Synthesis, X-Ray Crystal Structure and Tubulin-Binding Properties of a Benzofuran Analogue of the Potent Cytotoxic Agent Combretastatin A4

Article abstract of DOI:10.1071/CH99022

The benzofuran (4), a ring-fused analogue of the potent antimitotic agent combretastatin A4 (1), has been prepared by a convergent route involving 5-endo-dig iodocyclization of o-hydroxytolan (5) as the key step. Compound (4), which has been characterized crystallographically as well as spectroscopically, is inactive as a tubulin-binding agent.

Full text of DOI:10.1071/CH99022

C S I R O P U B L I S H I N G
Australian Journal
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Volume 52, 1999
© CSIRO Australia 1999
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Aust. J. Chem., 1999, 52, 767–774
.
Synthesis, X-Ray Crystal Structure and Tubulin-
Binding Properties of a Benzofuran Analogue of
the Potent Cytotoxic Agent Combretastatin A4†
Martin G. Banwell,A,B Bernard L. Flynn,A Anthony C. Willis A and
Ernest Hamel C
A
Research School of Chemistry, Institute of Advanced Studies,
The Australian National University, Canberra, A.C.T. 0200.
B
To whom correspondence should be addressed.
Laboratory of Drug Discovery, Research and Development,
C
Developmental Therapeutics Program, Division of Cancer Treatment and
Diagnosis, National Cancer Institute, Frederick Cancer Research and
Development Centre, Frederick, Maryland 21702, U.S.A.
The benzofuran (4), a ring-fused analogue of the potent antimitotic agent combretastatin A4 (1), has
been prepared by a convergent route involving 5-endo-dig iodocyclization of o-hydroxytolan (5) as the
key step. Compound (4), which has been characterized crystallographically as well as spectroscopically,
is inactive as a tubulin-binding agent.
Introduction
subsequently reported20 that compound (2) inhibits
tubulin polymerization (IC c. 1 5–2 5 M) and has
50
Combretastatin A4 (1) is one of a number of stilbene
natural products that has been isolated by Pettit and
coworkers from the bark of the South African tree
signi cant cell growth inhibitory activity (GI < 10
50
g/ml) against a selection of human cancer cell lines.
It is especially active against colon cancer (GI 0 049
50
Combretum ca rum. It is a powerful inhibitor of tubu-
g/ml).
4
lin assembly with an IC value of c. 2–3 M,1 and in
50
this respect is even more potent than the prototypical
antimitotic agent colchicine.5 Indeed, combretastatin
A4 has exceptional cytotoxic properties6 and is active
against murine lymphocyctic leukaemia (L1219, P388;
ED
c. 0 003 M) as well as human ovarian (A2780)
50
and human colon cancer cell lines (e.g. HCT-15; ED
50
c. 0 0009 M). Very recently, compound (1) has also
been shown to display potent and selective toxicity
toward tumour vasculature.7 Despite such promising
biological characteristics, combretastatin A4 has been
prevented from entering phase 1 clinical trials as an
antitumour agent because of its poor solubility in
pharmaceutically appropriate solvents.8 A further dif-
culty is that the compound readily isomerizes to its
less active (E)-isomer. This situation has prompted
considerable e orts directed towards identi cation of
11
soluble prodrugs8
and/or con gurationally stable
analogues of combretastatin A4.12
In connection
18
with such endeavours, the benzo[b]thiophens (2) and
(3) were recently prepared and structurally character-
ized by Pinney and coworkers.19 This same group has
† Aspects of the work described herein are the subject of patent applications [International Patent Application No. PCT/AU98/00312;
incorporating Australian Provisional Patent Application No. PO 6565 (see Chem. Abstr., 1999, 130, 3974) and Australian
Provisional Patent Application No. PP 7289, lodged 24 November 1998].
Manuscript received 22 February 1999
᭧ CSIRO 1999
0004-9425/99/080767$ 05.00
10.1071/CH99022

768
M. G. Banwell et al.
During the course of recent work21,22 on the total
dichloromethane solution of compound (5) was treated,
at 18 C, with 1 mol. equiv. of N -iodosuccinimide and
this resulted in a 5-endo-dig iodocyclization reaction
which produced the 2-aryl-3-iodo-benzofuran (13) in
quantitative yield. The presence of the C 3 iodo
substituent within this latter compound allows for a
palladium-catalysed cross-coupling reaction to be used
syntheses of certain members of the lamellarin class of
marine natural products, we developed a concise route
to o-hydroxytolans22 and noted the facility with which
25
such compounds cyclized to give 2-arylbenzofurans.23
This observation, together with the knowledge that
many benzofurans are physiologically active compounds,
prompted us to consider exploiting such chemistry for
the construction of 2,3-diarylbenzofurans that might
be expected to mirror the tubulin-binding properties of
compounds such as (1) and (2). In this connection, we
now report a concise synthesis of the combretastatin
A4 analogue (4), detail the solid-state structure of this
material and report on its capacity to bind to tubulin.
Results and Discussion
(a) Synthesis of Compound (4)
The synthesis of compound (4) is outlined in Scheme 1
and the key step involves 5-endo-dig iodocyclization26
of o-hydroxytolan (5).
The route to this latter
compound was based on a closely related reaction
sequence used for the synthesis of the marine natural
product lamellarin K.22 Thus, the readily available
isopropyl ether (6)27 of isovanillin was subjected to
a Corey–Fuchs ole nation reaction28 which provided
the , -dibromostyrene (7) in near quantitative yield.
Compound (7) was treated with 2 mol. equiv. of
butyllithium and the lithium acetylide (8) so formed
was transmetallated, in situ, with anhydrous zinc(II)
chloride. The resulting organozinc species (9) was then
subjected, again in situ, to palladium-catalysed Negishi
cross-coupling reaction29,30 with the aryl iodide (10)
which is itself readily prepared by silver(I)-mediated
iodination of the known isopropyl ether (6)31 of iso-
vanillin. The product of the cross-coupling reaction,
namely tolan (11), was obtained in excellent yield.
Baeyer–Villiger oxidation of the aromatic aldehyde
moiety within compound (11) was readily e ected with
m-chloroperoxybenzoic acid and the resulting formate
ester then hydrolysed to the target o-hydroxytolan
(5) which was produced in 92% overall yield from
(11). In the key step of the reaction sequence, a

Benzofuran Analogue of Combretastatin A4
769
Table 1. Atomic coordinates and displacement factors (A2) for (4), (2C25H24O8).CH2Cl2
In Tables 1–3, estimated standard deviations are given in parentheses. Beq = (8 2/3)
jU ijai aj ai . aj
i
Atom
x
y
z
Beq
Atom
x
y
z
Beq
Molecule 1
Molecule 2
O(1)
O(70)
0 60677(9)
0 5017(1)
0 1042(1)
0 6959(1)
0 3737(1)
0 0663(1)
0 5703(1)
0 2011(1)
0 5781(1)
0 3424(1)
0 5347(1)
0 5202(1)
0 2712(2)
0 4401(1)
0 4516(1)
0 5613(1)
0 1787(1)
0 3864(1)
0 6640(2)
0 1572(1)
0 4269(2)
0 7220(2)
0 2289(2)
0 5318(2)
0 6792(2)
0 3212(1)
0 5971(2)
0 5538(1)
0 1272(2)
0 2682(2)
0 8011(2)
0 0150(2)
0 2794(2)
0 01559(7)
0 25598(8)
0 05248(8)
0 27801(8)
0 22883(8)
0 13609(7)
0 24284(8)
0 15830(7)
0 0962(1)
0 0422(1)
0 0327(1)
0 1479(1)
0 0296(1)
0 0077(1)
0 0608(1)
0 2072(1)
0 0605(1)
0 1127(1)
0 2170(1)
0 1039(1)
0 1728(1)
0 1665(1)
0 1160(1)
0 1826(1)
0 1070(1)
0 0855(1)
0 1319(1)
0 0723(1)
0 0162(1)
0 2262(1)
0 2907(1)
0 1008(1)
0 1901(1)
0 63722(9)
0 5445(1)
0 42099(9)
0 6101(1)
0 6007(1)
0 52643(9)
0 6466(1)
0 66609(9)
0 6178(1)
0 5793(1)
0 6171(1)
0 5809(1)
0 5078(1)
0 5991(1)
0 6062(1)
0 5803(1)
0 4902(1)
0 5962(1)
0 6159(1)
0 5446(1)
0 6095(1)
0 6527(2)
0 6155(1)
0 6336(1)
0 6541(2)
0 6332(1)
0 6441(1)
0 6296(1)
0 3599(2)
0 5778(2)
0 6378(2)
0 5411(2)
0 7226(2)
3 72(3)
5 67(5)
4 58(4)
5 52(4)
5 91(5)
3 94(4)
5 78(5)
4 38(4)
3 29(4)
3 23(5)
3 26(4)
3 68(5)
3 47(5)
3 26(4)
3 34(4)
3 80(5)
3 37(5)
3 89(5)
4 07(5)
3 26(5)
4 18(5)
4 72(6)
3 36(5)
4 26(5)
4 32(5)
3 54(5)
4 23(5)
3 62(5)
5 48(7)
5 81(7)
6 71(8)
5 54(7)
6 09(7)
O(1A)
0 9814(1)
0 9600(1)
0 6811(1)
0 8158(1)
1 0729(1)
0 5416(1)
0 9471(1)
0 5462(1)
0 9677(1)
0 7800(1)
0 9307(1)
0 9464(1)
0 7743(2)
0 8603(1)
0 8698(1)
0 9827(1)
0 6939(2)
0 8230(1)
1 0417(2)
0 6196(1)
0 8506(1)
1 0644(2)
0 6252(1)
0 9225(2)
1 0274(2)
0 7051(2)
0 9685(1)
0 9423(1)
0 7533(2)
0 7355(2)
1 1339(2)
0 4501(2)
0 5397(2)
0 51521(7)
0 24378(8)
0 44473(9)
0 72895(7)
0 21935(8)
0 37886(7)
0 74259(8)
0 36791(7)
0 4031(1)
0 4594(1)
0 4670(1)
0 3523(1)
0 4665(1)
0 4923(1)
0 5607(1)
0 2923(1)
0 4402(1)
0 6129(1)
0 2811(1)
0 4069(1)
0 6730(1)
0 3310(1)
0 4001(1)
0 6825(1)
0 3915(1)
0 4263(1)
0 6317(1)
0 5717(1)
0 4803(2)
0 7258(1)
0 2049(1)
0 4133(1)
0 3666(2)
0 35055(9)
0 4541(1)
0 6178(1)
0 4417(1)
0 3546(1)
0 5123(1)
0 3554(1)
0 3596(1)
0 3716(1)
0 4409(1)
0 3797(1)
0 4168(1)
0 5187(1)
0 4133(1)
0 4093(1)
0 4093(1)
0 5425(1)
0 4347(1)
0 3562(2)
0 4878(1)
0 4178(1)
0 3118(1)
0 4094(1)
0 3733(1)
0 3194(1)
0 3856(1)
0 3480(1)
0 3688(1)
0 6748(2)
0 4792(2)
0 3022(2)
0 4939(2)
0 2774(2)
3 66(3)
4 95(4)
5 73(5)
4 98(4)
6 04(5)
4 56(4)
4 82(4)
4 61(4)
3 29(5)
3 24(4)
3 33(5)
3 45(5)
3 72(5)
3 32(5)
3 39(5)
3 80(5)
3 82(5)
3 72(5)
4 33(5)
3 50(5)
3 75(5)
4 38(6)
3 45(5)
3 84(5)
3 77(5)
3 47(5)
3 81(5)
3 44(5)
7 9(1)
O(70A)
O(700A)
O(8A)
O(700
)
O(80)
O(8)
O(80A)
O(900A)
O(10A)
O(10100A)
C(1 A)
C(100A)
C(2A)
O(900
O(10)
O(10100
C(1 )
)
)
C(100
C(2)
)
C(20)
C(20A)
C(200A)
C(3A)
C(200
C(3)
)
C(3a)
C(30)
C(3aA)
C(30A)
C(300A)
C(4A)
C(300
C(4)
C(40)
)
C(40A)
C(400A)
C(5A)
C(400
C(5)
C(50)
)
C(50A)
C(500A)
C(6A)
C(500
C(6)
C(60)
)
C(60A)
C(600A)
C(7A)
C(600
C(7)
C(7a)
)
C(7aA)
C(800A)
C(9A)
C(800
C(9)
)
6 00(8)
8 4(1)
8 1(1)
C(90)
C(1000
C(1200
C(90A)
C(1000A)
C(1200A)
)
)
8 50(9)
Solvate
Cl(1)A
Cl(2)A
Cl(3)A
Cl(4)A
C(51)A
C(52)A
0 3260(2)
0 42630(9)
0 340(1)
0 3936(8)
0 3630(4)
0 294(2)
0 46128(9)
0 40437(9)
0 4552(6)
0 3545(5)
0 3893(3)
0 408(1)
0 80864(9)
0 70140(8)
0 8424(7)
0 7536(7)
0 7767(3)
0 755(2)
10 67(5)
12 27(5)
10 7
12 3
11 8(2)
11 9
A
Cl(1), Cl(2) and C(51) have occupancy 0 857(2); Cl(3), Cl(4) and C(52) have occupancy 0 143.
Fig. 1. Thermal ellipsoid diagram of molecule 2 of (4) as determined in the X-
ray crystallographic structure analysis of (2C25H24O8).CH2Cl2. Ellipsoids show 50%
probability levels and hydrogen atoms are drawn as circles with small radii.

770
M. G. Banwell et al.
for introduction of the remaining aryl group associated
with the target molecule. To these ends, the aryl iodide
(14)21 was metallated with t-butyllithium at 78 C
and the resulting aryllithium (15) transmetallated with
zinc(II) chloride to give the arylzinc (16) which was
cross-coupled, in situ, with compound (13) in the
presence of tetrakis(triphenylphosphine)palladium(0).
In this manner the Negishi cross-coupling product (17)
was obtained in 73% yield. Twofold deisopropylation
of compound (17) was readily e ected by AlCl3 in
dichloromethane32 at 18 C to give the target compound
(4) in 92% yield. Full spectroscopic characterization
of this material was undertaken but nal con rmation
of structure followed from a single-crystal X-ray study,
details of which are provided in Fig. 1, Tables 1–3
and the Experimental section. This study also serves
to con rm the structures of all the intermediates en
route to compound (4).
(b) Tubulin-Binding Properties of Compound (4)
Compound (4) was evaluated for e ects on in vitro
tubulin polymerization and, disappointingly, found to
be inactive. Structural modi cations are being explored
in a search for active analogues.
Conclusion
The synthetic protocols outlined above will provide
ready access to a wide range of 2,3-disubstituted ben-
zofurans. In addition, relatively simple adjustments
to these protocols should allow for the preparation of
the corresponding benzo[b]thiophen and indole ana-
logues. Thus, further investigation of these biologically
signi cant19,20,25,26,33 classes of compound should be
facilitated by the chemistry described herein, especially
as it is likely to be capable of adaptation to the solid
phase24,34 and, thereby, permitting the production of
combinatorial libraries.
Experimental
Melting points were recorded with a Ko er hot-stage appa-
ratus and are uncorrected. Proton (1H) and carbon (13C)
n.m.r. spectra were recorded with a Varian Unity 300 or a
Varian Gemini 300 spectrometer operating at 300 MHz for
proton and 75 MHz for carbon. All such spectra were recorded
in (D)chloroform (CDCl3) solution at 22 C. The protonicities
of the carbon atoms observed in 13C n.m.r. spectra were deter-
mined by attached proton test (a.p.t.) experiments. Infrared
spectra ( max) were recorded, as potassium bromide disks, with
either a Perkin–Elmer 983G or a Perkin–Elmer 1800 Fourier-
transform infrared spectrophotometer. Low-resolution electron
impact mass spectra (m/z) were recorded at 70 eV on either a
VG Micromass 7070F mass spectrometer or a JEOL AX-505H
mass spectrometer. High-resolution mass spectra were recorded
with a VG Micromass 7070F instrument. Diethyl ether and
tetrahydrofuran were distilled under nitrogen from sodium
benzophenone ketyl. Dichloromethane and hexane were each
distilled from calcium hydride.
Table 2. Selected interatomic distances (A) for (4),
(2C25H24O8).CH2Cl2
Atoms
Distance
Atoms
Distance
O(1)–C(2)
1 397(3)
1 383(4)
1 355(4)
1 366(4)
1 406(4)
1 372(4)
1 402(4)
1 365(4)
1 424(4)
1 383(3)
1 421(4)
1 366(4)
1 370(4)
O(1A)–C(2A)
1 396(3)
1 374(4)
1 366(4)
1 366(4)
1 413(5)
1 372(4)
1 424(4)
1 367(4)
1 422(5)
1 385(3)
1 414(4)
1 362(4)
1 373(4)
O(10)–C(7a)
O(700)–C(30)
O(7 )–C(300)
O(700)–C(800)
O(8)–C(5)
O(10A)–C(7aA)
O(700A)–C(30A)
O(7 A)–C(300A)
O(700A)–C(800A)
O(8A)–C(5A)
O(8)–C(9)
O(8A)–C(9A)
O(800)–C(40)
O(800)–C(90)
O(9 )–C(400)
O(900)–C(1000)
O(10)–C(6)
O(1100)–C(500)
O(800A)–C(40A)
O(800A)–C(90A)
O(9 A)–C(400A)
O(900A)–C(1000A)
O(10A)–C(6A)
O(1100A)–C(500A)
O(1100)–C(1200) 1 416(4)
O(1100A)–C(1200A) 1 403(5)
, -Dibromo-3-isopropoxy-4-methoxystyrene (7)
C(10)–C(2)
C(100)–C(20)
C(100)–C(60)
C(1 )–C(200)
C(100)–C(3)
C(100)–C(600)
C(2)–C(3)
C(20)–C(30)
C(200)–C(300)
C(3a)–C(3)
C(3a)–C(4)
C(3a)–C(7a)
C(30)–C(40)
C(300)–C(400)
C(4)–C(5)
C(40)–C(50)
C(400)–C(500)
C(5)–C(6)
C(50)–C(60)
C(500)–C(600)
C(6)–C(7)
C(7a)–C(7)
Cl(1)–C(51)
Cl(2)–C(51)
1 459(4)
1 395(4)
1 386(4)
1 387(4)
1 486(4)
1 387(4)
1 361(4)
1 369(4)
1 388(4)
1 449(4)
1 391(4)
1 378(4)
1 401(4)
1 397(4)
1 375(4)
1 378(4)
1 381(4)
1 407(4)
1 382(5)
1 383(4)
1 373(4)
1 380(4)
1 731(9)
1 778(7)
C(10A)–C(2A)
C(100A)–C(20A)
C(100A)–C(60A)
C(1 A)–C(200A)
C(100A)–C(3A)
C(100A)–C(600A)
C(2A)–C(3A)
C(20A)–C(30A)
C(200A)–C(300A)
C(3aA)–C(3A)
C(3aA)–C(4A)
C(3aA)–C(7aA)
C(30A)–C(40A)
C(300A)–C(400A)
C(4A)–C(5A)
C(40A)–C(50A)
C(400A)–C(500A)
C(5A)–C(6A)
C(50A)–C(60A)
C(500A)–C(600A)
C(6A)–C(7A)
C(7aA)–C(7A)
Cl(3)–C(52)
1 455(4)
1 398(4)
1 395(4)
1 379(4)
1 486(4)
1 392(4)
1 363(4)
1 372(4)
1 393(4)
1 446(4)
1 399(4)
1 383(4)
1 399(4)
1 385(4)
1 372(4)
1 384(4)
1 388(4)
1 421(4)
1 387(4)
1 386(4)
1 369(4)
1 383(4)
1 77(2)A
1 78(2)A
Carbon tetrabromide (51 3 g, 154 7 mmol) was added
portionwise to a magnetically stirred mixture of zinc dust (10 1
g, 154 5 mmol) and PPh3 (40 5 g, 154 4 mmol) in CH2Cl2
(350 ml) maintained at 0 C on an ice-salt bath. The resulting
suspension was allowed to warm to 18 C and then stirred
at this temperature for a further 22 h. After this time the
reaction mixture was recooled to 0 C and aldehyde (6)27 (15 0
g, 77 3 mmol) was added dropwise over 2 min. The resulting
mixture was allowed to stir at 18 C for 1 h then diluted
with hexane (200 ml) and ltered through a No. 3 porosity
sintered-glass funnel. The ltrate was concentrated onto silica
gel (400–200 mesh, 30 g) and the resulting solid added to the
top of a ash chromatography column (20 cm long by 10 cm
wide) which was subjected to gradient elution with 2 : 1, 1 : 1
then 1 : 2 hexane/CH2Cl2. Concentration of the appropriate
fractions then a orded the title compound (7)22 (27 0 g, 99%)
(RF 0 5 in 1 : 1 hexane/CH2Cl2) as white crystalline masses,
m.p. 67–69 C (Found: C, 41 1; H, 3 7: Br, 45 3. Calc. for
C12H14Br2O2: C, 41 2; H, 4 0; Br, 45 7%).
(KBr)
max
3009, 2975, 2929, 1597, 1572, 1508, 1463, 1441, 1429, 1373,
1
1301, 1276, 1260, 1233, 1144, 1110, 999 cm
.
1H n.m.r.
7 38, s, 1H; 7 24, d, J 2 1 Hz, 1H; 7 08, dd, J 8 4 and 2 1
Hz, 1H; 6 84, d, J 8 4 Hz, 1H; 4 53, septet, J 6 0 Hz, 1H;
3 86, s, 3H; 1 38, d, J 6 0 Hz, 6H. 13C n.m.r. 150 5 (C),
146 7 (C), 136 4 (CH), 127 7 (C), 122 1 (CH), 115 3 (CH),
Cl(4)–C(52)
A
Restraint applied during re nement.

Benzofuran Analogue of Combretastatin A4
771
111 3 (CH), 87 0 (C), 71 4 (CH), 55 8 (CH3), 22 0 (CH3).
Mass spectrum m/z 352 (20%) 350 (40) 348 (22) (M+ ), 310
(50) 308 (100) 306 (50) [(M C3H6)+ ], 295 (30), 293 (61)
291 (33) [(M C3H6 CH3 )+].
Iodine (14 4 g, 56 7 mmol) was then added portionwise (6
portions) over 0 6 h and the reaction mixture heated at re ux
for a further 6 5 h. The cooled reaction mixture was ltered
and the solids thus retained were rinsed with chloroform (50
ml). The combined ltrates were washed with Na2S2O5 (10%
w/w solution in water, 150 ml), NaHCO3 (saturated aqueous
solution, 150 ml) and water (150 ml) then dried (MgSO4),
ltered and concentrated under vacuum. The solid residue was
suspended in hexane (200 ml) and the resulting suspension
stirred vigorously for 1 h then cooled in an ice bath for 1
h and ltered, rinsing with ice-cold hexane (200 ml), to give
2-Iodo-5-isopropoxy-4-methoxybenzaldehyde (10)
Silver tri uoroacetate (12 5 g, 56 7 mmol) was added to
a solution of 3-isopropoxy-4-methoxybenzaldehyde (6) (10 0
g, 51 5 mmol) in dry chloroform (120 ml) maintained under
nitrogen and the resultant slurry stirred and heated to re ux.
Table 3. Selected interatomic angles (degrees) for (4), (2C25H24O8).CH2Cl2
Atoms Angle Atoms
106 2(2)
Angle
C(2)–O(1)–C(7a)
C(300)–O(700)–C(800)
C(50)–O(8)–C(9)
C(2A)–O(1A)–C(7aA)
106 1(2)
117 3(3)
118 2(3)
117 2(3)
115 5(3)
118 2(3)
121 3(3)
120 2(3)
118 4(3)
120 2(3)
120 2(3)
119 3(3)
114 3(2)
110 7(3)
134 8(3)
120 7(3)
120 0(3)
129 2(3)
124 1(3)
106 4(3)
135 0(3)
106 1(3)
118 9(3)
119 1(3)
120 5(3)
120 4(3)
124 6(3)
115 5(3)
120 0(3)
118 3(3)
114 4(3)
126 0(3)
119 6(3)
119 8(3)
120 2(3)
119 9(3)
125 7(3)
113 1(3)
121 2(3)
119 8(3)
115 1(3)
124 6(3)
120 2(3)
120 3(3)
119 0(3)
120 8(3)
121 0(3)
119 7(3)
116 8(3)
110 6(3)
125 5(3)
123 9(3)
105(1)A
117 5(3)
118 8(3)
117 9(3)
114 4(2)
117 2(3)
121 5(3)
120 9(3)
117 6(3)
119 7(3)
120 1(3)
120 2(3)
113 5(2)
110 5(3)
135 9(3)
121 5(3)
119 8(3)
128 2(3)
125 1(3)
106 7(3)
135 5(3)
106 1(3)
118 4(3)
119 3(3)
120 6(3)
120 1(3)
124 5(3)
115 4(3)
120 1(3)
118 5(3)
114 4(3)
126 7(3)
119 0(3)
120 3(3)
120 2(3)
119 4(3)
125 9(3)
112 6(3)
121 5(3)
120 3(3)
115 7(3)
123 6(3)
120 7(3)
120 4(3)
118 8(3)
120 7(3)
121 4(3)
119 9(3)
116 2(3)
110 5(3)
124 8(3)
124 7(3)
108 8(5)A
C(300A)–O(700A)–C(800A)
C(50A)–O(8A)–C(9A)
C(4 )–O(80)–C(90)
C(400)–O(900)–C(1000)
C(500)–O(1100)–C(1200)
C(2)–C(10)–C(20)
C(20)–C(10)–C(60)
C(2 )–C(10)–C(60)
C(200)–C(100)–C(3)
C(200)–C(100)–C(600)
C(3)–C(100)–C(600)
O(1)–C(2)–C(10)
O(1)–C(2)–C(3)
C(4 A)–O(80A)–C(90A)
C(400A)–O(900A)–C(1000A)
C(500A)–O(1100A)–C(1200A)
C(2A)–C(10A)–C(20A)
C(20A)–C(10A)–C(60A)
C(2 A)–C(10A)–C(60A)
C(200A)–C(100A)–C(3A)
C(200A)–C(100A)–C(600A)
C(3A)–C(100A)–C(600A)
O(1A)–C(2A)–C(10A)
O(1A)–C(2A)–C(3A)
C(100A)–C(2A)–C(3A)
C(100A)–C(20A)–C(30A)
C(1 A)–C(200A)–C(300A)
C(100A)–C(3A)–C(2A)
C(100A)–C(3A)–C(3aA)
C(2A)–C(3A)–C(3aA)
C(3A)–C(3aA)–C(4A)
C(3A)–C(3aA)–C(7aA)
C(4A)–C(3aA)–C(7aA)
O(70A)–C(30A)–C(20A)
O(700A)–C(30A)–C(40A)
C(20A0 )–C(30A)–C(40A)
O(7 A)–C(300A)–C(200A)
O(700A)–C(300A)–C(400A)
C(200A)–C(300A)–C(400A)
C(3aA)–C(4A)–C(5A)
O(80A)–C(40A)–C(30A)
O(800A)–C(40A)–C(50A)
C(30A0 )–C(40A)–C(50A)
O(9 A)–C(400A)–C(300A)
O(900A)–C(400A)–C(500A)
C(300A)–C(400A)–C(500A)
O(8A)–C(5A)–C(4A)
C(100)–C(2)–C(3)
C(100)–C(20)–C(30)
C(1 )–C(200)–C(300)
C(100)–C(3)–C(2)
C(100)–C(3)–C(3a)
C(2)–C(3)–C(3a)
C(3)–C(3a)–C(4)
C(3)–C(3a)–C(7a)
C(4)–C(3a)–C(7a)
O(70)–C(30)–C(20)
O(700)–C(30)–C(40)
C(20)0–C(30)–C(40)00
O(7 )–C(300)–C(2 )
O(700)–C(300)–C(400)
C(200)–C(300)–C(400)
C(3a)–C(4)–C(5)
O(80)–C(40)–C(30)
O(800)–C(40)–C(50)
C(30)0–C(40)–C(50)
O(9 )–C(4000)–C(300)
O(900)–C(4 )–C(500)
C(300)–C(400)–C(500)
O(8)–C(5)–C(4)
O(8)–C(5)–C(6)
C(4)–C(5)–C(6)
O(8A)–C(5A)–C(6A)
C(4A)–C(5A)–C(6A)
C(40)–C(50)–C(60)
O(1100)–C(500)–C(400)
O(1100)–C(500)–C(600)
C(400)–C(500)–C(600)
O(10)–C(6)–C(5)
O(10)–C(6)–C(7)
C(5)–C(6)–C(7)
C(40A)–C(50A)–C(60A)
O(1100A)–C(500A)–C(400A)
O(1100A)–C(500A)–C(600A)
C(400A)–C(500A)–C(600A)
O(10A)–C(6A)–C(5A)
O(10A)–C(6A)–C(7A)
C(5A)–C(6A)–C(7A)
C(10)–C(60)–C(50)
C(100)–C(600)–C(500)
C(6)–C(7)–C(7a)
O(1)–C(7a)–C(3a)
O(1)–C(7a)–C(7)
C(3a)–C(7a)–C(7)
Cl(1)–C(51)–Cl(2)
C(10A)–C(60A)–C(50A)
C(100A)–C(600A)–C(500A)
C(6A)–C(7A)–C(7aA)
O(1A)–C(7aA)–C(3aA)
O(1A)–C(7aA)–C(7A)
C(3aA)–C(7aA)–C(7A)
Cl(3)–C(52)–Cl(4)
A
Restraint applied during re nement.

772
M. G. Banwell et al.
2-iodo-5-isopropoxy-4-methoxybenzaldehyde (10) (15 3 g, 93%)
as a cream solid, m.p. 75–76 C (Found: C, 41 1; H, 3 8; I,
of a column of silica (40–10 mesh t.l.c. grade, 10 cm wide by 5
cm long) and eluted with 2 : 1, 1 : 1 and 1 : 2 hexane/CH2Cl2
then neat CH2Cl2 (250 ml of each). The appropriate fractions
were concentrated under reduced pressure to give the title
compound (5) (16 2 g, 93%) (RF 0 3 in 1 : 2 hexane/CH2Cl2)
as white crystalline masses, m.p. 139–140 C (Found: C, 71 5;
39 6. C11H13IO3 requires C, 41 3; H, 4 1; I, 39 6%).
max
(KBr) 3072, 2978, 2932, 1673, 1581, 1503, 1438, 1385, 1332,
1
1260, 1215, 1174, 1157, 1133, 1105, 1024, 939 cm
.
1H n.m.r.
9 77, s, 1H; 7 34, s, 1H; 7 24, s, 1H; 4 57, septet, J 6 0 Hz,
1H; 3 86, s, 3H; 1 31, d, J 6 0 Hz, 6H. 13C n.m.r. 194 7
(CH), 155 5 (C), 147 9 (C), 128 2 (C), 122 2 (CH), 114 1
(CH), 92 4 (C), 71 3 (CH), 56 4 (CH3), 21 8 (CH3). Mass
spectrum (70 eV) m/z 320 (M+ , 43%), 278 (100), 249 (17),
207 (12), 150 (40).
H, 7 1. C22H26O5 requires C, 71 3; H, 7 1%).
(KBr)
max
3431, 2983, 2934, 1513, 1461, 1332, 1267, 1241, 1210, 1136,
1
1110, 1024 and 991 cm
.
1H n.m.r. 7 12, dd, J 8 1 and
2 1 Hz, 1H; 7 10, d, J 2 1 Hz, 1H; 6 88, s, 1H; 6 84, d,
J 8 1 Hz, 1H; 6 56, s, 1H; 5 61, s, 1H; 4 55, septet, J 6 0
Hz, 2 1H; 3 88, s, 3H; 3 82, s, 3H; 1 38, 2 d, J 6 0 Hz,
5-Isopropoxy-2-[2 0-(3 00-isopropoxy-4 00-methoxyphenyl)-
ethynyl]-4-methoxybenzaldehyde (11)
2
6H. 13C n.m.r. 151 8 (C), 151 1 (C), 149 6 (C), 147 0
(C), 143 9 (C), 125 1 (CH), 118 4 (CH), 114 8 (C), 114 2
(CH), 111 7 (CH), 101 9 (CH), 100 0 (C), 95 2 (C), 81 8 (C),
71 6 (CH), 71 2 (CH), 56 7 (CH3), 56 0 (CH3), 22 1 (CH3),
21 9 (CH3). Mass spectrum m/z 370 (68, M+ ), 328 [24,
Butyllithium (45 8 ml of a 2 5 M solution in hexane, 114 5
mmol) was added dropwise over 0 2 h to a magnetically stirred
solution of dibromostyrene (7) (20 0 g, 57 2 mmol) in tetrahy-
drofuran (250 ml) maintained at 78 C on a dry-ice/acetone
bath. The slightly tan-coloured solution thereby obtained was
stirred at 78 C for 0 5 h then the reaction vessel was removed
from the cooling bath. After 0 1 h anhydrous ZnCl2 (7 79 g,
57 2 mmol, dried at 120 C/0 01 mmHg for 20 h) was added
to the reaction mixture which slowly became colourless as it
was warmed to 18 C over 1 h. Aldehyde (10) (17 8 g, 55 6
mmol) then PdCl2(PPh3)2 (195 mg, 0 128 mmol) were added
and the reaction mixture was stirred at 18 C for 6 h. After this
time the reaction mixture was diluted with ethyl acetate (600
ml) and washed with water (2 500 ml) then dried (MgSO4),
ltered and concentrated under reduced pressure. The solid
thereby obtained was suspended in ether/hexane (100 ml of a
4 : 1 v/v mixture) and the resulting suspension was subjected to
vacuum ltration and the solid thus retained was washed with
ether/hexane (2 50 ml of a 4 : 1 v/v mixture) to a ord tolan
(11) (16 5 g, 78%) as white crystalline masses, m.p. 110–113 C.
Subjection of the combined ltrates to ash chromatography
(silica, 1 : 1, 1 : 2 hexane/CH2Cl2, CH2Cl2 and then CH2Cl2
gradient elution) followed by concentration of the appropriate
fractions a orded additional quantities of compound (11) (3 64
(M H2C=CHCH3)+ ], 286 [70, (M
2
H2C=CHCH3)+ ],
271 [100, (M
2
H2C=CHCH3 CH3 )+].
3-Iodo-6-isopropoxy-2-(3 0-isopropoxy-4 0-methoxyphenyl)-5-
methoxybenzofuran (13)
N -Iodosuccinimide (139 mg, 0 618 mmol) was added to a
solution of o-hydroxytolan (5) (218 mg, 0 588 mmol) in dry
dimethylformamide (4 ml) at 18 C. After stirring for 1 h the
reaction mixture was transferred to a separatory funnel, diluted
with ethyl acetate (30 ml) and washed with Na2S2O5 (1 30
ml of a 10% w/v aqueous solution) and water (2 20 ml).
The organic phase was dried (MgSO4), ltered and concen-
trated under reduced pressure. The residue thus obtained was
subjected to ash chromatography (silica, 7 : 1 hexane/ether
elution) and the relevant fractions were collected and concen-
trated under reduced pressure to give the title compound (13)
(291 mg, 99%) (RF 0 7 in CH2Cl2) as a white solid, m.p.
115–117 C.
(KBr) 3089, 3006, 2982, 2930, 1619, 1603,
max
1587, 1563, 1504, 1483, 1469, 1452, 1439, 1314, 1285, 1255,
1
1236, 1205, 1151, 1113, 975 cm
.
1H n.m.r. 7 70, s, 1H;
7 68, d, J 8 1 Hz, 1H; 7 08, s, 1H; 6 96, d, J 8 1 Hz, 1H;
6 83, s, 1H; 4 66, septet, J 6 0 Hz, 1H; 4 55, s, J 6 0 Hz,
1H; 3 95, s, 3H; 3 91, s, 3H; 1 44, d, J 6 0 Hz, 6H; 1 41, d,
J 6 0 Hz, 6H. 13C n.m.r. 150 4 (C), 148 4 (C), 148 1 (C),
147 0 (C), 146 8 (C), 146 6 (C), 122 3 (C), 120 7 (C), 119 0
(CH), 113 0 (CH), 111 7 (CH), 106 1 (C), 100 0 (CH), 99 4
(CH), 72 0 (CH), 71 4 (CH), 56 3 (CH3), 55 8 (CH3), 22 0
g, 14%) (RF 0 4 in CH2Cl2).
(KBr) 2978, 2933, 2837,
max
2203, 1685, 1589, 1515, 1508, 1448, 1397, 1387, 1376, 1358,
1
1322, 1276, 1240, 1216, 1156, 1132, 1091 cm
.
1H n.m.r.
10 49, s, 1H; 7 41, s, 1H; 7 21, dd, J 8 4 and 2 4 Hz, 1H;
7 06, d, J 2 4 Hz, 1H; 7 03, s, 1H; 6 84, d, J 8 4 Hz, 1H; 4 70,
septet, J 6 0 Hz, 1H; 4 57, septet, J 6 0 Hz, 1H; 3 97, s, 3H;
3 88, s, 3H; 1 40, 2 d, J 6 0 Hz, 2 6H. 13C n.m.r. 190 5
(CH), 154 5 (C), 151 2 (C), 147 8 (C), 146 9 (C), 129 7 (C),
125 2 (CH), 121 5 (C), 118 2 (CH), 114 4 (CH), 111 7 (CH),
110 7 (CH), 95 0 (C), 83 4 (C), 71 4 (CH), 71 1 (CH), 56 1
(CH3), 55 8 (CH3), 21 9 (CH3), 21 8 (CH3). Mass spectrum
(CH3), 21 8 (CH3). Mass spectrum (70 eV) m/z 496 (M+
14%), 454 (8, M+
CH2=CHCH3), 404 (84), 362 (72), 320
,
(100), 305 (67). High-resolution mass spectrum m/z 496 0739
(C22H25IO5 requires 496 0747).
6-Isopropoxy-2-(3 0-isopropoxy-4 0-methoxyphenyl)-5-
methoxy-3-(3 00,4 00,5 00-trimethoxyphenyl)benzofuran (17)
m/z 382 (31%, M+ ), 298 [100, (M
2
H2C=CHCH3)+ ], 283
[46, (M
2
H2C=CHCH3 CH3 )+]. High-resolution mass
spectrum m/z 382 1781 (C23H26O5 requires 382 1780).
t-Butyllithium (0 53 ml of a 1 7 M solution in pentane,
0 90 mmol) was added dropwise to a magnetically stirred
solution of 5-iodo-1,2,3-trimethoxybenzene (14) (132 mg, 0 45
mmol) in dry tetrahydrofuran (3 ml) maintained at 78 C
(dry-ice/acetone bath). Stirring was continued for a further
0 2 h then anhydrous zinc chloride (62 0 mg, 0 46 mmol) was
added and the cold bath removed. Whilst warming, compound
(13) (180 mg, 0363) and Pd(PPh3)4 (21 5 mg, 0 019 mmol)
were added and the reaction mixture was then stirred at 18 C
for 21 h. The reaction mixture was concentrated onto silica (3
g) and the residue subjected to ash chromatography (silica,
4 : 1 hexane/ethyl acetate). Concentration of the appropriate
fractions gave the title compound (17) (142 mg, 73%) (RF
0 4 in 4 : 1 hexane/ethyl acetate) as white crystalline masses,
5-Isopropoxy-2-[2 0-(3 00-isopropoxy-4 00-methoxyphenyl)-
ethynyl]-4-methoxyphenol (5)
m-Chloroperoxybenzoic acid [19 4 g, Aldrich, 50% (remain-
der 3-chlorobenzoic acid and water), c. 56 mmol] was added
in portions over 0 25 h to a magnetically stirred mixture of
compound (11) (18 0 g, 47 1 mmol) and KHCO3 (14 1 g,
141 0 mmol) in CH2Cl2 (220 ml) maintained at 0 C (ice
bath). The resulting slurry was stirred for a further 1 h
between 0 and 18 C then ltered through CeliteTM and the
solids thus retained were rinsed with CH2Cl2 (1 200 ml). The
combined ltrates were concentrated under reduced pressure
and the residue was treated with NH3 (1 300 ml of a saturated
methanolic solution). After 1 h at 18 C the reaction mixture
was concentrated under reduced pressure and the residue redis-
solved in CH2Cl2 (200 ml) then concentrated onto silica gel
(20 g, 400–200 mesh). The resulting powder was loaded on top
m.p. 118–120 C.
(KBr) 3089, 3006, 2982, 2930, 1619,
max
1603, 1587, 1563, 1504, 1483, 1469, 1452, 1439, 1314, 1285,
1
1255, 1236, 1205, 1151, 1113, 975 cm
dd, J 8 4 and 1 8 Hz, 1H; 7 14, s, 1H; 7 09, d, J 1 8 Hz,
.
1H n.m.r. 7 68,

Benzofuran Analogue of Combretastatin A4
773
1H; 6 88, s, 1H; 6 85, d, J 8 4 Hz, 1H; 6 70, s, 2H; 4 57,
septet, J 6 0 Hz, 1H; 4 27, s, J 6 0 Hz, 1H; 3 93, s, 3H;
3 87, s, 3H; 3 86, s, 3H; 3 82, s, 6H; 1 43, d, J 6 0 Hz,
re ned in the least-squares procedure; the remaining hydrogen
atoms were included at idealized positions and not re ned. All
calculations were performed with the teXsan structure analysis
software of Molecular Structure Corporation.36
6H; 1 27, d, J 6 0 Hz, 6H. 13C n.m.r.
153 7 (C), 149 9
(C), 149 8 (C), 148 1 (C), 146 8 (C), 146 0 (C), 137 2 (C),
128 9 (C), 123 5 (C), 123 0 (C), 119 2 (CH), 116 2 (C), 113 1
(CH), 111 5 (CH), 106 5 (CH), 101 5 (CH), 99 5 (CH), 72 1
(CH), 71 0 (CH), 60 9 (CH3), 56 6 (CH3), 56 0 (CH3), 55 9
(CH3), 22 0 (CH3), 21 9 (CH3). Mass spectrum (70 eV) m/z
Atomic coordinates, bond lengths and angles, and displace-
ment parameters have been deposited along with structure
factor listings (copies are available, until 31 December 2004,
from the Australian Journal of Chemistry, P.O. Box 1139,
Collingwood, Vic. 3066).
536 (M+ , 100%), 494 (71, M+
M+
CH2=CHCH3). High-resolution mass spectrum m/z
CH2=CHCH3), 452 (22,
2
Acknowledgment
536 2417 (C31H36O8 requires 536 2410).
We thank the Institute of Advanced Studies at the
Australian National University for nancial support
including the provision of a postdoctoral stipend to
B.L.F.
2-(3 0-Hydroxy-4 0-methoxyphenyl)-5-methoxy-3-(3 00,4 00,5 00
trimethoxyphenyl)benzofuran-6-ol (4)
-
Aluminium chloride (29 2 mg, 0 220 mmol) was added, in
one portion, to a magnetically stirred solution of compound
(17) (42 0 mg, 0 078 mmol) in dry CH2Cl2 (2 0 ml) main-
tained under a nitrogen atmosphere. Stirring was continued
at 18 C for 24 h then the reaction mixture was quenched
with NH4Cl (2 ml of a saturated aqueous solution). The
resulting mixture was transferred to a separatory funnel and
diluted with ethyl acetate (15 ml). The separated organic
phase was washed with brine (2 15 ml) then dried (MgSO4),
ltered and concentrated onto silica (1 0 g). The residue was
subjected to ash chromatography (silica, 20 : 1 CH2Cl2/ether)
and the appropriate fractions were concentrated under reduced
pressure to give the title compound (4) (32 5 mg, 92%) (RF
0 3 in 20 : 1 CH2Cl2/ether) as pale-yellow crystalline masses,
References
1
Lin, C. M., Singh, S. B., Chu, P. S., Dempcy, R. O., Schmidt,
J. M., Pettit, G. R., and Hamel, E., Mol. Pharmacol., 1988,
34, 200.
Pettit, G. R., Singh, S. B., Hamel, E., Lin, C. M., Alberts,
2
D. S., and Garcia-Kendall, D., Experientia, 1989, 45, 209.
Lin, C. M., Ho, H. H., Pettit, G. R., and Hamel, E.,
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3
4
Woods, J. A., Had eld, J. A., Pettit, G. R., Fox, B. W.,
and McGown, A. T., Br. J. Cancer, 1995, 71, 705.
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For a review in the area see: Sackett, D. L., Pharmacol.
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Dark, G. G., Hill, S. A., Prise, V. E., Tozer, G. M., Pettit,
5
m.p. 186–188 C.
(KBr) 3426, 3006, 2936, 1606, 1584,
max
1512, 1489, 1469, 1431, 1413, 1392, 1359, 1323, 1297, 1240,
6
1
1212, 1147, 1126, 1029, 1003 cm
.
1H n.m.r. 7 26, d, J
2 2 Hz, 1H; 7 14, dd, J 8 7 and 2 2 Hz, 1H; 7 13, s, 1H;
6 86, s, 1H; 6 79, d, J 8 7 Hz, 1H; 6 70, s, 2H; 5 85, s, 1H;
5 61, s, 1H; 3 96, s, 3H; 3 90, s, 3H; 3 89, s, 3H; 3 82, s,
6H. 13C n.m.r. 153 7 (C), 149 3 (C), 148 5 (C), 146 5 (C),
145 4 (C), 144 3 (C), 137 4 (C), 128 7 (C), 124 3 (C), 122 4
(C), 118 8 (CH), 116 5 (C), 112 7 (CH), 110 5 (CH), 106 8
(CH), 100 3 (CH), 97 6 (CH), 61 1 (CH3), 56 5 (CH3), 56 2
7
G. R., and Chaplin, D. J., Cancer Res., 1997, 57, 1829.
Bedford, S. B., Quarterman, C. P., Rathbone, D. L., Slack,
8
J. A., Gri n, R. J., and Stevens, M. F. G., Bioorg. Med.
Chem. Lett., 1996, 6, 157.
Brown, R. T., Fox, B. W., Had eld, J. A., McGown, A.
9
T., Mayalarp, S. P., Pettit, G. R., and Woods, J. A., J.
Chem. Soc., Perkin Trans. 1, 1995, 577.
Pettit, G. R., Temple, C., Jr, Narayanan, V. L., Varma, R.,
(CH3), 55 9 (CH3). Mass spectrum (70 eV) m/z 452 (M+
100%), 437 (12, M+
CH3). High-resolution mass spectrum
,
10
m/z 452 1467 (C25H24O8 requires 452 1471).
Simpson, M. J., Boyd, M. R., Rener, G. A., and Bansal,
N., Anti-Cancer Drug Des., 1995, 10, 299.
Dorr, R. T., Dvorakova, K., Snead, K., Alberts, D. S.,
Structure Determination
11
Crystal data. Compound (4): (2C25H24O8).CH2Cl2, M
989 85, pale-yellow crystal, 0 23 by 0 16 by 0 10 mm, T
298(1) K, monoclinic, space group P 21/n, a 13 768(2), b
20 980(2)(3), c 17 319(2) A, 105 331(8) , V 4824 7(9) A3,
Dc(Z = 4) 1 363 g cm 3, F(000) 2072, (Cu K ) 18 23
cm 1, analytical absorption correction (transmission factors:
Salmon, S. E., and Pettit, G. R., Invest. New Drugs, 1996,
14, 131.
Nandy, P., Banerjee, S., Gao, H., Hui, M. B. V., and Lien,
E. J., Pharm. Res., 1991, 8, 776.
Lin, C. M., Kang, G. J., Roach, M. Ca., Jiang, J. B., Hesson,
D. P., Luduena, R. F., and Hamel, E., Mol. Pharmacol.,
1991, 40, 827.
Andres, C. J., Bernardo, J. E., Yan, Q., Hastie, S. B., and
Macdonald, T. L., Bioorg. Med. Chem. Lett., 1993, 3, 565.
Shirai, R., Tokuda, K., Koiso, Y., and Iwasaki, S., Bioorg.
Med. Chem. Lett., 1994, 4, 699.
Ohsumi, K., Tsuji, T., Morinaga, Y., and Ohishi, K., Eur.
Pat. Appl., EP 641767 A1 950308 (Chem. Abstr., 1995, 122,
265183); Hatanaka, T., Fujita, K., Ohsumi, K., Nakagawa,
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12
13
0 65–0 79); 7413 unique data (2
120 1 ), 4952 with I
max
14
> 3 (I ); R 0 046, Rw 0 055, goodness of t 2 17, residual
3
electron density maximum 0 32 e A
.
15
Data collection, structure solution and re nement. Data
were measured on a Rigaku AFC6R rotating-anode di rac-
tometer (graphite crystal monochromator, 1 54178 A). The
structure was solved by direct methods,35 which revealed that
there were two independent molecules of C25H24O8 and one
molecule of CH2Cl2 in the crystallographic asymmetric unit,
the latter being disordered over two orientations of relative
occupancies 0 857(2) : 0 143. The structure of molecule 2 is
shown in Fig. 1. Molecule 1 is identical with the exception that
the dihedral angle between the mean planes of the C(3) aryl
ring and the benzofuran moiety is 59 in one case and 65 in
the other. Re nement was by full-matrix least-squares analysis
on F. Anisotropic displacement parameters were used for all
non-hydrogen atoms except the minor sites of the disordered
dichloromethane molecule. Hydrogen atoms of the alcohol
groups were located in di erence electron-density maps and
16
17
18
19
A. D., and Sappen eld, E. L., J. Chem. Crystallogr., 1996,
26, 801.

774
M. G. Banwell et al.
20
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No. M118, Book of Abstracts, 35th National Organic Chem-
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For examples of related chemistry which has been con-
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21
22
23
24
25
26
27
28
29
34
35
36
teXsan: Single Crystal Structure Analysis Software, Ver-
sion 1.9, Molecular Structure Corporation, The Woodlands,
Texas 77381, U.S.A., 1997.
30
31
32
33
Note Added in Proof
Pinney and coworkers (Pinney, K. G., Bounds, A. D.,
Dingeman, K. M., Mocharla, V. P., Pettit, G. R., Bai, R.,
and Hamel, E., Bioorg. Med. Chem. Lett., 1999, 9, 1081) have
recently published details of their work on the synthesis and
biological evaluation of compound (2).