueous NaHCO3. The THF was removed under reduced
pressure, precipitating a white solid, which was filtered and
dried under suction. TLC (4 : 1 hexane : EtOAc) showed the
presence of starting material and a polar material (baseline). A
5 hour Soxhlet extraction with hexane separated these two
compounds. The starting material was extracted into the
reaction flask leaving the product as cream needles in the
C᎐N); δ 8.18 (1H, dd, J 8.4, 1.3, H-5), 8.03 (1H, dd, J 8.5, 1.0,
᎐
H
H-8), 7.79 (1H, ddd, J 8.5, 7.0, 1.3, H-7), 7.65, (1H, ddd, J 8.4,
7.0, 1.0, H-6), 7.50 (1H, s, H-3); δC 149.8 (C-2), 148.1 (C-8a),
144.4 (C-4), 131.5 (C-7), 129.0 (C-8), 127.9 (C-6), 125.2 (C-4a),
124.2 (C-5), 121.9 (C-3); m/z: 201 (15%, Mϩ 37Cl2), 199 (72, Mϩ
37Cl 35Cl), 197 (100, Mϩ 35Cl2), 162 (69, Mϩ Ϫ Cl) (Found:
Mϩ(35Cl2) 196.9792. C9H535Cl2N requires 196.9799).
thimble (1.0 g, 54%), mp 249–252 ЊC (lit.21 250–253 ЊC); νmax
/
2,4-Dimethoxyquinoline, 8 and 4-chloro-2-methoxyquinoline 10
cmϪ1: 3100 (w, N–H), 1674 (s, C᎐O), 1634, 1607 (s, C᎐C); δ
᎐
᎐
H
7.90 (1H, dd, J 8.1, 1.1, H-5), 7.52 (1H, dd, J 8.1, 1.1, H-7), 7.40
(1H, dd, J 8.1, 1.1, H-8), 7.20 (1H, dd, J 8.1, 1.1, H-6), 6.03 (1H,
s, H-3), 3.99 (3H, s, OMe); δC 166.3 (C-2), 165.0 (C-4), 138.4
(C-8a), 131.2 (C-7), 122.8 (C-8), 122.2 (C-6), 116.1 (C-5), 115.6
(C-4a), 96.0 (C-3), 56.0 (O-Me); m/z 175 (100%, Mϩ), 132 (63,
Mϩ Ϫ CONH), 76 (28, C6H4ϩ) (Found Mϩ: 175.0629.
C10H9NO2 requires 175.0633).
2,4-Dichloroquinoline (2.8 g, 14 mmol) was heated under reflux
in methanolic sodium methoxide solution (from 2.0 g, 86 mmol
Na in 50 ml MeOH) for 24 hours. The reaction mixture was
cooled and poured into ice-cold water, and the resulting white
precipitate was filtered off. Column chromatography (9 : 1
hexane : EtOAc) yielded the two products 2,4-dimethoxy-
quinoline, (1.85 g, 70%) and 4-chloro-2-methoxyquinoline,
(0.32 g, 12%), both as white needles.
4-Hydroxy-2-methoxy 3-(3-methylbut-2-enyl)quinoline 13
2,4-Dimethoxyquinoline. Mp 78–80 ЊC (lit.19 81–82 ЊC); Rf
(9 : 1 hexane : EtOAc) 0.48; νmax/cmϪ1: 1640, 1580 (s, C᎐C,
Sodium hydride (0.67 g of a 60% mineral oil dispersion, washed
with hexane, 17 mmol) was suspended in dimethylformamide
(10 ml). 2-Propanethiol (0.51 g, 6.7 mmol) was added and
the mixture was stirred for 10 minutes. Then a solution of 2,4-
dimethoxy-3-(3-methylbut-2-enyl)quinoline (0.7 g, 2.7 mmol) in
DMF (10 ml) was added, and the mixture heated under reflux
for 4 hours. After cooling and neutralisation with 2 M HCl the
solution was extracted with ether (4 × 50 ml), the combined
ether extracts were dried over MgSO4, and the solvent removed
in vacuo to give a brown oil. Column chromatography (4 : 1
hexane:ethyl acetate) followed by recrystallisation (ethanol)
yielded the pure product (0.25 g, 38%) as off-white needles,
mp 154–155 ЊC (lit.22 137–138 ЊC); Rf (4 : 1 hexane : EtOAc)
᎐
C᎐N); δ 8.04 (1H, dd, J 8.2, 1.5, H-5), 7.78 (1H, dd, J 8.5, 1.2,
᎐
H
H-8), 7.60 (1H, ddd, J 8.5, 7.0, 1.5, H-7), 7.33 (1H, ddd, J 8.2,
7.0, 1.2, H-6), 6.21(1H, s, H-3), 4.05 (3H, s, 2-OMe), 3.97 (3H, s,
4-OMe); δC 163.9 (C-4), 163.84 (C-2), 147.1 (C-8aC, 130.0
(C-7), 126.9 (C-8), 123.3 (C-6), 121.8 (C-5), 119.3 (C-4a), 90.7
(C-3), 55.7 (4-OMe), 53.4 (2-OMe); m/z 189 (100%, Mϩ), 188
(93, Mϩ Ϫ H) (Found: Mϩ 189.0797. C11H11NO2 requires
189.0790).
4-Chloro-2-methoxyquinoline. Mp 70–72 ЊC (lit.20 70–71 ЊC);
Rf (9 : 1 hexane : EtOAc) 0.61; νmax/cmϪ1: 1610, 1580 (s, C᎐N
᎐
and C᎐C); δ 8.10 (1H, dd, J 8.2, 1.3, H-5), 7.86 (1H, dd, J 8.0,
᎐
H
0.30; νmax/cmϪ1: 3200–3000 (br, O–H), 1627, 1580 (s, C᎐C,
᎐
1.2, H-8), 7.67 (1H, ddd, J 8.0, 7.0, 1.3, H-7), 7.46 (1H, ddd,
J 8.2, 7.0, 1.2, H-6), 7.03 (1H, s, H-3), 4.06 (3H, s, –OCH3);
δC 161.9 (C-2), 147.0 (C-8a), 143.7 (C-4), 130.5 (C-7), 127.6
(C-8), 124.8 (C-6), 124.1 (C-5), 123.3 (C-4a), 112.9 (C-3), 53.8
(OCH3); m/z 195 (33%, Mϩ 37Cl), 193 (100, Mϩ 35Cl), 192 (67,
Mϩ 35Cl–H), 163 (33, Mϩ–CH2O) (Found Mϩ: 193.0298.
C10H835ClNO requires 193.0294).
C᎐N); δ 7.98 (1H, dd, J 8.2, 1.3, H-5), 7.75 (1H, dd, J 8.2, 1.2,
᎐
H
H-8), 7.56 (1H, ddd, J 8.3, 6.9, 1.3, H-7), 7.32 (1H, ddd, J 8.2,
6.9, 1.2, H-6), 5.38 (1H, tq, J 7.3, 1.2, CH᎐), 4.06 (3H, s,
᎐
OCH ), 3.51 (2H, d, J 7.3, CH CH᎐), 1.86 (3H, s, CH᎐CCH ),
᎐
᎐
3
2
3
1.81 (3H, d, J 1.2, CH᎐CCH ), OH not observed in CDCl ;
᎐
3
3
NOESY (d6 DMSO) correlation between the OH proton at
δ11.5 ppm and the C-5 proton at δ7.98 ppm; δC 161.4 (C-2),
145.0 (C-8a), 137.0 (᎐C(CH ) ), 129.3, 126.5, 123.2, 121.6,
᎐
2,4-Dimethoxy-3-(3-methylbut-2-enyl)quinoline 11
3 2
121.1 (C-5,-6,-7,-8 and ᎐CH), 119.0 (C-4a), 105.2 (C-3), 53.9
᎐
2,4-Dimethoxyquinoline (2.0 g, 11 mmol) in dry THF (10 ml)
was cooled to 0 ЊC under argon and n-butyllithium (6.2 ml of a
2.5 M solution in hexane) was added dropwise, with stirring.
The mixture was stirred at 0 ЊC under argon for 30 minutes,
then 1-bromo-3-methylbut-2-ene (2.8 g, 19 mmol) was added
dropwise over 5 minutes. The mixture was stirred at 0 ЊC for 30
minutes and then allowed to warm to room temperature with
stirring for a further hour. The reaction mixture was poured
into water and extracted with ether (4 × 30 ml) to give the crude
product as a yellow–brown oil. Column chromatography (4 : 1
hexane : EtOAc) yielded the pure product as a yellow–brown oil
(2.4 g, 88%); Rf (4 : 1 hexane : EtOAc) 0.57; νmax/cmϪ1: 3070
(OMe), 25.9 (CH3), 23.0 (CH2), 18.0 (CH3), no signal observed
for C4; m/z 243 (26%, Mϩ), 228 (12, Mϩ Ϫ CH3), 188 (5% Mϩ Ϫ
CH᎐C(CH ) ), 83 (100) (Found: Mϩ 243.1246. C15H17NO2
᎐
3
2
requires 243.1259).
4-Methoxy-3-(3-methylbut-2-enyl)-1H-quinolin-2-one (atanine)
6
2,4-Dimethoxy-3-(3-methylbut-2-enyl)quinoline (0.50 g, 2.0
mmol) and 4-dimethylaminopyridine (0.24 g, 2.0 mmol) were
dissolved in dry dichloromethane (30 ml) and cooled to Ϫ78 ЊC
under argon. Iodotrimethylsilane (0.40 g, 2.0 mmol) was added
dropwise, and the mixture stirred at Ϫ78 ЊC for 2 hours. Then
the flask was left to warm to room temperature, with stirring,
(s, C–H), 1620, 1605, 1575 (s, C᎐C and C᎐N); δ 7.92 (1H, ddd,
᎐
᎐
H
J 8.2, 1.5, 0.5, H-5), 7.82 (1H, ddd, J 8.5, 1.2, 0.5, H-8), 7.56
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 3 8 0 – 4 3 8 3
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4 G. H. N. Towers, E. A. Graham, I. D. Spenser and Z. Abramowski,
Planta Med., 1981, 41, 136–142.
for a further 40 hours. The solution obtained was washed with
1 M aqueous sodium thiosulfate (2 × 30 ml), and then dried
(MgSO4) and the solvent removed under reduced pressure. A
brown oil was obtained which crystallised overnight to give a
pale brown solid. Recrystallisation (EtOH) gave the title
compound as off-white needles (0.3 g, 62%), mp 130–132 ЊC
(lit.12 132–134 ЊC) (Found: C, 72.44, H, 6.87, N, 5.69.
C15H17NO2.0.3H2O requires C, 72.44, H, 7.13, N, 5.63%);
νmax/ cmϪ1 3250 (w, N–H), 1653 (s, C᎐O), 1568 (m, C᎐C);
5 M. W. Biavatti, P. C. Vieira, M. F. D. F. daSilva, J. B. Fernandes,
S. R. Victor, F. C. Pagnocca, S. Albuquerque, I Caracelli and
J. Zukerman-Schpector, J. Braz. Chem. Soc., 2002, 13, 66–70.
6 J. L. McCormick, T. C. McTee, J. H. Cardellina and M. R. Boyd,
J. Nat. Prod., 1996, 59, 469–471.
7 I. T. Eshiett and D. A. H. Taylor, J. Chem. Soc. C, 1968, 481–484.
8 J. F. Collins, W. J. Donnelly, M. F. Grundon and K. J. James,
J. Chem. Soc., Perkin Trans. 1, 1974, 2177–2181.
9 S. Perrett and P. J. Whitfield, Planta Med., 1995, 61, 276–278.
10 R. M. Bowman and M. F. Grundon, J. Chem. Soc. C, 1966,
1504–1507.
11 D. R. Boyd, N. D. Sharma, S. A. Barr, J. G. Carroll,
D. Mackerracher and J. F. Malone, J. Chem. Soc., Perkin Trans. 1,
2000, 3397–3405.
᎐
᎐
δH 12.11 (1H, br s, NH/OH), 7.76 (1H, dd, J 8.1, 1.2, H-5), 7.47
(1H, ddd, J 8.2, 7.0, 1.2, H-7), 7.42 (1H, dd, J 8.2, 1.2, H-8),
7.22 (1H, ddd, J 8.1, 7.0, 1.2, H-6), 5.32 (1H, t, J 6.9, CH᎐
᎐
CMe ), 3.95 (3H, s, OMe), 3.45 (2H, d, J 6.9, CH –CH᎐CMe ),
᎐
2
2
2
1.86 (3H, s, CH3), 1.71 (3H, s, CH3); δC 165.9 (C-2), 162.1 (C-4),
12 J. F. Collins, G. A. Gray, M. F. Grundon, D. M. Harrison and
C. G. Spyropoulos, J. Chem. Soc., Perkin Trans. 1, 1973, 523–529.
13 E. Ziegler and K. Gelfert, Monatsh. Chem., 1959, 90, 822–826.
14 R. J. Rowlett and R. E. Lutz, J. Am. Chem. Soc., 1946, 68,
1288–1291.
137.6, 132.5 (C-8a, C᎐CMe ), 130.0 (CH), 122.8 (CH), 122.6,
᎐
2
122.2 (CH), 121.6 (CH), 117.2, 116.1 (CH), 61.8 (OCH3), 25.8
(CH᎐C(CH ) ), 23.5 (CЈH ), 18.1 (CH᎐C(CH ) ); m/z 243
᎐
᎐
3
2
2
3 2
(89%, Mϩ), 228 (39, Mϩ–OMe), 188 (100, C11H10NO2ϩ) (Found:
Mϩ 243.1252. C15H17NO2 requires 243.1259).
15 G. I. Feutrill and R. N. Mirrington, Aust. J. Chem., 1972, 25,
1719–1729.
16 R. M. Bowman, M. F. Grundon and K. J. James, J. Chem. Soc.,
Perkin Trans. 1, 1973, 1055–1059.
Acknowledgements
17 General experimental details can be found in S. A. Brunton and
K. Jones, J. Chem. Soc., Perkin Trans. 1, 2000, 763–768.
18 A. G. Osborne, J. M. Buley, H. Clarke, R. C. H. Dakin and
P. I. Price, J. Chem. Soc., Perkin Trans. 1, 1993, 2747–2754.
19 A. G. Osborne and J. F. Warmsley, J. Nat. Prod., 1992, 55,
589–595.
20 K. Shichiri, K. Funakoshi, S. Saeki and M. Hamana, Chem. Pharm.
Bull., 1980, 28, 493–499.
21 K. Nickisch, W. Klose, E. Nordhoff and F. Bohlmann, Chem. Ber.,
1980, 113, 3086–3088.
We would like to thank the Wellcome Trust for a studentship
(SR).
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O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 3 8 0 – 4 3 8 3
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