The first total synthesis of toddaquinoline, an alkaloid from Toddalia asiatica

Article abstract of DOI:10.1016/S0040-4020(01)00336-2

The paper describes the first total synthesis of toddaquinoline, an alkaloid from the root bark of Formosan Toddalia asiatica. The key step is cobalt(I) mediated radial cyclisation to a pyridine. Cobalt appears to play a dual role in the reaction, firstly initialising homolysis of the carbon to halogen bond then acting as a Lewis acid to promote cyclisation to C-6. Other approaches examined are also outlined. These include a photocyclisation of an azastilbene; a cyclisation induced by halogen to metal exchange and a tin mediated radical cyclisation.

Full text of DOI:10.1016/S0040-4020(01)00336-2

TETRAHEDRON
Pergamon
Tetrahedron 57 -2001) 4447±4454
The ®rst total synthesis of toddaquinoline, an alkaloid from
Toddalia asiatica
David C. Harrowven,a,p Michael I. T. Nunn,a Nigel J. Blumirea and David R. Fenwickb
aDepartment of Chemistry, The University, Southampton SO17 1BJ, UK
bDiscovery Chemistry, P®zer Global Research and Development, Sandwich, Kent CT13 9NJ, UK
Received 23February 2001; accepted 15 March 2001
AbstractÐThe paper describes the ®rst total synthesis of toddaquinoline, an alkaloid from the root bark of Formosan Toddalia asiatica. The
key step is cobalt-I) mediated radial cyclisation to a pyridine. Cobalt appears to play a dual role in the reaction, ®rstly initialising homolysis
of the carbon to halogen bond then acting as a Lewis acid to promote cyclisation to C-6. Other approaches examined are also outlined. These
include a photocyclisation of an azastilbene; a cyclisation induced by halogen to metal exchange and a tin mediated radical cyclisation.
q 2001 Elsevier Science Ltd. All rights reserved.
1. Background
mode of cyclisation was uncertain.5 Our synthesis of
azastilbene 8 was straightforward and began with 3,5-dibro-
mopyridine 2. Nucleophilic aromatic substitution of one of
the aryl halides with methoxide gave 3 which,6 on treatment
with butyllithium and quenching with DMF, was readily
transformed into aldehyde 4.6 A Wittig coupling with the
ylid derived from 7 then gave a 1:1 mixture of cis- and
trans-azastilbenes 8. Unfortunately, when a cyclohexane
solution of 8 was irradiated using a medium pressure lamp
the major product given was benzo[f]isoquinoline 10
-54%), resulting from cyclisation between C-4 of the
pyridine and C-6 of the benzo[1,3]dioxole.5 Toddaquinoline
methyl ether 9 was also isolated as a minor component in
20% yield together with 23% recovered azastilbenes 8
-Scheme 1).
In 1993, Chen et al. reported the isolation and
characterisation of an unusual alkaloid found in the root
bark of Formosan Toddalia asiatica,1 a constituent of
many Asian folk medicines.2 Named toddaquinoline, its
structure 1 was elucidated by a series of NMR and
derivatisation experiments, and featured a unique tetracyclic
skeleton. However, the low yield from natural sources
coupled with the inevitable losses suffered during structural
determination, left insuf®cient material to allow meaningful
biological testing to be completed. Thus, toddaquinoline
attracted our attention as a target for total synthesis.3
3. Using an intramolecular addition of an aryllithium to
a pyridine
Our second approach employed an intramolecular
cyclisation induced by the addition of a polar organo-
metallic species to the pyridine. In principle, this strategy
would bias the reaction in favour of addition to the more
electrophilic C-6 of the pyridine; the disadvantage being the
need to control the alkene geometry.7 To test its
effectiveness we prepared the phosphonium salt 12 and
coupled it with aldehyde 4 using standard Wittig chemistry.8
Pleasingly, the resulting azastilbenes 13 and 14 were formed
as a 2:5 mixture of diastereoisomers favouring the desired
-Z)-alkene.
2. A photocyclisation approach
The ®rst strategy involved photocyclisation of an
azastilbene, viz. 8!9.4 While this approach was convergent
and did not require a speci®c alkene geometry for 8, the
Keywords: radicals and radical reactions; natural products; polycyclic
heterocyclic compounds; cobalt and its compounds; photochemistry; pyri-
dines.
Corresponding author. Tel.: 144-23-8059-3302; fax: 144-23-8059-
3781; e-mail: dch2@soton.ac.uk
p
When a cooled THF solution of 14 was treated with n-BuLi
two tetracyclic products were obtained. The major
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020-01)00336-2

4448
D. C. Harrowven et al. / Tetrahedron 57 .2001) 4447±4454
Scheme 1.
component proved to be rather unstable and, though this
prevented full characterisation, it was clear that the reaction
had followed an unexpected course. Indeed, analysis
showed that a new carbon to carbon bond had been created
between C-4 of the benzodioxole and C-6 of the pyridine
moiety suggesting that the intermediate aryllithium 16 had
equilibrated to the thermodynamically favoured aryllithium
17 -presumably via a dilithiated species) prior to cyclisation
-Scheme 2).9 The minor component, given in 11% yield,
exhibited spectral characteristics identical to those reported
for toddaquinoline methyl ether 9.
rearrangement. Though intermolecular radical additions to
pyridines were known to be inef®cient,10 the intramolecular
variant had received scant attention.11 It therefore seemed
appropriate to examine this option. Gratifyingly, treat-
ment of 14 under standard tin mediated radical cyclisation
conditions led to a separable 1:1 mixture of benzo[h]-
quinoline 9 and benzo[f]isoquinoline 10 in 58% yield.
The less polar product was shown to be toddaquinoline
methyl ether 9 through comparison of our spectral and
physical data with those reported in the isolation paper.1
Notably, though the reaction had been conducted under
reducing conditions, no products derived from hydrogen
atom transfer to the intermediates 19 or 20 were observed
-Scheme 3).12
4. Radical approaches
One disappointing feature of the aforementioned reaction
was its lack of regiochemical control. In seeking to improve
We now sought a method of generating a reactive inter-
mediate at C-6 of the benzodioxole that was not prone to
Scheme 2.

D. C. Harrowven et al. / Tetrahedron 57 .2001) 4447±4454
4449
Scheme 3.
the ef®ciency of our key step, other methods of generating
aryl radicals were investigated. These studies led us to
discover an interesting dichotomy between tin and cobalt
mediated radical cyclisations to pyridines.13 Thus, when
azastilbene 14 was exposed to sodium cobalt-I)salophen it
underwent cyclisation to toddaquinoline methyl ether 9
exclusively. That the tin and cobalt-I) mediated radical
cyclisations followed a different regiochemical course was
quite unexpected and, by analogy with vitamin B12
chemistry, may be due to the Lewis acidic nature of cobalt.14
It seems plausible that single electron transfer from
cobalt-I)salophen ®rst generates radical anion 21 in which
Co-II)salophen is complexed to the pyridine. This Lewis
acid±Lewis base interaction enhances electrophilicity at
C-6 in the pyridine and, hence, accelerates addition of the
nucleophilic aryl radical to that centre relative to C-4 -viz.
22!23). A dehydrocobaltation then liberates toddaquino-
line methyl ether -Scheme 4).
Scheme 4.
Scheme 5.

4450
D. C. Harrowven et al. / Tetrahedron 57 .2001) 4447±4454
5. Toddaquinoline total synthesis
6.1.1. [-1,3-Benzodioxol-5-yl)methyl]triphenylphospho-
nium bromide 7. A solution of piperonyl bromide 6
-5.70 g, 26.51 mmol) and triphenylphosphine -8.33 g,
31.81 mmol) in xylene -60 ml) was stirred at re¯ux for 3 h
then cooled to RT. The resulting white precipitate was
collected by ®ltration, washed with cold xylene -2£20 ml)
and petrol -3£20 ml) then dried in vacuo to provide the title
compound 7 -11.92 g, 24.99 mmol, 94%) as a white solid;
mp 227±2298C -xylene) [lit. 236.5±238.58C -toluene)];8 IR
-nujol, cm21) nmax 1586 w, 1502 w, 1488 m, 1250 m, 1110
m, 1037 m; UV -MeOH, nm) lmax -emax) 286 -6360), 272
-7160), 224 -38,560); 1H NMR -300 MHz, CDCl3) dH 7.79±
7.58 -15H, m, 15£PhH), 6.60 -1H, ddd, Jˆ8.1, 3.3, 1.8 Hz,
ArH), 6.54±6.50 -2H, m, 2£ArH), 5.85 -2H, s, OCH2O),
5.30 -2H, d, JP±Hˆ14.0 Hz, CH2P); 13C NMR -75 MHz,
CDCl3) dC 147.9 -2£C [Ar]), 135.2 -3£CH [Ph]), 134.5
-d, JP±Cˆ9.7 Hz, 6£CH [Ph]), 130.3 -d, JP±Cˆ12.5 Hz,
6£CH [Ph]), 125.6 -d, JP±Cˆ6.3Hz, CH [Ar]), 120.2
-JP±Cˆ9.1 Hz, C [Ar]), 117.9 -d, JP±Cˆ85.4 Hz, 3£C
[Ph]), 111.5 -CH [Ar]), 108.7 -CH [Ar]), 101.4 -OCH2O),
Our attempts to remove the methyl ether in 9 using a host of
deprotection methods either failed or provided toddaquino-
line 1 in low yield.15 Indeed, to complete a synthesis of
toddaquinoline required us to change to a benzyl protecting
group: the synthesis being summarised in Scheme 5.
In conclusion, we have completed the ®rst total synthesis of
toddaquinoline 1. Notable features are the facile intramole-
cular addition of an aryl radical to a pyridine and the dual
role played by cobalt in the cyclisation of 14 to 9. We are
presently examining further the dichotomy between the
cobalt-I) and tin mediated radical cyclisation reactions and
investigating other intramolecular radical additions to
aromatic and heteroaromatic substrates.16
6. Experimental section
6.1. General remarks
30.7 -d, JP±Cˆ46.7 Hz, CH2P); LRMS -ES1)
3 97
-[M2Br]1, 100%).
6.1.2. -E)- and -Z)-3-[200--10,30-Benzodioxol-50-yl)]-100-
ethenyl-5-methoxypyridine 8. Phosphonium bromide 7
-3.90 g, 8.18 mmol) was suspended in tetrahydrofuran
-50 ml) and cooled to 2788C. n-Butyllithium -1.37 M in
hexanes, 6.0 ml, 8.18 mmol) was added dropwise over
5 min and the resulting solution was stirred at 2788C for
10 min, warmed to RT over 30 min, then re-cooled to
2788C. A solution of 5-methoxy-3-pyridinecarboxaldehyde
4 -800 mg, 5.84 mmol) in tetrahydrofuran -5 ml) was added
dropwise over 5 min, the mixture was stirred for 30 min
then warmed to RT. After 6 h the reaction mixture was
®ltered through Celitew and concentrated in vacuo.
Puri®cation by column chromatography -silica gel, 30%
ether in petrol) yielded ®rstly -Z)-8 as a pale yellow oil
-265 mg, 1.04 mmol, 18%); IR -neat, cm21) nmax 3009 w,
1582 m, 1504 s, 1487 s, 1443 s, 1273 m, 1239 s, 1039 s, 935
m, 880 m, 804 m; UV -EtOH, nm) lmax -emax) 317 -16500),
300 -15200), 235 -17,500); 1H NMR -300 MHz, CDCl3), dH
8.14 -1H, d, J 2.9 Hz, PyH), 8.10 -1H, d, J 1.7 Hz, PyH),
7.08 -1H, dd, J 2.9, 1.7 Hz, PyH), 6.73-1H, s, Ar H), 6.72
-1H, d, J 8.5 Hz, ArH), 6.71 -1H, d, J 8.5 Hz, ArH), 6.64
-1H, d, J 12.0 Hz, yCH), 6.44 -1H, d, J 12.0 Hz, yCH), 5.93
-2H, s, OCH2O), 3.73 -3H, s, OCH3); 13C NMR -75 MHz,
CDCl3) dC 155.3- C [Py]), 147.7 -C [Ar]), 147.2 -C [Ar]);
142.7 -CH [Py]), 136.2 -CH [Py]), 132.5 -CH [Py]), 133.7
-C [Py]), 130.5 -C [Ar]), 125.4 -yCH), 123.1 -yCH), 120.2
-CH [Ar]), 109.0 -CH [Ar]), 108.6 -CH [Ar]), 101.2
-OCH2O), 55.5 -OCH3); LRMS -CI) m/z 255 -M1, 100%),
226 -8%), 196 -14%), 154 -28%), 127 -17%), 101 -6%);
HRMS -CI) m/z Found MH1: 256.0981, C15H14NO3
requires 256.0974; then a mixture of -Z)-8 and -E)-8
-400 mg, 1.57 mmol, 27%), and ®nally -E)-8 as a white
solid -530 mg, 2.08 mmol, 36%); mp 100±1028C -ether/
petrol); IR -nujol, cm21) nmax 1582 m, 1503s, 1488 s,
1444 s, 1253 s, 1193 m, 1038 s, 930 m, 704 m; UV
-MeOH, nm) lmax -emax) 348 -21,400), 304 -10,500), 268
-10500), 224 -18900); 1H NMR -300 MHz, CDCl3) dH 8.31
-1H, d, J 1.7 Hz, PyH), 8.19 -1H, d, Jˆ2.8 Hz, PyH), 7.30
-1H, dd, Jˆ2.8, 1.7 Hz, PyH), 7.09 -1H, d, Jˆ1.7 Hz, ArH),
7.08 -1H, d, Jˆ16.4 Hz, yCH), 6.97 -1H, dd, Jˆ8.1, 1.7 Hz,
Melting points were obtained using a Mel-Temp -II)
apparatus and are uncorrected. UV spectra were recorded
on a Pye Unicam SP800 spectrometer. IR spectra of oils and
mulls were recorded on a Perkin Elmer 1600 series Fourier
transform infrared spectrometer using NaCl cells. For most
solids, IR spectra were recorded directly using a Bio-Rad
FTS 135 Fourier transform infrared spectrometer equipped
with a Golden Gate Single Re¯ection Diamond ATR. NMR
spectra were recorded on a Bruker AC300 -operating at
1
300 MHz for H and at 75 MHz for 13C). Chemical shifts
-dH) are reported as values in parts per million relative to
tetramethylsilane -dH 0.00, dC 0.00), CDCl3 -dC 77.2) or
residual CHCl3 -dH 7.27). Mass spectra were recorded on
a variety of instruments either in house or at the EPSRC
mass spectrometry centre, Swansea.
All reactions were magnetically stirred under an inert
atmosphere. Photochemical reactions were performed in a
quartz reaction vessel with irradiation from a 125 W
medium pressure mercury lamp and were water cooled.
Reactions were monitored by thin layer chromatography
using Macherey-Nagel Alugram Sil G/UV254 precoated
aluminium foil plates of layer thickness 0.25 mm.
Compounds were visualised ®rstly by UV irradiation, then
by exposure to iodine vapour and ®nally by heating plates
exposed to solutions of phosphomolybdic acid in ethanol or
basi®ed aqueous potassium permanganate. Column
chromatography was performed on Sorbsil 60 silica -230±
400 mesh), slurry packed and run under low pressure.
Ether refers to diethyl ether and petrol refers to the fraction
of petroleum ether in the boiling point range 40±608C.
5-Bromo-3-methoxypyridine 3, mp 3 3 ±38C5-petrol) [lit.
34±358C -hexanes)],6 and 5-methoxy-3-pyridinecarbox-
aldehyde 4 were prepared by the methods of Comins and
Killpack.6 Piperonyl bromide 6, mp 44±468C -petrol) [lit.
46±488C -petrol)],17 was prepared by the method of Beard et
al.17 [-6-Bromo-1,3-benzodioxolo-5-yl)methyl]bromide 11,
mp 83±858C -ethanol) [lit. 89±918C -hexanes)18 was
prepared by the method of Padwa et al.18

D. C. Harrowven et al. / Tetrahedron 57 .2001) 4447±4454
4451
ArH), 6.90 -1H, d, Jˆ16.4 Hz, yCH), 6.83-1H, d,
Jˆ8.1 Hz, ArH), 5.99 -2H, s, OCH2O), 3.94 -3H, s,
OCH3); 13C NMR -75 MHz, CDCl3) dC 155.9 -C [Py]),
148.4 -C [Ar]), 148.0 -C [Ar]), 141.2 -CH, [Py]), 137.7
-CH [Py]), 133.9 -C [Py]), 131.3 -C [Ar]), 130.8 -CH
[Py]), 123.1 -yCH), 122.1 -yCH), 116.7 -CH [Ar]), 108.6
-CH [Ar]), 105.7 -CH [Ar]), 101.4 -OCH2O), 55.7 -OCH3);
LRMS -CI) 255 -M1, 100%), 226 -6%), 196 -14%), 154
-25%), 127 -18%), 98 -10%), 77 -12%); HRMS -EI) m/z
Found M1: 255.0886, C15H13NO3 requires 255.0895.
1476 s, 1437 s, 1243 m, 1111 s, 1032 m, 923 m, 732 s; UV
-MeOH, nm) lmax -emax) 302 -3890), 271 -5000), 218
-28,910); 1H NMR -300 MHz, CDCl3) dH 7.90±7.55
-15H, m, 3£C6H5), 7.02 -1H, d, JP±Hˆ2.0 Hz, ArH), 6.80
-1H, s, ArH), 5.95 -2H, s, OCH2O), 5.52 -2H, d,
JP±Hˆ12.9 Hz, CH2P); 13C NMR -75 MHz, CDCl3) dC
149.1 -C [Ar]), 148.1 -C [Ar]), 135.4 -3£CH [Ph]), 134.5
-d, JP±Cˆ10.0 Hz, 6£CH [Ph]), 130.4 -d, JP±Cˆ12.5 Hz,
6£CH [Ph]), 120.1 -d, JP±Cˆ8.8 Hz, 3£C [Ph]), 117.6 -d,
JP±Cˆ85.6 Hz, C [Ar]), 117.0 -C [Ar]), 112.7 -CH [Ar]),
112.3- CH [Ar]), 102.4 -OCH2O), 31.2 -d, JP±Cˆ48.3Hz,
CH2P); LRMS -ES1) 477 -[M2Br{81Br}]1, 100%), 475
-[M2Br{79Br}]1, 90%); Anal. Found: C, 55.96; H, 3.77;
C26H21Br2O2P requires C, 56.14; H, 3.81.
6.1.3. 3--Methoxy)[1,3]dioxolo-[40,50:4,5]benzo[h]quinoline
-toddaquinoline methyl ether) 9 and 1--methoxy)[1,3]-
dioxolo--40,50:4,5]benzo[f]isoquinoline 10 by photo-
cyclisation of azastilbenes 8. A condensor jacketed
Quartz photochemical cell was charged with a solution of
azastilbenes 8 -1:1 mixture of -E)- and -Z)-isomers, 150 mg,
0.59 mmol) in cyclohexane -100 ml). After irradiation at RT
with a medium pressure mercury lamp for 16 h the reaction
mixture was concentrated in vacuo. Puri®cation by column
chromatography -silica gel, 40±100% ether/petrol) yielded
®rstly toddaquinoline methyl ether 9 -30 mg, 0.12 mmol,
20%) as an off-white solid; mp 151±1538C -ether/petrol)
[lit. 145±1488C -MeOH/CHCl3)];1 IR -solid, cm21) nmax
2932 w, 1604 m, 1498 s, 1406 m, 1382 m, 1255 s, 1169 s,
1036 s, 941 m, 874 m; UV -MeOH, nm) lmax -emax) 3 41
-6070), 296 -4430), 233 -5440); 1H NMR -300 MHz,
CDCl3) dH 8.70 -1H, d, Jˆ2.0 Hz, ArH), 8.55 -1H, s,
ArH), 7.68 -1H, d, Jˆ8.8 Hz, ArH), 7.55 -1H, d,
Jˆ8.8 Hz, ArH), 7.50 -1H, d, Jˆ2.0 Hz, ArH), 7.21 -1H,
s, ArH), 6.10 -2H, s, OCH2O), 3.99 -3H, s, OCH3); 13C NMR
-75 MHz, CDCl3) dC 154.6 -C), 148.6 -C), 148.2 -C), 141.2
-CH), 140.3- C), 129.0 -C), 127.9 -CH), 127.0 -C), 123.4
-C), 123.4 -CH), 114.3- CH), 105.0 -CH), 102.0 -CH), 101.5
-OCH2O), 55.8 -OCH3); LRMS -ES1) 254 -MH1, 100%);
HRMS -ES1) m/z Found MH1:254.0817, C15H12NO3
requires 254.0817 [these spectral and physical characteris-
tics were consistent with literature values];1 then a 1:1
mixture of -Z)-8 and -E)-8 -35 mg, 0.14 mmol, 23%) and
®nally benzoisoquinoline 10 -80 mg, 0.32 mmol, 54%) as
an off-white solid; mp 140±1418C -ether/petrol); IR -solid,
cm21) nmax 2924 w, 1471 s, 1370 m, 1279 m, 1246 m, 1215
m, 1090 m, 1038 m, 934 m, 863 m; UV -EtOH, nm) lmax
-emax) 383 -380), 371 -300), 315 -250), 303 -354), 292
-420), 288 -630), 272 -1900), 217 -400); 1H NMR
-300 MHz, CDCl3) dH 9.08 -1H, s, ArH), 8.88 -1H, s,
ArH), 8.33 -1H, s, ArH), 7.78 -1H, d, Jˆ8.8 Hz, ArH),
7.72 -1H, d, Jˆ8.8 Hz, ArH), 7.02 -1H, s, ArH), 6.15 -2H,
s, OCH2O), 4.19 -3H, s, OCH3); 13C NMR -75 MHz, CDCl3)
dC 153.6 -C), 148.2 -C), 148.1 -C), 145.1 -CH), 131.4 -C),
128.9 -CH), 128.1 -C), 127.6 -CH), 125.7 -C), 124.5 -C),
123.3 -CH), 107.6 -CH), 105.8 -CH), 101.7 -OCH2O), 56.4
-OCH3); LRMS -CI) 254 -MH1, 100%).
6.1.5. -E)-3-[2--6-Bromo-1,3-benzodioxol-5-yl)-1-ethenyl]-
-
5--methoxy)pyridine 13and
Z)-3-[2--6-bromo-1,3-
benzodioxol-5-yl)-1-ethenyl]5--methoxy)pyridine 14.
Sodium hydride -60% in mineral oil, 132 mg, 3.30 mmol),
pre-washed with tetrahydrofuran -10 ml), was suspended in
tetrahydrofuran -30 ml) and cooled to 08C. Phosphonium
bromide 12 -1.67 g, 3.00 mmol) was added in one portion
and the mixture stirred at RT for 2 h then cooled to 08C.
Aldehyde 4 -340 mg, 2.48 mmol) was added as a solution in
tetrahydrofuran -10 ml) and the mixture stirred at RT for 2 h
then ®ltered through Celitew and concentrated in vacuo.
Puri®cation by column chromatography -silica gel, 40%
ether/petrol) provided ®rstly azastilbene 14 -495 mg,
1.48 mmol, 60%) as a pale yellow solid; mp 106±1098C
-ether/petrol); IR -solid, cm21) nmax 2922 w, 1583m,
1501 m, 1476 s, 1283m, 1229 m, 1037 s, 878 m; UV
-MeOH, nm) lmax -emax) 336 -6350), 302 -8680), 214
1
-16,530); H NMR -300 MHz, CDCl3) dH 8.12 -1H, d,
Jˆ1.9 Hz, PyH), 8.05 -1H, d, Jˆ1.2 Hz, PyH), 7.06 -1H,
s, ArH), 6.98 -1H, app. t, Jˆ1.6 Hz, PyH), 6.67 -1H, d,
Jˆ11.8 Hz, yCH), 6.59 -1H, s, ArH), 6.54 -1H, d,
Jˆ11.8 Hz, yCH), 5.93-2H, OC H2O), 3.72 -3H, s,
OCH3), 13C NMR -75 MHz, CDCl3) dC 155.3- C [Py]),
148.2 -C [Ar]), 147.4 -C [Ar]), 142.8 -CH [Py]), 136.3
-CH [Py]), 132.8 -C [Py]), 132.1 -CH [Py]), 130.3
-C [Ar]), 127.2 -yCH), 120.0 -yCH), 114.9 -C [Ar]),
112.9 -CH [Ar]), 110.1 -CH [Ar]), 102.0 -OCH2O), 55.5
-OCH3); LRMS -ES1) 336 -[MH{81Br}]1, 100%), 334
-[MH{79Br}]1, 95% HRMS -EI) m/z Found M1:
332.9995, C15H1279BrNO3 requires 333.0001; then
azastilbene 13 -210 mg, 25%) as an off-white solid; mp
112±1148C -ether/petrol); IR -solid, cm21) nmax 2902 w,
1582 m, 1503m, 1475 s, 1411 m, 1245 m, 1170 m, 1037
s, 955 m, 932 m, 859 m, 843 m; UV -MeOH, nm) lmax
-e max) 342 -13,550), 304 -9920), 258 -9730), 220
1
-16,410); H NMR -300 MHz, CDCl3) dH 8.33 -1H, d,
Jˆ1.9 Hz, PyH), 8.22 -1H, d, Jˆ2.6 Hz, PyH), 7.43-1H,
d, Jˆ16.2 Hz, yCH), 7.31 -1H, app. t, Jˆ2.2 Hz, PyH), 7.12
-1H, s, ArH), 7.03-1H, s, Ar H), 6.84 -1H, d, Jˆ16.2 Hz,
yCH), 6.00 -2H, s, OCH2O), 3.90 -3H, s, OCH3); 13C NMR
-75 MHz, CDCl3) dC 156.0 -C [Py]), 148.6 -C [Ar]), 148.0
-C [Ar]), 141.4 -CH [Py]), 136.8 -CH [Py]), 129.9 -C [Py]),
129.7 -CH [Py]), 125.9 -yCH), 122.9 -C [Ar]), 117.0
-yCH), 115.8 -C [Ar]), 113.0 -CH [Ar]), 106.0 -CH [Ar]),
102.1 -OCH2O), 55.8 -OCH3); LRMS -ES1) 3 3 6
-MH{81Br}1, 100%), 334 -MH{79Br}1, 95%); HRMS -EI)
m/z Found M1: 333.0001, C15H1279BrNO3 requires
333.0001.
6.1.4. [-6-Bromo-1,3-dioxol-5-yl)methyl]triphenylphos-
phonium bromide 12. A solution of bromide 11 -8.00 g,
27.2 mmol) and triphenylphosphine -9.50 g, 36.4 mmol) in
xylene -50 ml) was heated at 808C for 4 h then cooled to RT.
The resulting white precipitate was collected by ®ltration,
washed with cold xylene -2£20 ml) and petrol -3£20 ml)
then dried in vacuo to provide the title compound 12 -9.40 g,
16.9 mmol, 62%) as a white solid; mp .2508C -EtOH); [lit.
278±2808C -ether /MeOH)];8 IR -nujol, cm21) nmax 1503m,

4452
D. C. Harrowven et al. / Tetrahedron 57 .2001) 4447±4454
6.1.6. 9--Methoxy)[1,3]dioxolo-[40,50:3,4]benzo[h]quinoline
15 and 3--methoxy)[1,3]dioxolo-[40,50:4,5]benzo[h]quinoline
-toddaquinoline methyl ether) 9. To a cooled -2788C)
solution of azastilbene 14 -374 mg, 1.12 mmol) in tetra-
hydrofuran -20 ml) was added dropwise via syringe over
5 min n-BuLi -1.16 M in hexanes, 1.1 ml, 1.28 mmol).
After 30 min the reaction was warmed to 08C, maintained
at that temperature for 30 min then partitioned between
ether -20 ml) and brine -20 ml). The aqueous phase was
extracted with ether -2£20 ml) and the combined organic
phases dried -K2CO3) and concentrated in vacuo.
Puri®cation by column chromatography gave ®rstly todda-
quinoline methyl ether 9 -30 mg, 0.12 mmol, 11%, data as
previously stated) then benzo[h]quinoline 15 -90 mg,
0.36 mmol, 32%) as an unstable off-white solid; mp
decomposed; IR -solid, cm21) nmax 2932 w, 1577 m, 1477
m, 1433 s, 1408 m, 1313 s, 1276 s, 1215 m, 1089 m, 945 m;
1H NMR -300 MHz, d6-acetone) dH 8.78 -1H, s, ArH), 8.42
-1H, s, ArH), 7.77 -1H, d, Jˆ10.0 Hz, ArH), 7.62 -1H, d,
Jˆ10.0 Hz, ArH), 7.55 -1H, d, Jˆ10.0 Hz, ArH), 7.37 -1H,
d, Jˆ10.0 Hz, ArH), 6.21 -2H, s, OCH2O), 4.12 -3H, s,
OCH3); 13C NMR -75 MHz, d6-acetone) dC 152.3- C [Ar]),
147.0 -C [Ar]), 144.8 -C [Ar]), 143.1 -CH [Ar]), 130.3
-C [Ar]), 130.1 -CH [Ar]), 129.6 -CH [Ar]), 128.9
-C [Ar]), 122.7 -CH [Ar]), 122.3- C [Ar]), 121.7 -CH
[Ar]), 112.4 -C [Ar]), 110.7 -CH [Ar]), 100.8 -OCH2O),
56.1 -OCH3); LRMS -ES1) 254 -MH1, 100%). Note: the
product deteriorated on standing and satisfactory Anal. or
HRMS could not be obtained.
Puri®cation by column chromatography -silica gel, 40%
ether/petrol) provided toddaquinoline methyl ether 9
-60 mg, 0.24 mmol, 61%) as an off-white solid [data as
previously stated].
6.1.9. 3--Benzyloxy)-5-bromopyridine 24. Sodium
-160 mg, 6.96 g atom) was added portionwise to benzyl
alcohol -10 ml) and upon complete dissolution -ca. 5 h)
the excess alcohol was removed by distillation under
reduced pressure. The resulting pale brown solid was
dissolved in N,N-dimethylformamide -20 ml) and 3,5-
dibromopyridine 2 -1.0 g. 4.22 mmol) added. The reaction
mixture was stirred at 658C for 90 min then cooled to RT.
Water -20 ml) was added and the mixture extracted with
ether -3£20 ml). The combined organic phases were washed
with water -15 ml) and brine -15 ml) then dried -MgSO4),
concentrated in vacuo and puri®ed by column chromato-
graphy -silica gel, 20% ether/petrol) to yield the title
compound 24 -625 mg, 2.37 mmol, 56%) as a white solid;
mp 64±658C -ether/petrol); IR -solid, cm21) nmax 3034 w,
1574 s, 1553 m, 1446 m, 1429 s, 1380 m, 1310 s, 1262 s,
1220 m, 1184 m, 1008 s, 887 m, 856 m, 736 m, 694 s; UV
-MeOH, nm) lmax -emax) 290 -5120), 212 -24,920); 1H NMR
-300 MHz, CDCl3) dH 8.34±8.30 -2H, m, 2£PyH), 7.46±
7.33 -6H, m, PyH1C6H5), 5.10 -2H, s, OCH2); 13C NMR
-75 MHz, CDCl3) dC 155.4 -C [Py]), 143.3 -CH [Py]), 136.8
-CH [Py]), 135.6 -C [Ph]), 129.0 -2£CH [Ph]), 128.7 -CH
[Ph]), 127.7 -2£CH [Ph]), 124.6 -CH [Py]), 120.6 -C [Py]),
70.8 -OCH2); LRMS -ES1) 307 -[MH1MeCN{81Br}]1,
42%),
305
-[MH1MeCN{79Br}]1,
40%),
266
6.1.7. 3--Methoxy)[1,3]dioxolo-[40,50:4,5]benzo[h]quinoline
-toddaquinoline methyl ether) 9 and 1--methoxy)[1,3]-
-[MH{81Br}]1, 27%), 264 -[MH{79Br}]1, 28%), 140
-38%), 138 -43%), 127 -100%); Anal. Found: C, 54.69; H,
3.80; N, 5.23; C12H10BrNO requires C, 54.57; H, 3.82; N,
5.30.
dioxolo-[40,50:4,5]benzo[f]isoquinoline
10
by
tin
mediated radical cyclisation of 14. Azastilbene 14
-220 mg, 0.66 mmol), tri-n-butyltin hydride -200 ml,
220 mg, 0.76 mmol) and azobisisobutyronitrile -16 mg,
0.10 mmol) were stirred in toluene -25 ml) at 808C for 4 h
then the reaction mixture was cooled to RT. Aqueous potas-
sium ¯uoride solution -10% w/v, 20 ml) was added and the
reaction vigorously stirred for 36 h. The mixture was diluted
with ether -50 ml) and the organic phase washed with water
-2£50 ml), dried -MgSO4), concentrated in vacuo and
puri®ed by column chromatography -silica gel, 40% ether/
petrol) to yield ®rstly toddaquinoline methyl ether 9 -47 mg,
0.19 mmol, 28%) as a white solid [data as previously
stated]; then recovered 14 -35 mg, 0.10 mmol, 16%) and
®nally benzo[f]isoquinoline 10 -50 mg, 0.20 mmol, 30%)
as a white solid [data as previously stated].
6.1.10. 5--Benzyloxy)nicotinaldehyde 25. 3--Benzyloxy)-
5-bromopyridine 24 -1.09 g, 4.11 mmol) was dissolved in
tetrahydrofuran -50 ml) and cooled to 21008C. n-Butyl-
lithium -1.37 M in hexanes, 3.6 ml, 4.93 mmol) was added
dropwise over 10 min and the mixture stirred at 21008C for
1 h. N,N-Dimethylformamide -1.2 ml, 1.16 g, 15.92 mmol)
was added dropwise over 5 min, the reaction mixture was
allowed to warm to 2608C over 30 min then quenched with
brine -25 ml) and extracted with diethyl ether -3£20 ml).
The combined organic phases were dried -K2CO3),
concentrated under reduced pressure and puri®ed by column
chromatography -silica gel, 30% ether/petrol) to yield the
title aldehyde 25 -704 mg, 3.31 mmol, 81%) as a white
solid; mp 62±648C -ether/petrol); IR -solid, cm21) nmax
1698 s, 1584 m, 1454 m, 1380 m, 1318 s, 1280 s, 1249 m,
1172 m, 741 m; UV -MeOH, nm) lmax -emax) 310 -910), 286
-4260), 220 -19,470); 1H NMR -300 MHz, CDCl3) dH 10.08
-1H, s, CHO), 8.68 -1H, d, Jˆ1.5 Hz, PyH), 8.63-1H, d,
Jˆ2.9 Hz, PyH), 7.69 -1H, dd, Jˆ2.9, 1.5 Hz, PyH), 7.46±
7.35 -5H, m, C6H5), 5.17 -2H, s, OCH2); 13C NMR
-75 MHz, CDCl3) dC 190.8 -CHO), 155.5 -C [Py]), 145.6
-CH [Py]), 145.4 -CH [Py]), 135.5 -C [Ph]), 132.2 -C [Py]),
129.0 -2£CH [Ph]), 128.7 -CH [Ph]), 127.8 -2£CH [Ph]),
117.8 -CH [Py]), 70.7 -OCH2); LRMS -ES1) 255
-[MH1MeCN]1, 55%), 214 -MH1, 43%), 186
-[MH2CO]1, 60%), 140 -46%), 127 -100%); Anal.
Found: C, 73.18; H, 5.20; N, 6.52; C13H11NO2 requires
C, 73.22; H, 5.20; N, 6.57.
6.1.8. 3--Methoxy)[1,3]dioxolo-[40,50:4,5]benzo[h]quinoline
-toddaquinoline methyl ether) 9 by cobalt-I) mediated
radical cyclisation of 14. Sodium -100 mg, 4.35 g atom)
was added portionwise to mercury -10 g, 49.5 g atom)
WITH CARE: EXOTHERMIC. Tetrahydrofuran -30 ml)
and cobalt-II)salophen -380 mg, 1.56 mmol) were added
and the reaction mixture vigorously stirred at RT under an
argon atmosphere for 3h. The resulting dark green solution
was transferred to a second ¯ask via cannula and cooled to
2788C. Azastilbene 14 -130 mg, 0.39 mmol) as a solution
in tetrahydrofuran -5 ml) was added dropwise over 2 min
and the solution stirred at 2788C for 2 h, at 08C for 1 h and
at RT for 16 h. The mixture was ®ltered through a pad of
silica -eluting with ether) then concentrated in vacuo.

D. C. Harrowven et al. / Tetrahedron 57 .2001) 4447±4454
4453
6.1.11.
-Z)-3--Benzyloxy)-5-[20--600-bromo-1,3-benzo-
hydrofuran -5 ml) was added dropwise over 2 min and the
solution stirred at 2788C for 2 h, at 08C for 1 h and at RT for
1 h. The mixture was left to stand in air for 16 h then ®ltered
through Celitew -eluting with ether) and concentrated in
vacuo. Puri®cation by column chromatography -silica gel,
20% ether/petrol) yielded toddaquinoline benzyl ether 28
-30 mg, 0.09 mmol, 61%) as a pale yellow solid; mp
129±1318C -ether/petrol); IR -solid, cm21) nmax 1603m,
1462 s, 1379 m, 1254 s, 1171 s, 1038 m, 874 m; UV
-MeOH, nm) lmax -emax) 360 -1320), 340 -2630), 292
-27,640), 241 -47,380); 1H NMR -300 MHz, CDCl3)
dH 8.78 -1H, d, Jˆ2.9 Hz, ArH), 8.52 -1H, s, ArH), 7.65
-1H, d, Jˆ2.9 Hz, ArH), 7.58±7.50 -6H, m, ArH and C6H5),
7.43-1H, d, Jˆ8.8 Hz, ArH), 7.21 -1H, s, ArH), 6.12 -2H,
s, OCH2O), 5.24 -2H, s, OCH2); 13C NMR -75 MHz, CDCl3)
dC 152.7 -C [Ar]), 148.4 -C [Ar]), 148.2 -C [Ar]), 141.2
-CH [Ar]), 136.2 -C [Ph]), 128.9 -C [Ar]), 128.8 -2£CH
[Ph]), 128.7 -C [Ar]), 128.3- CH [Ph]), 127.7 -CH [Ar]),
127.6 -C [Ar]), 127.6 -2£CH [Ph]), 126.2 -C [Ar]), 123.3
-CH [Ar]), 115.8 -CH [Ar]), 104.9 -CH [Ar]), 101.9 -CH
[Ar]), 101.3-O CH2O), 70.5 -OCH2); LRMS -ES1) 3 3 0
-MH1, 40%); HRMS -EI) m/z Found M1: 329.1055,
C21H15NO3 requires 329.1052.
dioxol-500-yl)-10-ethenyl]pyridine 27 and -E)-3--benzyl-
oxy)-5-[20--600-bromo-1,3-benzodioxol-500-yl)-10-ethenyl]-
pyridine -E)-27. Sodium hydride -60% in mineral oil),
-180 mg, 4.50 mmol) was pre-washed with petrol -10 ml)
then suspended in tetrahydrofuran -30 ml) and cooled to
08C. Phosphonium bromide 12 -1.79 g, 3.22 mmol) was
added and the reaction mixture stirred at RT for 2 h then
cooled to 08C and 5--benzyloxy)nicotinaldehyde 25
-527 mg, 2.47 mmol) in tetrahydrofuran -5 ml) was added.
After a further 2 h the reaction mixture was ®ltered through
Celitew -eluting through with ether) and the organic ®ltrate
concentrated in vacuo. Puri®cation by column
chromatography -silica gel, 40% ether/petrol) gave ®rstly
-Z)-azastilbene 27 -473mg, 1.15 mmol, 47%) as a colour-
less oil; IR -neat, cm21) nmax 3031 m, 2899 w, 1574 m, 1500
m, 1475 s, 1432 m, 1271 m, 1230 s, 1037 m, 697 m; UV
-MeOH, nm) lmax -emax) 296 -8920), 282 -8920), 228
1
-20,300); H NMR -300 MHz, CDCl3) dH 8.20 -1H, d,
Jˆ2.9 Hz, PyH), 8.05 -1H, d, Jˆ1.8 Hz, PyH), 7.44±7.33
-5H, m, C6H5), 7.06 -1H, s, ArH), 7.04 -1H, app. t,
Jˆ2.2 Hz, PyH), 6.67 -1H, d, Jˆ12.1 Hz, yCH), 6.58
-1H, s, ArH), 6.54 -1H, d, Jˆ12.1 Hz, yCH), 5.92 -2H, s,
OCH2O), 4.96 -2H, s, OCH2); 13C NMR -75 MHz, CDCl3)
dC 154.6 -C [Py]), 148.3- C [Ar]), 147.4 -C [Ar]), 143.0 -CH
[Py]), 137.2 -CH [Py]), 136.2 -C [Ph]), 132.8 -CH [Py]),
132.1 -C [Ar]), 130.2 -C [Py]), 128.9 -2£CH [Ph]), 128.4
-CH [Ph]), 127.6 -2£CH [Ph]), 127.1 -vCH), 121.3- CH
[Ar]), 114.9 -C [Ar]), 113.0 -vCH), 110.1 -CH [Ar]), 102.0
-OCH2O), 70.5 -OCH2); LRMS -ES1) 412 -MH{81Br}1,
100%); 410 -MH{79Br}1, 98%; HRMS -EI) m/z Found
M1: 409.0317, C21H1679BrNO3 requires 409.0314; then a
mixture of -Z)-27 and -E)-27 -~2:1, 140 mg, 0.38 mmol,
15%) and ®nally -E)-azastilbene -E)-27 -193mg,
0.47 mmol, 19%) as a pale yellow solid; mp 146±1478C
-ether/petrol); IR -solid, cm21) nmax 2900 w, 1580 m,
1502 m, 1474 s, 1410 m, 1292 m, 1244 m, 1173m, 1037
s, 698 m; UV -MeOH, nm) lmax -emax) 334 -15,500), 297
-11,100), 253-12,000), 226 -21,100); 1H NMR -300 MHz,
CDCl3) dH 8.35 -1H, d, Jˆ1.5 Hz, PyH), 8.28 -1H, d,
Jˆ2.9 Hz, PyH), 7.55±7.30 -7H, m, PyH, yCH and
C6H5), 7.17 -1H, s, ArH), 7.09 -1H, s, ArH), 6.83-1H, d,
Jˆ16.2 Hz, yCH), 6.02 -2H, s, OCH2O), 5.17 -2H, s,
OCH2); 13C NMR -75 MHz, CDCl3) dC 155.2 -C [Py]),
148.6 -C [Ar]), 148.1 -C [Ar]), 141.8 -CH [Py]), 137.1
-CH [Py]), 136.2 -C [Ph]), 133.7 -C [Ar]), 130.0 -C
[Py]), 129.8 -CH [Py]), 128.9 -2£CH [Ph]), 128.5 -CH
[Ph]), 127.8 -2£CH [Ph]), 125.8 -yCH), 118.1 -CH [Ar]),
115.9 -C [Ar]), 113.1 -yCH), 106.0 -CH [Ar]), 102.1
-OCH2O), 70.7 -OCH2); LRMS -ES1) 412 -[MH{81Br}]1,
100%), 410 -[MH{79Br}]1, 98%); Anal. Found: C, 61.27;
H, 3.96; N, 3.35; C21H16BrNO3 requires C, 61.48; H, 3.93;
N, 3.41.
6.1.13. [1,3]Dioxolo[40,50:4,5]benzo[h]quinolin-3-ol -todda-
quinoline) 1. Benzyl ether 28 -52 mg, 0.16 mmol) was
dissolved in acetic acid -5 ml). 5% Palladium on carbon
-65 mg, 0.03g atom Pd) was added and the reaction mixture
stirred at RT under an atmosphere of hydrogen for 16 h with
an additional portion of catalyst -2£25 mg) added after 4
and 8 h. Water -1 ml) and diethyl ether -5 ml) were added
and the mixture neutralised to pH 7 with sodium hydrogen
carbonate. The organic phases were washed with saturated
sodium hydrogen carbonate solution -2£5 ml), dried
-MgSO4) and concentrated in vacuo. Puri®cation by column
chromatography -silica gel, 1% MeOH/CHCl3) yielded
toddaquinoline 1 -32 mg, 0.13 mmol, 85%) as a white
solid; mp 229±2318C -CHCl3/MeOH) [lit. 235±2378C
-MeOH/ether)];1 IR -solid, cm21) nmax 3416 br m, 2916
m, 1463m, 1256 m, 1113m, 1054 s, 1028 s, 1008 m, 910
m, 740 s; UV -MeOH, nm) lmax -emax) 288 -1070), 236
1
-2550); H NMR -300 MHz, CDCl31d6-DMSO) dH 9.42
-1H, s, OH), 8.55 -1H, d, Jˆ2.9 Hz, ArH), 8.38 -1H, s,
ArH), 7.50 -1H, d, Jˆ8.8 Hz, ArH), 7.38 -1H, d,
Jˆ2.9 Hz, ArH), 7.35 -1H, d, Jˆ8.8 Hz, ArH), 7.08 -1H,
s, ArH), 5.99 -2H, s, OCH2O); 13C NMR -75 MHz,
CDCl31d6-DMSO) dC 151.4 -C [Ar]), 148.2 -C [Ar]),
147.7 -C [Ar]), 140.7 -CH [Ar]), 139.7 -C [Ar]), 128.4 -C
[Ar]), 128.3- C [Ar]), 127.3- CH [Ar]), 126.7 -C [Ar]), 123.2
-CH [Ar]), 117.8 -CH [Ar]), 104.9 -CH [Ar]), 101.6 -CH
[Ar]), 101.2 -OCH2O); LRMS -ES1) 240 -MH1, 100%);
HRMS -EI) m/z Found M1: 239.0584, C14H9NO3 requires
239.0582. These data were consistent with those reported in
the isolation paper.1
6.1.12. 3--Benzyloxy)[1,3]dioxolo[40,50:4,5]benzo[h]quino-
line 28 -toddaquinoline benzyl ether). Sodium -60 mg,
2.64 g atom) was added portionwise to mercury -6 g,
29.7 g atom) WITH CARE: EXOTHERMIC. The resulting
amalgam was covered with tetrahydrofuran -30 ml),
cobalt-II)salophen was added and the mixture stirred at
RT for 2 h. The resulting dark green solution was transferred
to a second ¯ask via cannula and cooled to 2788C.
Azastilbene 27 -62 mg, 0.15 mmol) as a solution in tetra-
Acknowledgements
The authors wish to thank P®zer, The Nuf®eld Foundation
and EPSRC for their ®nancial support and the EPSRC mass
spectrometry service, G. J. Langley and J. M. Herniman for
the provision of HRMS data.

4454
D. C. Harrowven et al. / Tetrahedron 57 .2001) 4447±4454
10. For reviews of the Minisci reaction, see: -a) Curran, D. P.
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