Insecticidal heterolignans-Tubuline polymerization inhibitors with activity against chewing pests

Article abstract of DOI:10.1016/j.bmc.2009.01.042

Starting from natural product podophyllotoxin 1 substituted heterolignans were identified with promising insecticidal in vivo activity. The impact of substitution in each segment of the core structure was investigated in a detailed SAR study, and variation of substituents in both aromatic moieties afforded derivatives 5 and 43 with broad insecticidal activity against lepidopteran and coleopteran species. In vitro measurements supported by modeling studies indicate that heterolignans 3-134 act as tubuline polymerization inhibitors interacting with the colchicine-binding site. Insect specific structure-activity effects were observed showing that the insecticidal SAR described herein differs from reported cytotoxicity studies.

Full text of DOI:10.1016/j.bmc.2009.01.042

Bioorganic & Medicinal Chemistry 17 (2009) 4160–4184
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Insecticidal heterolignans—Tubuline polymerization inhibitors with activity
against chewing pests
b
b
b
b
Jens Frackenpohl a, , Isabelle Adelt , Horst Antonicek , Christian Arnold , Patricia Behrmann ,
Nicole Blaha a, Jutta Böhmer b, , Oliver Gutbrod b, Roman Hanke b, Sabine Hohmann a, Marc van Houtdreve b,
Peter Lösel b, Olga Malsam b, Martin Melchers b, Valentina Neufert b, Elisabeth Peschel a, Udo Reckmann b,
Thomas Schenke b, Hans-Peter Thiesen b, Robert Velten b, Kathrin Vogelsang b, Hans-Christoph Weiss c
*
a Bayer CropScience AG, Industriepark Höchst, G836, D-65926 Frankfurt am Main, Germany
b Bayer CropScience AG, Alfred-Nobel-Strasse 50, D-40789 Monheim, Germany
c Currenta GmbH, Chemiepark Leverkusen, Q18, D-51368 Leverkusen, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Starting from natural product podophyllotoxin 1 substituted heterolignans were identified with promis-
ing insecticidal in vivo activity. The impact of substitution in each segment of the core structure was
investigated in a detailed SAR study, and variation of substituents in both aromatic moieties afforded
derivatives 5 and 43 with broad insecticidal activity against lepidopteran and coleopteran species. In vitro
measurements supported by modeling studies indicate that heterolignans 3–134 act as tubuline poly-
merization inhibitors interacting with the colchicine-binding site. Insect specific structure–activity
effects were observed showing that the insecticidal SAR described herein differs from reported cytotox-
icity studies.
Received 23 October 2008
Revised 14 January 2009
Accepted 20 January 2009
Available online 24 January 2009
Keywords:
Heterolignan
Dihydropyridine
Tubuline polymerization inhibitor
Insecticide
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
good initial activity against chewing insects with podophyllotoxin
1 being the most potent compound, in accordance with previous
Phytopathogenic microorganisms, weeds and insects cause sig-
nificant damage to agriculture. Where insect pests are not system-
atically controlled, significant amounts of a typical crop are lost
pre- and postharvest. Much of the increase in agricultural produc-
tivity over recent decades stems from the successful control of
these pests with synthetic chemical pesticides. However, agro-
chemical and insecticidal research in particular are driven by a
constant need to identify alternative chemical classes and new
modes of action due to development of resistance to current active
ingredients.1 Investigating natural products from terrestrial and
marine sources not only enhances diversity in the search for new
prototype insecticides, but may lead to new market products as
the prominent examples of spinosyns and avermectins underline.2
Natural products and their closely related analogs are thus an
important resource for new agrochemical agents and are regularly
tested in our initial in vivo screening. In a test sequence of a large
set of natural products from diverse sources, two lignans exhibited
reports.3 Podophyllotoxin 1 is a naturally occurring tetralin lignan
that has been found in a variety of plants, including Podophyllum
peltatum and Juniperus sabina.4 Meanwhile, in medicinal chemistry,
the corresponding glycosides of podophyllotoxin and related natu-
ral products have raised strong interest in total synthesis
approaches or semi-synthetic variations5 since etoposide and
teniposide are widely used as anti-cancer drugs.
Although structure anti-tumour activity relationships of podo-
phyllotoxin analogues were extensively investigated,6 only few
investigations have been published so far focusing on the impact
of structural variations of podophyllotoxin on its insecticidal activ-
ity. In first approaches podophyllotoxin 1 has been transformed at
its hydroxyl function into the corresponding esters,7 halides and
aryl amines,8 and into acylated amino derivatives.9 Most com-
pounds prepared also exhibited insecticidal activity in various ini-
tial test systems. In our approach we tried to identify analogues of
1 with reduced chemical complexity which could be accessed via
short and reliable synthetic routes. Taking natural product podo-
phyllotoxin 1 with its reported and internally confirmed insecti-
cidal potential as a starting point, we sought to reduce structural
complexity initially by selecting deoxypodophyllotoxin 2 as test
* Corresponding author. Tel.: +49 693055518; fax: +49 6930517768.
E-mail address: Jens.Frackenpohl@bayercropscience.com (J. Frackenpohl).
Present address: Syngenta, Jealott’s Hill Research Centre, Bracknell, Berkshire
RG42 6EY, UK.
compound (Scheme 1). Deoxypodophyllotoxin
2 retains full
0968-0896/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2009.01.042

J. Frackenpohl et al. / Bioorg. Med. Chem. 17 (2009) 4160–4184
4161
OH
H
H
5
H
H
H
3
4
6
7
N
N
O
O
O
O
O
O
O
O
O
O
B
C O
O
O
A
1
9
8
H
O
O
O
D
O
O
O
O
O
O
O
O
O
O
O
Podophyllotoxin 1
Deoxypodophyllotoxin 2
3
4
Scheme 1. Pathway towards heterolignan lead structure 4.
biological activity despite the missing hydroxy group. This obser-
vation prompted us to search for other tolerated structural simpli-
fications. Inspired by a concise review concerning heterocyclic
podophyllotoxin analogues10 and recent literature11–13 we also
simplified the synthetic approach by replacing carbocyclic ring B
with a dihydropyridine moiety. The resulting prototype 3 still
exhibited promising activity against mustard beetle Phaedon coch-
leariae. A slight variation of the substituents in aryl ring D from
3,4,5-trimethoxy to 3,5-dimethoxy afforded derivative 4 with sur-
prisingly good activity against P. cochleariae and fall armyworm
Spodoptera frugiperda at a level of 20 g/ha. Heterolignan 4 was
identified as a lead compound and a broad SAR study was started.
H
NH2
6
O
O
N
O
O
O
7
O
a)
O
HO
O
O
O
O
4 (56 %)
+
H
N
O
6
O
O
a)
O
O
NH2
O
2. Results and discussion
2.1. Chemistry
O
O
5 (18 %)
H
N
OH
6
In contrast to podophyllotoxin derivatives which are accessible
only in challenging multi-step syntheses aza-analogues 3 and 4
could be prepared using a well described one-pot reaction of the
corresponding aldehyde, tetronic acid and 3,4-methylenedioxy
aniline.11–13 The major advantages of this methodology are the rel-
atively mild conditions without further activation (EtOH, reflux),
acceptable reaction times (<2 h) and reported tolerance for struc-
tural diversity. Although heterocyclic amines were recently found
to be tolerated,11 initial synthetic studies of this multi component
reaction were only performed with polysubstituted aldehydes and
anilines carrying strongly electron-donating groups,12 for example,
3,4,5-trimethoxy benzaldehyde and 3,4-methylenedioxy- or 3,4-
dimethoxyaniline. A related three-step procedure has also been
studied with alkoxy substituents.13 As we wanted to a carry out
a detailed SAR-study including substitution patterns relevant for
agrochemistry, for example, halogen, haloalkyl and haloalkoxy
groups,14 we investigated the reported one-pot dihydropyridine
synthesis11–13 with selected substituents first in order to identify
potential limitations. Target molecule 4, with a 6,7-methylenedi-
oxy substitution pattern, was prepared in good yield and high pur-
ity via initial formation of an intermediate Knoevenagel adduct.
However, the corresponding 6-methoxy derivative 5 was synthe-
sized in much lower yield (18%) and a double addition product 6
(Scheme 2) was formed as the major product (42%). Due to the acti-
vated position at C7 dihydropyridine 5 could react with intermedi-
ate benzylidene 2,4-furandione to afford 6. Furthermore, benzyl
derivative 7 was observed as second side product.
O
O
O
O
O
Ar
Ar
O
6 (42 %)
H
N
6
O
Ar =
O
O
O
Ar
Ar
7 (6 %)
Scheme 2. Formation of heterolignans with electron-donating groups in ring A by a
three-component reaction. Reagents and conditions: (a) EtOH, 2 h, reflux.
Table 1
Variation of conditions for the one-pot synthesis of 5
Entry
Solvent
Time (h)
Temp (°C)
Concn (mol)
Yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
EtOH
EtOH
EtOH
MeOH
2
2
1
4
2
1
4
1
1
4
1
2
2
1
1
2
1
1
78
40
78
40
40
120
120
40
80
80
0.25
0.01
0.5
0.01
0.5
0.01
0.5
0.01
0.25
0.5
0.25
0.5
0.01
0.5
0.01
0.25
0.5
18
9
26
6
MeOH
12
31
45
11
16
28
26
49
42
50
53
61
47
62
2-Methoxy-ethanol
2-Methoxy-ethanol
MeCN
MeCN
MeCN
We thus carefully varied temperature, solvent and concentra-
tion to improve the yield of desired heterolignan 5. High boiling
protic solvents such as 2-pentanol, 3-pentanol or 3-methyl-1-buta-
nol proved to be beneficial for high and stable yields (Table 1), but
isolation was hampered as 5 did not precipitate readily from those
solvents. The use of acetonitrile and 2-methoxyethanol afforded 5
in slightly enhanced medium yield (20–30%), but in high purity
due to clean precipitation. On the other hand, MeOH and water
2-BuOH
2-BuOH
40
98
3-Methyl-1-butanol
3-Methyl-1-butanol
2-Pentanol
2-Pentanol
3-Pentanol
3-Pentanol
120
120
120
120
80
120
0.5

4162
J. Frackenpohl et al. / Bioorg. Med. Chem. 17 (2009) 4160–4184
NH2
CCl3
O
CF3
O
O
N
HO
O
OH
Cl
a)
b)
c)
O
O
O
O
7
+
Cl
Cl
O
a)
O
d)
OMe
MeO
H
O
8
6
O
N
CF3
O
F3C
O
b)
e)
O
H
N
NH2
O
O
O
O
12
O
7
Scheme 5. Heterolignans with agrolike aniline precursors. Reagents and condi-
tions: (a) Me2SO4, NaOH, H2O; (b) Cl2, CCl4, hm; (c) HF; (d) NH3, NaNH2; (e) EtOH,
1 h, reflux.
O
O
9
were tolerated in the one-pot approach, heterolignans with elec-
tron-withdrawing groups in ring A had to be prepared following
an alternative pathway. 2-amino-4-chloro-benzonitrile was thus
transformed via Grignard reaction into a bis-arylated ketone which
readily formed quinoline intermediate 10 upon condensation with
tetronic acid in toluene. The desired dihydropyridine 11 was
obtained after NaBH3CN-mediated reduction. The three-step pro-
cedure (Scheme 4) proceeded in high yield and good purity. Alter-
natively, heterolignan 11 could also be synthesized via reduction of
the ketone intermediate with NaBH4 followed by condensation of
the resulting alcohol with tetronic acid.
Some aniline building blocks were not readily available from
commercial sources and were thus prepared following literature
procedures to complement our SAR-study. 3-Trifluoromethoxy
aniline, for example, could be prepared from 2-chlorophenol with
a regiospecific arynic amination of 2-chloro-trifluoromethoxyben-
zene as key step15 to afford 6-OCF3-substituted heterolignan 12 in
the three-component reaction described above. Selected 3-alkoxy-
or 2,3-bisalkoxy anilines were synthesized via Curtius rearrange-
ment or Hofmann degradation of corresponding benzoic acids or
starting from suitable nitrophenol precursors16 (Scheme 5).
To further complement the structural variations of the dihydro-
pyridine ring B selected oxy-analogues were synthesized via
Scheme 3. Stepwise synthesis of heterolignans with electron-donating substitu-
ents in ring A. Reagents and conditions: (a) EtOH, 2 h, reflux; (b) NaBH3CN, HOAc,
3 h, rt.
gave the lowest yield. In general, high concentrations and high
temperatures led to increased yields of 5 and side reactions were
suppressed. The use of microwave conditions did not have a signif-
icant impact on resulting yields and purity, but could be used to
shorten reaction times. Due to the promising initial yields further
reactions were carried out in 2- and 3-pentanol showing that 2-
pentanol was the best solvent evaluated. Selected experiments car-
ried out to optimize the formation of 5 are summarized in Table 1.
In contrast to 6-alkoxy-monosubstituted heterolignans, corre-
sponding 7-alkoxy-substituted analogs were mostly obtained as
pyridines. Thus, with p-methoxyaniline as coupling partner the
three-component reaction yielded pyridine derivative 8 as single
product which could be reduced with NaBH3CN in acetic acid
affording desired 7-methoxy substituted dihydropyridine
9
(Scheme 3). In other cases related pyridines were only obtained
as easily separable side products. Furthermore, the three-compo-
nent reaction could also be applied to acetophenones yielding cor-
responding 9-methyl-substituted dihydropyridines in fair yield.
Although benzaldehydes and acetophenones with a wide vari-
ety of electron-withdrawing and electron-donating substituents
OH
O
O
O
NH2
MgBr
N
OH
+
O
NH2
O
O
a)
O
a)
Cl
+
Cl
CN
O
O
Cl
O
O
Cl
O
HO
HO
O
O
b)
b)
O
O
H
N
OH
OH
N
O
O
O
O
O
O
c)
O
c)
Cl
Cl
7
7
O
O
O
O
O
Cl
Cl
O
O
O
O
11
10
13
Scheme 4. Synthesis of analogues with electron-withdrawing groups in ring A.
Reagents and conditions: (a) (1) THF, 1 h, reflux; (2) aq HCl, 2 h, 30 °C; (c) NaBH3CN,
HOAc, 3 h, rt.
Scheme 6. Synthetic approach towards oxa-Heterolignans. Reagents and condi-
tions: (a) morpholine, MeOH; (b) tetronic acid, AcOH–H2O; (c) H2SO4, AcOH.

J. Frackenpohl et al. / Bioorg. Med. Chem. 17 (2009) 4160–4184
4163
Table 2 (continued)
Table 2
In vivo SAR—variation of ring A at positions C6 and C7
Compound
R2
Phaedon
Cochl.
Spod. Frugip.
1R
6
H
6
N
A
1R
1R
7
A
O
7
O
In vivo
In vivo
activitya
activitya
2R
Cl
16
3,4,5-
(OMe)3
n.a.
n.a.
Compound
R2
Phaedon
Cochl.
Spod. Frugip.
1R
1R
6
7
A
O
O
In vivo
In vivo
17
18
3,5-(OMe)2
+
+
activitya
activitya
O
1b
3,4,5-
++
++
n.a.
(OMe)3
O
O
O
3,4,5-
(OMe)3
n.a.
n.a.
O
O
2b
3,4,5-
(OMe)3
+
O
O
F
F
19
20
3,5-(OMe)2
+
n.a.
n.a.
O
O
O
O
F
F
3
3,4,5-
(OMe)3
+++
n.a.
3,4,5-
(OMe)3
++
O
O
O
O
4
5
3,5-(OMe)2
3,5-(OMe)2
3,5-(OMe)2
3-Cl
+++
+++
+++
n.a.
n.a.
+
+++
++++
++
21
22
23
24
25
3,5-(OMe)2
3,5-(OMe)2
3,5-(OMe)2
+
+
+
++
O
O
O
++
O
9
++++
O
O
11
12
14
n.a.
n.a.
+++
3,5-(OMe)2 n.a.
3,5-(OMe)2 n.a.
+
Cl
O
F3C
Ph
Ph
O
3,5-(OMe)2
n.a.
O
O
O
3,4,5-
(OMe)3
26
27
3,5-(OMe)2 n.a.
3,5-(OMe)2 n.a.
n.a.
n.a.
O
O
15
3,4,5-
(OMe)3
+++
n.a.
(continued on next page)

4164
J. Frackenpohl et al. / Bioorg. Med. Chem. 17 (2009) 4160–4184
Table 2 (continued)
Mannich-reaction of substituted benzaldehydes with electron-rich
phenols in the presence of morpholine. Subsequent addition to
tetronic acid and ring closure afforded desired oxa-heterolignans
in good yield, for example, furochromenone 13.17 (Scheme 6).
Compound
R2
Phaedon
Cochl.
Spod. Frugip.
1R
6
7
A
1R
2.2. In vivo SAR-study
In vivo
In vivo
activitya
activitya
In view of our goal to identify a heterolignan with broad activity
against chewing pests, all four ring segments of initial lead structure
4 were varied thoroughly. All derivatives described below possessing
one chiral centre were tested as racemates. The impact of stereo-
chemistry at position C9 was investigated and will be described in
detail in Section 2.3. Keeping substitution in ring D constant in most
cases we first introduced alternative substituents at positions C6 and
C7 in ring A to replace the methylenedioxy group. We tested all ana-
loguespreparedagainst two representativechewing insects, mustard
beetle P. cochleariae and the fall armyworm S. frugiperda. With these
initial results in hand we could directly deduce that ring A was highly
sensitive to minor structural changes. While 6-methoxy derivative 5
showed improved activity against S. frugiperda down to a level of 4 g/
ha the corresponding 7-methoxy isomer 9 exhibited good activity
against P. cochleariae, but performed significantly weaker against S.
frugiperda. This effect could also be observed clearly with related iso-
meric methoxy-pair 14 and 15 both carrying a 3,4,5-trimethoxy-phe-
nyl moiety (ring D) (Table 2). Again, 14 (6-OMe) showed good activity
against S. frugiperda, whereas 15 (7-OMe) was only active against P.
cochleariae. In good accordance, 6-ethoxy substituted derivative 23
showed excellent selective efficacy against S. frugiperda.
S
28
29
3,5-
(OMe)2
+
+
++
3,5-
(OMe)2
+++
30
31
32
3,5-
(OMe)2
n.a.
+
n.a.
++
O
3,5-
(OMe)2
3,5-
(OMe)2
n.a.
n.a.
O
We then tested whether larger 6-alkoxy groups might further
improve activity against S. frugiperda, but we soon reached the lim-
its of steric tolerance with cyclo-propyl and isopropyl analogues
31, 24 and 32 being less active. Furthermore, corresponding ben-
zyloxy and phenoxy derivatives 25, 26 as well as non-cyclized
6,7-bis alkoxy-substituted compounds 17, 18, 27 performed poorly
or were inactive. Introducing fluorine in the methylenedioxy group
(19, 20, Table 2) and enlarging the ring size (21, 22) of this privi-
leged naturally occurring substituent also decreased the biological
efficacy sharply. Interestingly, the latter observation was in clear
contrast to the cytotoxic SAR established in recent years. In those
studies larger alkoxy and alkyl groups were tolerated without loss
of activity, and electronic effects were claimed not to be
important.13
Disappointingly, introducing halogen or fluoroalkoxy substitu-
ents, for example, 6-Cl (16), 7-Cl (11), 6-OMe-7-Cl (39), 6-OCF3
(12) and bis-6,7-OCHF2 (33) led to a complete loss of activity.
The best non-alkoxy substituted analogues were thioether 28
and methyl derivative 29 but their efficacy was lower than that
of the initial lead structure 4.
Introducing alkoxy and alkyl substituents at position C5 gave
rise to surprisingly good insecticidal activities (Table 3). 5,7-Dime-
thoxy and related 5-methoxy-7-methyl heterolignans 41 and 49
exhibited strong efficacy against P. cochleariae, whereas 5,6-dime-
thoxy derivative 43 showed the strongest performance of all ana-
logues 3–49 with high activity against both test organisms. Also
5,6-dimethyl-substituted heterolignan 47 was active against both
P. cochleariae and S. frugiperda underlining the positive effect of
C5 substitution.
In summary, only small electron-donating alkoxy substituents
are well tolerated in ring A, preferably at positions 5, 6 and 7. Ste-
rically more demanding and less electron-donating substituents
afforded reduced efficacies with isopropoxy being at the limit of
steric tolerance. Likewise, halogen and most fluoroalkoxy ana-
logues as well as large alkoxy, phenoxy and alkyl groups proved
to be inactive. Promising efficacies were obtained with the 5,6-
dimethoxy and 6-methoxy group affording 5 and 43 as most
potent derivatives. Activity against the two test organisms could
F
O
O
F
33
3,5-
(OMe)2
n.a.
n.a.
F
F
O
34
35
36
3,5-
(OMe)2
++
n.a.
n.a.
n.a.
3,5-
(OMe)2
n.a.
n.a.
Ph
3,5-
(OMe)2
HO
O
37
38
39
40
3,5-
(OMe)2
n.a.
+++
n.a.
n.a.
n.a.
3,5-
(OMe)2
+
O
3,5-
(OMe)2
n.a.
n.a.
Cl
Ph
O
3,5-
(OMe)2
Br
a
++++ = activity at 4 g/ha; +++ = activity at 20 g/ha; ++ = activity at 100 g/ha;
+ = activity at 500 g/ha; n.a. = no activity in the test systems.
Natural products 1 and 2 contain a tetraline core instead of the dihydroquin-
oline moiety shown above.
b

J. Frackenpohl et al. / Bioorg. Med. Chem. 17 (2009) 4160–4184
4165
Table 3
be discriminated with the help of derivatives carrying one alkoxy
substituent either at C6 or C7. Substituents at position C8 (e.g., in
42, 44 and 45) were not beneficial for biological in vivo activity,
whereas most compounds carrying a substituent at C5 were active.
We turned our attention next to variations in other parts of the
core structure. Although promising cytotoxic and antiproliferative
activity combined with a simple synthetic access makes hetero-
lignans an attractive target for detailed SAR studies few efforts
have been described exploring structural changes in rings B and
C (Scheme 1). To our knowledge, lactone moiety C of the heterolig-
nan core structure has been varied in two recent studies only by
structurally related analogs also leaving the dihydropyridine part
unchanged.13,18 In our insecticidal in vivo SAR study, introducing
substituents in the dihydropyridine moiety (ring B) showed that
N-alkylation is tolerated in some cases affording derivatives with
in vivo activity, for example, 52 and 55, whereas alkylation at C9
totally erased biological activity (e.g., 58, Table 4). Nevertheless,
all compounds modified in ring B exhibited weaker activity than
initial lead structure 4.
In vivo SAR—variation of ring A involving positions C5 and C8
H
5
A
8
N
1R
O
O
2R
Phaedon Cochl.
Compound
R2
Spod. Frugip.
5
A
8
1R
In vivo activitya In vivo activitya
O
41
3,5-(OMe)2 ++++
+
A similar trend could be observed for variations of the lactone
moiety in ring C where only few minor structural changes were tol-
erated. Although a highly diverse set of heterolignans with lactone-
replacing groups including ketones, lactams, oxazinones and cyclic
sulfonates and sulfones was synthesized, in vivo activity against
both target organisms was preserved only in methyl lactone 79,
ketone 87, lactam 74 and the 6-membered lactones 65 and 76. Activ-
ity of these five derivatives did not exceed a level of 100 g/ha. All
other structural analogs exhibited only weak, for example, partial
activity at 500 g/ha for 66, 67, 69, 83 and 84, or no activity at all.
Interestingly, most free lactams (e.g., 72, 82, 91) showed in vivo effi-
cacy, whereas alkylated or Boc-protected analogues were inactive.
To make sure that these effects might not be different with other
substituents in rings A and D, some analogues were prepared with
a m-chlorine substituent in ring D. Results were comparable with
unsubstituted lactam 74 and 6-membered lactone 65 being more
potent than their analogues carrying a 3,5-dimethoxy-substituted
phenyl ring D. Hence, an unsubstituted 5-membered lactone, origi-
nating from tetronic acid, remained the subunit of choice for ring C
and was not replaced in the broad variations of rings A and D. Our
observations are in line with results obtained in the course of the
two cytotoxicity studies mentioned above13,17 where only a ketone
similar to 87 exhibited submicromolar affinity (Table 5).
O
O
42
43
3,5-(OMe)2 n.a.
n.a.
O
O
O
3,5-(OMe)2 +++
++++
O
O
44
45
3,5-(OMe)2 n.a.
n.a.
n.a.
O
3,5-(OMe)2 n.a.
In contrast to the concurring biological results for rings B and C,
insecticidal and anti-cancer SAR differ with respect to the impact of
variations in ring D. In our work alkoxy and halogen substituents in
the para-position led to significantly reduced activity as examples
93 (p-OMe), 94 (m,p-(OMe)2), 97 (p-Cl), 109 (difluoro-methylene-
dioxy) and 127 (m-OMe-p-Cl) underline (Table 6). Related ana-
logues from the pharmacological studies, however, show
moderate to good activity against cancer cell lines still reaching
nanomolar levels. Important exceptions in our insecticidal SAR
are 3,4,5-trisubstituted derivatives with alkoxy groups similar to
the natural product podophyllotoxin 1 and p-fluorine containing
compounds. Analogues such as 121, 123, 124, 125 and 130 show
good efficacy against P. cochleariae as is observed for natural prod-
ucts 1 and 2, but are not effective to control S. frugiperda. 3,4-disub-
stituted derivatives 128 and 131 with fluorine in the para-position
exhibit moderate activity. Furthermore, substituents in the ortho-
position were generally not tolerated affording inactive com-
pounds, for example, 95 (2-Cl), 110 (2,3,5-Cl3), 112 (2,3-Cl2), 124
(2,5-Cl2), except for fluorinated heterolignan 115 with a special
2-F-3-Cl-5-CF3 substitution pattern. This particular derivative
was more active than natural products 1 and 2, and parent com-
pound 3, respectively. It nearly reached the level of activity of ini-
tial lead structure 4 indicating that there is space in our insecticidal
study for variations of substituents in ring D beyond well described
O
46
47
48
3,5-(OMe)2 ++
3,5-(OMe)2 ++
3,5-(OMe)2 n.a.
3,5-(OMe)2 +++
+
O
++
n.a.
+
O
49
a
++++ = activity at 4 g/ha; +++ = activity at 20 g/ha; ++ = activity at 100 g/ha;
+ = activity at 500 g/ha; n.a. = no activity in the test systems.

4166
J. Frackenpohl et al. / Bioorg. Med. Chem. 17 (2009) 4160–4184
Table 4
Table 5
In vivo SAR—variation of ring B
In vivo SAR—variation of ring C
H
N
O
3R
N
O
C
O
1R
O
B
O
4R
O
2R
2R
R2
Compound
R2
Phaedon Cochl. Spod. Frugip.
6R
Y
Compound
R1
Phaed.
Cochl.
Spod.
Frugip.
5
3R
N
X R
O
B
4R
In vivo activitya In vivo activitya
In vivo
In vivo
activitya
activitya
O
4
3,5-
(OMe)2
+++
n.a.
+++
n.a.
H
N
O
50
51
6-Cl
7-Cl
3,4,5-
(OMe)3
n.a.
n.a.
n.a.
n.a.
59
3-Cl
H
N
O
O
3-Cl
60
3-Cl
n.a.
n.a.
CH3
N
O
O
O
52
3,4,5-
(OMe)3
++
n.a.
61
62
63
64
65
3-Cl
3-Cl
3-Cl
3-Cl
3-Cl
n.a.
n.a.
n.a.
n.a.
++
n.a.
n.a.
n.a.
n.a.
++
CH3
N
O
53
54
55
6,7-
(OMe)2
3,4,5-
(OMe)3
n.a.
n.a.
+
n.a.
n.a.
+
CH3
N
6-Me
4-Cl
CH3
O
O
N
N
3,5-
(OMe)2
CH3
O
O
56
57
6,7-
(OMe)2
3,5-
(OMe)2
n.a.
n.a.
O
CH3
N
6-OMe
3,5-
(OMe)2
n.a.
n.a.
++
O
N
66
67
3-Cl
3-Cl
n.a.
+
O
S
H
N
O
O
58
3,5-
(OMe)2
n.a.
+
n.a.
O
a
O O
++++ = activity at 4 g/ha; +++ = activity at 20 g/ha; ++ = activity at 100 g/ha;
+ = activity at 500 g/ha; n.a. = no activity in the test systems.

J. Frackenpohl et al. / Bioorg. Med. Chem. 17 (2009) 4160–4184
4167
Table 5 (continued)
Table 5 (continued)
Compound
R2
Phaedon Cochl.
Spod. Frugip.
Compound
R2
Phaedon Cochl.
Spod. Frugip.
6R
Y
6R
Y
5
5
X R
X R
O
O
In vivo activitya In vivo activitya
In vivo activitya In vivo activitya
NH
68
3-Cl
3-Cl
n.a.
n.a.
n.a.
80
3,5-(OMe)2
n.a.
n.a.
S
O
O
O
boc
H
N
81
82
83
3,5-(OMe)2
3,5-(OMe)2
3-Cl
n.a.
+
n.a.
n.a.
n.a.
O
69
70
+
S
O
O
O
O
N
3-Cl
n.a.
n.a.
O
S
O
O
+
O
71
72
73
74
75
76
3-Cl
3-Cl
3-Cl
3-Cl
n.a.
n.a.
n.a.
n.a.
++
S
O
O
84
85
3-Cl
3-Cl
+
n.a.
n.a.
O
O
NH
+
O
n.a.
O
N
boc
n.a.
O
O
86
87
88
3,5-(OMe)2
3,5-(OMe)2
3,5-(OMe)2
n.a.
+
n.a.
++
NH
+
O
O
O
3,5-(OMe)2 n.a.
n.a.
O
O
N
O
O
n.a.
n.a.
O
3,5-(OMe)2
+
+
89
90
3,5-(OMe)2
n.a.
n.a.
NH
O
O
N
77
3,5-(OMe)2 n.a.
n.a.
N
boc
H
3,4,5-
(OMe)3
n.a.
n.a.
n.a.
O
S
O
78
79
3,5-(OMe)2 n.a.
n.a.
O
N
91
3,4,5-
(OMe)3
+
O
O
O
a
++++ = activity at 4 g/ha; +++ = activity at 20 g/ha; ++ = activity at 100 g/ha;
+ = activity at 500 g/ha; n.a. = no activity in the test systems.
O
3,5-(OMe)2 ++
+
O

4168
J. Frackenpohl et al. / Bioorg. Med. Chem. 17 (2009) 4160–4184
Table 6 (continued)
Table 6
In vivo SAR—variation of ring D
Compound
Phaedon Cochl.
Spod. Frugip.
H
N
O
O
O
In vivo activitya
In vivo activitya
O
2R
2R
Compound
Phaedon Cochl.
Spod. Frugip.
101
102
103
104
105
106
107
108
109
110
111
++
+++
+++
+++
++
F
F
In vivo activitya
In vivo activitya
2R
n.a.
++
92
93
n.a.
n.a.
n.a.
n.a.
+
++
O
Br
n.a.
n.a.
n.a.
++
n.a.
++
O
O
CH3
94
+++
+++
+
O
F
Cl
95
++
OCF3
96
n.a.
++
Cl
O
97
n.a.
++
n.a.
+++
+
+++
n.a.
n.a.
n.a.
Cl
CH3
H3C
98
n.a.
n.a.
n.a.
O
Cl
Cl
O
F
F
Cl
Cl
99
n.a.
++
NC
Cl
O
100
++
F3C
O

J. Frackenpohl et al. / Bioorg. Med. Chem. 17 (2009) 4160–4184
4169
Table 6 (continued)
Table 6 (continued)
Compound
Phaedon Cochl.
Spod. Frugip.
Compound
Phaedon Cochl.
Spod. Frugip.
In vivo activitya
In vivo activitya
In vivo activitya
In vivo activitya
2R
2R
Cl
Cl
123
124
125
126
127
128
129
130
131
132
++
++
+++
+
n.a.
112
113
114
115
116
117
118
119
120
121
122
n.a.
++
n.a.
++
n.a.
++
n.a.
++
+
O
O
O
OH
O
O
n.a.
S
O
Cl
n.a.
+++
++
+
Cl
O
O
F
Cl
CF3
Br
++
O
CN
O
O
+
+
O
Cl
n.a.
n.a.
n.a.
++
N
Br
n.a.
++
Cl
N
F
S
Br
+
+
O
++
Br
N
Br
++
+
Br
O
+
O
F
F
+
++
++
++
+++
O
Cl
Br
Cl
O
F
n.a.
+
+
F
F
F
(continued on next page)

4170
J. Frackenpohl et al. / Bioorg. Med. Chem. 17 (2009) 4160–4184
Table 6 (continued)
Table 7
In vivo SAR—oxa-analogues
Compound
Phaedon Cochl.
Spod. Frugip.
6
7
O
1R
O
A
In vivo activitya
In vivo activitya
O
2R
F
2R
Compound
R2
Phaedon Cochl. Spod. Frugip.
F
133
++
++
F
1R
O
A
F
In vivo
In vivo
activitya
activitya
134
n.a.
+++
O
O
OH
13
3,5-(OMe)2
3,5-Cl2
3-Cl
+
+
O
a
++++ = activity at 4 g/ha; +++ = activity at 20 g/ha; ++ = activity at 100 g/ha;
+ = activity at 500 g/ha; n.a. = no activity in the test systems.
O
O
135
136
n.a.
n.a.
n.a.
n.a.
methoxy and methylenedioxy groups. Likewise, the aryl D-ring
could be replaced by pyridines with meta-substituted derivatives
117 and 120 (Table 6) showing the best in vivo results. As can pre-
liminarily be deduced from the selected examples discussed above,
substituents in the meta-position turned out to be beneficial for
insecticidal activity. m-Cl-Substituted heterolignan 96, as well as
monosubstituted closely related analogues 100 (m-CF3), 103
(m-Br), 105 (m-F) and 106 (m-OCF3) showed good activity against
both target organisms down to 20 g/ha. Similarly strong results
were obtained with 3,5-disubstituted analogues, for example, with
98 (3,5-Cl2), 101 (3,5-F2) and 108 (3,5-Me2). Among all derivatives
listed in Table 6 highest efficacies were in fact achieved with hal-
ogen-disubstituted heterolignans 98 and 101. Electron-donating
alkoxy groups in ring D are thus not crucial for high in vivo efficacy,
contrary to what has been observed for ring A.
Furthermore, some sterically more demanding alkoxy substitu-
ents are also tolerated in the meta-position with isopropoxy-deriv-
ative 107 being at the upper limit. Ethoxy (113), tetrafluoroethoxy
(133), and cyano methyleneoxy (126) groups afforded heterolign-
ans with fair activity against both species. Interestingly, the addi-
tional hydroxyl group in 134 further enhanced the efficacy
against S. frugiperda.
O
O
O
O
137
138
139
3-Br
n.a.
n.a.
n.a.
n.a.
n.a.
n.a.
O
O
3-OCF3
3-Cl
O
O
O
140
3-Br-4,5-
(OMe)2
+
n.a.
Replacing the dihydropyridine unit by a pyran, however, led to a
sharp decrease in biological activity. Only the closest analogue of
lead structure 4, methylenedioxy-substituted furochromenone
13, showed in vivo activity against both target organisms, albeit
at a high concentration (Table 7). Other pyran derivatives prepared
were mostly inactive.
O
O
141
142
3-OCHF2
n.a.
n.a.
n.a.
n.a.
O
3,5-(OMe)2
In summary, a wide variety of substituents can be introduced in
the meta-positions with insecticidal activity being preserved or
enhanced. Nevertheless, the most potent insecticidal heterolignans
identified in the course of our initial SAR study are derivatives5, 23
and 43 with modified alkoxy groups in ring A. By combining the
best substituents emerging from variations of rings A and D we
have identified further highly potent analogues which are
disclosed in a patent.18 Presenting all results obtained so far would
go far beyond the scope of our work outlined herein.
O
O
143
144
3,5-(OMe)2
3,5-Cl2
n.a.
n.a.
n.a.
+
O
2.3. Mode of action studies
O
O
145
3,5-Cl2
n.a.
+
A number of experiments using permanent insect cell cultures
were carried out to determine the mode of action of the heterolign-
ans. Insect Sf9 cell cultures were incubated and analysed with
fluorescent markers under a fluorescence microscope for viabil-
a
++++ = activity at 4 g/ha; +++ = activity at 20 g/ha; ++ = activity at 100 g/ha;
+ = activity at 500 g/ha; n.a. = no activity in the test systems.

J. Frackenpohl et al. / Bioorg. Med. Chem. 17 (2009) 4160–4184
4171
ity/cytotoxicity, changes in cell shape/cell membrane, chromatin,
cytoskeleton, or mitochondrial membrane potential.
the hypothesis was formulated that the mode of action of the
heterolignans is by inhibition of the polymerization of the microtu-
bular system.
To strengthen the hypothesis that heterolignans are interfering
with tubulin polymerization, a tubulin polymerization assay with
purified bovine tubulin was performed.19 Similar to colchicine,
in vivo active heterolignan 43 was able to inhibit the in vitro poly-
merization of tubulin in clear contrast to taxol which strongly
enhanced polymerization (Fig. 2).
Most striking were the activities of the enantiomeric pair S-5
and R-5, where in vivo active enantiomer R-5 not only was cyto-
toxic in vitro in Sf9 cells (Table 8), but also showed the typical
changes in chromatin/cell nucleus phenotype seen with colchicine,
whereas the in vivo inactive enantiomer S-5 was also inactive
in vitro on Sf9 cells and did not show any cellular symptoms
typical for interfering with microtubules. Absolute stereochemistry
First, a set of representative compounds selected on the basis of
different levels of in vivo activities was analysed in the toxicity/via-
bility test using the Spodoptera Sf9 cell line and a related mamma-
lian CHO cell line. It turned out that activities in vitro in SF9 cells
correlated very well to the activities observed in vivo, as those
compounds which were toxic to S. frugiperda in vivo (e.g., most
promising derivatives 23 and 43) also showed strong cytotoxic
activity in the insect Sf9 cell line at the same level as colchicine
(Entries 5 and 7, Table 8). The moderate in vitro activity of hetero-
lignans 17 and 55 correlated with weak in vivo activity. Likewise,
heterolignans with weak in vitro effects, for example, 94 and 59,
were inactive in our in vivo tests.
After 24 and 48 h heterolignans produced symptoms in CHO
and Sf9 cells which looked very similar to those induced by colchi-
cine. These cellular symptoms included a stop in cell division, the
induction of polyploid cells with abnormal bubble-like chromatin
and enhancement of cell volume (Fig. 1). From these observations
at carbon C9 was determined by X-ray analysis using Cu-Ka radi-
ation. The measurement was performed at 100 K to produce more
4500
Absorbance
4000
Table 8
In vitro–in vivo correlation of selected heterolignans
3500
3000
Entry
Compound
Spod. Frugip. SF9 cells
Spod. Frugip.
In vitro toxicitya
In vivo activityb
1
2
3
4
5
6
7
8
9
94
95
59
17
23
24
43
55
++
+
++
+++
++++
++
++++
+++
o
n.a.
n.a.
n.a.
+
++++
+
++++
+
n.a.
++++
10µM
2500
Tubulin
2000
1500
1000
500
0
Colchicine
Taxol
S-5
R-5
Colchicine
10
12
++++
++++
t [min]
31
a
++++ = activity at 0.14 ppm; +++ = activity at 1 ppm; ++ = activity at 3 ppm;
+ = activity at 10 ppm; o = activity at concentrations >10 ppm.
1
6
11
16
21
26
b
++++ = activity at 4 ppm; +++ = activity at 20 ppm; ++ = activity at 100 ppm;
Figure 2. Inhibition of tubulin polymerisation in the presence of heterolignan 43
(–N–).
+ = activity at 500 ppm; n.a. = no activity in the test systems.
Figure 1. Analysis of subcellular changes in chromatin structure; (a) nuclear staining after 48 h of incubation with colchicine (B) or heterolignan 4 (C) in CHO cells; (b)
nuclear staining of Sf9 cells after 48 h of incubation with colchicine (B) and heterolignan 4 (C). Normal dividing cells cultured without compounds were stained in A.

4172
J. Frackenpohl et al. / Bioorg. Med. Chem. 17 (2009) 4160–4184
accurate data for the measurement. Both enantiomers of heterolig-
nan 5 were carefully separated by chiral HPLC before. As the
biologically inactive enantiomer was more prone to crystallize its
X-ray structure was thoroughly analyzed first showing that sub-
stituents at carbon C9 carried an S configuration (Fig. 3). Interest-
ingly, the most important interactions within the crystal lattice
are hydrogen bonds between the NH group of dihydropyridine ring
B and the lactone carbonyl group of ring C.
Taking all results together it can be concluded that heterolign-
ans inhibit the polymerization of microtubules analogous to the
activity of colchicine.
Based upon the co-crystal structure of tubuline with the closely
related inhibitor molecule podophyllotoxin (PDB 1SA1, derived
from Protein Data Bank),20 modeling studies were undertaken to
augment the chemical optimization procedure of the heterolignan
the hydrophobic binding pocket surrounding the trimethoxy-
phenyl moiety. Differences between our insect SAR and preceding
medicinal chemistry studies observed for substituent effects of
heterolignan ring D can thus be explained. In line with in vivo re-
sults described above only a small set of variations in m-position is
favourable in our models. A close look at the binding model shown
in Figure 4 also rationalises the striking impact of stereochemistry
on activity as only one enantiomer fits into the T-like binding pock-
et. Due to a conserved part of the colchicine binding pocket, struc-
tural changes in ring A have a strong impact on the fit of
heterolignans, also in accord with in vivo results (cf. Tables 2 and
3).
However, the important role of the lactone moiety (ring C) for
in vivo activity remains unclear; although vital for high insecticidal
activity, neither the carbonyl group nor the oxygen atom seem to
be involved in any (polar) interactions.
compound class. Tubuline is composed of two non-identical (a/b)
chains, each about 450 residues in length. The so-called ‘Colchicine
Site’ is located at the b subunit, right at the interface between a and
b chains. In the crystal structure of rat tubuline (1SA1) the trime-
thoxyphenyl moiety is deeply buried within a hydrophobic pocket
of b-tubuline, while the hydroxyl group from ring B forms a hydro-
3. Conclusion
More than 140 heterolignan derivatives have been prepared in
the course of our study covering all major parts of the core struc-
ture.21 The three-component reaction used to prepare target mol-
ecules turned out to be highly sensitive to solvent, temperature
and concentration effects with ethanol, 2-pentanol and MeCN giv-
ing the best yields. Various unprecedented substituents have been
introduced to investigate the structure–insecticidal activity
relationship in detail. Variations in ring A had a high impact on bio-
logical activity with small alkoxy substituents at positions 5 and 6,
for example, 5, 23 and 43, affording promising improved activity
against coleopteran and lepdiopteran target organisms. Activity
against the two test insects could be discriminated with the help
of derivatives carrying one alkoxy substituent either at C6 or C7.
gen bond to the backbone carbonyl group of Thr179 from the
a-
tubuline chain laying adjacent to the colchicine binding site. As
crystal structures of bound and unbound tubulines are currently
available only for mammals but not for insects, protein homology
techniques were applied to construct a model of the colchicine
binding site of Heliothis. Therefore, a sequence alignment was car-
ried out for the b-tubuline subunits from rat (X-ray) and Heliothis,
showing an overall identity level of more than 90%. Despite the
high overall identity two mutations could be identified next to
the colchicine binding site, which may influence the biological
activity of the heterolignans. Both residues are positioned around
H
H
O
N
O
N
O
O
O
O
(R)-5
(S)-5
O
O
O
O
Figure 3. X-ray crystal structures of (S)-5 and (R)-5.

J. Frackenpohl et al. / Bioorg. Med. Chem. 17 (2009) 4160–4184
4173
Figure 4. Receptor binding of heterolignans; (a) crystal structure of
96 in the colchicine binding site of tubulin.
a,b-tubulin dimer from rat bound with podophyllotoxin 1 (colchicine site) and GTP; (b) docking pose for
All structural changes in rings B and C, however, led to decreased
efficacy compared with initial lead structure 4. This observation
is in good accordance with molecular modeling studies indicating
the interaction of rings B and C with a highly conservative binding
site. In the case of substituent effects of ring D, groups in meta-sub-
stitution enhanced biological activity, while ortho- and para-sub-
stituents (except for fluorine) reduced the corresponding activity.
With the help of in vitro experiments it was clearly shown that
the heterolignans described herein act as insecticides by inhibiting
the polymerisation of the microtubular system.
used: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br,
broadened. LC–MS spectra were recorded using either a Shimadzu
LC–MS-QP8000a system (EI/CI, pH 2 or pH 7, UVk = 230 nm) or an
Agilent Series 1100 system (ES, pH 2.4, UVk = 230 nm and 254 nm).
Microwave reactions were carried out using a Biotage (Personal
Chemistry) Smith Synthesiser, operating at 300 W. Unless other-
wise stated, silica gel chromatography was performed using an Isco
CombiflashÒ parallel system with Teledyne Isco RediSepÒ 12 g or
40 g column cartridges at a flow rate of approximately 10 ml/min.
4.1.2. Single crystal X-ray structure analysis
4. Experimental
4.1. Chemistry
The Crystal structure determination was carried out using a dif-
fractometer (Oxford Diffraction, Xcalibur series) equipped with a
CCD area detector (model Ruby), a sealed tube with Cu K
a radia-
tion, osmic mirrors as monochromator and a Cryojet low tempera-
ture device (T = 100 K), as well as fullsphere data collection with
omega and phi scans. Programs used: Data collection and reduc-
tion Crysalis (Oxford Diffraction 2007). Crystal structure solution
was achieved using direct methods as implemented in SHELXTL Ver-
sion 6.10 (Sheldrick, Universtität Göttingen (Germany), 2000) and
visualized using XP program. Missing atoms were subsequently
located from difference Fourier synthesis and added to the atom
list. Least-squares refinement on F2 using all measured intensities
was carried out using the program SHELXTL Version 6.10 (Sheldrick,
Universtität Göttingen (Germany), 2000). All non-hydrogen atoms
were refined including anisotropic displacement parameters. Fur-
4.1.1. General
Unless otherwise stated, all reagents and building blocks were
purchased from commercial sources. Solvents were distilled prior
to use or purchased in reagent-grade quality. All melting points
where given, were determined in open capillary tubes using a
Büchi B-545 melting point apparatus and are uncorrected. 1H
NMR spectra were obtained with either a 400 MHz Varian Unity
Inova instrument or a 300 MHz Varian Mercury Vx instrument in
CDCl3 or DMSO using tetramethylsilane as an internal standard.
Chemical shifts are given in delta (d) values and coupling constants
(J) in Hertz (Hz). The following peak multiplicity abbreviations are

4174
J. Frackenpohl et al. / Bioorg. Med. Chem. 17 (2009) 4160–4184
Table 9
of active compound in the desired concentration and, after they
Crystal data and structure refinement for (S)-5
have dried, are populated with larvae of the army worm (S. fru-
giperda). After the desired time the activity is determined. Good
activity indicated by ‘+’ here means that at least 80% of the lar-
vae have been killed at the given concentration; ‘n.a.’ here
means that no larvae have been killed.
Data for (S)-5
Empirical formula
Formula weight
Temperature (K)
Wavelength (Å)
Crystal system
Space group
Unit cell dimensions
a (Å)
C20H19NO5
353.36
100
1.54178
Orthorhombic
P2(1)2(1)2(1)
4.3. Biochemistry
6.23860(10)
12.86480(10)
21.2606(2)
90
90
90
1706.34(3)
4
1.376
0.821
4.3.1. Analysis of in vitro microtubule polymerization
b (Å)
c (Å)
The CytoDYNA-MIX ScreenTM3 (CDS-03) kits purchased from
Cytoskeleton Inc. (Denver, CO) were used for the detection of
in vitro polymerization of tubulin.19 Tubulin proteins (>99% purity)
a
(°)
b (°)
(°)
were suspended (300 lg/sample) in 100 ll of G-PEM buffer
c
Volume (Å)
(80 mM PIPES, 2 mM MgCl2, 0.5 mM EGTA, 1.0 mM GTP, pH 6.9)
with 5% of glycerol added in the absence or presence of the test
compounds including standard compounds colchicine and taxol
at 4 °C. Then, the sample mixture was transferred to the pre-
warmed 96-well plate, and the polymerization of tubulin was mea-
sured by the change in absorbance at 340 nm every 1 min for up to
60 min at 37 °C (Tecan Spectrafluor Plus).
Z
Dcalcd (Mg/m3)
Absorption coefficient (mmꢁ1
F(000)
)
744
Crystal size (mm3)
0.20 ꢀ 0.15 ꢀ 0.13
Theta range for data collection (°)
Index ranges
4.02–66.93
ꢁ7 6 h 6 3,
ꢁ15 6 k 6 14,
ꢁ24 6 l 6 24
9010
4.3.2. Measurement of chromatin condensation by
Reflections collected
Independent reflections
Completeness to theta = 66.93°
Absorption correction
2869 [R(int) = 0.0164]
95.6%
fluorescence microscopy
All selected test compounds were analysed on S. frugiperda (Sf9)
and Chinese Hamster Ovary (CHO) cells. The cells were seeded into
an 8-well slide chamber the day before treatment. In brief, after the
cells were incubated with compounds for 48 h, they were washed
twice with phosphate-buffered saline (PBS). Then, cells were fixed
with ice-cold methanol for 10 min on ice followed by two short
washes with acetone. After rehydrating the cells with PBS, the cells
None
Refinement method
Full-matrix least-squares on F2
2869/0/311
1.065
Data/restraints/parameters
Goodness-of-fit on F2
Final R indices [I > 2sigma(I)]
R indices (all data)
R1 = 0.0255, wR2 = 0.0653
R1 = 0.0267, wR2 = 0.0660
ꢁ0.05(15)
Absolute structure parameter
Largest diff. peak and hole (e Åꢁ3
)
0.123 and ꢁ0.136
were incubated with Dapi solution (2 lM) for 30 min and subse-
quently analysed under a Zeiss Axiovert fluorescence microscope
using a ꢀ40 objective to detect the presence of chromatin conden-
sation/fragmentation.
ther details are given in Table 9, and complete crystal structure
data were deposited at the Cambridge Crystallographic Data Centre
(ref. no. to be announced).
4.4. Chemistry—experimental procedures
4.4.1. General procedure 1 for the three-component reaction
with electron-rich anilines
4.2. Biology
Tetronic acid (1 equiv), the corresponding aldehyde (1 equiv)
and an aniline with electron-donating substituents (1 equiv) were
added to a suitable polar solvent (e.g., ethanol, 2-pentanol, 3-pent-
anol or acetonitrile) and refluxed under Ar. After cooling to room
temperature the precipitate formed was filtered off, dried and puri-
fied if necessary. When no precipitate was formed, the resulting
crude reaction mixture was concentrated under reduced pressure
and purified by preparative HPLC to afford desired heterolignan.
In most cases, the three-component reaction was carried out on
millimolar scale (i.e., 1–4 mmol).
4.2.1. P. cochleariae larvae test (spray treatment)
Seventy eight parts by weight of acetone and 1.5 parts by
weight of dimethylformamide were used as solvents with 0.5 part
by weight of alkyl polyglycol ether added as emulsifier. An appro-
priate preparation of active compound is prepared by mixing 1 part
by weight of active compound with the stated amounts of solvent
and emulsifier and diluting the concentrate with emulsifier-con-
taining water to the desired concentration. Disks of Chinese
cabbage leaf (Brassica pekinensis) are sprayed with a preparation
of active compound in the desired concentration and, after they
have dried, are populated with larvae of the mustard beetle (P.
cochleariae). After the desired time the activity is determined. Good
activity indicated by ‘+’ here means that at least 80% of the beetle
larvae have been killed at the given concentration; ‘n.a.’ here
means that no beetle larvae have been killed.
4.4.2. General procedure 2 for the conversion of quinolines into
desired dihydroquinoline target compounds
The quinoline derivative (1 equiv) or its corresponding mixture
with desired dihydroquinoline was dissolved in glacial acetic acid
(5 ml/mmol). Subsequent to 15 min stirring at rt under Ar
NaBH3CN (2 equiv) was added and stirring was continued for 3 h.
The reaction mixture was concentrated under reduced pressure
and purified by flash chromatography.
4.2.2. S. frugiperda larvae test (spray treatment)
Seventy eight parts by weight of acetone and 1.5 parts by
weight of dimethylformamide were used as solvents with 0.5
part by weight of alkyl polyglycol ether added as emulsifier.
An appropriate preparation of active compound is prepared by
mixing 1 part by weight of active compound with the stated
amounts of solvent and emulsifier and diluting the concentrate
with emulsifier-containing water to the desired concentration.
Disks of maize leaf (Zea mays) are sprayed with a preparation
4.4.3. General procedure 3 for the synthesis of heterolignans
with electron-withdrawing substituents in ring A
If the suitable Grignard reagent was not available from com-
mercial sources it was freshly prepared as follows: Magnesium
turnings (2 equiv) and some drops of the aryl bromide were added
to abs tetrahydrofuran (1 ml/mmol), and the resulting reaction

J. Frackenpohl et al. / Bioorg. Med. Chem. 17 (2009) 4160–4184
4175
mixture was heated to reflux. Then, the major portion of the aryl
bromide (2 equiv in total) was added and refluxing was continued
for 2 h. After cooling to rt the corresponding amino-chlorobenzoni-
trile (1 equiv, dissolved in abs tetrahydrofuran) was added drop-
wise. The reaction mixture was refluxed again for 1 h, and
subsequent to cooling to rt aq HCl (2 N) was added carefully, and
stirring was continued for 2 h at a temperature of 30 °C. After the
reaction mixture had been neutralized with aq NaOH (2 N), the
aqueous layer was extracted thoroughly with methyl-t-butyl ether.
The combined organic layer was dried, filtered and concentrated
under reduced pressure to afford the crude ketone intermediate
which was purified by flash chromatography. In the following step
intermediate ketone (1 equiv) was dissolved in abs toluene and
tetronic acid (1 equiv) and p-toluenesulfonic acid (0.1 equiv) were
added. The resulting reaction mixture was refluxed for 1 h. After
cooling to rt the precipitate obtained was filtered off and washed
with toluene to yield a substituted quinoline. Without purification
the quinoline was further reduced with sodium cyanoborohydride
following procedure 2 to afford desired heterolignan with electron-
withdrawing substituents.
water and acetic acid. After some minutes the product precipitates.
The cooled mixture is triturated with 2-propanol, the crystals are
filtered with suction, washed with 2-propanol and dried. The crude
intermediate (1 mmol) is then suspended in 3 ml of acetic acid,
two drops of concd sulfuric acid are added and the mixture is
heated to 110 °C until all crystals are dissolved. After cooling the
reaction mixture to room temperature water is added, and the
resulting crystals are removed by filtration, washed with 2-propa-
nol and dried to afford desired oxa-heterolignans.
4.4.6. 9-(3,4,5-Trimethoxyphenyl)-6,9-dihydro[1,3]dioxolo[4,5-
g]furo[3,4-b]quinolin-8(5H)-one (3)
Following general procedure 1 heterolignan 3 was isolated as a
colourless solid (1536 mg, 77%). 1H NMR (DMF-d7) (d): 6.73 (s, 1H),
6.65 (s, 2H), 6.62 (s, 1H), 5.98 (d, 2H), 5.05 (d, 1H), 4.98 (s, 1H), 4.92
(d, 1H), 3.78 (s, 6H), 3.66 (s, 3H).
4.4.7. 9-(3,5-Dimethoxyphenyl)-6,9-dihydro[1,3]dioxolo[4,5-
g]furo[3,4-b]quinolin-8(5H)-one (4)
Following general procedure 1 heterolignan 4 was obtained as
colourless solid (980 mg, 73%); mp >310 °C. 1H NMR (DMSO-d6)
(d): 9.85 (s, NH), 6.64 (s, 1H), 6.52 (s, 1H), 6.33 (m, 3H), 5.97 (s,
1H), 5.90 (s, 1H), 4.97 (d, 1H), 4.86 (d, 1H), 4.82 (s, 1H), 3.70 (s,
6H). MS (ES+) m/z: 368 (M++1, 100).
4.4.4. General procedure 4 for the synthesis of heterolignans
with electron-withdrawing groups in ring A and further
substituents in ring B
If the suitable Grignard reagent was not available from com-
mercial sources it was freshly prepared as follows: Magnesium
turnings (2 equiv) and some drops of the aryl bromide were
added to abs tetrahydrofuran (1 ml/mmol), and the resulting
reaction mixture was heated to reflux. Then, the major portion
of the aryl bromide (2 equiv in total) was added and refluxing
was continued for 2 h. After cooling to rt the corresponding ami-
no-chlorobenzonitrile (1 equiv, dissolved in abs tetrahydrofuran)
was added dropwise. The reaction mixture was refluxed again
for 1 h, and subsequent to cooling to rt aq HCl (2 N) was added
carefully, and stirring was continued for 2 h at a temperature of
30 °C. After the reaction mixture had been neutralized with aq
NaOH (2 N), the aqueous layer was extracted thoroughly with
methyl-t-butyl ether. The combined organic layer was dried, fil-
tered and concentrated under reduced pressure to afford the
crude ketone intermediate which was purified by flash chroma-
tography. In the following step the aryl substituted ketone was
suspended in diethyl ether, cooled to 0 °C and mixed dropwise
with 1.3 ml of a 3 M solution of methyl magnesium bromide in
diethyl ether (3 equiv). After the mixture had been stirred at
room temperature for 5 h, ice was added cautiously, and with
ice cooling, and then the mixture was adjusted to a pH of 6
using 1 N hydrochloric acid. The organic layer was extracted by
shaking with saturated aqueous sodium chloride solution, dried
over sodium sulfate and concentrated under reduced pressure.
The residue was purified by column chromatography to yield
the corresponding tertiary alcohol. Then, the intermediate alco-
hol (1 equiv) was dissolved in abs toluene, and tetronic acid
(1 equiv) and p-toluenesulfonic acid (0.1 equiv) were added.
The resulting reaction mixture was refluxed for 1 h. After cooling
to rt the precipitate obtained was filtered off and washed with
toluene to yield desired heterolignan with alkyl substituent in
ring B.
4.4.8. 9-(3,5-Dimethoxyphenyl)-6-methoxy-4,9-
dihydrofuro[3,4-b]quinolin-1(3H)-one (5)
Following general procedure 1 with 2-pentanol as solvent het-
erolignan 5 was obtained as colourless solid (400 mg, 66%) after
HPLC purification; mp 254 °C. 1H NMR (DMSO-d6) (d): 9.92 (br s,
NH), 6.98 (d, 1H), 6.50 (dd, 1H), 6.43 (d, 1H), 6.29 (m, 3H), 4.95
(d, 1H), 4.84 (s, 1H), 4.82 (d, 1H), 3.69 (s, 3H), 3.67 (s, 6H). MS
(ES+) m/z: 353 (M+), 351 (M+ꢁ2H); MS (CI) m/z: 354 (M++1, 100).
4.4.9. 9-(3,5-Dimethoxyphenyl)-7-[(3,5-dimethoxyphenyl)(4-
hydroxy-2-oxo-2,5-dihydrofuran-3-yl)methyl]-6-methoxy-4,9-
dihydrofuro[3,4-b]quinolin-1(3H)-one (6)
Heterolignan 6 was isolated as side product upon HPLC purifica-
tion of crude 5 (40 mg); mp 296 °C. 1H NMR (DMSO-d6) (d): 11.80 (br
s, OH), 9.94 (br s, NH), 7.09 (m, 1H), 6.44 (s, 1H), 6.22 (m, 1H), 6.19 (m,
3H), 6.12 (m, 2H), 5.19 (s, 1H), 4.94 (d, 1H), 4.80 (d, 1H), 4.76 (s, 1H),
4.59 (m, 2H), 3.69 (s, 3H), 3.64 (s, 6H), 3.51 (s, 6H). MS (ES+) m/z: 602
(M+), 600 (M+ꢁ2H); MS (CI) m/z: 603 (M++1, 100).
4.4.10. 9-(3,5-Dimethoxyphenyl)-7-methoxy-4,9-
dihydrofuro[3,4-b]quinolin-1(3H)-one (9)
Following general procedures 1 and 2 heterolignan 9 was ob-
tained as colourless solid (21 mg, 3%) after HPLC purification; mp
235 °C. 1H NMR (DMSO-d6) (d): 9.88 (br s, NH), 6.86 (d, 1H), 6.74
(dd, 1H), 6.65 (d, 1H), 6.34 (m, 2H), 6.30 (m, 1H), 4.94 (d, 1H),
4.90 (s, 1H), 4.83 (d, 1H), 3.67 (s, 6H), 3.63 (s, 3H). MS (ES+) m/z:
353 (M+), 351 (M+ꢁ2H); MS (CI) m/z: 354 (M++1, 100).
4.4.11. 9-(3,5-Dimethoxyphenyl)-6-(trifluoromethoxy)-4,9-
dihydrofuro[3,4-b]quinolin-1(3H)-one (12)
Following general procedure 1 heterolignan 12 was purified by
preparative HPLC and isolated as colourless solid (30 mg, 4%); mp
231 °C. 1H NMR (DMSO-d6) (d): 10.20 (br s, NH), 7.21 (d, 1H),
7.05 (dd, 1H), 6.86 (d, 1H), 6.38 (m, 3H), 5.02 (d, 1H), 4.99 (s,
1H), 4.87 (d, 1H), 3.68 (s, 6H). MS (ES+) m/z: 408 (M++1), 405
(M+ꢁ2H); MS (CI) m/z: 408 (M++1, 100).
4.4.5. General procedure 5 for the synthesis of oxa-
heterolignans
5 mmol of each a substituted benzaldehyde, a substituted phe-
nol and morpholine are heated in methanol (5 ml) for 2 h under re-
flux and stirred over night at room temperature. The solvent is
removed and the residue is treated with 2-propanol, the solid ob-
tained is filtered with suction and dried. Resulting crystals and
tetronic acid (1.5 equiv) are heated in a mixture of each 3 ml of
4.4.12. 9-(3,5-Dimethoxyphenyl)-6,9-dihydro-8H-
[1,3]dioxolo[4,5-g]furo[3,4-b]chromen-8-one (13)
Following general procedure 5 heterolignan 13 was isolated as
colourless solid (60 mg, 19%). 1H NMR (CH3CN-d3) (d): 6.70 (s,

4176
J. Frackenpohl et al. / Bioorg. Med. Chem. 17 (2009) 4160–4184
1H), 6.55 (s, 1H), 6.40 (m, 2H), 6.36 (m, 1H), 5.95 (m, 2H), 4.83 (m,
4.4.21. 11-(3,5-Dimethoxyphenyl)-3,4,8,11-tetrahydro-2H-
[1,4]dioxepino[2,3-g]furo[3,4-b]quinolin-10(7H)-one (22)
Following general procedure 1 heterolignan 22 was obtained as
colourless solid (160 mg, 33%); mp 289 °C. 1H NMR (DMSO-d6) (d):
9.89 (br s, NH), 6.71 (s, 1H), 6.54 (s, 1H), 6.32 (m, 3H), 4.96 (d, 1H),
4.83 (d, 1H), 4.81 (s, 1H), 4.06 (m, 2H), 3.97 (m, 2H), 3.66 (s, 6H),
2.02 (m, 2H). MS (ES+) m/z: 395 (M+), 393 (M+ꢁ2H), 258; MS (CI)
m/z: 396 (M++1, 100),
3H). MS (ES+) m/z: 369 (MH+).
4.4.13. 6-Methoxy-9-(3,4,5-trimethoxyphenyl)-4,9-
dihydrofuro[3,4-b]quinolin-1(3H)-one (14)
Following general procedure 1 heterolignan 14 was obtained as
colourless solid (300 mg, 19%); mp 284–286 °C. 1H NMR (DMSO-
d6) (d): 9.75 (br s, NH), 7.01 (d, 1H), 6.53 (dd, 1H), 6.48 (d, 1H),
6.47 (s, 2H), 4.92 (d, 1H), 4.88 (s, 1H), 4.81 (d, 1H), 3.71 (s, 3H),
3.70 (s, 6H), 3.62 (s, 3H). MS (ES+) m/z: 384 (M++1, 90), 216 (100).
4.4.22. 9-(3,5-Dimethoxyphenyl)-6-ethoxy-4,9-
dihydrofuro[3,4-b]quinolin-1(3H)-one (23)
4.4.14. 7-Methoxy-9-(3,4,5-trimethoxyphenyl)-4,9-
dihydrofuro[3,4-b]quinolin-1(3H)-one (15)
Following general procedure 1 heterolignan 23 was obtained as
colourless solid (160 mg, 27%); mp 259 °C. 1H NMR (DMSO-d6) (d):
9.96 (br s, NH), 6.97 (d, 1H), 6.48 (dd, 1H), 6.42 (d, 1H), 6.30 (m,
3H), 4.95 (d, 1H), 4.84 (s, 1H), 4.82 (d, 1H), 3.94 (q, 2H), 3.67 (s,
6H), 1.28 (t, 3H). MS (ES+) m/z: 367 (M+), 365 (M+ꢁ2H), 230; MS
(CI) m/z: 368 (M++1, 100).
Following general procedure 2 heterolignan 15 was obtained as
colourless solid (240 mg, 92%); mp 217–218 °C. 1H NMR (DMSO-
d6) (d): 9.90 (s, NH), 6.90 (d, 1H), 6.77 (dd, 1H), 6.73 (d, 1H), 6.52
(s, 2H), 5.02 (d, 1H), 4.95 (s, 1H), 4.87 (d, 1H), 3.70 (s, 6H), 3.65
(s, 3H), 3.61 (s, 3H). MS (ES+) m/z: 384 (M++1, 100), 216 (98).
4.4.23. 9-(3,5-Dimethoxyphenyl)-6-(propan-2-yloxy)-4,9-
dihydrofuro[3,4-b]quinolin-1(3H)-one (24)
4.4.15. 6-Chloro-9-(3,4,5-trimethoxyphenyl)-4,9-
dihydrofuro[3,4-b]quinolin-1(3H)-one (16)
Following general procedure 1 heterolignan 24 was isolated
as colourless solid (70 mg, 14%); mp 267 °C. 1H NMR (DMSO-
d6) (d): 9.88 (br s, NH), 6.96 (d, 1H), 6.46 (dd, 1H), 6.41 (d,
1H), 6.29 (m, 3H), 4.96 (d, 1H), 4.83 (s, 1H), 4.82 (d, 1H),
4.47 (sept, 1H), 3.67 (s, 6H), 1.25 (d, 3H), 1.22 (d, 3H). MS
(ES+) m/z: 381 (M+), 379 (M+ꢁ2H), 244, 202; MS (CI) m/z:
382 (M++1, 100).
Following general procedures 2 and 3 heterolignan 16 was iso-
lated by simple filtration as a colourless solid (25 mg, 68%); mp
249 °C. 1H NMR (DMSO-d6) (d): 10.16 (br s, NH), 7.19 (m, 2H),
6.96 (d, 1H), 6.52 (s, 2H), 5.01 (s, 1H), 4.99 (d, 1H), 4.85 (d, 1H),
3.72 (s, 6H), 3.61 (s, 3H). MS (ES+) m/z: 388 (M+), 386 (M+ꢁ2H).
4.4.16. 9-(3,5-Dimethoxyphenyl)-6,7-dimethoxy-4,9-
dihydrofuro[3,4-b]quinolin-1(3H)-one (17)
4.4.24. 6-(Benzyloxy)-9-(3,5-dimethoxyphenyl)-4,9-
dihydrofuro[3,4-b]quinolin-1(3H)-one (25)
Following general procedure 1 heterolignan 17 was obtained as
colourless solid (200 mg, 40%); mp 259 °C. 1H NMR (CDCl3) (d):
6.64 (br s, NH), 6.56 (s, 1H), 6.40 (m, 2H), 6.36 (s, 1H), 6.28 (m,
1H), 5.02 (s, 1H), 4.78 (d, 1H), 4.68 (d, 1H), 3.85 (s, 3H), 3.74 (s,
9H). MS (ES+) m/z: 383 (M+), 381 (M+ꢁ2H), 246.
Following general procedures 1 and 2 heterolignan 25 was
obtained as colourless solid after HPLC purification (20 mg, 5%);
mp 277 °C. 1H NMR (DMSO-d6) (d): 9.94 (br s, NH), 7.35 (m,
5H), 6.98 (d, 1H), 6.57 (dd, 1H), 6.49 (d, 1H), 6.28 (m, 3H),
5.05 (s, 2H), 4.94 (d, 1H), 4.83 (s, 1H), 4.81 (d, 1H), 3.66 (s,
6H). MS (ES+) m/z: 429 (M+), 427 (M+ꢁ2H); MS (CI) m/z: 431
(M++1, 100).
4.4.17. 6,7-Dimethoxy-9-(3,4,5-trimethoxyphenyl)-4,9-
dihydrofuro[3,4-b]quinolin-1(3H)-one (18)
Following general procedure 2 heterolignan 18 was isolated by
simple filtration as a colourless solid (78 mg, 94%). 1H NMR
(MeOD) (d): 6.58 (s, 1H), 6.52 (s, 1H), 6.48 (s, 2H), 4.98 (s, 1H),
4.88 (d, 1H), 4.80 (d, 1H), 3.85 (s, 3H), 3.78 (s, 6H), 3.75 (s, 3H),
3.70 (s, 3H).
4.4.25. 9-(3,5-Dimethoxyphenyl)-6-(phenoxy)-4,9-
dihydrofuro[3,4-b]quinolin-1(3H)-one (26)
Following general procedures 1 and 2 heterolignan 26 was iso-
lated as colourless solid after HPLC purification (40 mg, 9%); mp
281 °C. 1H NMR (DMSO-d6) (d): 9.98 (br s, NH), 7.36 (m, 2H),
7.12 (m, 1H), 7.06 (d, 1H), 6.99 (m, 2H), 6.55 (dd, 1H), 6.48 (d,
1H), 6.33 (m, 2H), 6.29 (m, 1H), 4.93 (d, 1H), 4.89 (s, 1H), 4.80 (d,
1H), 3.66 (s, 6H). MS (ES+) m/z: 415 (M+), 413 (M+ꢁ2H), 278; MS
(CI) m/z: 416 (M++1, 100).
4.4.18. 2,2-Difluoro-9-(3,5-dimethoxyphenyl)-6,9-
dihydro[1,3]dioxolo[4,5-g]furo[3,4-b]quinolin-8(5H)-one (19)
Following general procedure 1 heterolignan 19 was afforded as
colourless solid (250 mg, 53%); mp >300 °C. 1H NMR (DMSO-d6)
(d): 10.18 (br s, NH), 7.17 (s, 1H), 6.96 (s, 1H), 6.36 (m, 3H), 5.01
(d, 1H), 4.95 (s, 1H), 4.84 (d, 1H), 3.69 (s, 6H). MS (ES+) m/z: 404
(M++1), 401 (M+ꢁ2H), 266; MS (CI) m/z: 404 (M++1, 100).
4.4.26. 9-(3,5-Dimethoxyphenyl)-6,7-diethoxy-4,9-
dihydrofuro[3,4-b]quinolin-1(3H)-one (27)
Following general procedure 1 heterolignan 27 was isolated
as colourless solid (210 mg, 53%); mp 285 °C. 1H NMR (DMSO-
d6) (d): 9.77 (br s, NH), 6.65 (s, 1H), 6.48 (s, 1H), 6.32 (m,
2H), 6.28 (m, 1H), 4.93 (d, 1H), 4.82 (s, 1H), 4.80 (d, 1H),
3.94 (q, 2H), 3.79 (q, 2H), 3.67 (s, 6H), 1.28 (t, 3H), 1.20 (t,
3H). MS (ES+) m/z: 411 (M+), 409 (M+ꢁ2H); MS (CI) m/z: 412
(M++1, 100).
4.4.19. 2,2-Difluoro-9-(3,4,5-trimethoxyphenyl)-6,9-
dihydro[1,3]dioxolo[4,5-g]furo[3,4-b]quinolin-8(5H)-one (20)
Following general procedure 1 heterolignan 20 was isolated by
flash chromatography as a colourless solid (287 mg, 33%). 1H NMR
(MeOD) (d): 6.83 (s, 1H), 6.75 (s, 1H), 6.50 (s, 2H), 5.02 (s, 1H), 4.92
(d, 1H), 4.84 (d, 1H), 3.80 (s, 6H), 3.73 (s, 3H).
4.4.20. 10-(3,5-Dimethoxyphenyl)-2,3,7,10-
4.4.27. 9-(3,5-Dimethoxyphenyl)-6-(methylsulfanyl)-4,9-
dihydrofuro[3,4-b]quinolin-1(3H)-one (28)
tetrahydro[1,4]dioxino[2,3-g]furo[3,4-b]quinolin-9(6H)-one (21)
Following general procedure 1 heterolignan 21 was afforded as
colourless solid (150 mg, 29%); mp >300 °C. 1H NMR (DMSO-d6)
(d): 9.82 (br s, NH), 6.58 (s, 1H), 6.42 (s, 1H), 6.31 (m, 3H), 4.94
(d, 1H), 4.81 (d, 1H), 4.80 (s, 1H), 4.19 (m, 2H), 4.12 (m, 2H), 3.68
(s, 6H). MS (ES+) m/z: 382 (M++1), 379 (M+ꢁ2H), 244; MS (CI) m/
z: 382 (M++1, 100).
Following general procedure 1 heterolignan 28 was isolated as
colourless solid (66 mg, 12%); mp 283 °C. 1H NMR (DMSO-d6) (d):
9.98 (br s, NH), 7.01 (d, 1H), 6.78 (dd, 1H), 6.75 (d, 1H), 6.29 (m,
3H), 4.96 (d, 1H), 4.87 (s, 1H), 4.82 (d, 1H), 3.66 (s, 6H), 2.42 (s,
3H). MS (ES+) m/z: 369 (M+), 367 (M+ꢁ2H); MS (CI) m/z: 370
(M++1, 100).

J. Frackenpohl et al. / Bioorg. Med. Chem. 17 (2009) 4160–4184
4177
4.4.28. 9-(3,5-Dimethoxyphenyl)-6-methyl-4,9-
dihydrofuro[3,4-b]quinolin-1(3H)-one (29)
(d): 10.09 (br s, NH), 7.58 (m, 2H), 7.44 (m, 2H), 7.37 (d, 1H),
7.20 (m, 2H), 7.16 (m, 1H), 6.40 (m, 2H), 6.34 (m, 1H), 5.03 (d,
1H), 4.98 (s, 1H), 4.86 (d, 1H), 3.68 (s, 6H). MS (ES+) m/z: 399
(M+), 397 (M+ꢁ2H), 262; MS (CI) m/z: 400 (M++1, 100).
Following general procedure 1 heterolignan 29 was isolated as
colourless solid (140 mg, 21%); mp 269 °C. 1H NMR (DMSO-d6)
(d): 9.93 (br s, NH), 6.97 (d, 1H), 6.70 (m, 2H), 6.29 (m, 3H), 4.97
(d, 1H), 4.87 (s, 1H), 4.82 (d, 1H), 3.67 (s, 6H), 2.22 (s, 3H). MS
(ES+) m/z: 337 (M+), 335 (M+ꢁ2H); MS (CI) m/z: 338 (M++1, 100).
4.4.36. 9-(3,5-Dimethoxyphenyl)-6-hydroxy-4,9-
dihydrofuro[3,4-b]quinolin-1(3H)-one (37)
Following general procedure 1 heterolignan 37 was obtained as
colourless solid (110 mg, 33%); mp 251 °C. 1H NMR (DMSO-d6) (d):
9.83 (br s, NH), 9.40 (br s, OH), 6.84 (d, 1H), 6.29 (m, 5H), 4.93 (d,
1H), 4.82 (d, 1H), 4.79 (s, 1H), 3.66 (s, 6H). MS (ES+) m/z: 339 (M+),
337 (M+ꢁ2H); MS (CI) m/z: 340 (M++1, 100).
4.4.29. 9-(3,5-Dimethoxyphenyl)-6-(methylsulfanyl)-4,9-
dihydrofuro[3,4-b]quinolin-1(3H)-one (30)
Following general procedure 1 heterolignan 30 was obtained as
colourless solid (200 mg, 39%); mp 243 °C. 1H NMR (DMSO-d6) (d):
9.98 (br s, NH), 7.02 (d, 1H), 6.92 (dd, 1H), 6.88 (d, 1H), 6.31 (m,
3H), 4.98 (d, 1H), 4.86 (s, 1H), 4.82 (d, 1H), 3.68 (s, 6H), 1.22 (s,
9H). MS (ES+) m/z: 379 (M+), 377 (M+ꢁ2H); MS (CI) m/z: 380
(M++1, 100).
4.4.37. 9-(3,5-Dimethoxyphenyl)-6-methoxy-7-methyl-4,9-
dihydrofuro[3,4-b]quinolin-1(3H)-one (38)
Following general procedure 1 heterolignan 38 was obtained as
colourless solid (220 mg, 40%); mp 234 °C. 1H NMR (DMSO-d6) (d):
9.84 (br s, NH), 6.81 (s, 1H), 6.45 (s, 1H), 6.29 (m, 3H), 4.96 (d, 1H),
4.81 (d, 1H), 4.80 (s, 1H), 3.76 (s, 3H), 3.67 (s, 6H), 1.99 (s, 3H). MS
(ES+) m/z: 367 (M+), 365 (M+ꢁ2H), 230; MS (CI) m/z: 368 (M++1,
100).
4.4.30. 6-(Cyclopropyloxy)-9-(3,5-dimethoxyphenyl)-4,9-
dihydrofuro[3,4-b]quinolin-1(3H)-one (31)
Following general procedure 1 heterolignan 31 was obtained as
colourless solid (60 mg, 10%) after HPLC purification; mp 244 °C. 1H
NMR (DMSO-d6) (d): 9.98 (br s, NH), 6.88 (d, 1H), 6.60 (m, 1H), 6.30
(m, 2H), 6.21 (m, 1H), 6.14 (d, 1H), 4.96 (d, 1H), 4.86 (s, 1H), 4.74 (d,
1H), 4.58 (m, 1H), 3.68 (s, 6H), 0.74 (m, 2H), 0.65 (m, 2H). MS (ES+)
m/z: 379 (M+), 377 (M+ꢁ2H); MS (CI) m/z: 380 (M++1, 100).
4.4.38. 7-Chloro-9-(3,5-dimethoxyphenyl)-6-methoxy-4,9-
dihydrofuro[3,4-b]quinolin-1(3H)-one (39)
Following general procedure 1 heterolignan 39 was obtained as
colourless solid (38 mg, 7%); mp 273 °C. 1H NMR (DMSO-d6) (d):
10.09 (br s, NH), 7.11 (s, 1H), 6.62 (s, 1H), 6.33 (m, 3H), 4.99 (d,
1H), 4.87 (s, 1H), 4.84 (d, 1H), 3.82 (s, 3H), 3.68 (s, 6H). MS (ES+)
m/z: 387 (M+), 385 (M+ꢁ2H); MS (CI) m/z: 388 (M++1, 100).
4.4.31. 9-(3,5-Dimethoxyphenyl)-7-(propan-2-yloxy)-4,9-
dihydrofuro[3,4-b]quinolin-1(3H)-one (32)
Following general procedure 1 heterolignan 32 was obtained as
colourless solid (39 mg, 8%) after HPLC purification; mp 244 °C. 1H
NMR (DMSO-d6) (d): 9.86 (br s, NH), 6.84 (d, 1H), 6.70 (dd, 1H),
6.65 (d, 1H), 6.36 (m, 2H), 6.31 (m, 1H), 4.95 (d, 1H), 4.89 (s, 1H),
4.82 (d, 1H), 4.39 (sept, 1H), 3.67 (s, 6H), 1.18 (d, 3H), 1.15 (d, 3H).
MS (ES+) m/z: 381 (M+), 379 (M+ꢁ2H); MS (CI) m/z: 382 (M++1, 100).
4.4.39. 6-Benzyloxy-7-bromo-9-(3,5-dimethoxyphenyl)-4,9-
dihydrofuro[3,4-b]quinolin-1(3H)-one (40)
Following general procedure 1 heterolignan 40 was obtained as
colourless solid (100 mg, 26%); mp 235 °C. 1H NMR (DMSO-d6) (d):
10.06 (br s, NH), 7.32 (m, 5H), 7.25 (s, 1H), 6.65 (s, 1H), 6.36 (m,
3H), 5.19 (s, 2H), 4.98 (d, 1H), 4.88 (s, 1H), 4.82 (d, 1H), 3.68 (s,
6H). MS (ES+) m/z: 508 (M+), 506 (M+ꢁ2H); MS (CI) m/z: 509
(M++1, 100).
4.4.32. 6,7-Bis(difluoromethoxy)-9-(3,5-dimethoxyphenyl)-4,9-
dihydrofuro[3,4-b]quinolin-1(3H)-one (33)
Following general procedure 1 heterolignan 33 was obtained as
colourless solid (39 mg, 8%) after HPLC purification; mp 244 °C. 1H
NMR (DMSO-d6) (d): 10.18 (br s, NH), 7.13 (s, 1H), 7.00 (t, 1H), 6.86
(s, 1H), 6.73 (t, 1H), 6.38 (m, 2H), 6.35 (m, 1H), 5.04 (d, 1H), 4.95 (s,
1H), 4.86 (d, 1H), 3.68 (s, 6H). MS (ES+) m/z: 455 (M+), 453
(M+ꢁ2H); MS (CI) m/z: 456 (M++1, 100).
4.4.40. 9-(3,5-Dimethoxyphenyl)-5,7-dimethoxy-4,9-
dihydrofuro[3,4-b]quinolin-1(3H)-one (41)
Following general procedure 1 heterolignan 41 was obtained as
colourless solid (70 mg, 94%); mp 204 °C. 1H NMR (DMSO-d6) (d):
9.48 (br s, NH), 6.49 (d, 1H), 6.31 (m, 3H), 6.26 (d, 1H), 4.88 (d,
1H), 4.87 (s, 1H), 4.77 (d, 1H), 3.84 (s, 3H), 3.67 (s, 6H), 3.64 (s,
3H). MS (ES+) m/z: 383 (M+), 381 (M+ꢁ2H); MS (CI) m/z: 384
(M++1, 100).
4.4.33. 9-(3,5-Dimethoxyphenyl)-6-ethoxy-7-methyl-4,9-
dihydrofuro[3,4-b]quinolin-1(3H)-one (34)
Following general procedure 2 heterolignan 34 was obtained as
colourless solid (110 mg, 95%); mp 182 °C. 1H NMR (DMSO-d6) (d):
9.84 (br s, NH), 6.80 (s, 1H), 6.44 (s, 1H), 6.30 (m, 3H), 4.94 (d, 1H),
4.81 (s, 1H), 4.80 (d, 1H), 3.95 (q, 2H), 3.66 (s, 6H), 1.99 (s, 3H), 1.33
(t, 3H). MS (ES+) m/z: 381 (M+), 379 (M+ꢁ2H); MS (CI) m/z: 382
(M++1, 100).
4.4.41. 9-(3,5-Dimethoxyphenyl)-5,8-dimethoxy-4,9-
dihydrofuro[3,4-b]quinolin-1(3H)-one (42)
Following general procedure 1 heterolignan 42 was isolated
as colourless solid (30 mg, 6%) after HPLC purified by HPLC;
mp 228 °C. 1H NMR (CDCl3) (d): 7.14 (br s, NH), 6.74 (d, 1H),
6.44 (d, 1H), 6.42 (m, 2H), 6.25 (m, 1H), 5.24 (s, 1H), 4.80 (d,
1H), 4.72 (d, 1H), 3.88 (s, 3H), 3.76 (s, 6H), 3.62 (s, 3H). MS
(ES+) m/z: 383 (M+), 381 (M+ꢁ2H); MS (CI) m/z: 384 (M++1,
100).
4.4.34. 9-(3,5-Dimethoxyphenyl)-6,7-dimethyl-4,9-
dihydrofuro[3,4-b]quinolin-1(3H)-one (35)
Following general procedure 1 heterolignan 35 was obtained as
colourless solid (150 mg, 25%) after HPLC purification; mp 268 °C.
1H NMR (DMSO-d6) (d): 9.82 (br s, NH), 6.83 (s, 1H), 6.69 (s, 1H),
6.31 (m, 3H), 4.95 (d, 1H), 4.83 (s, 1H), 4.81 (d, 1H), 3.66 (s, 6H),
2.14 (s, 3H), 2.07 (s, 3H). MS (ES+) m/z: 351 (M+), 349 (M+ꢁ2H),
214; MS (CI) m/z: 352 (M++1, 100).
4.4.42. 9-(3,5-Dimethoxyphenyl)-5,6-dimethoxy-4,9-
dihydrofuro[3,4-b]quinolin-1(3H)-one (43)
Following general procedure 1 heterolignan 43 was isolated as
colourless solid (180 mg, 34%); mp 278 °C. 1H NMR (DMSO-d6)
(d): 9.73 (br s, NH), 6.78 (d, 1H), 6.62 (d, 1H), 6.30 (m, 3H), 4.92
(d, 1H), 4.84 (s, 1H), 4.80 (d, 1H), 3.78 (s, 6H), 3.68 (s, 6H). MS
(ES+) m/z: 383 (M+), 381 (M+ꢁ2H), 244, 202; MS (CI) m/z: 384
(M++1, 100).
4.4.35. 9-(3,5-Dimethoxyphenyl)-6-phenyl-4,9-
dihydrofuro[3,4-b]quinolin-1(3H)-one (36)
Following general procedure 1 heterolignan 36 was isolated as
colourless solid (110 mg, 22%); mp 275 °C. 1H NMR (DMSO-d6)

4178
J. Frackenpohl et al. / Bioorg. Med. Chem. 17 (2009) 4160–4184
4.4.43. 9-(3,5-Dimethoxyphenyl)-6,7,8-trimethoxy-4,9-
dihydrofuro[3,4-b]quinolin-1(3H)-one (44)
(d): 6.60 (s, 1H), 6.58 (s, 1H), 6.40 (s, 2H), 5.95 (dd, 2H), 5.0 (s, 1H),
4.87 (d, 1H), 4.80 (d, 1H), 3.80 (s, 9H), 3.20 (s, 3H).
Following general procedure 1 using 2-pentanol as solvent het-
erolignan 44 was isolated as colourless solid (290 mg, 63%); mp
201 °C. 1H NMR (DMSO-d6) (d): 9.84 (br s, NH), 6.38 (s, 1H), 6.27
(m, 1H), 6.22 (m, 2H), 4.87 (s, 1H), 4.84 (d, 1H), 4.75 (d, 1H), 3.90
(s, 3H), 3.65 (s, 6H), 3.63 (s, 3H), 3.43 (s, 3H). MS (ES+) m/z: 413
(M+), 411 (M+ꢁ2H), 276; MS (CI) m/z: 414 (M++1, 100).
4.4.51. 6,7-Dimethoxy-5-methyl-9-(3,4,5-trimethoxyphenyl)-
4,9-dihydrofuro[3,4-b]quinolin-1(3H)-one (53)
Following general procedure 1 heterolignan 53 was isolated as a
colourless solid (44 mg, 12%). 1H NMR (DMSO-d6) (d): 6.75 (s, 2H),
6.41 (s, 2H), 5.16 (d, 1H), 4.99 (d, 1H), 4.85 (s, 1H), 3.82 (s, 3H), 3.73
(s, 3H), 3.64 (s, 9H), 3.60 (s, 3H). MS (ES+) m/z: 427 (M+), 425
(M+ꢁ2H); MS (CI) m/z: 428 (M++1, 100).
4.4.44. 9-(3,5-Dimethoxyphenyl)-6,8-dimethyl-4,9-
dihydrofuro[3,4-b]quinolin-1(3H)-one (45)
Following general procedure 1 heterolignan 45 was obtained as
colourless solid (100 mg, 17%); mp 232 °C. 1H NMR (DMSO-d6) (d):
9.82 (br s, NH), 6.62 (s, 2H), 6.29 (m, 1H), 6.20 (m, 2H), 4.91 (s, 1H),
4.83 (d, 1H), 4.76 (d, 1H), 3.64 (s, 6H), 2.22 (s, 3H), 1.98 (s, 3H). MS
(ES+) m/z: 351 (M+), 349 (M+ꢁ2H), 214; MS (CI) m/z: 352 (M++1,
100).
4.4.52. 9-(4-Chlorophenyl)-4,6-dimethyl-4,9-dihydrofuro[3,4-
b]quinolin-1(3H)-one (54)
Following general procedure 1 heterolignan 54 was isolated as a
colourless solid (90 mg, 13%). 1H NMR (CDCl3) (d): 7.20 (d, 2H),
7.12 (d, 2H), 6.94 (d, 1H), 6.85 (d, 1H), 6.80 (s, 1H), 5.10 (s, 1H),
4.90 (d, 1H), 4.82 (d, 1H), 3.25 (s, 3H), 2.36 (s, 3H).
4.4.45. 9-(3,5-Dimethoxyphenyl)-6,8-dimethoxy-4,9-
dihydrofuro[3,4-b]quinolin-1(3H)-one (46)
4.4.53. 9-(3,5-Dimethoxyphenyl)-5-ethyl-6,9-
dihydro[1,3]dioxolo[4,5-g]furo[3,4-b]quinolin-8(5H)-one (55)
Following general procedure 1 heterolignan 55 was isolated as a
colourless solid (80 mg, 16%); mp 238 °C. 1H NMR (DMSO-d6) (d):
6.96 (s, 1H), 6.71 (s, 1H), 6.30 (m, 3H), 5.99 (d, 1H), 5.92 (d, 1H),
5.14 (d, 1H), 5.98 (d, 1H), 4.82 (s, 1H), 3.70 (q, 2H), 3.67 (s, 6H),
1.19 (t, 3H). MS (ES+) m/z: 395 (M+), 393 (M+ꢁ2H); MS (CI) m/z:
396 (M++1, 100).
Following general procedure 1 heterolignan 46 was obtained as
colourless solid (150 mg, 28%); mp >300 °C. 1H NMR (DMSO-d6)
(d): 9.91 (br s, NH), 6.32 (d, 1H), 6.26 (m, 1H), 6.22 (m, 1H), 6.14
(dd, 1H), 5.82 (dd, 1H), 4.88 (d, 1H), 4.85 (s, 1H), 4.78 (d, 1H),
3.75 (s, 3H), 3.64 (s, 6H), 3.62 (s, 3H). MS (ES+) m/z: 383 (M+),
381 (M+ꢁ2H); MS (CI) m/z: 384 (M++1, 100).
4.4.46. 9-(3,5-Dimethoxyphenyl)-5,6-dimethyl-4,9-
dihydrofuro[3,4-b]quinolin-1(3H)-one (47)
4.4.54. 9-(3,5-Dimethoxyphenyl)-4-ethyl-6,7-dimethoxy-4,9-
dihydrofuro[3,4-b]quinolin-1(3H)-one (56)
Following general procedure 1 heterolignan 47 was obtained as
colourless solid (100 mg, 16%); mp 259 °C. 1H NMR (DMSO-d6) (d):
9.28 (br s, NH), 6.82 (d, 1H), 6.73 (d, 1H), 6.30 (m, 3H), 4.95 (d, 1H),
4.88 (s, 1H), 4.82 (d, 1H), 3.66 (s, 6H), 2.19 (s, 3H), 2.17 (s, 3H). MS
(ES+) m/z: 351 (M+), 349 (M+ꢁ2H); MS (CI) m/z: 352 (M++1, 100).
Following general procedure 1 heterolignan 56 was isolated as a
colourless solid (200 mg, 39%); mp 200 °C. 1H NMR (DMSO-d6) (d):
6.75 (s, 2H), 6.28 (m, 3H), 5.16 (d, 1H), 4.99 (d, 1H), 4.85 (s, 1H),
3.82 (s, 3H), 3.77 (q, 2H), 3.66 (s, 6H), 3.62 (s, 3H), 1.23 (t, 3H). MS
(ES+) m/z: 411 (M+), 409 (M+ꢁ2H); MS (CI) m/z: 412 (M++1, 100).
4.4.47. 9-(3,5-Dimethoxyphenyl)-5,7-dimethyl-4,9-
dihydrofuro[3,4-b]quinolin-1(3H)-one (48)
4.4.55. 9-(3,5-Dimethoxyphenyl)-4-methyl-6-methoxy-4,9-
dihydrofuro[3,4-b]quinolin-1(3H)-one (57)
Following general procedure 2 heterolignan 48 was obtained as
colourless solid (100 mg, 65%); mp 284 °C. 1H NMR (DMSO-d6) (d):
9.31 (br s, NH), 6.82 (s, 1H), 6.75 (s, 1H), 6.31 (m, 3H), 4.92 (d, 1H),
4.85 (s, 1H), 4.80 (d, 1H), 3.66 (s, 6H), 2.22 (s, 3H), 2.12 (s, 3H). MS
(ES+) m/z: 351 (M+), 349 (M+ꢁ2H); MS (CI) m/z: 352 (M++1, 100).
Following general procedure 1 heterolignan 57 was isolated as a
colourless solid (15 mg, 12%); mp 216 °C. 1H NMR (CDCl3) (d): 7.06
(d, 1H), 6.58 (dd, 1H), 6.52 (d, 1H), 6.37 (m, 1H), 6.30 (m, 1H), 6.27
(m, 1H), 5.04 (s, 1H), 4.86 (d, 1H), 4.78 (d, 1H), 3.82 (s, 3H), 3.74 (s,
6H), 3.21 (s, 3H). MS (ES+) m/z: 367 (M+), 365 (M+ꢁ2H); MS (CI) m/
z: 368 (M++1, 100).
4.4.48. 9-(3,5-Dimethoxyphenyl)-5-methoxy-7-methyl-4,9-
dihydrofuro[3,4-b]quinolin-1(3H)-one (49)
4.4.56. 9-(3,5-Dimethoxyphenyl)-9-methyl-6,9-
Following general procedure 2 heterolignan 49 was obtained as
colourless solid (80 mg, 14%); mp >300 °C. 1H NMR (DMSO-d6) (d):
9.52 (br s, NH), 6.66 (m, 1H), 6.45 (m, 1H), 6.28 (m, 3H), 4.85 (d,
1H), 4.83 (s, 1H), 4.76 (d, 1H), 3.83 (s, 3H), 3.66 (s, 6H), 2.16 (s, 3H).
MS (ES+) m/z: 367 (M+), 365 (M+ꢁ2H); MS (CI) m/z: 368 (M++1, 100).
dihydro[1,3]dioxolo[4,5-g]furo[3,4-b]quinolin-8(5H)-one (58)
Following general procedure 1 using a benzophenone precursor
instead of a benzaldehyde heterolignan 4 was obtained as colour-
less solid (41 mg, 21%). 1H NMR (DMSO-d6) (d): 9.88 (s, NH), 6.60
(s, 1H), 6.47 (s, 1H), 6.43 (m, 2H), 6.33 (m, 1H), 5.94 (s, 1H), 5.92
(s, 1H), 4.92 (d, 1H), 4.83 (d, 1H), 3.70 (s, 6H), 1.88 (s, 3H). MS
(ES+) m/z: 382 (M++1, 100).
4.4.49. 6-Chloro-9-methyl-9-(3,4,5-trimethoxyphenyl)-4,9-
dihydrofuro[3,4-b]quinolin-1(3H)-one (50)
Following general procedure 4 heterolignan 50 was obtained as
colourless solid (280 mg, 94%); mp 240–242 °C. 1H NMR (DMSO-
d6) (d): 9.95 (br s, NH), 7.10 (d, 1H), 6.91 (m, 2H), 6.54 (s, 2H),
4.90 (d, 1H), 4.82 (d, 1H), 3.70 (s, 6H), 3.64 (s, 3H), 1.90 (s, 3H).
MS (ES+) m/z: 402 (M++1, 45), 234 (100).
4.4.57. 9-(3-Chlorophenyl)-5,6,7,9-tetrahydro-8H-cyclopenta[b]-
[1,3]dioxolo[4,5-g]quinolin-8-one (59)
Following general procedure 1 heterolignan 59 was obtained as
colourless solid (900 mg, 72%); mp 285–290 °C. 1H NMR (DMSO-
d6) (d): 10.03 (s, NH), 7.27 (dd, 1H), 7.18 (m, 2H), 7.12 (d, 1H),
6.62 (s, 1H), 6.57 (s, 1H), 5.96 (s, 1H), 5.90 (s, 1H), 4.92 (s, 1H),
2.68 (m, 2H), 2.28 (m, 2H). MS (ES+) m/z: 340 (M++1, 100).
4.4.50. 5-Methyl-9-(3,4,5-trimethoxyphenyl)-6,9-
dihydro[1,3]dioxolo[4,5-g]furo[3,4-b]quinolin-8(5H)-one (52)
K2CO3 (1 equiv) and MeI (3 equiv) were successively added to a
solution of heteolignan 3 (0.5 mmol, 1 equiv) in dry THF. The reac-
tion mixture was refluxed overnight and then evaporated. The
crude product was purified by flash chromatography. Heterolignan
52 was isolated as a colourless solid (39 mg, 11%). 1H NMR (CDCl3)
4.4.58. 9-(3-Chlorophenyl)-7-phenyl-5H-cyclopenta[b][1,3]dio-
xolo[4,5-g]quinoline-6,8(7H,9H)-dione (60)
Following general procedure 1 heterolignan 60 was obtained as
colourless solid (940 mg, 60%); mp 205–207 °C. MS (ES+) m/z: 431
(M++1, 100).

J. Frackenpohl et al. / Bioorg. Med. Chem. 17 (2009) 4160–4184
4179
4.4.59. 10-(3-Chlorophenyl)-6,7,8,10-tetrahydro[1,3]dioxolo[4,5-
b]acridin-9(5H)-one (61)
4.4.67. 10-(3-Chlorophenyl)-3,3-dimethyl-4,10-dihydro-3H-[1,3]
dioxolo[4,5-g][1,2]oxathiolo[4,3-b]quinoline 1,1-dioxide (69)
Following general procedure 1 heterolignan 69 was obtained as
colourless solid (910 mg, 61%); mp 240–243 °C. 1H NMR (DMSO-
d6) (d): 9.63 (s, NH) 7.29 (m, 3H), 7.20 (m, 1H), 6.58 (s, 1H), 6.55
(s, 1H), 5.97 (s, 1H), 5.91 (s, 1H), 5.23 (s, 1H), 1.72 (s, 3H), 1.66
(s, 3H). MS (ES+) m/z: 406 (M++1, 100).
Following general procedure 1 heterolignan 61 was obtained as
colourless solid (78 mg, 6%) after HPLC purification; mp 280–
285 °C. 1H NMR (DMSO-d6) (d): 9.18 (br s, NH), 7.12 (m, 3H),
6.69 (s, 1H), 6.55 (s, 1H), 5.90 (s, 1H), 5.86 (s, 1H), 5.05 (s, 1H),
2.55 (m, 2H), 2.19 (m, 2H), 1.92 (m, 1H), 1.83 (m, 1H). MS (ES+)
m/z: 354 (M++1, 100).
4.4.68. 9-(3-Chlorophenyl)-5,6,7,9-tetrahydro[1,3]dioxolo[4,5-
g]thieno[3,2-b]quinoline 8,8-dioxide (70)
Following general procedure 1 heterolignan 70 was obtained as
colourless solid (330 mg, 40%); mp 240–243 °C. MS (ES+) m/z: 376
(M++1, 100).
4.4.60. 9-(3-Chlorophenyl)-6,7,8,9-tetrahydro-5H-cyclopenta[b]-
[1,3]dioxolo[4,5-g]quinoline (62)
Following general procedure 1 heterolignan 62 was obtained as
colourless solid (90 mg, 7%) after HPLC purification; mp 106–
110 °C. MS (ES+) m/z: 326 (M++1, 100).
4.4.69. 9-(3-Chlorophenyl)-6,6-dimethyl-5,6,7,9-tetrahydro
[1,3]dioxolo[4,5-g]thieno[3,2-b]quinoline 8,8-dioxide (71)
Following general procedure 1 heterolignan 71 was obtained as
colourless solid (510 mg, 57.7%); mp 280–283 °C. MS (ES+) m/z:
404 (M++1, 100).
4.4.61. 10-(3-Chlorophenyl)-5,6,7,8,9,10-hexahydro[1,3]dioxolo-
[4,5-b]acridine (63)
Following general procedure 1 heterolignan 63 was obtained
as colourless solid (190 mg, 15%); mp 173–175 °C. 1H NMR
(DMSO-d6) (d): 7.47 (m, 1H), 7.39 (m, 3H), 6.98 (s, 1H), 6.26
(s, 1H), 6.02 (br s, NH), 5.87 (s, 1H), 5.82 (s, 1H), 3.80 (d,
1H), 2.38 (m, 1H), 2.15 (m, 2H), 1.68 (m, 1H), 1.37 (m, 1H),
1.15 (m, 1H), 1.01 (m, 1H). MS (ES+) m/z: 340 (M++1, 100),
216 (98).
4.4.70. 9-(3-Chlorophenyl)-6,6-dimethyl-5,6,7,9-tetrahydro-8H-
[1,3]dioxolo[4,5-g]pyrrolo[3,4-b]quinolin-8-one (72)
Following general procedure 1 heterolignan 72 was obtained as
colourless solid (810 mg, 60%); mp 297–302 °C. 1H NMR (DMSO-
d6) (d): 9.22 (s, NH) 7.32 (s, NH), 7.28 (t, 1H), 7.19 (m, 2H), 7.12
(d, 1H), 6.62 (s, 1H), 6.52 (s, 1H), 5.93 (s, 1H), 5.87 (s, 1H), 4.88
(s, 1H), 1.38 (s, 3H), 1.33 (s, 3H). MS (ES+) m/z: 369 (M++1, 100).
4.4.62. 10-(3-Chlorophenyl)-7,7-dimethyl-6,7,8,10-
tetrahydro[1,3]dioxolo[4,5-b]acridin-9(5H)-one (64)
Following general procedure 1 heterolignan 64 was obtained as
colourless solid (1080 mg, 77%); mp 144–147 °C. 1H NMR (DMSO-
d6) (d): 9.34 (s, NH) 7.22 (m, 2H), 7.13 (m, 2H), 6.75 (s, 1H), 6.54 (s,
1H), 5.94 (s, 1H), 5.88 (s, 1H), 5.01 (s, 1H), 2.43 (d, 1H), 2.35 (dd,
1H), 2.18 (d, 1H), 1.99 (d, 1H), 1.03 (s, 3H), 0.94 (s, 3H). MS (ES+)
m/z: 382 (M++1, 100).
4.4.71. tert-Butyl 9-(3-chlorophenyl)-8-oxo-5,6,8,9-tetrahydro-
7H-[1,3]dioxolo[4,5-g]-pyrrolo[3,4-b]quinoline-7-carboxylate (73)
Following general procedure 1 heterolignan 73 was obtained as
colourless solid (600 mg, 60%); mp 220–222 °C. 1H NMR (DMSO-
d6) (d): 9.60 (s, NH) 7.20 (m, 4H), 6.52 (d, 1H), 5.90 (d, 1H), 4.92
(s, 1H), 4.41 (d, 1H), 4.28 (d, 1H), 1.44 (s, 9H). MS (ES+) m/z: 439
(M++1, 100).
4.4.63. 10-(3-Chlorophenyl)-7-methyl-5,6,7,10-tetrahydro-9H-
[1,3]dioxolo[4,5-g]pyrano-[4,3-b]quinolin-9-one (65)
Following general procedure 1 heterolignan 65 (2:1 mixture of
diastereomers) was obtained as colourless solid (1200 mg, 89%);
mp 288–290 °C. 1H NMR (DMSO-d6) (d): 9.49 (2s, NH) 7.20 (m,
4H), 6.75 + 6.70 (2s, 1H), 6.50 (s, 1H), 5.96 (s, 1H), 5.89 + 5.88 (2s,
1H), 5.05 + 4.85 (2s, 1H), 4.53 + 4.38 (2m, 1H), 2.60 (m, 2H),
1.31 + 1.31 (2d, 3H). MS (ES+) m/z: 370 (M++1, 100).
4.4.72. 9-(3-Chlorophenyl)-5,6,7,9-tetrahydro-8H-
[1,3]dioxolo[4,5-g]pyrrolo[3,4-b]-quinolin-8-one (74)
250 mg (0.57 mmol) of tert-butyl 9-(3-chlorophenyl)-8-oxo-
5,6,8,9-tetrahydro-7H-[1,3]dioxolo[4,5-g]-pyrrolo[3,4-b]quinoline-
7-carboxylate 73 and 0.14 ml of 4 M hydrogen chloride solution in
dioxane were stirred for 24 h at 50 °C. The solvent was removed
and the solid triturated with 2-propanol, filtered and dried to yield
74 as colourless solid (180 mg, 83%); mp 218–222 °C. 1H NMR
(DMSO-d6) (d): 9.19 (s, NH) 7.24 (t, 1H), 7.14 (m, 3H), 6.52 (d,
1H), 5.88 (d, 1H), 4.92 (s, 1H), 4.00 (d, 1H), 3.83 (d, 1H), 3.57 (s,
6H). MS (ES+) m/z: 341 (M++1, 100).
4.4.64. 10-(3-Chlorophenyl)-6,6,8-trimethyl-6,10-dihydro-5H-
[1,3]dioxolo[4,5-g][1,2]-oxazino[5,4-b]quinolin-9(8H)-one (66)
Following general procedure 1 heterolignan 66 was obtained
as colourless solid (780 mg, 53%); mp 300–303 °C. 1H NMR
(DMSO-d6) (d): 8.69 (s, NH) 7.25 (t, 1H), 7.17 (m, 2H), 7.10 (m,
1H), 6.75 (s, 1H), 6.68 (s, 1H), 5.92 (s, 1H), 5.88 (s, 1H), 5.08 (s,
1H), 2.97 (s, 3H), 1.57 (s, 3H), 1.48 (s, 3H). MS (ES+) m/z: 399
(M++1, 100).
4.4.73. 10-(3,5-Dimethoxyphenyl)-6,6-dimethyl-5,6,7,10-tetra-
hydro-9H-[1,3]dioxolo[4,5-g]pyrano[4,3-b]quinolin-9-one (75)
Following general procedure 1 heterolignan 75 was obtained as
colourless solid 830 mg, 55%); mp 302–305 °C. 1H NMR (DMSO-d6)
(d): 8.81 (s, NH), 6.78 (s, 1H), 6.76 (s, 1H), 6.36 (m, 2H), 6.26 (m,
1H), 5.93 (s, 1H), 5.88 (s, 1H), 4.88 (s, 1H), 3.93 (m, 2H), 3.67 (s,
6H), 1.29 (s, 3H), 1.23 (s, 3H). MS (ES+) m/z: 410 (M++1, 100).
4.4.65. 11-(3-Chlorophenyl)-4,4-dimethyl-3,4,5,11-tetrahydro
[1,3]dioxolo[4,5-g][1,2]-oxathiino[4,3-b]quinoline 1,1-dioxide (67)
Following general procedure 1 heterolignan 67 was obtained as
colourless solid (570 mg, 37%); mp 250–252 °C. 1H NMR (DMSO-
d6) (d): 8.69 (s, NH) 7.28 (m, 2H), 7.18 (m, 2H), 6.85 (s, 1H), 6.75
(s, 1H), 5.94 (s, 1H), 5.89 (s, 1H), 5.07 (s, 1H), 4.47 (d, 1H), 4.36
(d, 1H), 1.35 (s, 6H). MS (ES+) m/z: 420 (M++1, 100).
4.4.74. 10-(3,5-Dimethoxyphenyl)-7-methyl-5,6,7,10-tetra-
hydro-9H-[1,3]dioxolo[4,5-g]pyrano[4,3-b]quinolin-9-one (76)
Following general procedure 1 heterolignan 76 (1:1 mixture of
diastereomers) was obtained as colourless solid (1220 mg, 84%);
mp 304–306 °C. 1H NMR (DMSO-d6) (d): 9.18 (br s, NH),
6.69 + 6.68 (2s, 1H), 6.50 (s, 1H), 6.35 (m, 2H), 6.25 (m, 1H), 5.90
(s, 1H), 5.85 + 5.84 (2s, 1H), 4.92 + 4.75 (2s, 1H), 4.53 + 4.38 (2m,
1H), 3.67 (s, 6H), 2.60 (m, 2H), 1.32 + 1.31 (2d, 3H). MS (ES+) m/
z: 396 (M++1, 100).
4.4.66. 10-(3-Chlorophenyl)-6,7,8,10-tetrahydro-5H-[1,3]dio-
xolo[4,5-g]thiopyrano[3,2-b]-quinoline 9,9-dioxide (68)
Following general procedure 1 heterolignan 68 was obtained as
colourless solid (200 mg, 18%); mp 268–270 °C. MS (ES+) m/z: 390
(M++1, 100).

4180
J. Frackenpohl et al. / Bioorg. Med. Chem. 17 (2009) 4160–4184
4.4.75. 10-(3,5-Dimethoxyphenyl)-6,6,8-trimethyl-6,10-dihydro-
5H-[1,3]dioxolo[4,5-g][1,2]oxazino[5,4-b]quinolin-9(8H)-one (77)
Following general procedure 1 heterolignan 77 was obtained as
colourless solid 1200 mg, 78%); mp 295–297 °C. 1H NMR (DMSO-
d6) (d): 8.70 (s, NH), 6.79 (s, 1H), 6.66 (s, 1H), 6.34 (m, 2H), 6.25
(m, 1H), 5.93 (s, 1H), 5.88 (s, 1H), 4.96 (s, 1H), 3.67 (s, 6H), 2.97
(s, 3H), 1.57 (s, 3H), 1.47 (s, 3H). MS (ES+) m/z: 425 (M++1, 100).
d6) (d): 9.83 (s, NH) 7.30 (t, 1H), 7.22 (m, 2H), 7.12 (d, 1H), 6.60
(s, 1H), 6.56 (s, 1H), 5.97 (s, 1H), 5.91 (s, 1H), 4.97 (s, 1H), 2.10
(m, 2H), 1.80 (m, 6H). MS (ES+) m/z: 396 (M++1, 100).
4.4.83. 90-(3-Chlorophenyl)-50,90-dihydro-80H-
spiro[cyclohexane-1,60-[1,3]dioxolo[4,5-g]furo[3,4-b]quinolin]-
80-one (85)
Following general procedure 1 heterolignan 77 was obtained as col-
1
4.4.76. 11-(3,5-Dimethoxyphenyl)-4,4-dimethyl-3,4,5,11-tetra-
hydro[1,3]dioxolo[4,5-g][1,2]oxathiino[4,3-b]quinoline 1,1-
dioxide (78)
Following general procedure 1 heterolignan 78 was obtained
as colourless solid (340 mg, 20%); mp 290–292 °C. 1H NMR
(DMSO-d6) (d): 8.70 (s, NH) 6.89 (s, 1H), 6.71 (s, 1H), 6.41 (m,
2H), 6.28 (m, 1H), 5.93 (s, 1H), 5.87 (s, 1H), 4.90 (s, 1H), 4.47
(d, 1H), 4.36 (d, 1H), 3.67 (s, 6H), 1.32 (s, 6H). MS (ES+) m/z:
446 (M++1, 100).
ourless solid (470 mg, 38%); mp 323–325 °C. H NMR (DMSO-d6) (d):
10.18 (s, NH) 7.30 (t, 1H), 7.22 (m, 2H), 7.12 (d, 1H), 6.67 (s, 1H),
6.60 (s, 1H), 5.97 (s, 1H), 5.90 (s, 1H), 4.94 (s, 1H), 1.97 (m, 2H), 1.70
(m, 2H), 1.55 (m, 4H), 1.25 (m, 2H). MS (ES+) m/z: 410 (M++1, 100).
4.4.84. 10-(3,5-Dimethoxyphenyl)-6,7,8,10-
tetrahydro[1,3]dioxolo[4,5-b]acridin-9(5H)-one (86)
Following general procedure 1 heterolignan 86 was obtained as
colourless solid (870 mg, 62%); mp 269–272 °C. 1H NMR (DMSO-
d6) (d): 9.30 (s, NH), 6.79 (s, 1H), 6.51 (s, 1H), 6.32 (m, 2H), 6.22
(m, 1H), 5.93 (s, 1H), 5.87 (s, 1H), 4.93 (s, 1H), 3.66 (s, 6H), 2.55
(m, 2H), 2.19 (m, 2H), 1.92 (m, 1H), 1.83 (m, 1H). MS (ES+) m/z:
380 (M++1, 100).
4.4.77. 9-(3,5-Dimethoxyphenyl)-6-methyl-6,9-dihydro[1,3]dio-
xolo[4,5-g]furo[3,4-b]quinolin-8(5H)-one (79)
Following general procedure 1 heterolignan 79 (1:1 mixture of
diastereomers) was obtained as colourless solid (760 mg, 54%); mp
295–296 °C. 1H NMR (DMSO-d6) (d): 9.63 + 9.60 (s, NH), 6.62–6.52
(4s, 2H), 6.33 (m, 2H), 6.30 (m, 1H), 5.92 (s, 1H), 5.88 (s, 1H),
5.12 + 5.05 (2q, 1H), 4.81 (s, 1H), 3.68 (s, 6H), 1.49 + 1.47 (2d,
3H). MS (ES+) m/z: 382 (M++1, 100).
4.4.85. 9-(3,5-Dimethoxyphenyl)-5,6,7,9-tetrahydro-8H-
cyclopenta[b][1,3]dioxolo[4,5-g]quinolin-8-one (87)
Following general procedure 1 heterolignan 87 was obtained as
colourless solid (224 mg, 16%); mp 277–280 °C. 1H NMR (DMSO-
d6) (d): 9.88 (s, NH), 6.66 (s, 1H), 6.53 (s, 1H), 6.29 (m, 2H), 6.27
(m, 1H), 5.96 (s, 1H), 5.89 (s, 1H), 4.78 (s, 1H), 3.67 (s, 6H), 2.71
(dt, 1H), 2.60 (dt, 1H), 2.27 (m, 2H). MS (ES+) m/z: 366 (M++1, 100).
4.4.78. 9-(3,5-Dimethoxyphenyl)-6,6-dimethyl-5,6,7,9-tetra-
hydro-8H-[1,3]dioxolo[4,5-g]pyrrolo[3,4-b]quinolin-8-one (80)
Following general procedure 1 heterolignan 80 was obtained
as colourless solid (460 mg, 31%); mp 290–292 °C. 1H NMR
(DMSO-d6) (d): 9.14 (s, NH), 7.30 (s, NH), 6.67 (s, 1H), 6.50 (s,
1H), 6.34 (m, 2H), 6.27 (m, 1H), 5.93 (s, 1H), 5.87 (s, 1H), 4.74
(s, 1H), 3.67 (s, 6H), 1.39 (s, 3H), 1.34 (s, 3H). MS (ES+) m/z:
395 (M++1, 100).
4.4.86. 9-(3,5-Dimethoxyphenyl)-7-(propan-2-yl)-5,6,7,9-tetra-
hydro-8H-[1,3]dioxolo[4,5-g]pyrrolo[3,4-b]quinolin-8-one (88)
Following general procedure 1 heterolignan 88 was obtained as
colourless solid (150 mg, 12%); mp 270–273 °C. MS (ES+) m/z: 409
(M++1, 100).
4.4.79. tert-Butyl 9-(3,5-dimethoxyphenyl)-8-oxo-5,6,8,9-
tetrahydro-7H-[1,3]dioxolo[4,5-g]pyrrolo[3,4-b]quinoline-7-
carboxylate (81)
4.4.87. 9-(3,5-Dimethoxyphenyl)-6-methyl-6-(2-
methylpropyl)-5,6,7,9-tetrahydro-8H-[1,3]dioxolo[4,5-
g]pyrrolo[3,4-b]quinolin-8-one (89)
Following general procedure 1 heterolignan 81 was obtained as
colourless solid (630 mg, 58%). MS (ES+) m/z: 411 (M++1ꢁC4H8, 50),
367 (M++1ꢁCOOC4H9, 100).
Following general procedure 1 heterolignan 89 was obtained as
colourless solid (360 mg, 46%); mp 300–303 °C. MS (ES+) m/z: 437
(M++1, 100).
4.4.80. 9-(3,5-Dimethoxyphenyl)-5,6,7,9-tetrahydro-8H-
[1,3]dioxolo[4,5-g]pyrrolo[3,4-b]-quinolin-8-one (82)
300 mg (0.64 mmol) of tert-Butyl 9-(3,5-dimethoxy-phenyl)-8-
oxo-5,6,8,9-tetrahydro-7H-[1,3]dioxolo[4,5-g]pyrrolo[3,4-b]quino-
line-7-carboxylate 81 and 0.14 ml of 4 M hydrogen chloride solu-
tion in dioxane were stirred for 24 h at 50 °C. The solvent was
removed and the solid triturated with 2-propanol, filtered and
dried to afford 82 as colourless solid (200 mg, 80%); mp >300 °C.
MS (ES+) m/z: 367 (M++1, 100).
4.4.88. tert-Butyl 8-oxo-9-(3,4,5-trimethoxyphenyl)-5,6,8,9-
tetrahydro-7H-[1,3]dioxolo[4,5-g]pyrrolo[3,4-b]quinoline-7-
carboxylate (90)
Following general procedure 1 heterolignan 90 was obtained as
colourless solid (690 mg, 54%). 1H NMR (DMSO-d6) (d): 7.65 (s,
NH), 6.54 (s, 1H), 6.50 (2, 2H), 6.44 (s, 1H), 5.86 (s, 1H), 5.84 (s,
1H), 4.83 (s, 1H), 4.36 (d, 1H), 4.24 (d, 1H), 3.75 (s, 6H), 3.67 (s,
3H), 1.48 (s, 9H). MS (ES+) m/z: 441 (M++1ꢁC4H8, 100).
4.4.89. 9-(3,4,5-Trimethoxyphenyl)-5,6,7,9-tetrahydro-8H-
[1,3]dioxolo[4,5-g]pyrrolo[3,4-b]quinolin-8-one (91)
300 mg (0.6 mmol) of tert-butyl 8-oxo-9-(3,4,5-trimethoxy-
phenyl)-5,6,8,9-tetrahydro-7H-[1,3]dioxolo[4,5-g]pyrrolo[3,4-
b]quinoline-7-carboxylate 90 and 0.15 ml of 4 M hydrogen chlo-
ride solution in dioxane were stirred for 24 h at 50 °C. The solvent
was removed and the solid triturated with 2-propanol, filtered and
dried to yield free lactam 91 as colourless solid (210 mg, 90%). MS
(ES+) m/z: 397 (M++1, 100).
4.4.81. 9-(3-Chlorophenyl)-6,6-dimethyl-6,9-
dihydro[1,3]dioxolo[4,5-g]furo[3,4-b]quinolin-8(5H)-one (83)
Following general procedure 1 heterolignan 83 was obtained as
colourless solid (210 mg, 15%); mp 273–277 °C. 1H NMR (DMSO-
d6) (d): 9.88 (s, NH) 7.32 (t, 1H), 7.24 (m, 2H), 7.13 (d, 1H), 6.60
(s, 1H), 6.56 (s, 1H), 5.97 (s, 1H), 5.90 (s, 1H), 4.95 (s, 1H), 1.52
(s, 3H), 1.50 (s, 3H). MS (ES+) m/z: 370 (M++1, 100).
4.4.82. 90-(3-Chlorophenyl)-50,90-dihydro-80H-
spiro[cyclopentane-1,60-[1,3]dioxolo[4,5-g]furo[3,4-
b]quinolin]-80-one (84)
4.4.90. 9-(3-Methoxyphenyl)-6,9-dihydro[1,3]dioxolo[4,5-
g]furo[3,4-b]quinolin-8(5H)-one (92)
Following general procedure 1 heterolignan 84 was obtained as
Following general procedure 1 heterolignan 92 was obtained as
colourless solid (370 mg, 25%); mp 257–259 °C. 1H NMR (DMSO-
colourless solid (1130 mg, 91%); mp >310 °C. 1H NMR (DMSO-d6)

J. Frackenpohl et al. / Bioorg. Med. Chem. 17 (2009) 4160–4184
4181
(d): 9.89 (s, NH), 7.18 (t, 1H), 6.75 (m, 3H), 6.62 (s, 1H), 6.54 (s, 1H),
5.97 (s, 1H), 5.90 (s, 1H), 4.97 (d, 1H), 4.88 (s, 1H), 4.86 (d, 1H), 3.72
(s, 3H). MS (ES+) m/z: 338 (M++1, 100).
1H), 5.93 (s, 1H), 5.89 (s, 1H), 5.10 (s, 1H), 4.92 (d, 1H), 4.82 (d,
1H). MS (ES+) m/z: 376 (M++1, 100).
4.4.99. 9-(3,5-Difluorophenyl)-6,9-dihydro[1,3]dioxolo[4,5-g]
furo[3,4-b]quinolin-8(5H)-one (101)
4.4.91. 9-(4-Methoxyphenyl)-6,9-dihydro[1,3]dioxolo[4,5-
g]furo[3,4-b]quinolin-8(5H)-one (93)
Following general procedure 1 heterolignan 101 was obtained
as colourless solid (540 mg, 41%); mp 296–299 °C. 1H NMR
(DMSO-d6) (d): 9.78 (br s, NH), 6.90 (m, 3H), 6.61 (s, 1H), 6.55 (s,
1H), 5.95 (s, 1H), 5.91 (s, 1H), 5.01 (s, 1H), 4.95 (d, 1H), 4.82 (d,
1H). MS (ES+) m/z: 344 (M++1, 100).
Following general procedure 1 heterolignan 93 was obtained as
colourless solid (1200 mg, 97%); mp 295–297 °C. 1H NMR (DMSO-
d6) (d): 9.63 (br s, NH), 7.09 (d, 2H), 6.80 (d, 2H), 6.51 (s, 2H), 5.92
(s, 1H), 5.88 (s, 1H), 4.87 (d, 1H), 4.85 (s, 1H), 4.78 (d, 1H), 3.70 (s,
3H). MS (ES+) m/z: 338 (M++1, 48), 230 (100).
4.4.100. 9-Phenyl-6,9-dihydro[1,3]dioxolo[4,5-g]furo[3,4-b]
quinolin-8(5H)-one (102)
4.4.92 9-(3,4-Dimethoxyphenyl)-6,9-dihydro[1,3]dioxolo[4,5-
g]furo[3,4-b]quinolin-8(5H)-one (94)
Following general procedure 1 heterolignan 102 was obtained
as colourless solid (770 mg, 66%); mp 295–298 °C. 1H NMR
(DMSO-d6) (d): 9.67 (br s, NH), 7.19 (m, 5H), 6.52 (s, 2H), 5.92 (s,
1H), 5.88 (s, 1H), 4.90 (s, 1H), 4.89 (d, 1H), 4.80 (d, 1H). MS (ES+)
m/z: 308 (M++1, 100).
Following general procedure 1 heterolignan 94 was obtained as
colourless solid (900 mg, 67%); mp 305–310 °C. 1H NMR (DMF-d7)
(d): 9.90 (br s, NH), 7.01 (d, 1H), 6.89 (d, 1H), 6.72 (dd, 1H), 6.69 (s,
1H), 6.62 (s, 1H), 6.01 (s, 1H), 5.97 (s, 1H), 5.00 (d, 1H), 4.96 (s, 1H),
4.90 (d, 1H), 3.70–3.85 (2s, 6H). MS (ES+) m/z: 368 (M++1, 43), 230
(100).
4.4.101. 9-(3-Bromophenyl)-6,9-dihydro[1,3]dioxolo[4,5-g]
furo[3,4-b]quinolin-8(5H)-one (103)
4.4.93. 9-(2-Chlorophenyl)-6,9-dihydro[1,3]dioxolo[4,5-
g]furo[3,4-b]quinolin-8(5H)-one (95)
Following general procedure 1 heterolignan 103 was obtained
as colourless solid (800 mg, 56%); mp 305–307 °C. 1H NMR
(DMSO-d6) (d): 9.67 (br s, NH), 7.34 (m, 2H), 7.20 (m, 2H),
6.55 (s, 1H), 6.53 (s, 1H), 5.93 (s, 1H), 5.90 (s, 1H), 4.96 (s,
1H), 4.92 (d, 1H), 4.81 (d, 1H). MS (ES+) m/z: 388 (100), 386
(M++1, 99).
Following general procedure 1 heterolignan 95 was obtained as
colourless solid (155 mg, 11%); mp >320 °C. 1H NMR (DMF-d7) (d):
10.05 (br s, NH), 7.42 (dd, 1H), 7.35 (dd, 1H), 7.25 (m, 2H), 6.63 (s,
1H), 6.52 (s, 1H), 6.01 (s, 1H), 5.97 (s, 1H), 5.57 (s, 1H), 5.02 (d, 1H),
4.95 (d, 1H). MS (ES+) m/z: 342 (M++1, 100).
4.4.102. 9-(3-Methylphenyl)-6,9-dihydro[1,3]dioxolo[4,5-
g]furo[3,4-b]quinolin-8(5H)-one (104)
4.4.94. 9-(3-Chlorophenyl)-6,9-dihydro[1,3]dioxolo[4,5-g]furo
[3,4-b]quinolin-8(5H)-one (96)
Following general procedure 1 heterolignan 104 was obtained
as colourless solid (780 mg, 66%); mp 308–312 °C. 1H NMR
(DMSO-d6) (d): 1H NMR (DMSO-d6) (d): 9.85 (s, NH), 7.15 (m,
1H), 6.97 (m, 3H), 6.55 (s, 1H), 6.52 (s, 1H), 5.95 (s, 1H), 5.89 (s,
1H), 4.96 (d, 1H), 4.87 (s, 1H), 4.85 (d, 1H), 2.24 (s, 3H). MS (ES+)
m/z: 322 (M++1, 100).
Following general procedure 1 heterolignan 96 was obtained as
colourless solid (340 mg, 27%); mp 290–294 °C. 1H NMR (DMF-d7)
(d): 10.05 (br s, NH), 7.35 (m, 2H), 7.26 (m, 2H), 6.67 (s, 1H), 6.65 (s,
1H), 6.03 (s, 1H), 5.99 (s, 1H), 5.09 (s, 1H), 5.03 (d, 1H), 4.92 (d, 1H).
MS (ES+) m/z: 342 (M++1, 100).
4.4.95. 9-(4-Chlorophenyl)-6,9-dihydro[1,3]dioxolo[4,5-g]furo
[3,4-b]quinolin-8(5H)-one (97)
4.4.103. 9-(3-Fluorophenyl)-6,9-dihydro[1,3]dioxolo[4,5-
g]furo[3,4-b]quinolin-8(5H)-one (105)
Following general procedure 1 heterolignan 97 was obtained as
colourless solid (290 mg, 23%); mp >310 °C. 1H NMR (DMF-d7) (d):
10.00 (s, NH), 7.35 (m, 4H), 6.65 (s, 1H), 6.63 (s, 1H), 6.02 (s, 1H),
5.98 (s, 1H), 5.06 (s, 1H), 4.99 (d, 1H), 4.91 (d, 1H). MS (ES+) m/z:
342 (M++1, 100).
Following general procedure 1 heterolignan 105 was obtained
as colourless solid (490 mg, 41%); mp 295–298 °C. 1H NMR
(DMSO-d6) (d): 9.72 (br s, NH), 7.28 (m, 2H), 6.95 (m, 2H), 6.56
(s, 1H), 6.53 (s, 1H), 5.93 (s, 1H), 5.89 (s, 1H), 4.97 (s, 1H), 4.91
(d, 1H), 4.80 (d, 1H). MS (ES+) m/z: 326 (M++1, 100).
4.4.96. 9-(3,5-Dichlorophenyl)-6,9-dihydro[1,3]dioxolo[4,5-g]
furo[3,4-b]quinolin-8(5H)-one (98)
4.4.104. 9-[3-(Trifluoromethoxy)phenyl]-6,9-dihydro[1,3]dio-
xolo[4,5-g]furo[3,4-b]quinolin-8(5H)-one (106)
Following general procedure 1 heterolignan 98 was obtained as
colourless solid (770 mg, 56%); mp 308–312 °C. 1H NMR (DMSO-
d6) (d): 9.79 (br s, NH), 7.35 (m, 1H), 7.21 (d, 2H), 6.58 (s, 1H),
6.56 (s, 1H), 5.95 (s, 1H), 5.92 (s, 1H), 5.02 (s, 1H), 4.96 (d, 1H),
4.82 (d, 1H). MS (ES+) m/z: 376 (M++1, 100).
Following general procedure 1 heterolignan 106 was obtained
as colourless solid (530 mg, 37%); mp 277–283 °C. 1H NMR
(DMSO-d6) (d): 9.75 (br s, NH), 7.38 (t, 1H), 7.15 (m, 3H), 6.57 (s,
1H), 6.54 (s, 1H), 5.93 (s, 1H), 5.90 (s, 1H), 5.03 (s, 1H), 4.91 (d,
1H), 4.81 (d, 1H). MS (ES+) m/z: 392 (M++1, 100).
4.4.97. 3-(8-Oxo-5,6,8,9-tetrahydro[1,3]dioxolo[4,5-g]furo[3,4-b]
quinolin-9-yl)benzonitrile (99)
4.4.105. 9-[3-(Propan-2-yloxy)phenyl]-6,9-dihydro[1,3]dioxolo
[4,5-g]furo[3,4-b]quinolin-8(5H)-one (107)
Following general procedure 1 heterolignan 99 was obtained as
colourless solid (730 mg, 60%); mp 305–310 °C. 1H NMR (DMSO-
d6) (d): 9.78 (br s, NH), 7.60 (m, 2H), 7.50 (m, 2H), 6.56 (s, 1H),
6.55 (s, 1H), 5.94 (s, 1H), 5.90 (s, 1H), 5.05 (s, 1H), 4.92 (d, 1H),
4.82 (d, 1H). MS (ES+) m/z: 333 (M++1, 100).
Following general procedure 1 heterolignan 107 was obtained as
colourless solid (890 mg, 66%); mp 279–282 °C. 1H NMR (DMSO-d6)
(d): 9.65 (br s, NH), 7.12 (t, 1H), 6.68 (m, 3H), 6.57 (s, 1H), 6.53 (s, 1H),
5.93 (s, 1H), 5.89 (s, 1H), 4.89 (d, 1H), 4.87 (s, 1H), 4.79 (d, 1H), 4.51
(m, 1H), 1.24 (d, 6H). MS (ES+) m/z: 366 (M++1, 100).
4.4.98. 9-[3-(Trifluoromethyl)phenyl]-6,9-dihydro[1,3]dioxolo
[4,5-g]furo[3,4-b]quinolin-8(5H)-one (100)
Following general procedure 1 heterolignan 100 was obtained
as colourless solid (510 mg, 37%); mp 303–306 °C. 1H NMR
(DMSO-d6) (d): 9.75 (br s, NH), 7.49 (m, 4H), 6.55 (s, 1H), 6.54 (s,
4.4.106. 9-(3,5-Dimethylphenyl)-6,9-dihydro[1,3]dioxolo[4,5-g]
furo[3,4-b]quinolin-8(5H)-one (108)
Following general procedure 1 heterolignan 108 was obtained
as colourless solid (800 mg, 65%). 1H NMR (DMSO-d6) (d): 1H

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NMR (DMSO-d6) (d): 9.81 (s, NH), 6.78 (s, 3H), 6.53 (s, 1H), 6.51 (s,
1H), 5.94 (s, 1H), 5.89 (s, 1H), 4.96 (d, 1H), 4.85 (d, 1H), 4.81 (s, 1H),
2.20 (s, 6H). MS (ES+) m/z: 336 (M++1, 100).
4.4.115. 9-(5-Bromopyridin-3-yl)-6,9-dihydro[1,3]dioxolo[4,5-
g]furo[3,4-b]quinolin-8(5H)-one (117)
Following general procedure 1 heterolignan 117 was obtained
as colourless solid (319 mg, 54%). 1H NMR (DMSO-d6) (d): 10.04
(s, NH), 8.53 (s, 1H), 8.48 (s, 1H), 7.80 (s, 1H), 6.63 (s, 1H), 6.57
(s, 1H), 5.98 (s, 1H), 5.92 (s, 1H), 5.07 (s, 1H), 4.98 (d, 1H), 4.87
(d, 1H). MS (ES+) m/z: 389 (100), 387 (M++1, 98).
4.4.107. 9-(2,2-Difluoro-1,3-benzodioxol-5-yl)-6,9-dihydro[1,3]
dioxolo[4,5-g]furo[3,4-b]quinolin-8(5H)-one (109)
Following general procedure 1 heterolignan 109 was isolated as
a colourless solid (1.46 g, 75%). 1H NMR (MeOD) (d): 7.1–7.0 (m,
3H), 6.46 (s, 2H), 5.88 (dd, 2H), 5.02 (s, 1H), 4.94–4.82 (m, 2H).
4.4.116. 9-(4-Bromothiophen-2-yl)-6,9-
dihydro[1,3]dioxolo[4,5-g]furo[3,4-b]quinolin-8(5H)-one (118)
Following general procedure 1 heterolignan 118 was obtained
as colourless solid (436 mg, 74%). 1H NMR (CDCl3) (d): 9.70 (s,
NH), 7.71 (s, 1H), 6.84 (s, 1H), 6.61 (s, 1H), 6.47 (s, 1H), 5.95 (s,
1H), 5.93 (s, 1H), 5.25 (s, 1H), 4.83 (d, 1H), 4.75 (d, 1H). MS (ES+)
m/z: 394 (35), 392 (M++1, 35), 230 (100).
4.4.108. 9-(2,3,5-Trichlorophenyl)-6,9-dihydro[1,3]dioxolo[4,5-g]
furo[3,4-b]quinolin-8(5H)-one (110)
Following general procedure 1 heterolignan 110 was obtained
as colourless solid (292 mg, 47%). 1H NMR (DMSO-d6) (d): 10.05
(br s, NH), 7.72 (s, 1H), 7.32 (br s, 1H), 6.56 (s, 1H), 6.39 (s, 1H),
5.98 (s, 1H), 5.92 (s, 1H), 5.52 (s, 1H), 4.97 (d, 1H), 4.88 (d, 1H).
MS (ES+) m/z: 412 (98), 410 (M++1, 100).
4.4.117. 9-(3,5-Dibromophenyl)-6,9-dihydro[1,3]dioxolo[4,5-
g]furo[3,4-b]quinolin-8(5H)-one (119)
4.4.109. 9-(2,3-Dimethoxyphenyl)-6,9-dihydro[1,3]dioxolo[4,5-g]
furo[3,4-b]quinolin-8(5H)-one (111)
Following general procedure 1 heterolignan 119 was obtained
as colourless solid (280 mg, 40%). 1H NMR (DMSO-d6) (d): 10.00
(br s, NH), 7.64 (s, 1H), 7.40 (s, 2H), 6.62 (s, 1H), 6.57 (s, 1H),
5.97 (s, 1H), 5.93 (s, 1H), 5.01 (s, 1H), 5.01 (d, 1H), 4.87 (d, 1H).
MS (ES+) m/z: 468 (57), 466 (100), 464 (M++1, 55).
Following general procedure 1 heterolignan 111 was obtained
as colourless solid (290 mg, 52%). 1H NMR (DMSO-d6) (d): 9.82 (s,
NH), 6.95 (t, 1H), 6.85 (d, 1H), 6.65 (d, 1H), 6.49 (s, 1H), 6.41 (s,
1H), 5.93 (s, 1H), 5.87 (s, 1H), 5.23 (s, 1H), 4.95 (d, 1H), 4.85 (d,
1H), 3.79 (s, 3H), 3.75 (s, 3H). MS (ES+) m/z: 368 (M++1, 100).
4.4.118. 9-[5-(4-Fluorophenyl)pyridin-3-yl]-6,9-
dihydro[1,3]dioxolo[4,5-g]furo[3,4-b]quinolin-8(5H)-one (120)
Following general procedure 1 heterolignan 120 was obtained
as colourless solid (206 mg, 38%). 1H NMR (DMSO-d6) (d): 10.00
(br s, NH), 8.72 (d, 1H), 8.45 (d, 1H), 7.89 (s, 1H), 7.75 (m, 2H),
7.36 (m, 2H), 6.71 (s, 1H), 6.59 (s, 1H), 6.00 (s, 1H), 5.93 (s, 1H),
5.13 (s, 1H), 5.02 (d, 1H), 4.90 (d, 1H). MS (ES+) m/z: 403 (M++1,
100).
4.4.110. 9-(2,3-Dichlorophenyl)-6,9-dihydro[1,3]dioxolo[4,5-g]
furo[3,4-b]quinolin-8(5H)-one (112)
Following general procedure 1 heterolignan 112 was obtained
as colourless solid (295 mg, 52%). 1H NMR (DMSO-d6) (d): 10.05
(s, NH), 7.49 (d, 1H), 7.28 (m, 2H), 6.55 (s, 1H), 6.39 (s, 1H), 5.97
(s, 1H), 5.90 (s, 1H), 5.52 (s, 1H), 4.94 (d, 1H), 4.88 (d, 1H). MS
(ES+) m/z: 376 (M++1, 100).
4.4.119. 9-(3,5-Dichloro-4-methoxyphenyl)-6,9-
4.4.111. 9-(3-Ethoxyphenyl)-6,9-dihydro[1,3]dioxolo[4,5-
g]furo[3,4-b]quinolin-8(5H)-one (113)
dihydro[1,3]dioxolo[4,5-g]furo[3,4-b]quinolin-8(5H)-one (121)
Following general procedure 1 heterolignan 121 was obtained
as colourless solid (234 mg, 38%). 1H NMR (DMSO-d6) (d): 10.00
(br s, NH), 7.30 (s, 2H), 6.66 (s, 1H), 6.58 (s, 1H), 5.99 (s, 1H),
5.95 (s, 1H), 5.01 (d, 1H), 5.00 (s, 1H), 4.88 (d, 1H), 3.80 (s, 3H).
MS (ES+) m/z: 406 (M++1, 100).
Following general procedure 1 heterolignan 113 was obtained
as colourless solid (366 mg, 69%). 1H NMR (DMSO-d6) (d): 9.87
(br s, NH), 7.16 (t, 1H), 6.73 (m, 3H), 6.60 (s, 1H), 6.54 (s, 1H),
5.96 (s, 1H), 5.89 (s, 1H), 4.96 (d, 1H), 4.87 (s, 1H), 4.85 (d, 1H),
3.97 (m, 2H), 1.28 (t, 3H). MS (ES+) m/z: 352 (M++1, 100).
4.4.120. 9-(3-Bromo-4-fluorophenyl)-6,9-
4.4.112. 9-(2,5-Dichlorophenyl)-6,9-dihydro[1,3]dioxolo[4,5-
g]furo[3,4-b]quinolin-8(5H)-one (114)
dihydro[1,3]dioxolo[4,5-g]furo[3,4-b]quinolin-8(5H)-one (122)
Following general procedure 1 heterolignan 122 was obtained
as colourless solid (374 mg, 61%). 1H NMR (DMSO-d6) (d): 9.98
(br s, NH), 7.53 (dd, 1H), 7.25 (m, 2H), 6.60 (s, 1H), 6.54 (s, 1H),
5.97 (s, 1H), 5.92 (s, 1H), 5.00 (s, 1H), 4.97 (d, 1H), 4.86 (d, 1H).
MS (ES+) m/z: 406 (85), 404 (M++1, 100).
Following general procedure 1 heterolignan 114 was obtained
as colourless solid (374 mg, 66%). 1H NMR (DMSO-d6) (d): 10.05
(br s, NH), 7.46 (d, 1H), 7.28 (m, 1H), 6.57 (s, 1H), 6.40 (s, 1H),
5.97 (s, 1H), 5.91 (s, 1H), 5.43 (s, 1H), 4.97 (d, 1H), 4.88 (d, 1H).
MS (ES+) m/z: 376 (M++1, 100).
4.4.121. 9-(3-Hydroxy-4,5-dimethoxyphenyl)-6,9-
dihydro[1,3]dioxolo[4,5-g]furo[3,4-b]quinolin-8(5H)-one (123)
Following general procedure 1 heterolignan 123 was obtained
as colourless solid (404 mg, 70%). 1H NMR (DMSO-d6) (d): 9.86
(br s, NH), 6.63 (s, 1H), 6.52 (s, 1H), 6.46 (d, 1H), 6.17 (d, 1H),
5.97 (s, 1H), 5.91 (s, 1H), 4.94 (d, 1H), 4.85 (d, 1H), 4.76 (s,
1H), 3.73 (s, 3H), 3.60 (s, 3H). MS (ES+) m/z: 384 (M++1, 100),
230 (46).
4.4.113. 9-[3-Chloro-2-fluoro-5-(trifluoromethyl)phenyl]-6,9-
dihydro[1,3]dioxolo[4,5-g]furo[3,4-b]quinolin-8(5H)-one (115)
Following general procedure 1 heterolignan 115 was obtained
as colourless solid (260 mg, 40%). 1H NMR (DMSO-d6) (d): 10.08
(s, NH), 7.97 (m, 1H), 7.63 (m, 1H), 6.57 (s, 1H), 6.51 (s, 1H), 5.98
(s, 1H), 5.93 (s, 1H), 5.38 (s, 1H), 4.97 (d, 1H), 4.88 (d, 1H). MS
(ES+) m/z: 428 (M++1, 100).
4.4.114. 9-(3-Bromo-4,5-dimethoxyphenyl)-6,9-
4.4.122. 9-[3,4-Dimethoxy-5-(methylsulfanyl)phenyl]-6,9-
dihydro[1,3]dioxolo[4,5-g]furo[3,4-b]quinolin-8(5H)-one (124)
Following general procedure 1 heterolignan 124 was obtained
as colourless solid (436 mg, 70%). 1H NMR (DMSO-d6) (d): 9.88 (s,
NH), 6.69 (s, 1H), 6.68 (s, 1H), 6.58 (s, 1H), 6.55 (s, 1H), 5.97 (s,
1H), 5.91 (s, 1H), 4.98 (d, 1H), 4.89 (s, 1H), 4.87 (d, 1H), 3.74 (s,
3H), 3.66 (s, 3H). MS (ES+) m/z: 414 (M++1, 50), 230 (100).
dihydro[1,3]dioxolo[4,5-g]furo[3,4-b]quinolin-8(5H)-one (116)
Following general procedure 1 heterolignan 116 was obtained
as colourless solid (470 mg, 70%). 1H NMR (DMSO-d6) (d): 9.90 (s,
NH), 7.03 (s, 1H), 6.83 (s, 1H), 6.67 (s, 1H), 6.55 (s, 1H), 5.98 (s,
1H), 5.93 (s, 1H), 5.00 (d, 1H), 4.92 (s, 1H), 4.87 (d, 1H), 3.81 (s,
3H), 3.69 (s, 3H). MS (ES+) m/z: 448 (80), 446 (M++1, 100), 230 (50).

J. Frackenpohl et al. / Bioorg. Med. Chem. 17 (2009) 4160–4184
4183
4.4.123. 9-(7-Methoxy-1,3-benzodioxol-5-yl)-6,9-
4.4.131. 9-[3-(1,1,2,2-Tetrafluoroethoxy)phenyl]-6,9-
dihydro[1,3]dioxolo[4,5-g]furo[3,4-b]quinolin-8(5H)-one (125)
Following general procedure 1 heterolignan 125 was obtained
as colourless solid (463 mg, 78%). 1H NMR (DMSO-d6) (d): 9.88
(s, NH), 6.65 (s, 1H), 6.56 (s, 1H), 6.52 (s, 1H), 6.34 (s, 1H),
5.97 (s, 1H), 5.92 (s, 1H), 5.91 (s, 2H), 4.97 (d, 1H), 4.93 (d,
1H), 4.92 (s, 1H), 3.81 (s, 3H). MS (ES+) m/z: 382 (M++1, 100),
230 (87).
dihydro[1,3]dioxolo[4,5-g]furo[3,4-b]quinolin-8(5H)-one (133)
Following general procedure 1 heterolignan 133 was obtained
as colourless solid (417 mg, 65%). 1H NMR (DMSO-d6) (d): 9.94
(br s, NH), 7.38 (t, 1H), 7.17 (d, 1H), 7.08 (m, 2H), 6.77 (tt, 1H),
6.60 (s, 1H), 6.55 (s, 1H), 5.97 (s, 1H), 5.91 (s, 1H), 5.03 (s, 1H),
4.96 (d, 1H), 4.87 (d, 1H). MS (ES+) m/z: 424 (M++1, 100).
4.4.132. 9-[3-(2-Hydroxyethoxy)phenyl]-6,9-
4.4.124. [3-(8-Oxo-5,6,8,9-tetrahydro[1,3]dioxolo[4,5-
g]furo[3,4-b]quinolin-9-yl)-phenoxy]acetonitrile (126)
Following general procedure 1 heterolignan 126 was obtained
as colourless solid (220 mg, 40%). 1H NMR (DMSO-d6) (d): 9.92
(br s, NH), 7.28 (t, 1H), 6.90 (m, 3H), 6.65 (s, 1H), 6.56 (s, 1H),
5.98 (s, 1H), 5.91 (s, 1H), 5.14 (s, 2H), 4.97 (d, 1H), 4.92 (s, 1H),
4.87 (d, 1H). MS (ES+) m/z: 363 (M++1, 100).
dihydro[1,3]dioxolo[4,5-g]furo[3,4-b]quinolin-8(5H)-one (134)
Following general procedure 1 heterolignan 134 was obtained
as colourless solid (374 mg, 68%). 1H NMR (DMSO-d6) (d): 9.88
(br s, NH), 7.16 (t, 1H), 6.74 (m, 3H), 6.60 (s, 1H), 6.54 (s, 1H),
5.95 (s, 1H), 5.88 (s, 1H), 4.96 (d, 1H), 4.87 (s, 1H), 4.85 (d, 1H),
4.84 (br s, OH), 3.92 (m, 2H), 3.69 (m, 2H). MS (ES+) m/z: 368
(M++1, 100).
4.4.125. 9-(4-Chloro-3-methoxyphenyl)-6,9-
4.4.133. 9-(3,5-Dichlorophenyl)-6,9-dihydro-8H-
dihydro[1,3]dioxolo[4,5-g]furo[3,4-b]quinolin-8(5H)-one (127)
Following general procedure 1 heterolignan 127 was obtained
as colourless solid (146 mg, 26%). 1H NMR (DMSO-d6) (d): 9.92 (s,
NH), 7.30 (d, 1H), 7.11 (s, 1H), 6.68 (d, 1H), 6.67 (s, 1H), 6.55 (s,
1H), 5.98 (s, 1H), 5.91 (s, 1H), 4.96 (d, 1H), 4.95 (s, 1H), 4.88 (d,
1H), 3.86 (s, 3H). MS (ES+) m/z: 372 (M++1, 100).
[1,3]dioxolo[4,5-g]furo[3,4-b]chromen-8-one (135)
Following general procedure 5 heterolignan 135 was isolated as
colourless solid (144 mg, 34%); mp 166 °C. 1H NMR (CH3CN-d3) (d):
7.33 (s, 1H), 7.24 (s, 2H), 6.74 (s, 1H), 6.49 (s, 1H), 5.95 (m, 2H), 4.83
(m, 3H). MS (ES+) m/z: 377 (MH+).
4.4.134. 9-(3-Chlorophenyl)-6,9-dihydro-8H-[1,3]dioxolo[4,5-
g]furo[3,4-b]chromen-8-one (136)
Following general procedure 5 heterolignan 136 was obtained
as colourless solid (253 mg, 35%). 1H NMR (CH3CN-d3) (d): 7.26
(m, 4H), 6.73 (s, 1H), 6.48 (s, 1H), 5.95 (m, 2H), 4.86 (m, 3H). MS
(ES+) m/z: 343 (MH+).
4.4.126. 9-(3-Chloro-4-fluorophenyl)-6,9-
dihydro[1,3]dioxolo[4,5-g]furo[3,4-b]quinolin-8(5H)-one (128)
Following general procedure 1 heterolignan 128 was obtained
as colourless solid (325 mg, 60%). 1H NMR (DMSO-d6) (d): 10.00
(br s, NH), 7.40 (dd, 1H), 7.34 (t, 1H), 7.21 (m, 1H), 6.63 (s, 1H),
6.58 (s, 1H), 6.00 (s, 1H), 5.95 (s, 1H), 5.02 (s, 1H), 4.98 (d, 1H),
4.88 (d, 1H). MS (ES+) m/z: 360 (M++1, 100).
4.4.135. 9-(3-Bromophenyl)-6,9-dihydro-8H-[1,3]dioxolo[4,5-
g]furo[3,4-b]chromen-8-one (137)
Following general procedure 5 heterolignan 137 was isolated as
colourless solid (270 mg, 29%); mp 228 °C. 1H NMR (CH3CN-d3) (d):
7.40 (m, 2H), 7.23 (m, 2H), 6.73 (s, 1H), 6.48 (s, 1H), 5.94 (m, 2H),
4.85 (m, 3H). MS (ES+) m/z: 387 (MH+), 389 (MH+).
4.4.127. 9-(6-Methoxypyridin-3-yl)-6,9-
dihydro[1,3]dioxolo[4,5-g]furo[3,4-b]quinolin-8(5H)-one (129)
Following general procedure
1 heterolignan 129 was ob-
tained as colourless solid (354 mg, 69%). 1H NMR (DMSO-d6)
(d): 9.90 (s, NH), 8.06 (d, 1H), 7.44 (dd, 1H), 6.74 (d, 1H),
6.59 (s, 1H), 6.55 (s, 1H), 5.98 (s, 1H), 5.92 (s, 1H), 4.96 (s,
1H), 4.96 (d, 1H), 4.87 (d, 1H), 3.82 (s, 3H). MS (ES+) m/z:
339 (M++1, 100).
4.4.136. 9-[3-(Trifluoromethoxy)phenyl]-6,9-dihydro-8H-
[1,3]dioxolo[4,5-g]furo[3,4-b]chromen-8-one (138)
Following general procedure 5 heterolignan 138 was isolated as
slightly greenish solid (270 mg, 59%); mp 130 °C. 1H NMR (CH3CN-
d3) (d): 7.28 (m, 4H), 6.73 (s, 1H), 6.48 (s, 1H), 5.94 (m, 2H), 4.87 (m,
3H). MS (ES+) m/z: 393 (MH+).
4.4.1289-(7-Bromo-1,3-benzodioxol-5-yl)-6,9-
dihydro[1,3]dioxolo[4,5-g]furo[3,4-b]quinolin-8(5H)-one (130)
Following general procedure 1 heterolignan 130 was obtained
as colourless solid (476 mg, 73%). 1H NMR (DMSO-d6) (d): 9.95 (s,
NH), 6.87 (s, 1H), 6.77 (s, 1H), 6.64 (s, 1H), 6.55 (s, 1H), 6.09 (s,
1H), 6.08 (s, 1H), 5.98 (s, 1H), 5.93 (s, 1H), 4.98 (d, 1H), 4.89 (s,
1H), 4.87 (d, 1H). MS (ES+) m/z: 432 (85), 430 (M++1, 100).
4.4.137. 9-(3-Chlorophenyl)-6-methoxy-3,9-dihydro-1H-
furo[3,4-b]chromen-1-one (139)
Following general procedure 5 heterolignan 139 was obtained
as colourless solid (30 mg, 5%) after flash chromatography. 1H
NMR (CH3CN-d3) (d): 7.25 (m, 4H), 6.99 (m, 1H), 6.74 (m, 2H),
4.88 (m, 3H), 3.79 (s, 3H). MS (ES+) m/z: 329 (MH+).
4.4.129. 9-(4-Fluoro-3-methoxyphenyl)-6,9-
dihydro[1,3]dioxolo[4,5-g]furo[3,4-b]quinolin-8(5H)-one (131)
Following general procedure 1 heterolignan 131 was obtained
as colourless solid (391 mg, 73%). 1H NMR (DMSO-d6) (d): 9.90 (s,
NH), 7.08 (m, 2H), 6.66 (m, 1H), 6.66 (s, 1H), 6.55 (s, 1H), 5.98 (s,
1H), 5.92 (s, 1H), 4.97 (d, 1H), 4.94 (s, 1H), 4.87 (d, 1H), 3.83 (s,
3H). MS (ES+) m/z: 356 (M++1, 100).
4.4.138. 9-(3-Bromo-4,5-dimethoxyphenyl)-6,9-dihydro-8H-
[1,3]dioxolo[4,5-g]furo[3,4-b]chromen-8-one (140)
Following general procedure 5 heterolignan 140 was isolated as
colourless solid (90 mg, 14%) after flash chromatography. 1H NMR
(CH3CN-d3) (d): 6.98 (m, 1H), 6.92 (m, 1H), 6.72 (s, 1H), 6.53 (s, 1H),
5.95 (m, 2H), 4.85 (m, 3H), 3.82 (s, 3H), 3.76 (s, 3H). MS (ES+) m/z:
447 (MH+), 449 (MH+).
4.4.130. 9-(3,4,5-Trifluorophenyl)-6,9-dihydro[1,3]dioxolo[4,5-
g]furo[3,4-b]quinolin-8(5H)-one (132)
Following general procedure 1 heterolignan 132 was obtained
as colourless solid (361 mg, 66%). 1H NMR (DMSO-d6) (d): 10.00
(br s, NH), 7.17 (m, 2H), 6.67 (s, 1H), 6.56 (s, 1H), 5.97 (s, 1H),
5.92 (s, 1H), 5.00 (s, 1H), 4.97 (d, 1H), 4.87 (d, 1H). MS (ES+) m/z:
362 (M++1, 100).
4.4.139. 9-[3-(Difluoromethoxy)phenyl]-6,9-dihydro-8H-
[1,3]dioxolo[4,5-g]furo[3,4-b]chromen-8-one (141)
Following general procedure 5 heterolignan 141 was isolated as
colourless solid (100 mg, 23%) after flash chromatography; mp
193–195 °C. 1H NMR (CH3CN-d3) (d): 7.35 (t, 1H), 7.14 (d, 1H),

4184
J. Frackenpohl et al. / Bioorg. Med. Chem. 17 (2009) 4160–4184
Prinsen, M.; Krupa, D.; Wideman, M. A. J. Agric. Food. Chem. 2003, 51, 2246; (b)
El Sayed, K. A.; Dunbar, D. C.; Perry, T. L.; Wilkins, S. P.; Hamann, M. T.;
Greenplate, J. T.; Wideman, M. A. J. Agric. Food. Chem. 1997, 45, 2246.
3. (a) Gao, R.; Gao, C.; Yu, X.; Di, Y.; Xiao, H.; Zhang, X. Pest. Manag. Sci. 2004, 60,
1131; (b) Miyazawa, M.; Fukuyama, M.; Yoshio, K.; Kato, T.; Ishikawa, Y. J. Agric.
Food Chem. 1999, 47, 5108; (c) Inamori, Y.; Kubo, M.; Tsujibo, H.; Ogawa, M.;
Baba, K.; Kozawa, M.; Fujita, E. Chem. Pharm. Bull. 1986, 34, 3928.
4. (a) Feliciano, A. S.; Miguel del Corral, J. M.; Gordaliza, M.; Castro, M. A.
Phytochemistry 1989, 28, 659; (b) Gordaliza, M.; Garcia, P. A.; Miguel del Corral,
J. M.; Castro, M. A.; Gomez-Zurita, M. A. Toxicon 2004, 44, 441; (c) Liu, Y. Q.;
Yang, L.; Tian, X. Curr. Bioact. Compd. 2007, 3, 37.
7.01 (m, 2H), 6.73 (s, 1H), 6.72 (t, 1H), 6.49 (s, 1H), 5.94 (m, 2H),
4.87 (m, 3H). MS (ES+) m/z: 375 (MH+).
4.4.140. 9-(3,5-Dimethoxyphenyl)-6-methoxy-3,9-dihydro-1H-
furo[3,4-b]chromen-1-one (142)
Following general procedure 5 heterolignan 142 was ob-
tained as colourless solid (58 mg, 14%) after flash chromatogra-
phy. 1H NMR (CH3CN-d3) (d): 7.04 (m, 1H), 6.72 (m, 2H), 6.37
(m, 3H), 4.87 (m, 3H), 3.78 (s, 3H), 3.73 (s, 6H). MS (ES+) m/z:
355 (MH+).
5. Duca, M.; Guianvarc’h, D.; Meresse, P.; Bertounesque, E.; Dauzonne, D.; Kraus-
Berthier, L.; Thirot, S.; Léonce, S.; Pierré, A.; Pfeiffer, B.; Renard, P.; Arimondo, P.
B.; Monneret, C. J. Med. Chem. 2005, 48, 593.
6. (a) Desbène, S.; Giorgi-Renault, S. Curr. Med. Chem.—Anti-Cancer Agents 2002, 2,
71; (b) You, Y. Curr. Pharm. Design 2005, 11, 1695; (c) Castro, M. A.; Miguel del
Corral, J. M.; Gordaliza, M.; Gomez-Zurita, M. A.; Luz de la Puente, M.;
Betancur-Galvis, L. A.; Sierra, J.; San Feliciano, A. Eur. J. Med. Chem. 2003, 38,
899.
7. Di, X.; Liu, Y.; Liu, Y.; Yu, X.; Xiao, H.; Tian, X.; Gao, R. Pest. Biochem. Phys. 2007, 89,
81.
8. (a) Liu, Y.-Q.; Liu, Y.; Xiao, H.; Gao, R.; Tian, X. Pest. Biochem. Phys. 2008, 91, 116;
(b) Liu, Y.-Q.; Yang, L.; Liu, Y.; Di, X.; Xiao, H.; Tian, X.; Gao, R. Nat. Prod. Res. 2007,
21, 967.
4.4.141. 9-(3,5-dimethoxyphenyl)-5,6-dimethoxy-3,9-dihydro-
1H-furo[3,4-b]chromen-1-one (143)
Following general procedure
5 heterolignan 143 was ob-
tained as colourless solid (40 mg, 14%) after flash chromatogra-
phy. 1H NMR (CH3CN-d3) (d): 6.81 (m, 2H), 6.38 (m, 3H), 4.90
(m, 3H), 3.85 (s, 3H), 3.82 (s, 3H), 3.73 (s, 6H). MS (ES+) m/z:
385 (MH+).
9. Xu, H.; Zhang, X.; Tian, X.; Lu, M.; Wang, Y.-G. Chem. Pharm. Bull. 2002, 50, 399.
10. Ramos, A. C.; Peláez-Lamamié de Clairac, R.; Medarde, M. Heterocycles 1999, 51,
1443.
11. Magedov, I. V.; Manpadi, M.; van Slambrouck, S.; Steelant, W. F. A.; Rozhkova,
E.; Przheval’skii, N. M.; Rogelj, S.; Kornienko, A. J. Med. Chem. 2007, 50, 5183.
12. (a) Tratrat, C.; Giorgi-Renault, S.; Husson, H.-P. Org. Lett. 2002, 4, 3187; (b)
Giorgi-Renault, S. Ann. Pharm. Fr. 2005, 63, 63.
4.4.142. 9-(3,5-Dichlorophenyl)-6-methoxy-3,9-dihydro-1H-
furo[3,4-b]chromen-1-one (144)
Following general procedure 5 heterolignan 144 was obtained
as colourless solid (69 mg, 38%). 1H NMR (CH3CN-d3) (d): 7.32
(m, 1H), 7.23 (m, 2H), 7.00 (m, 1H), 6.75 (m, 2H), 4.88 (m, 3H),
3.80 (s, 3H). MS (ES+) m/z: 363 (MH+).
13. Hitotsuyanagi, Y.; Fukuyo, M.; Tsuda, K.; Kobayashi, M.; Ozeki, A.; Itokawa, H.;
Takeya, K. Bioorg. Med. Chem. Lett. 2000, 10, 315.
14. (a) Jeschke, P. CHEMBIOCHEM 2004, 5, 571; (b) Maienfisch, P.; Hall, R. G. Chimia
2004, 58, 93.
15. (a) Langlois, B.; Soula, G. Bull. Soc. Chim. Fr. 1986, 925; (b) Langlois, B.; Desbois,
M. Ann. Chim. Fr. 1984, 9, 729.
4.4.143. 9-(3,5-Dichlorophenyl)-5,6-dimethoxy-3,9-dihydro-
1H-furo[3,4-b]chromen-1-one (145)
Following general procedure 5 heterolignan 145 was isolated as
colourless solid (60 mg, 32%). 1H NMR (CH3CN-d3) (d): 7.32 (m,
1H), 7.24 (m, 2H), 6.82 (m, 1H), 6.76 (m, 1H), 4.91 (m, 3H), 3.87
(s, 3H), 3.83 (s, 3H). MS (ES+) m/z: 393 (MH+).
16. (a) Whiteley, C. G. Bioorg. Med. Chem. 2002, 10, 1221; (b) Stuart, J. G.; Khora, S.;
McKenney, J. D.; Castle, R. N. J. Heterocycl. Chem. 1987, 24, 1589; (c) Huang, D.;
Poon, S. F.; Chapman, D. F.; Chung, J.; Cramer, M.; Reger, T. S.; Roppe, J. R.; Tehrani,
L.; Cosford, N. D. P.; Smith, N. D. Bioorg. Med. Chem. Lett. 2004, 14, 5473.
17. Jurd, L. J. Heterocycl. Chem. 1996, 33, 1227.
18. Husson, H.-P.; Giorgi-Renault, S.; Desbene, S.; Hickman, J.; Pierre, A.; Kraus-
Berthier, L.; Pfeiffer, B.; Renard, P. WO02094835, 2002.
19. Huang, Y. T.; Huang, D. M.; Guh, J. H.; Chen, I. L.; Tzeng, C. C.; Teng, C. M. J. Biol.
Chem. 2005, 280, 2771–2779.
References and notes
20. Ravelli, R. B.; Gigant, B.; Curmi, P. A.; Jourdain, I.; Lachkar, S.; Sobel, A.;
Knossow, M. Nature 2004, 428, 198.
1. Jeschke, P.. In Modern Crop Protection Compounds; Krämer, W., Schirmer, U.,
Eds.; Wiley-VCH: Weinheim, 2007; Vol. 3, pp 1185–1237.
21. Velten, R.; Adelt, I.; Böhmer, J.; Frackenpohl, J.; Schenke, T.; Lösel, P.; Malsam,
O.; Arnold, C. WO 05097802, 2005.
2. (a) Peng, L.; Shen, X.; El Sayed, K. A.; Dunbar, D. C.; Perry, T. L.; Dunbar, D. C.;
Perry, T. L.; Wilkins, S. P.; Hamann, M. T.; Bobzin, S.; Huesing, J.; Camp, R.;