1-Aryltetralin privileged structure-based libraries: parallel synthesis of N-aryl and N-biaryl γ-lactam lignans

Article abstract of DOI:10.1016/j.tet.2006.09.026

The parallel solution-phase synthesis of two libraries of product-like compounds derived from a 1-aryltetralin privileged structure is described. The N-aryl picropodophyllone γ-lactams were synthesized from methyl ester thuriferic acid via InCl₃

Full text of DOI:10.1016/j.tet.2006.09.026

Tetrahedron 62 (2006) 11766–11781
1-Aryltetralin privileged structure-based libraries: parallel
synthesis of N-aryl and N-biaryl g-lactam lignans
a
Matthieu Dorbec,a Jean-Claude Florent,a, Claude Monneret,
*
b
Marie-Noelle Rager and Emmanuel Bertounesque
a,
*
€
aUMR 176 CNRS-Institut Curie, Centre de Recherche, 26 rue d’Ulm, 75248 Paris Cedex 05, France
´
Departement de RMN, Ecole Nationale Superieure de Chimie de Paris, 11 rue P. et M. Curie, 75231 Paris Cedex 05, France
b
´
Received 21 June 2006; revised 1 September 2006; accepted 12 September 2006
Available online 20 October 2006
Abstract—The parallel solution-phase synthesis of two libraries of product-like compounds derived from a 1-aryltetralin privileged structure
is described. The N-aryl picropodophyllone g-lactams were synthesized from methyl ester thuriferic acid via InCl3-tandem aza-Michael
addition–cyclization reaction of anilines. Bromo-aryl compounds from this library were subjected to a ligandless palladium Suzuki cross-
coupling to give the expected N-biaryl picropodophyllin g-lactams.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
as well as the biaryl subunit21 are also valuable pharmaco-
phoric groups found in a variety of molecules presenting bio-
logical properties. The combination of such fragments may
qualitatively enrich the compounds collection. In the field
of podophyllotoxin chemistry, it is worth noting that only
two syntheses exemplifying the combination of 1 with g-lac-
tam rings have been reported so far, i.e., the semi-synthesis
of etoposide-lactam derivatives22 and the total synthesis of
(ꢀ)-demethoxy epiisopicropodophyllin N-benzyl lactam.23
There is growing current interest in using specific structures,
generally found within a class of natural products, as starting
points for library design.1 The core scaffold of a natural
product can provide a biologically validated framework
with diverse functional groups. The resulting libraries can
then be used to address a variety of biological targets.2
Within this context, we initiated the synthesis of g-lactam
lignans based on the 1-aryltetralin skeleton 1 as a privileged
structure3–9 (Fig. 1). Lignans of 1-aryltetralin type possess
a diverse range of biological activities10–13 including inhibi-
tion of the tubulin polymerization, inhibition of DNA
topoisomerase II, and immunosuppressive, anti-HIV, and
antidepressant activities. Recently, cyclolignans as inhibi-
tors of the phosphorylation of the insuline-like growth factor
receptor (IGF-1R) have been reported.14–20 g-Lactam motif
Our first approach involved a synthesis of N-aryl picropodo-
phyllone g-lactams24 via aza-Michael addition from thuri-
feric acid methyl ester 2 under basic conditions. In this
paper, we describe the extension of our work with the paral-
lel solution-phase synthesis of N-aryl g-lactam lignans 3 via
a tandem aza-Michael addition–cyclization from 225–31
using a catalytic amount of InCl3, and then the parallel
O
O
OH
Ar
O
O
O
O
O
O
NAr
N
CO2Me
OMe
O
O
MeO
MeO
OMe
MeO
OMe
OMe
OMe
OMe
3
1
4
2
Figure 1.
Keywords: Biaryls; Lactam lignans; Privileged structure; Tandem reaction; InCl3; Ligandless Suzuki reaction; Parallel solution-phase synthesis.
* Corresponding authors. Tel.: +33142346659; fax: +33142346631 (E.B.); e-mail: emmanuel.bertounesque@curie.fr
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.09.026

M. Dorbec et al. / Tetrahedron 62 (2006) 11766–11781
11767
solution-phase synthesis of N-biaryl g-lactam lignans 4 from
the corresponding bromo adducts via a ligandless palladium
Suzuki cross-coupling (Fig. 1).
with the cis- and trans-b-amino ketones 6n was obtained
under InCl3 catalysis59 (1H NMR analysis). Addition of
DBU to the reaction mixture favored the cyclization step
providing the cis-g-lactam 3n in 66% yield. The scope of
this tandem reaction found to be limited. Deactivated ani-
lines 4-nitroaniline and 4-trifluoroaniline behave differently
during the necessary one-pot process since no cyclization
products were obtained by using only InCl3: following addi-
tion of DBU, while the formation of the desired cis-g-lactam
3o was observed (50%), demonstrating the reactivity of
the aza-Michael adduct 6o obtained from 4-nitro-aniline
(Fig. 2), no cyclization occurred from the cis- and trans-b-
amino ketones 6p.59 Furthermore, reaction of deactivated
5-aminoanthraquinone resulted only in recovered starting
material 2. Reaction of ortho-substituted anilines such as
2-bromoaniline, 2,4-dibromoaniline, 5-chloro-2-methylani-
line, 1-amino-5,6,7,8-tetrahydronaphthalene, and 2,3-di-
methylaniline furnished the corresponding aza-Michael
adduct 6 in the presence of the starting material 2 (1H NMR
analysis of the crude product). For example, for 1-amino-
5,6,7,8-tetrahydronaphthalene and 2,3-dimethylaniline we
obtained a mixture of starting material 2 and aza-Michael
adduct 6 in 33 and 66% yields, respectively. Finally, in the
case of 4-iodoaniline, the expected products (6 and/or 3)
could not be observed in the NMR spectra, only an unidenti-
fied mixture of products being obtained.
2. Results and discussion
2.1. Parallel solution-phase synthesis of N-aryl g-lactam
lignans
Michael addition of amines to a,b-unsaturated ketones usu-
ally require basic conditions or acid catalysis. In the past few
years, a number of alternative procedures have been devel-
oped and in particular, various Lewis acid-induced and tran-
sition metal salts catalyzed reactions have been reported.32–42
Recently, indium salts have emerged as powerful catalysts
in many chemical processes both in aqueous and organic
media.43–50 Loh and co-workers have reported indium
trichloride as an excellent catalyst in the Mukaiyama aldol
reactions,51–53 Diels–Alder reactions,54 aldol-type Mannich
reactions,55 and Michael reaction56,57 under mild conditions.
As indium trichloride has these unique properties compared
to other Lewis acids—which include stability and recover-
ability from water56—and since indium salts allowed tan-
dem reactions49,50 and one-pot multistep transformation,47
we decided to exploit this catalyst to construct our small
g-lactam lignans libraries from methyl ester thuriferic acid
2 with the aim to develop a one-pot protocol, which would
be an improvement over our previous synthesis.24
2.2. Parallel solution-phase synthesis of N-biaryl
g-lactam lignans
Methyl ester thuriferic acid 2 was obtained in a three-step se-
quence24 from podophyllotoxin 5, as outlined in Scheme 1.
To our delight, the N-aryl picropodophyllone g-lactams 3
were synthesized from 2 via InCl3-catalyzed tandem aza-
Michael addition–cyclization reaction of substituted ani-
lines. g-Lactams 3 were obtained as a single isomer and their
stereochemistry were determined to be cis by NOESYexper-
iment.24 The parallel solution-phase synthesis of N-aryl
picropodophyllone lactams was conducted on the Quest
210Ò (Argonaut Technologies) using 10 mL Teflon reaction
vessels (Table 1). We used sulfonyl chloride resin as a poly-
mer-supported scavenger58 for anilines in order to facilitate
the purification of products.
The synthesis of libraries of biaryl small molecules is vitally
important to the pharmaceutical industry in the search for
biologically active compounds. Consequently, we turned
out our attention to the parallel solution-phase synthesis of
N-biaryl g-lactam lignans 4 from the bromo adducts 3a
and 3b. We used ‘ligandless’ palladium catalytic conditions,
which have demonstrated many advantages over classical
coupling methodologies.60–68
We therefore decided to apply this methodology from com-
pounds 3a and 3b for the parallel solution-phase synthesis of
N-biaryl g-lactam lignans on the Quest 210Ò. The Suzuki–
Miyaura coupling of 3a with substituted phenylboronic
acids (i.e., phenylboronic acid, 4-chlorophenylboronic
acid, and 4-methoxyphenylboronic acid) was examinated
under a variety of conditions. Unfortunately, the reaction
afforded partial conversion of 3a into the desired biaryl de-
For monohalogenated anilines (Table 1, entries 1–6) and ac-
tivated anilines (Table 1, entries 7–13), the tandem reaction
with 2 catalyzed by InCl3 (0.5 equiv) afforded exclusively
cis-g-lactams 3a–f and 3g–m after 48 h at 80 ꢁC in DCE
in 61–94% yields. Surprisingly, one activated aniline (entry
14) required addition of a base for the synthesis of 3n under
these catalytic conditions. Indeed, for 2-aminofluorene,
a mixture of the cis-g-lactam 3n as a major product together
1
rivative and/or degradation products. In the latter case, H
NMR analysis of the crude product revealed the disappear-
ance of the signals of the H1, H2, and H3 protons and appear-
ance of other aromatic protons. Given the acidity of the H3
proton, this result is likely due to aromatization reaction
O
OH
O
O
O
O
O
O
a, b, c
d, e
O
N Ar
O
CO2Me
OMe
O
O
MeO
MeO
OMe
MeO
OMe
OMe
OMe
OMe
3
5
2
Scheme 1. (a) PCC, DCM, rt; (b) t-BuOK, t-BuOH, reflux; (c) MeI, NaHCO3, DMF, rt; (d) ArNH2, InCl3, DCE, 80 ꢁC; (e)
ArSO2Cl, Et3N.

11768
M. Dorbec et al. / Tetrahedron 62 (2006) 11766–11781
Table 1
Entry
Aniline
Producta (%) Yieldb (%) Purityc (%) Entry
Aniline
Producta (%) Yieldb (%) Purityc (%)
Br
Br
OMe
1d
2d
3d
4d
5d
6d
7d
3a
3b
3c
3d
3e
3f
94
91
85
91
76
85
87
89
92
94
79
92
9d
3i
90
91
77
79
81
87
86
80
H2N
H2N
H2N
OMe
OMe
10d
11d
12d
13d
14e
3j
90
H2N
H2N
OMe
Me
Me
Br
3k
3l
92
H2N
Cl
81
H2N
H2N
H2N
O
O
3m
3n
61
Cl
F
H2N
6659
H2N
H2N
SMe
NO2
CF3
3g
3h
82
71
88
79
15e
16f
3o
3p
5059
H2N
H2N
H2N
O
8d
059
H2N
All products were characterized by 1H NMR, 13C NMR, IR, and mass spectroscopy.
Isolated yields.
a
b
c
d
e
f
1H NMR estimation after scavenging with sulfonyl chloride resin and filtration on silica pad.
InCl3 (0.5 equiv), 48 h.
InCl3 (0.5 equiv), 48 h, then DBU (5 equiv), 24 h.
Obtention of b-aminoketone 6p and recovered starting material 2.
O
gave the best results to obtain the 4-OH group in the a-con-
figuration, thereby leading to 7a (75%, dr¼87%) and 8a
(67%, dr¼87%) from 3a and 3b, respectively (Scheme 2).
In contrast, the use of L-Selectride at ꢂ78 ꢁC allowed the op-
posite selectivity, 7b (86%) and 8b (80%) were thus prepared
with an excellent diastereoisomeric excess (dr>95%). The
relative stereochemistry of these compounds was deduced
from the J3,4 coupling constants (8.2 Hz for 7a, 5.0 Hz for
O
O
NHAr
CO2Me
MeO
OMe
OMe
6n (aniline = 2-aminofluorene)
6o (aniline = 4-nitroaniline)
6p (aniline = 4-trifluoroaniline)
O
R2
R1
O
O
R3
O
O
R
a or b
Figure 2.
N
N
O
O
occurring during cross-coupling. To circumvent this prob-
lem, we opted for a reduction of the carbonyl function at
C-4 on the picropodophyllone derivatives 3a and 3b.
MeO
OMe
MeO
OMe
OMe
OMe
Accordingly, we examined the reduction of the carbonyl
function at C-4 of the picropodophyllone N-4-bromophenyl
g-lactam 3a and the picropodophyllone N-3-bromophenyl
g-lactam 3b under different reducing conditions (i.e.,
NaBH4, NaBH4/CeCl3, NaHB(OAc)3, L-Selectride, cate-
cholboranehydride). It was found that NaBH4 at ꢂ78 ꢁC
3a: R = 4-Br
3b: R = 3-Br
7a: R1 = H, R2 = OH, R3 = 4-Br
7b: R1 = OH, R2 = H, R3 = 4-Br
8a: R1 = H, R2 = OH, R3 = 3-Br
8b: R1 = OH, R2 = H, R3 = 3-Br
Scheme 2. (a) NaBH4, THF, MeOH, ꢂ78 ꢁC; (b) L-Selectride, THF,
ꢂ78 ꢁC.

M. Dorbec et al. / Tetrahedron 62 (2006) 11766–11781
R2
11769
R2
R1
R1
O
R3
O
O
R3
ArB(OH)2, Pd(OAc)2
CsF, DMF, 85 °C
N
N
O
O
O
MeO
OMe
MeO
OMe
OMe
OMe
7a: R1 = H, R2 = OH, R3 = 4-Br
7b: R1 = OH, R2 = H, R3 = 4-Br
8a: R1 = H, R2 = OH, R3 = 3-Br
8b: R1 = OH, R2 = H, R3 = 3-Br
4aa-ai: R1 = H, R2 = OH, R3 = 4-aryl
4ba-bd: R1 = OH, R2 = H, R3 = 4-aryl
4ca,cb: R1 = H, R2 = OH, R3 = 3-aryl
4da,db: R1 = OH, R2 = H, R3 = 3-aryl
Scheme 3. Suzuki–Miyaura cross-coupling reaction.
7b, 7.5 Hz for 8a, and 4.5 Hz for 8b) and was confirmed from
Table 2. (continued)
Entrya Substrate
0
NOESY correlations (H3/H2, H1/H4, H2 –H6 /H2 for 7a).
0
ArB(OH)2
Time Product Yieldb
(h)
(%)
Since the Suzuki–Miyaura reaction is tolerant of a broad
range of functional groups including hydroxyl group,68–71
the biphenyl synthesis from 7 or 8 was realized without
the protection of the benzyl alcohol.
B(OH)2
8
7a
7a
8a
8a
20
4ah
4ai
95
MeO
OMe
OMe
MeO
MeO
B(OH)2
B(OH)2
The optimized reaction conditions have been determined by
coupling 7a with 2-chlorophenylboronic acid, 4-fluorophe-
nylboronicacid, andthestericallyhindered2,3,4-trimethoxy-
phenylboronic acid. The best results were obtained with
2.5 equiv of boronic acid in the presence of CsF (7.5 equiv)
and Pd(OAc)2 (10%) in DMF at 85 ꢁC for 20 h (Scheme 3).
DMF was chosen since the substrates 7 and 8 exhibit poor
solubility in other solvent systems. The results of the parallel
Suzuki–Miyaura coupling (Quest 210Ò) from 7a with a vari-
ety of phenylboronic acids are summarized in Table 2.
9
20
20
20
66
72
63
10
11
4ca
4cb
MeO
MeO
MeO
B(OH)2
B(OH)2
Table 2
Entrya Substrate
ArB(OH)2
Time Product Yieldb
12
7b
5
4ba
70f
(h)
(%)
Cl
B(OH)2
B(OH)2
F
1
2
7a
7a
20
4aa
4ab
59c
13
14
7b
7b
5
5
4bb
4bc
79
81
Cl
B(OH)2
B(OH)2
20
67d
MeO
Cl
OMe
OMe
B(OH)2
MeO
MeO
B(OH)2
B(OH)2
15
16
7b
5
4bd
67
3
4
5
6
7
7a
7a
7a
7a
7a
20
20
20
20
20
4ac
4ad
4ae
4af
4ag
67e
82
81
85
Cl
B(OH)2
8b
8b
5
5
4da
4db
75
59
F
MeO
B(OH)2
MeO
MeO
B(OH)2
17
F
B(OH)2
B(OH)2
a
ArB(OH)2 (2.5 equiv), Pd(OAc)2 (10%), CsF (10 equiv), DMF, 85 ꢁC.
Isolated yields with purity>95% after workup (i.e., extraction and silica
pad filtration).
Triphenyl (11%), starting material (15%) (HPLC/LC–MS analysis).
Triphenyl (15%), tetraphenyl (2%), starting material (11%) (HPLC/LC–
MS analysis).
b
F3C
Me2N
c
d
18
e
f
Triphenyl (25%), tetraphenyl (4%) (HPLC/LC–MS analysis).
Polyphenyls (e), starting material (10%).
(continued)

11770
M. Dorbec et al. / Tetrahedron 62 (2006) 11766–11781
Cross-coupling of 7a with halogenated phenylboronic acids
provided biaryls 4aa–ae in 59–82% yields (entries 1–5). In
addition, triphenyl and tetraphenyl derivatives resulting
from successive Suzuki coupling of 4aa and 4ab with the
corresponding chlorophenylboronic acid were formed in low
yields. The electron-deficient 4-(trifluoromethyl)phenyl-
boronic acid afforded biaryl 4af in 85% yield (entry 6).
Surprisingly, the reaction of the electron-rich 4-(dimethyl-
amino)phenylboronic acid gave low conversion of 7a (entry
7). In contrast, 4-methoxyphenylboronic acid furnished the
biaryl 4ah in 95% yield (entry 8). Sterically hindered
2,3,4-trimethoxyphenylboronic acid was also reactive and
the desired product 4ai was isolated in 66% (entry 9). An at-
tempt to couple this boronic acid with 7a failed using K2CO3
as base and a shorter reaction time, this is likely due to the
formation of the deprotoboranation product under these con-
ditions.72 Suzuki reaction of 8a with 4-methoxyphenyl-
boronic and 2,3,4-trimethoxyphenylboronic acids gave the
corresponding biaryls 4ca (72%) and 4cb (63%). The Suzuki
coupling proceeds faster from the substrates 7b and 8b with
some representative boronic acids. Indeed, the biaryls 4ba–
bd (67–81%) and 4da and 4db (59 and 75%) were obtained
in good yields after 5 h. This observation suggests that the
stereochemistry of the alcohol at C-4 may exert an influence
on the kinetic of the coupling reaction.
spectrometer. Optical rotations were measured with Per-
kin–Elmer 241 polarimeter. Mass spectra were recorded on
a Nermag R10-10C.
4.2. Preparation of the methyl ester of thuriferic acid 3
4.2.1. Podophyllotoxone. To a solution of podophyllotoxin
(5, 8.05 g, 19.4 mmol) in anhydrous dichloromethane was
added pyridinium chlorochromate (6.55 g, 30.4 mmol).
The mixture was stirred at room temperature for 2 h, then fil-
tered on Celite and washed with distilled water. The organic
layer was dried with MgSO4, filtered, and concentrated
under reduced pressure. The residue was purified by silica
gel column (cyclohexane/ethyl acetate 3/2) to give podo-
phyllotoxone (80%) as a white solid. Spectral and physical
properties were identical to those described in Ref. 29.
4.2.2. Methyl ester of thuriferic acid 2. To a solution of
podophyllotoxone (7.74 g, 18.8 mmol) in t-BuOH (280 mL)
was added t-BuOK (19 mmol). The mixture was stirred at re-
flux for 2.5 h under nitrogen atmosphere. The solvent was
then removed in vacuo and the residue was dissolved in
DMF. Iodomethane (6.60 mL, 0.1 mol) and NaHCO3 were
added to the mixture, which was stirred at room temperature
for 24 h. The reaction mixture was quenched with water
(250 mL). The aqueous layer was extracted with ethyl ace-
tate (3ꢃ300 mL) and the combined organic layers were
washed with water and brine (300 mL), dried with MgSO4,
filtered, and concentrated under reduced pressure. The
residue was purified by silica gel column (cyclohexane/ethyl
acetate 1/1) to yield 2 (95%) as a off-white solid. Spectral
and physical properties of 2 were identical to those described
in Refs. 25 and 73.
3. Conclusion
We have synthesized two small libraries of N-aryl g-lactam
lignans and N-biaryl g-lactam lignans based on the 1-aryl-
tetralin privileged structure with parallel solution-phase
methodologies. In particular, the above-descripted proce-
dure catalyzed by indium(III) chloride represents an efficient
synthesis of N-aryl picropodophyllone g-lactams from the
methyl ester of thuriferic acid via tandem aza-Michael addi-
tion–cyclization reaction of anilines. We are currently exam-
ining the biological activity of these compounds as well as
the preparation of larger and more diverse 1-aryltetralin-
based libraries.
4.3. Representative experimental procedure for tandem
addition–cyclization catalyzed by InCl3
To a 10 mL Quest 210 Teflon reaction vessel was added a
solution of the methyl ester of thuriferic acid 2 (50 mg,
0.117 mmol) in DCE (3 mL) followed by InCl3 (13 mg,
0.058 mmol) and 4-bromoaniline (101 mg, 0.585 mmol,
5 equiv). The solution was stirred for 48 h at 80 ꢁC. Chloro-
sulfonyl resin (560 mg, 12 equiv) and Et3N (0.25 mL,
15 equiv) were added and the reaction mixture was stirred
for 24 h at 60 ꢁC in order to scavenge excess of aniline. Fil-
tration and evaporation of the solvent under reduced pressure
afforded a residue, which was purified by filtration on silica
pad(H3.5 cm, Ø1.7 cm)withcyclohexanethencyclohexane/
EtOAc gradient [9/1 to 2/8] to give 62 mg (94%) of 3a.
4. Experimental
4.1. General
Reactions were carried out in dried glassware under an argon
atmosphere and parallel synthesis with the Quest 210Ò
(Argonaut Technologies) in dried Teflon reactors. All com-
mercial reagents were used without purification, and all sol-
vents were reaction grade and dried over molecular sieves.
THF was freshly distilled from sodium/benzophenone under
argon and dichloromethane from phosphorus pentoxide. All
reaction mixtures were stirred magnetically and monitored
by thin-layer chromatography using Merck silica gel 60
F256, visualized with UV light, and then developed by using
Merck silica gel 60 (230–400 mesh). 1H NMR and 13C NMR
spectra (1D and 2D) were recorded on a Bruker AM 300
spectrometer. Deuteriated chloroform was used as the
solvent, and chemical shift values (d) are reported in parts
per million relative to the residual signals of this solvent (d
7.26 for 1H, d 77.0 for 13C). Melting points were determined
with Electrothermal (Digital Melting Point Apparatus).
Infrared spectra were recorded on a Perkin–Elmer 1710
4.3.1. (1R,2S,3R)-N-(4-Bromophenyl)-picropodophyl-
lone-cis-g-lactam 3a.
O
O
N
Br
O
O
MeO
OMe
OMe
White solid; 62 mg; yield: 94%; mp: 143–145 ꢁC; [a]D20
ꢂ252 (c 0.25, CHCl3); IR 3014, 2980–2900, 1702, 1668,

M. Dorbec et al. / Tetrahedron 62 (2006) 11766–11781
11771
1591, 1505, 1481 cmꢂ1; 1H NMR (300 MHz, CDCl3): d 7.43
4.24 (d, J¼9.7 Hz, 1H, H11a), 3.96 (m, J¼9.8, 6.3 Hz, 1H,
0 0 0
00
(m, 5H, H5, H2 , H3 , H5 , H6 ), 6.72 (s, 1H, H8), 6.27 (s, 2H,
00
00
00
H11b), 3.81 (s, 3H, OMe(4 )), 3.76 (s, 6H, OMe(3 ,5 )), 3.33
(dd, J¼7.5, 1.7 Hz, 1H, H2), 3.21 (m, 1H, H3), 2.36 (s, 3H,
Ph-Me); 13C NMR (75 MHz, CDCl3): d 194.8 (C4), 171.7
0
0
H2 , H6 ), 6.03 (m, 2H, OCH2O), 4.79 (d, J¼1.6 Hz, 1H, H1),
4.24 (d, J¼9.7 Hz, 1H, H11a), 3.95 (dd, J¼9.7, 6.3 Hz, 1H,
0
0
0
0 0
(C13), 153.7 (C7), 153.6 (C3 , C5 ), 148.2 (C6), 139.9 (C9),
H11b), 3.81 (s, 3H, OMe(4 )), 3.76 (s, 6H, OMe(3 ,5 )), 3.34
(dd, J¼7.5, 1.6 Hz, 1H, H2), 3.23 (m, 1H, H3); 13C NMR
0
00
00
0
138.6 (C1 ), 138.5 (C1 ), 138.0 (C3 ), 137.0 (C4 ), 132.5
0
(75 MHz, CDCl3): d 194.7 (C4), 171.7 (C13), 153.7 (C3 ,
00 00 00 00
(C5 ), 127.2 (C10), 121.8 (C2 ), 120.4 (C4 ), 118.4 (C6 ),
0
C5 ), 153.6 (C7), 148.2 (C6), 139.9 (C9), 138.6 (C1 ), 137.9
0
0 0
109.5 (C8), 105.9 (C5), 104.8 (C2 , C6 ), 102.1 (OCH2O),
00
(C1 ), 137.1 (C4 ), 131.8 (C3 , C5 ), 127.2 (C10), 121.0
0
00
00
0
0
0
60.8 (OMe(4 )), 56.2 (OMe(3 ,5 )), 51.0 (C11), 50.5 (C2),
43.1 (C1), 40.0 (C3), 23.1 (Ph-Me); HRMS (DCI/NH3): calcd
for C29H27NO7Br 580.0971 and 582.0956, found 580.0970
and 582.0954.
00
00
(C2 , C6 ), 117.8 (C4 ), 109.5 (C8), 105.9 (C5), 104.8 (C2 ,
00
0
0
0
0
0
C6 ), 102.1 (OCH2O), 60.8 (OMe(4 )), 56.2 (OMe(3 ,5 )),
50.9 (C11), 50.5 (C2), 43.1 (C1), 39.9 (C3); HRMS (DCI/
NH3): calcd for C28H25BrNO7 566.0814 and 568.0799,
found 566.0809 and 568.0798.
4.3.4. (1R,2S,3R)-N-(4-Chlorophenyl)-picropodophyl-
lone-cis-g-lactam 3d.
4.3.2. (1R,2S,3R)-N-(3-Bromophenyl)-picropodophyl-
lone-cis-g-lactam 3b.
O
O
N
Cl
O
Br
O
O
N
O
O
O
MeO
OMe
OMe
MeO
OMe
White solid; 56 mg; yield: 91%; mp: 138–140 ꢁC; [a]D20
ꢂ211 (c 0.22, CHCl3); IR 3012, 2960–2900, 1702, 1671,
OMe
White solid; 60 mg; yield: 91%; mp: 128–130 ꢁC; [a]D20
ꢂ187 (c 0.17, CHCl3); IR (CHCl3) 3028, 3012, 2970–
1592, 1495, 1481 cmꢂ1
;
1H NMR (300 MHz, CDCl3):
00
00
d 7.50 (d, J¼9 Hz, 2H, H2 , H6 ), 7.45 (s, 1H, H5), 7.27 (d,
2900, 1704, 1669, 1592, 1506, 1480 cmꢂ1
;
1H NMR
00
00
0
J¼9 Hz, 2H, H3 , H5 ), 6.70 (s, 1H, H8), 6.26 (s, 2H, H2 ,
00
0
(300 MHz, CDCl3): d 7.79 (d, J¼1.7 Hz, 1H, H2 ), 7.46
H6 ), 6.00 (m, 2H, OCH2O), 4.79 (d, J¼1.7 Hz, 1H, H1),
00
(dd, J¼8.0, 1.7 Hz, 1H, H6 ), 7.45 (s, 1H, H5), 7.24 (m,
4.23 (d, J¼9.7 Hz, 1H, H11a), 3.95 (dd, J¼9.7, 6.3 Hz, 1H,
00
00
0
0
0
1H, H4 ), 7.16 (t, J¼8 Hz, 1H, H5 ), 6.70 (s, 1H, H8), 6.26
H11b), 3.79 (s, 3H, OMe(4 )), 3.74 (s, 6H, OMe(3 ,5 )), 3.34
(dd, J¼7.5, 1.7 Hz, 1H, H2), 3.21 (m, 1H, H3); 13C NMR
(75 MHz, CDCl3): d 194.8 (C4), 171.7 (C13), 153.7 (C7),
0
0
(s, 2H, H2 , H6 ), 6.01 (m, 2H, OCH2O), 4.79 (d, J¼1.6 Hz,
1H, H1), 4.26 (d, J¼9.7 Hz, 1H, H11a), 3.96 (dd, J¼9.7,
0
6.3 Hz, 1H, H11b), 3.81 (s, 3H, OMe(4 )), 3.76 (s, 6H,
0
153.6 (C3 , C5 ), 148.2 (C6), 139.9 (C9), 138.6 (C1 ), 137.4
0
0
0
0
00
(C1 ), 137.0 (C4 ), 130.0 (C4 ), 128.9 (C3 , C5 ), 127.2
0
00
00
00
OMe(3 ,5 )), 3.35 (dd, J¼7.5, 1.6 Hz, 1H, H2), 3.23 (m, 1H,
H3); 13C NMR (75 MHz, CDCl3): d 194.6 (C4), 171.8
00
00
(C10), 120.7 (C2 , C6 ), 109.5 (C8), 105.9 (C5), 104.8 (C2 ,
0
0
(C13), 153.7 (C7), 153.6 (C3 , C5 ), 148.2 (C6), 140.1 (C1 ),
0
00
0
0
0
0
C6 ), 102.1 (OCH2O), 60.8 (OMe(4 )), 56.2 (OMe(3 ,5 )),
50.9 (C11), 50.5 (C2), 43.1 (C1), 39.9 (C3); HRMS (DCI/
NH3): calcd for C28H25ClNO7 522.1320 and 524.1305,
found 522.1318 and 524.1311.
0
0
139.9 (C9), 138.5 (C1 ), 137.1 (C4 ), 130.1 (C5 ), 127.8
00
00
(C4 ), 127.2 (C10), 122.6 (C3 ), 122.5 (C2 ), 117.8 (C6 ),
00
00
00
0
109.5 (C8), 105.9 (C5), 104.8 (C2 , C5 ), 102.1 (OCH2O),
0
0
0
0
60.8 (OMe(4 )), 56.2 (OMe(3 ,5 )), 50.9 (C11), 50.5 (C2), 43.1
(C1), 39.9 (C3); HRMS (DCI/NH3): calcd for C28H25BrNO7
566.0814 and 568.0799, found 566.0803 and 568.0794.
4.3.5. (1R,2S,3R)-N-(3-Chlorophenyl)-picropodophyl-
lone-cis-g-lactam 3e.
4.3.3. (1R,2S,3R)-N-(3-Bromo-4-methyl-phenyl)-picro-
podophyllone-cis-g-lactam 3c.
O
Cl
O
N
O
O
Me
O
O
N
Br
MeO
OMe
O
OMe
O
White solid; 46 mg; yield: 76%; mp: 124–126 ꢁC; [a]D20
ꢂ124 (c 0.32, CHCl3); IR (CHCl3) 3036, 2978–2900,
MeO
OMe
OMe
1
1706, 1671, 1594, 1505, 1481 cmꢂ1; H NMR (300 MHz,
White solid; 58 mg; yield: 85%; mp: 121–123 ꢁC; [a]D20
ꢂ230 (c 0.18, CHCl3); IR (CHCl3) 2940, 1699, 1669,
CDCl3): d 7.68 (t, J¼1.8 Hz, 1H, H2 ), 7.47 (s, 1H, H5),
00
00
7.43 (dd, J¼8.2, 1.0 Hz, 1H, H6 ), 7.25 (t, J¼8.2 Hz, 1H,
1592, 1506, 1481 cmꢂ1
d 7.46 (m, 1H, H5), 7.44 (m, 2H, H2 , H5 ), 7.24 (dd,
;
1H NMR (300 MHz, CDCl3):
H5 ), 7.11 (dd, J¼8.2, 1.0 Hz, 1H, H4 ), 6.72 (s, 1H, H8),
00
00
00
00
0 0
6.30 (s, 2H, H2 , H6 ), 6.02 (m, 2H, OCH2O), 4.80 (d,
00
0
J¼8.3, 2.5 Hz, 1H, H6 ), 6.72 (s, 1H, H8), 6.27 (s, 2H, H2 ,
J¼1.7 Hz, 1H, H1), 4.27 (d, J¼9.7 Hz, 1H, H11a), 3.97
0
0
H6 ), 6.03 (m, 2H, OCH2O), 4.79 (d, J¼1.7 Hz, 1H, H1),
(dd, J¼9.7, 6.4 Hz, 1H, H11b), 3.81 (s, 3H, OMe(4 )), 3.76

11772
M. Dorbec et al. / Tetrahedron 62 (2006) 11766–11781
0
0
0 0 00
139.9 (C9), 138.7 (C1 ), 137.1 (C4 ), 136.4 (C1 ), 134.6
(s, 6H, OMe(3 ,5 )), 3.35 (dd, J¼7.5, 1.7 Hz, 1H, H2), 3.23 (m,
1H, H3); 13C NMR (75 MHz, CDCl3): d 194.7 (C4), 171.9
00
00
00
00
00
(C4 ), 127.5 (C3 , C5 ), 127.3 (C10), 120.1 (C2 , C6 ),
0
(C13), 153.7 (C7), 153.6 (C3 , C5 ), 148.2 (C6), 139.9 (C9),
0
0 0
109.6 (C8), 105.9 (C5), 104.8 (C2 , C6 ), 102.1 (OCH2O),
00
0
0
00
139.8 (C1 ), 138.5 (C1 ), 137.0 (C4 ), 134.6 (C3 ), 129.8
0
0
0
60.8 (OMe(4 )), 56.2(OMe(3 ,5 )), 51.0 (C11), 50.5 (C2), 43.2
(C1), 40.1 (C3), 16.4 (S-Me); HRMS (DCI/NH3): calcd for
C29H28NO7S 534.1586, found 534.1591.
00
(C5 ), 127.2 (C10), 124.9 (C4 ), 119.7 (C2 ), 117.3 (C6 ),
0
109.5 (C8), 105.9 (C5), 104.7 (C2 , C6 ), 102.1 (OCH2O),
00
00
00
0
0
0
0
60.8 (OMe(4 )), 56.2 (OMe(3 ,5 )), 50.9 (C11), 50.5 (C2),
43.1 (C1), 39.9 (C3); HRMS (DCI/NH3): calcd for
C28H25ClNO7 522.1320 and 524.1305, found 522.1312
and 524.1312.
4.3.8. (1R,2S,3R)-N-(4-Phenoxyphenyl)-picropodophyl-
lone-cis-g-lactam 3h.
O
4.3.6. (1R,2S,3R)-N-(4-Fluorophenyl)-picropodophyl-
lone-cis-g-lactam 3f.
O
N
O
O
O
O
O
MeO
OMe
N
F
OMe
O
O
Off-white solid; 48 mg; yield: 71%; mp: 218–220 ꢁC; [a]D20
ꢂ113 (c 0.22, CHCl3); IR (CHCl3) 3025, 2970–2900, 1696,
1670, 1591, 1507, 1481 cmꢂ1; 1H NMR (300 MHz, CDCl3):
MeO
OMe
OMe
00
00
d 7.50 (d, J¼9 Hz, 2H, H2 , H6 ), 7.48 (s, 1H, H5), 7.29 (m,
White solid; 50 mg; yield: 85%; mp: 127–129 ꢁC; [a]D20
ꢂ202 (c 0.23, CHCl3); IR 3022, 3011, 2970–2900, 1699,
2H, H3 , H5 ), 7.07 (t, J¼7.5 Hz, 1H, H4 ), 6.97 (m, 4H, H3 ,
00
00
000
00
00
000
000
0
0
H5 , H2 , H6 ), 6.72 (s, 1H, H8), 6.28 (s, 2H, H2 , H6 ), 6.01
(m, 2H, OCH2O), 4.81 (d, J ¼1.6 Hz, 1H, H1), 4.25 (d,
J¼9.7 Hz, 1H, H11a), 3.97 (dd, J¼9.7, 6.3 Hz, 1H, H11b),
1668, 1592, 1510, 1481 cmꢂ1
;
1H NMR (300 MHz,
CDCl3): d 7.49 (m, 2H, H2 , H6 ), 7.46 (s, 1H, H5), 7.00 (t,
00
00
00
00
0
0
0
0
J¼8.6 Hz, 2H, H3 , H5 ), 6.71 (s, 1H, H8), 6.27 (s, 2H, H2 ,
3.81 (s, 3H, OMe(4 )), 3.76 (s, 6H, OMe(3 ,5 )), 3.35 (dd,
J¼7.4, 1.6 Hz, 1H, H2), 3.23 (m, 1H, H3); 13C NMR
0
H6 ), 6.01 (m, 2H, OCH2O), 4.79 (d, 1.6 Hz, 1H, H1), 4.23
000
(75 MHz, CDCl3): d 195.0 (C4), 171.5 (C13), 157.3 (C1 ),
(d, J¼9.7 Hz, 1H, H11a), 3.96 (dd, J¼9.7, 6.3 Hz, 1H,
0
0
0
00 0 0
154.0 (C4 ), 153.6 (C3 , C5 , C7), 148.2 (C6), 139.9 (C9),
000
138.7 (C1 ), 136.9 (C4 ), 134.3 (C1 ), 129.7 (C3 , C5 ),
000
127.3 (C10), 123.2 (C4 ), 121.3 (C2 , C6 ), 119.3 (C2 ,
H11b), 3.80 (s, 3H, OMe(4 )), 3.75 (s, 6H, OMe(3 ,5 )), 3.34
(dd, J¼7.5, 1.6 Hz, 1H, H2), 3.21 (m, 1H, H3); 13C NMR
(75 MHz, CDCl3): d 194.9 (C4), 171.6 (C13), 161.4 (d,
0
0
00
000
00
00
000
00
0
0
000 00 00 0
C6 ), 118.5 (C3 , C5 ), 109.5 (C8), 105.9 (C5), 104.8 (C2 ,
J¼249 Hz, C4 ), 153.7 (C7), 153.6 (C3 , C5 ), 148.2 (C6),
0
139.9 (C9), 138.7 (C1 ), 137.0 (C4 ), 135.0 (C1 ), 127.3
0
00
0
0
0
0
C6 ), 102.0 (OCH2O), 60.8 (OMe(4 )), 56.1 (OMe(3 ,5 )),
51.3 (C11), 50.4 (C2), 43.2 (C1), 40.1 (C3); HRMS (DCI/
NH3): calcd for C34H30NO8 580.1971, found 580.1968.
00
00
(C10), 121.5 (d, J¼7.5 Hz, C2 , C6 ), 115.6 (d, J¼22.5 Hz,
00
00
0
0
C3 , C5 ), 109.6 (C8), 105.9 (C5), 104.8 (C2 , C6 ), 102.1
0
0
0
(OCH2O), 60.8 (OMe(4 )), 56.2 (OMe(3 ,5 )), 51.3 (C11),
50.4 (C2), 43.2 (C1), 40.1 (C3); MS (DCI/NH3): 506
[M+H]+, 523 [M+NH4]+.
4.3.9. (1R,2S,3R)-N-(4-Methoxyphenyl)-picropodophyl-
lone-cis-g-lactam 3i.
4.3.7. (1R,2S,3R)-N-(4-Thiomethylphenyl)-picropodo-
phyllone-cis-g-lactam 3g.
O
O
N
OMe
O
O
O
O
N
SMe
MeO
OMe
O
OMe
O
Off-white solid; 54 mg; yield: 90%; mp: 124–126 ꢁC; [a]D20
ꢂ246 (c 0.18, CHCl3); IR (CHCl3) 3022, 3016, 2965–2900,
MeO
OMe
OMe
1
1694, 1670, 1592, 1512, 1481 cmꢂ1; H NMR (300 MHz,
Off-white solid; 51 mg; yield: 82%; mp: 120–122 ꢁC; [a]D20
ꢂ306 (c 0.16, CHCl3); IR (CHCl3) 3021, 3012, 2971–2900,
CDCl3): d 7.46 (s, 1H, H5), 7.42 (d, J¼9 Hz, 2H, H2 ,
00
00
00
00
H6 ), 6.84 (d, J¼9 Hz, 2H, H3 , H5 ), 6.71 (s, 1H, H8),
1697, 1669, 1592, 1498, 1481 cmꢂ1; H NMR (300 MHz,
1
0
0
6.27 (s, 2H, H2 , H6 ), 6.01 (m, 2H, OCH2O), 4.80 (d,
00
00
CDCl3): d 7.47 (d, J¼8.8 Hz, 2H, H3 , H5 ), 7.46 (s, 1H,
J¼1.7 Hz, 1H, H1), 4.21 (d, J¼9.8 Hz, 1H, H11a), 3.96 (dd,
00
00
0
H5), 7.21 (d, J¼8.8 Hz, 2H, H2 , H6 ), 6.71 (s, 1H, H8),
J¼9.8, 6.4 Hz, 1H, H11b), 3.80 (s, 3H, OMe(4 )), 3.76 (s,
0
0
6.28 (s, 2H, H2 , H6 ), 6.01 (m, 2H, OCH2O), 4.79 (d,
0
0
00
6H, OMe(3 ,5 )), 3.75 (s, 3H, OMe(4 )), 3.33 (dd, J¼7.4,
J¼1.6 Hz, 1H, H1), 4.23 (d, J¼9.8 Hz, 1H, H11a), 3.96 (dd,
1.7 Hz, 1H, H2), 3.20 (m, 1H, H3); 13C NMR (75 MHz,
0
00 0
CDCl3): d 195.2 (C4), 171.3 (C13), 156.8 (C4 ), 153.6 (C3 ,
0 0 0
C5 , C7), 148.1 (C6), 139.9 (C9), 138.8 (C1 ), 136.9 (C4 ),
J¼9.8, 6.4 Hz, 1H, H11b), 3.80 (s, 3H, OMe(4 )), 3.75 (s,
0
0
6H, OMe(3 ,5 )), 3.34 (dd, J¼7.5, 1.6 Hz, 1H, H2), 3.20 (m,
1H, H3), 2.43 (s, 3H, S-Me); 13C NMR (75 MHz, CDCl3):
00
132.1 (C1 ), 127.3 (C10), 121.4 (C2 , C6 ), 114.0 (C3 ,
00
00
00
0
d 195.0 (C4), 171.6 (C13), 153.6 (C3 , C5 , C7), 148.2 (C6),
0
00 0 0
C5 ), 109.5 (C8), 105.8 (C5), 104.8 (C2 , C6 ), 102.0

M. Dorbec et al. / Tetrahedron 62 (2006) 11766–11781
11773
0
0
0
00
(OCH2O), 60.8 (OMe(4 )), 56.1 (OMe(3 ,5 )), 55.4 (OMe(4 )),
51.5 (C11), 50.3 (C2), 43.2 (C1), 40.2 (C3); HRMS (DCI/
NH3): calcd for C29H28NO8 518.1815, found 518.1807.
4.3.12. (1R,2S,3R)-N-Indan-5-yl-picropodophyllone-cis-
g-lactam 3l.
O
4.3.10. (1R,2S,3R)-N-(3,4,5-Trimethoxyphenyl)-picro-
podophyllone-cis-g-lactam 3j.
O
N
O
O
O
OMe
O
MeO
OMe
N
OMe
OMe
OMe
O
O
Off-white solid; 50 mg; yield: 81%; mp: 114–116 ꢁC; [a]D20
ꢂ258 (c 0.20, CHCl3); IR (CHCl3) 3029, 3012, 2973–2900,
MeO
OMe
1
1695, 1669, 1592, 1505, 1481 cmꢂ1; H NMR (300 MHz,
OMe
00
CDCl3): d 7.46 (s, 1H, H5), 7.40 (d, J¼1.5 Hz, 1H, H4 ),
Pale yellow solid; 61 mg; yield: 90%; mp: 125–127 ꢁC; [a]D20
ꢂ244 (c 0.16, CHCl3); IR 3023, 3010, 2970–2900, 1698,
00
7.21 (dd, J¼8.2, 1.5 Hz, 1H, H6 ), 7.15 (d, J¼8.2 Hz, 1H,
00
0
0
H7 ), 6.72 (s, 1H, H8), 6.28 (s, 2H, H2 , H6 ), 6.01 (m, 2H,
OCH2O), 4.81 (d, J¼1.6 Hz, 1H, H1), 4.22 (d, J¼9.8 Hz,
1H, H11a), 3.97 (dd, J¼9.8, 6.4 Hz, 1H, H11b), 3.80 (s, 3H,
1668, 1593, 1508, 1481 cmꢂ1
CDCl3): d 7.47 (s, 1H, H5), 6.87 (s, 2H, H2 , H6 ), 6.71 (s,
;
1H NMR (300 MHz,
00
00
0
1H, H8), 6.26 (s, 2H, H2 , H6 ), 6.01 (m, 2H, OCH2O), 4.78
0
0
0
0
OMe(4 )), 3.75 (s, 6H, OMe(3 ,5 )), 3.33 (dd, J¼7.4, 1.6 Hz,
(d, J¼1.3 Hz, 1H, H1), 4.28 (d, J¼9.7 Hz, 1H, H11a), 3.95
00
00
1H, H2), 3.19 (m, 1H, H3), 2.84 (m, 4H, H1 , H3 ), 2.04
00
(m, 2H, H2 ); 13C NMR (75 MHz, CDCl3): d 195.2 (C4),
00 00
(dd, J¼9.7, 6.4 Hz, 1H, H11b), 3.84 (s, 6H, OMe(3 ,5 )),
0
3.81 (s, 3H, OMe(4 )), 3.76 (s, 6H, OMe(4 )), 3.74 (s, 6H,
00
0
171.4 (C13), 153.6 (C3 , C5 , C7), 148.1 (C6), 145.1 (C3a ),
0
00
0
0
OMe(3 ,5 )), 3.35 (dd, J¼7.4, 1.3 Hz, 1H, H2), 3.20 (m, 1H,
00
141.1 (C7a ), 140.0 (C9), 138.8 (C1 ), 137.1 (C5 ), 137.0
0
00
H3); 13C NMR (75 MHz, CDCl3): d 194.8 (C4), 171.7
0
(C4 ), 127.4 (C10), 124.4 (C7 ), 118.0 (C6 ), 116.5 (C4 ),
00
00
00
0
(C13), 153.7 (C3 , C5 , C7), 153.2 (C3 , C5 ), 148.2 (C6),
0
00
00
0
109.5 (C8), 105.8 (C5), 104.8 (C2 , C6 ), 102.0 (OCH2O),
0
60.8 (OMe(4 )), 56.1 (OMe(3 ,5 )), 51.7 (C11), 50.4 (C2),
0
0
139.9 (C9), 138.7 (C1 ), 137.1 (C4 ), 135.6 (C4 ), 135.0
0
00
0
0
00
(C1 ), 127.2 (C10), 109.6 (C8), 105.9 (C5), 104.9 (C2 , C6 ),
0
0
00
00
00
43.2 (C1), 40.2 (C3), 33.0 (C3 ), 32.3 (C1 ), 25.6 (C2 );
HRMS (DCI/NH3): calcd for C31H30NO7 528.2022, found
528.2028.
00
00
102.1 (OCH2O), 97.6 (C2 , C6 ), 60.9 (OMe), 60.8 (OMe),
0
0
00 00
56.2 (OMe(3 ,5 ,3 ,5 )), 51.3 (C11), 50.7 (C2), 43.2 (C1), 39.8
(C3); HRMS (DCI/NH3): calcd for C31H32NO10 578.2026,
found 578.2021.
4.3.13. (1R,2S,3R)-N-(3,4-Methylenedioxyphenyl)-picro-
podophyllone-cis-g-lactam 3m.
4.3.11. (1R,2S,3R)-N-(4-Methylphenyl)-picropodophyl-
lone-cis-g-lactam 3k.
O
O
O
O
O
N
O
O
N
Me
O
O
O
MeO
OMe
OMe
MeO
OMe
OMe
Off-white solid; 38 mg; yield: 61%; yellow powder; mp
187–190 ꢁC; [a]D20 ꢂ91 (c 0.15, CHCl3); IR 3023, 2970–
White solid; 54 mg; yield: 92%; mp: 129–130 ꢁC; [a]D20
ꢂ259 (c 0.60, CHCl3); IR (CHCl3) 3012, 2975–2900,
2900, 1714, 1672, 1597, 1505, 1480 cmꢂ1 1H NMR
;
1
1693, 1669, 1592, 1506, 1482 cmꢂ1; H NMR (300 MHz,
(400 MHz, CDCl3): d 7.47 (s, 1H, H5), 7.22 (d, J¼1.8 Hz,
00
00
00
CDCl3): d 7.47 (s, 1H, H5), 7.41 (d, J¼8.4 Hz, 2H, H2 ,
1H, H2 ), 6.78 (dd, J¼10.4, 1.8 Hz, 1H, H6 ), 6.73 (d,
00
00
00
00
0
H6 ), 7.13 (d, J¼8.4 Hz, 2H, H3 , H5 ), 6.72 (s, 1H, H8),
J¼10.4 Hz, 1H, H5 ), 6.71 (s, 1H, H8), 6.27 (s, 2H, H2 ,
0
6.28 (s, 2H, H2 , H6 ), 6.02 (m, 2H, OCH2O), 4.81 (d,
0
0
H6 ), 6.02 (m, 2H, OCH2O(6,7)), 5.92 (d, J¼1.0 Hz, 2H,
00 00
J¼1.8 Hz, 1H, H1), 4.24 (d, J¼9.9 Hz, 1H, H11a), 3.95 (dd,
OCH2O(3 ,4 )), 4.79 (d, J¼1.7 Hz, 1H, H1), 4.18 (d,
0
J¼9.9, 6.2 Hz, 1H, H11b), 3.81 (s, 3H, OMe(4 )), 3.76 (s,
J¼9.7 Hz, 1H, H11a), 3.93 (dd, J¼9.7, 6.3 Hz, 1H, H11b),
0
0
0
0
0
6H, OMe(3 ,5 )), 3.34 (dd, J¼7.5, 1.8 Hz, 1H, H2), 3.21 (m,
3.80 (s, 3H, OMe(4 )), 3.75 (s, 6H, OMe(3 ,5 )), 3.32 (dd,
J¼7.4, 1.7 Hz, 1H, H2), 3.19 (dd, J¼7.4, 6.3 Hz, 1H, H3);
13C NMR (75 MHz, CDCl3): d 195.1 (C4), 171.4 (C13),
1H, H3), 2.30 (s, 3H, Ph-Me); 13C NMR (75 MHz,
0
CDCl3): d 195.2 (C4), 171.5 (C13), 153.7 (C7, C3 , C5 ),
0
0
148.1 (C6), 139.9 (C9), 138.8 (C1 ), 136.9 (C4 ), 136.4
0
0 0 00
153.6 (C7), 153.5 (C3 , C5 ), 148.2 (C6), 147.8 (C3 ), 144.8
00
00
00
(C1 ), 134.6 (C4 ), 129.4 (C3 , C5 ), 127.3 (C10), 119.7
00
00
(C4 ), 139.2 (C1 ), 138.8 (C1 ), 136.9 (C4 ), 133.2 (C9),
0
00
0
00
(C2 , C6 ), 109.5 (C8), 105.9 (C5), 104.7 (C2 , C6 ), 102.0
00
0
0
00
00
127.3 (C10), 112.9 (C6 ), 109.5 (C8), 107.9 (C5 ), 105.8
0
0
0
0 0 00
(C5), 104.7 (C2 , C6 ), 102.6 (C2 ), 102.1 (OCH2O(6,7)),
(OCH2O), 60.8 (OMe(4 )), 56.1 (OMe(3 ,5 )), 51.2 (C11),
50.4 (C2), 43.2 (C1), 40.1 (C3), 20.8 (Ph-Me); HRMS
(DCI/NH3): calcd for C29H28NO7 502.1866, found
502.1865.
00 00
0
0
0
101.3 (OCH2O(3 ,4 )), 60.8 (OMe(4 )), 56.1 (OMe(3 ,5 )),
51.8 (C11), 50.3 (C2), 43.2 (C1), 40.1 (C3); MS (ES+): 532
[M+H]+, 554 [M+Na]+.

11774
M. Dorbec et al. / Tetrahedron 62 (2006) 11766–11781
4.4. Representative experimental procedure for
sequential one-pot addition–cyclization catalyzed
by InCl3
Yellow solid; 31 mg; yield: 50%; yellow powder; mp 235–
240 ꢁC; [a]D20 ꢂ110 (c 0.34, CHCl3); IR 3020, 2970–2900,
1
1713, 1670, 1596, 1504, 1481 cmꢂ1; H NMR (400 MHz,
00
00
CDCl3): d 8.22 (d, J¼9.3 Hz, 2H, H3 , H5 ), 7.79 (d,
00
00
To a 10 mL Quest 210 Teflon reaction vessel was added a
solution of the methyl ester of thuriferic acid 2 (50 mg,
0.117 mmol) in DCE (3 mL) followed by InCl3 (13 mg,
0.058 mmol) and 2-aminofluorene (106 mg, 0.585 mmol,
5 equiv). The solution was stirred for 48 h at 80 ꢁC and
then DBU (88 mL, 0.585 mmol) was added and the solution
was stirred for 24 h at 80 ꢁC. Chlorosulfonyl resin (560 mg,
12 equiv) and Et3N (0.25 mL, 15 equiv) were added and the
reaction mixture was stirred for 24 h at 60 ꢁC in order to
scavenge excess of aniline. Filtration and evaporation of
the solvent under reduced pressure gave a residue, which
was purified by filtration on silica pad with cyclohexane
then cyclohexane/EtOAc gradient [9/1 to 2/8] to furnish
44 mg (66%) of 3n.
J¼9.3 Hz, 2H, H2 , H6 ), 7.48 (s, 1H, H5), 6.73 (s, 1H,
0 0
H8), 6.27 (s, 2H, H2 , H6 ), 6.04 (m, 2H, OCH2O), 4.81 (d,
J¼1.7 Hz, 1H, H1), 4.38 (d, J¼9.7 Hz, 1H, H11a), 4.01 (m,
0
0
0
1H, H11b), 3.81 (s, 3H, OMe(4 )), 3.76 (s, 6H, OMe(3 ,5 )),
3.40 (dd, J¼7.6, 1.7 Hz, 1H, H2), 3.29 (m, 1H, H3); 13C
NMR (75 MHz, CDCl3): d 193.9 (C4), 172.3 (C13), 153.7
0
(C7), 153.5 (C3 , C5 ), 148.2 (C6), 144.1 (C1 ), 143.6 (C4 ),
0
00
00
0
0
139.6 (C9), 138.1 (C1 ), 137.0 (C4 ), 126.9 (C10), 124.5
00
00
00
00
(C2 , C6 ), 118.6 (C3 , C5 ), 109.3 (C8), 105.8 (C5), 104.6
0
0
0
0
0
(C2 , C6 ), 102.0 (OCH2O), 60.6 (OMe(4 )), 56.0 (OMe(3 ,5 )),
50.5 (C2), 43.3 (C11), 42.9 (C1), 39.5 (C3); MS (DCI/NH3):
533 [M+H]+, 550 [M+NH4]+.
4.5. Reduction procedures of bromo N-aryl lactam
lignans
4.4.1. (1R,2S,3R)-N-Fluoren-2-yl-picropodophyllone-cis-
g-lactam 3n.
4.5.1. (1R,2S,3R,4R)-N-(4-Bromophenyl)-picropodo-
phyllin-cis-g-lactam 7a.
O
O
N
O
OH
O
N
Br
O
O
O
MeO
OMe
OMe
MeO
OMe
OMe
Yellow solid; 44 mg; yield: 66%; mp: 139–141 ꢁC; [a]D20
ꢂ227 (c 0.19, CHCl3); IR (CHCl3) 3026, 3014, 2974–
To a mixture of 3a (247 mg, 0.436 mmol) in THF (4 mL)
was added MeOH (4 mL). The solution was cooled to
ꢂ78 ꢁC and NaBH4 (25 mg, 0.654 mmol) was added. The
reaction mixture was removed from the cold bath and was
stirred for 3 h, water was added and the mixture was
extracted with EtOAc. The organic layer was washed with
brine, dried over MgSO4, filtered, and concentrated under re-
duced pressure. The crude product was purified by silica gel
chromatography (cyclohexane/EtOAc 3/2) and recrystal-
lized from cyclohexane and EtOAc to yield 186 mg (75%)
of 7a as a white solid.
2900, 1696, 1668, 1592, 1505, 1481 cmꢂ1
;
1H NMR
00
(300 MHz, CDCl3): d 7.82 (d, J¼2.0 Hz, 1H, H1 ), 7.72
00
(m, 2H, H4 , H5 ), 7.51 (m, 1H, H8 ), 7.49 (s, 1H, H5),
00
00
00
00
7.48 (m, 1H, H3 ), 7.35 (t, J¼7.2 Hz, 1H, H6 ), 7.27 (dt,
00
0
J¼7.2, 1.2 Hz, 1H, H7 ), 6.74 (s, 1H, H8), 6.30 (s, 2H, H2 ,
0
H6 ), 6.03 (m, 2H, OCH2O), 4.84 (d, J¼1.8 Hz, 1H, H1),
4.34 (d, J¼9.8 Hz, 1H, H11a), 4.06 (dd, J¼9.8, 6.3 Hz, 1H,
00
H11b), 3.87 (s, 2H, H9 ), 3.82 (s, 3H, OMe(4 )), 3.77 (s, 6H,
0
0
0
OMe(3 ,5 )), 3.39 (dd, J¼7.5, 1.8 Hz, 1H, H2), 3.25 (dd,
J¼7.5, 6.3 Hz, 1H, H3); 13C NMR (75 MHz, CDCl3):
0
d 195.1 (C4), 171.7 (C13), 153.6 (C7, C3 , C5 ), 148.2 (C6),
0
0
0
00
0
144.0 (C9a ), 143.2 (C8a ), 141.2 (C4b ), 139.9 (C1 ), 138.8
Compound 7a: 186 mg; yield: 75%; mp: 228–230 ꢁC; [a]D20
ꢂ69 (c 0.25, CHCl3); IR (CHCl3) 3500–3300, 3008, 2960–
00
(C9), 138.6 (C2 ), 137.7 (C4a ), 136.9 (C4 ), 127.3 (C10),
00
0
00
00
00
00
126.8 (C7 ), 126.6 (C6 ), 125.0 (C8 ), 120.0 (C4 ), 119.7
1
2900, 1695, 1592, 1504, 1483 cmꢂ1; H NMR (300 MHz,
00
(C5 ), 118.4 (C3 ), 116.9 (C1 ), 109.6 (C8), 105.9 (C5),
0
104.7 (C2 , C6 ), 102.1 (OCH2O), 60.8 (OMe(4 )), 56.2
0
(OMe(3 ,5 )), 51.5 (C11), 50.6 (C2), 43.2 (C1), 40.2 (C3),
00
37.0 (C9 ); HRMS (DCI/NH3): calcd for C35H29NO7S
576.2056, found 576.2013.
00
00
00
00
CDCl3): d 7.56 (d, J¼8.6 Hz, 2H, H2 , H6 ), 7.45 (d,
0
0
00
00
0
J¼8.6 Hz, 2H, H3 , H5 ), 7.03 (s, 1H, H5), 6.47 (s, 2H, H2 ,
0
0
H6 ), 6.37 (s, 1H, H8), 5.92 (m, 2H, OCH2O), 4.51 (t,
J¼8.0 Hz, 1H, H4), 4.20 (d, J¼4.9 Hz, 1H, H1), 3.95 (m,
0
0
0
2H, H11), 3.85 (s, 3H, OMe(4 )), 3.82 (s, 6H, OMe(3 ,5 )),
3.35 (dd, J¼9.2, 4.9 Hz, 1H, H2), 2.69 (m, 1H, H3), 2.15
(d, J¼8.0 Hz, 1H, OH); 13C NMR (75 MHz, CDCl3):
4.4.2. (1R,2S,3R)-N-(4-Nitrophenyl)-picropodophyllone-
cis-g-lactam 3o.
0
0
d 174.0 (C13), 153.5 (C3 , C5 ), 147.2 (C7), 146.8 (C6),
0
140.1 (C1 ), 138.2 (C1 ), 136.7 (C4 ), 132.2 (C9), 131.8
00
0
O
00
(C2 , C6 ), 131.1 (C10), 121.0 (C3 , C5 ), 117.5 (C4 ),
00
00
00
00
O
0
0
109.3 (C8), 105.5 (C2 , C6 ), 105.3 (C5), 101.1 (OCH2O),
N
NO2
0
0
0
O
70.2 (C4), 60.9 (OMe(4 )), 56.1 (OMe(3 ,5 )), 50.2 (C11),
48.9 (C2), 44.2 (C1), 38.7 (C3); HRMS (FAB+): calcd for
C28H26NO7Br 567.0893 and 569.0877, found 567.0886
and 569.0887; HRMS (DIC/NH3): calcd for C28H27NO7Br
568.0971 and 570.0955, found 568.0956 and 570.0966.
O
MeO
OMe
OMe

M. Dorbec et al. / Tetrahedron 62 (2006) 11766–11781
11775
4.5.2. (1R,2S,3R,4S)-N-(4-Bromophenyl)-epipicropodo-
phyllin-cis-g-lactam 7b.
recrystallized from hexane and benzene to yield 147 mg
(67%) of 8a as a white solid.
Compound 8a: 147 mg; yield: 67%; mp: 216–218 ꢁC; [a]D20
ꢂ59 (c 0.20, CHCl3); IR (CHCl3) 3500–3300, 3020, 3012,
OH
O
2970–2900, 1702, 1592, 1504, 1480 cmꢂ1
;
1H NMR
N
Br
O
00
(300 MHz, CDCl3): d 7.88 (d, J¼1.8 Hz, 1H, H2 ), 7.59
O
00
00
00
(m, 1H, H6 ), 7.27 (m, 1H, H4 ), 7.22 (m, 1H, H5 ), 7.04
0
0
(s, 1H, H5), 6.48 (s, 2H, H2 , H6 ), 6.35 (s, 1H, H8), 5.92
(m, 2H, OCH2O), 4.48 (t, J¼7.5 Hz, 1H, H4), 4.19 (d,
J¼5.1 Hz, 1H, H1), 3.97 (m, 2H, H11), 3.85 (s, 3H,
MeO
OMe
OMe
0
0
0
OMe(4 )), 3.82 (s, 6H, OMe(3 ,5 )), 3.36 (dd, J¼9.3, 5.1 Hz,
To a mixture of 3a (199 mg, 0.351 mmol) in anhydrous THF
(5 mL) at ꢂ78 ꢁC was added 1 M L-Selectride solution in
THF (422 mL, 0.422 mmol) dropwise. The reaction mixture
was removed from the cold bath and was stirred for 2 h. A
saturated solution of NH4Cl was added and the mixture
was extracted with EtOAc. The organic layer was washed
with brine, dried over MgSO4, filtered and concentrated
under reduced pressure. The crude product was purified by
silica gel chromatography (cyclohexane/EtOAc 3/2) to yield
172 mg (86%) of 7b as a white solid.
1H, H2), 2.69 (m, 1H, H3), 2.31 (d, J¼7.5 Hz, 1H, OH);
13
0
C NMR (75 MHz, CDCl3): d 174.2 (C13), 153.4 (C3 ,
0
00
0
C5 ), 147.2 (C7), 146.8 (C6), 140.4 (C1 ), 140.1 (C1 ), 136.7
0
(C4 ), 132.2 (C9), 131.1 (C10), 130.1 (C5 ), 127.6 (C4 ),
00
00
00
00
122.6 (C3 ), 122.5 (C2 ), 117.9 (C6 ), 109.3 (C8), 105.5
00
0
(C2 , C6 ), 105.3 (C5), 101.1 (OCH2O), 70.1 (C4), 60.9
0
0
0
0
(OMe(4 )), 56.1 (OMe(3 ,5 )), 50.2 (C11), 48.9 (C2), 44.2
(C1), 38.8 (C3); MS (ES+): m/z¼568, 570 [M+H]+, 590,
592 [M+Na]+.
4.5.4. (1R,2S,3R,4S)-N-(3-Bromophenyl)-epipicropodo-
phyllin-cis-g-lactam 8b.
Compound 7b: 172 mg; yield: 86%; mp: 149–152 ꢁC; [a]D20
+51 (c 0.23, CHCl3); IR (CHCl3) 3500–3300, 3020, 3013,
2970–2900, 1692, 1591, 1505, 1491 cmꢂ1
;
1H NMR
OH
Br
O
N
O
00
00
(300 MHz, CDCl3): d 7.47 (d, J¼10.4 Hz, 2H, H2 , H6 ),
00
00
7.41 (d, J¼10.4 Hz, 2H, H3 , H5 ), 7.07 (s, 1H, H5), 6.66
0
(s, 1H, H8), 6.34 (s, 2H, H2 , H6 ), 5.95 (m, 2H, OCH2O),
0
4.89 (t, J¼4.7 Hz, 1H, H4), 4.55 (d, J¼2.2 Hz, 1H, H1),
O
0
3.82 (s, 3H, OMe(4 )), 3.80 (m, 1H, H11a), 3.77 (s, 6H,
0
0
OMe(3 ,5 )), 3.67 (m, 1H, H11b), 3.61 (dd, J¼10.6, 2.2 Hz,
13
MeO
OMe
1H, H2), 3.20 (m, 1H, H3), 2.08 (d, J¼4.7 Hz, 1H, OH);
OMe
0
C NMR (75 MHz, CDCl3): d 174.6 (C13), 153.2 (C3 ,
0
C5 ), 147.1 (C6, C7), 138.2 (C1 or C1 ), 138.0 (C1 or C1 ),
0
00
00
0
To a mixture of 3b (196 mg, 0.346 mmol) in anhydrous THF
(5 mL) at ꢂ78 ꢁC was added 1 M L-Selectride solution in
THF (415 mL, 0.415 mmol) dropwise. The reaction mixture
was removed from the cold bath and was stirred for 2 h. A
saturated solution of NH4Cl was added and the mixture
was extracted with EtOAc. The organic layer was washed
with brine, dried over MgSO4, filtered, and concentrated
under reduced pressure. The crude product was purified by
silica gel chromatography (cyclohexane/EtOAc 3/2) to yield
157 mg (80%) of 8b as a white solid.
0
00
136.6 (C4 ), 131.7 (C3 , C5 ), 131.6 (C9), 129.7 (C10),
00
00
121.4 (C2 , C6 ), 117.5 (C4 ), 109.9 (C8), 105.7 (C5), 104.7
00
00
0
0
0
(C2 , C6 ), 101.1 (OCH2O), 67.6 (C4), 60.9 (OMe(4 )), 56.2
0
0
(OMe(3 ,5 )), 48.7 (C2), 48.2 (C11), 45.7 (C1), 35.4 (C3);
HRMS (FAB+): calcd for C28H27NO7Br 568.0971 and
570.0955, found 568.0980 and 570.0940.
4.5.3. (1R,2S,3R,4R)-N-(3-Bromophenyl)-picropodo-
phyllin-cis-g-lactam 8a.
Compound 8b: 157 mg; yield: 80%; mp: 149–153 ꢁC; [a]D20
+46 (c 2.30, CHCl3); IR (CHCl3) 3500–3300, 3011, 2980–
OH
Br
O
N
O
1
2900, 1694, 1591, 1505, 1482 cmꢂ1; H NMR (300 MHz,
00
00
CDCl3): d 7.76 (d, J¼1.7 Hz, 1H, H2 ), 7.53 (m, 1H, H6 ),
O
00
7.23 (m, 1H, H4 ), 7.13 (m, 1H, H5 ), 7.08 (s, 1H, H5),
00
0
6.65 (s, 1H, H8), 6.34 (s, 2H, H2 , H6 ), 5.95 (m, 2H,
0
MeO
OMe
OCH2O), 4.89 (t, J¼4.5 Hz, 1H, H4), 4.55 (d, J¼2.0 Hz,
OMe
0
1H, H1), 3.82 (s, 3H, OMe(4 )), 3.80 (m, 1H, H11a), 3.77 (s,
0
0
6H, OMe(3 ,5 )), 3.67 (m, 1H, H11b), 3.61 (dd, J¼10.7,
2.0 Hz, 1H, H2), 3.20 (m, 1H, H3), 2.16 (d, J¼4.5 Hz, 1H,
OH); 13C NMR (75 MHz, CDCl3): d 174.6 (C13), 153.3
To a mixture of 3b (218 mg, 0.385 mmol) in THF (4 mL)
was added MeOH (4 mL). The solution was cooled to
ꢂ78 ꢁC and NaBH4 (29 mg, 0.770 mmol) was added. The
reaction mixture was removed from the cold bath and was
stirred for 3 h, water was added and the mixture was ex-
tracted with EtOAc. The organic layer was washed with
brine, dried over MgSO4, filtered, and concentrated under
reduced pressure. The crude product was purified by silica
gel chromatography (cyclohexane/EtOAc 3/2) and then
0
(C3 , C5 ), 147.2 (C6, C7), 140.3 (C1 ), 138.1 (C1 ), 136.7
0
0
00
0
(C4 ), 131.4 (C9), 130.0 (C5 ), 129.8 (C10), 127.5 (C4 ),
00
00
00
122.6 (C2 ), 122.5 (C3 ), 118.1 (C6 ), 109.9 (C8), 105.7
00
00
0
(C5), 104.7 (C2 , C6 ), 101.1 (OCH2O), 67.7 (C4), 60.9
0
0
0
0
(OMe(4 )), 56.1 (OMe(3 ,5 )), 48.7 (C2), 48.1 (C11), 45.7
(C1), 35.4 (C3); MS (ES+): m/z¼568, 570 [M+H]+, 590,
592 [M+Na]+.

11776
M. Dorbec et al. / Tetrahedron 62 (2006) 11766–11781
4.6. Representative experimental procedure for Suzuki
cross-coupling
4.49 (t, J¼7.0 Hz, 1H, H4), 4.22 (d, J¼4.8 Hz, 1H, H1),
0
4.01 (m, 2H, H11), 3.85 (s, 3H, OMe (4 )), 3.82 (s, 6H,
0
0
OMe(3 ,5 )), 3.37 (dd, J¼9.2, 4.8 Hz, 1H, H2), 2.69 (m, 1H,
To a 10 mL Quest 210 Teflon reaction vessel was added a
solution of N-4-bromophenyl g-lactam lignan 7b (30 mg,
0.053 mM) and Pd(OAc)2 (1.2 mg, 10 mol %) in DMF
(3 mL) followed by substituted phenylboronic acid
(0.132 mM, 2.5 equiv) and CsF (Table 2). The reaction
mixture was stirred at 85 ꢁC, filtered, and poured into water.
After extraction with EtOAc (3ꢃ7 mL), the combined or-
ganic phases were washed with brine and evaporated under
reduced pressure. The residue was purified on silica pad
with cyclohexane then cyclohexane/EtOAc gradient [9/1 to
2/8] to give the desired biaryl product.
H3), 2.42 (d, J¼7.0 Hz, 1H, OH); 13C NMR (75 MHz,
0
0
CDCl3): d 174.1 (C13), 153.5 (C3 , C5 ), 147.2 (C7), 146.8
000
(C6), 142.1 (C3 ), 140.3 (C1 ), 138.9 (C1 ), 136.7 (C4 ),
0
00
0
000
135.9 (C1 ), 134.7 (C4 ), 132.3 (C9), 131.1 (C10), 130.0
00
000
00
00
000
000
(C5 ), 127.4 (C3 , C5 ), 127.2 (C4 ), 126.9 (C2 ), 125.0
000
(C6 ), 119.9 (C2 , C6 ), 109.3 (C8), 105.6 (C2 , C6 ), 105.3
00
00
0
0
0
(C5), 101.1 (OCH2O), 70.1 (C4), 60.9 (OMe(4 )), 56.2
0
0
(OMe(3 ,5 )), 50.3 (C11), 49.0 (C2), 44.2 (C1), 38.8 (C3);
HRMS (DCI/NH3): calcd for C34H31NO7Cl 600.1789 and
602.1779, found 600.1787 and 602.1752.
4.6.3. (1R,2S,3R,4R)-N-(40-Chlorobiphenyl)-picropodo-
phyllin-cis-g-lactam 4ac.
4.6.1. (1R,2S,3R,4R)-N-(20-Chlorobiphenyl)-picropodo-
phyllin-cis-g-lactam 4aa.
OH
OH
O
Cl
N
Cl
O
N
O
O
O
O
MeO
OMe
OMe
MeO
OMe
OMe
White solid; 21.3 mg; yield: 67%; mp: 125–130 ꢁC; [a]D20
ꢂ29 (c 0.11, CHCl3); IR (CHCl3) 3500–3200, 3022, 3014,
Whitesolid;18.8 mg; yield:59%;mp:151–155 ꢁC;[a]D20 ꢂ72
(c 0.29, CHCl3); IR (CHCl3) 3500–3300, 3019, 2960–2900,
1696, 1593, 1505, 1483 cmꢂ1; 1H NMR (300 MHz, CDCl3):
2975–2900, 1702, 1592, 1505, 1481 cmꢂ1
;
1H NMR
00
00
(300 MHz, CDCl3): d 7.75 (d, J¼8.7 Hz, 2H, H2 , H6 ),
00
00
00
00
00
00
d 7.71 (d, J¼8.7 Hz, 2H, H2 , H6 ), 7.45 (m, 3H, H3 , H5 ,
7.55 (d, J¼8.7 Hz, 2H, H3 , H5 ), 7.49 (d, J¼8.6 Hz, 2H,
000
H6 ), 7.24 (m, 3H, H3 , H4 , H5 ), 7.04 (s, 1H, H5), 6.50 (s,
000
000
000
000
000
000
000
H3 , H5 ), 7.39 (d, 2H, J¼8.6 Hz, H2 , H6 ), 7.04 (s, 1H,
0
2H, H2 , H6 ), 6.40 (s, 1H, H8), 5.93 (m, 2H, OCH2O), 4.51
0
0
H5), 6.49 (s, 2H, H2 , H6 ), 6.40 (s, 1H, H8), 5.94 (m, 2H,
0
(dd, J¼8.0, 7.1 Hz, 1H, H4), 4.25 (d, J¼4.7 Hz, 1H, H1),
OCH2O), 4.56 (t, J¼7.4 Hz, 1H, H4), 4.26 (d, J¼4.6 Hz,
0
4.02 (m, 2H, H11), 3.85 (s, 3H, OMe(4 )), 3.83 (s, 6H,
0
1H, H1), 4.03 (m, 2H, H11), 3.86 (s, 3H, OMe(4 )), 3.83 (s,
0
0
0
0
OMe(3 ,5 )), 3.38 (dd, J¼9.2, 4.7 Hz, 1H, H2), 2.73 (m, 1H,
6H, OMe(3 ,5 )), 3.40 (dd, J¼9.4, 4.6 Hz, 1H, H2), 2.74 (m,
H3), 2.08 (d, J¼7.1 Hz, 1H, OH); 13C NMR (75 MHz,
1H, H3), 2.06 (d, J¼7.4 Hz, 1H, OH); 13C NMR (75 MHz,
0
CDCl3): d 174.0 (C13), 153.5 (C3 , C5 ), 147.4 (C7), 146.8
0
0
CDCl3): d 174.4 (C13), 153.7 (C3 , C5 ), 147.1 (C7), 146.7
0
0
(C6), 139.7 (C1 ), 138.5 (C4 ), 137.6 (C1 ), 136.6 (C4 ),
00
000
0
0 000 00 0
(C6), 140.2 (C1 ), 138.9 (C1 ), 138.7 (C4 ), 136.8 (C4 ,
00
135.8 (C1 ), 132.5 (C2 ), 132.1 (C9), 131.3 (C10, C3 ), 130.0
000
000
00 000 000
C1 ), 134.6 (C4 ), 132.3 (C9), 131.2 (C10), 128.8 (C3 ,
00
(C3 , C5 , C6 ), 128.6 (C4 ), 126.9 (C5 ), 119.1 (C2 , C6 ),
00
000
000
000
00
00
000
00
00
000
000
00
00
C5 ), 127.7 (C3 , C5 , C2 , C6 ), 120.0 (C2 , C6 ), 109.5
0
109.5 (C8), 105.5 (C5, C2 , C6 ), 101.1 (OCH2O), 70.5 (C4),
0
0 0
(C8), 105.5 (C5, C2 , C6 ), 101.1 (OCH2O), 70.4 (C4), 60.9
0
0
0
0
0
60.9 (OMe), 56.1 (OMe(3 ,5 )), 50.4 (C11), 49.0 (C2), 44.3
(C1), 38.8 (C3); HRMS (DCI/NH3): calcd for C34H31NO7Cl
600.1789 and 602.1779, found 600.1774 and 602.1768.
(OMe(4 )), 56.2 (OMe(3 ,5 )), 50.4 (C11), 49.0 (C2), 44.3
(C1), 38.9 (C3); HRMS (DCI/NH3): calcd for C34H31NO7Cl
600.1789 and 602.1779, found 600.1774 and 602.1768.
4.6.2. (1R,2S,3R,4R)-N-(30-Chlorobiphenyl)-picropodo-
phyllin-cis-g-lactam 4ab.
4.6.4. (1R,2S,3R,4R)-N-(20-Fluorobiphenyl)-picropodo-
phyllin-cis-g-lactam 4ad.
OH
OH
Cl
O
N
O
O
N
O
F
O
O
MeO
OMe
MeO
OMe
OMe
OMe
White solid; 21.3 mg; yield: 67%; [a]2D0 ꢂ90 (c 0.83,
White solid; 25.4 mg; yield: 82%; mp: 82 ꢁC; [a]D20 ꢂ44 (c
CHCl3); IR (CHCl3) 3600–3300, 3020, 2970–2900, 1697,
;
0.13, CHCl3); IR (CHCl3) 3550–3300, 3031, 3011, 2974–
1593, 1505, 1481 cmꢂ1
1H NMR (300 MHz, CDCl3):
2900, 1693, 1591, 1504, 1484 cmꢂ1; H NMR (300 MHz,
1
00
00
00
00
00
00
d 7.72 (d, J¼8.6 Hz, 2H, H2 , H6 ), 7.53 (m, 3H, H3 , H5 ,
CDCl3): d 7.73 (d, J¼8.7 Hz, 2H, H2 , H6 ), 7.53 (d,
000
H2 ), 7.36 (m, 3H, H4 , H5 , H6 ), 7.05 (s, 1H, H5), 6.49
000
000
000
0
0
0
0
0
0
0
J¼8.7 Hz, 2H, H3 , H5 ), 7.40 (dt, J¼7.8, 1.6 Hz, 1H, H6 ),
000 000 000
0
(s, 2H, H2 , H6 ), 6.37 (s, 1H, H8), 5.92 (m, 2H, OCH2O),
0
7.29 (m, 1H, H4 ), 7.20 (m, 1H, H5 ), 7.13 (m, 1H, H3 ),

M. Dorbec et al. / Tetrahedron 62 (2006) 11766–11781
11777
0
7.05 (s, 1H, H5), 6.49 (s, 2H, H2 , H6 ), 6.38 (s, 1H, H8), 5.92
0
5.93 (m, 2H, OCH2O), 4.55 (d, J¼8.0 Hz, 1H, H4), 4.27
(d, J¼4.8 Hz, 1H, H1), 4.05 (m, 2H, H11), 3.86 (s, 3H,
1H, H2), 2.75 (m, 1H, H3); 13C NMR (75 MHz, CDCl3):
(m, 2H, OCH2O), 4.50 (dd, J¼7.0, 4.1 Hz, 1H, H4), 4.24 (d,
0
0
0
0
J¼4.8 Hz, 1H, H1), 4.01 (m, 2H, H11), 3.85 (s, 3H, OMe(4 )),
OMe(4 )), 3.83 (s, 6H, OMe(3 ,5 )), 3.41 (dd, J¼9.2, 4.8 Hz,
0
0
3.82 (s, 6H, OMe(3 ,5 )), 3.37 (dd, J¼9.2, 4.8 Hz, 1H, H2),
2.71 (m, 1H, H3), 2.35 (br s, 1H, OH); 13C NMR (75 MHz,
0
d 174.1 (C13), 153.5 (C3 , C5 ), 147.3 (C7), 146.8 (C6),
0
000
000 0 00 0
143.5 (C1 ), 140.2 (C1 ), 139.4 (C1 ), 136.6 (C4 ), 135.9
00 000 00
(C4 ), 132.1 (C9), 131.1 (C10), 130.1 (m, C4 ), 127.7 (C3 ,
CDCl3): d 174.8 (C13), 158.3 (d, J¼247.4 Hz, C2 ), 153.2
0
0
0
00
(C3 , C5 ), 147.1 (C6, C7), 140.3 (C1 ), 138.5 (C1 ), 136.6
0
(C4 ), 132.3 (C9), 131.0 (C10), 130.5 (C4 , C6 ), 129.3 (C3 ,
00
000
00
00 000 000 000 000
C5 ), 127.1 (C2 , C6 ), 125.7 (m, C3 , C5 ), 122.4 (q,
00
000
000
00
00
0
C5 ), 129.1 (d, J¼8.1 Hz, C4 ), 128.5 (d, J¼13.3 Hz, C1 ),
J¼251 Hz, CF3), 120.0 (C2 , C6 ), 109.4 (C8), 105.5 (C2 ,
000
00
00
000
0 0
C6 , C5), 101.1 (OCH2O), 70.4 (C4), 60.9 (OMe(4 )), 56.1
124.4 (C5 ), 119.7 (C2 , C6 ), 116.3 (d, J¼22.6 Hz, C3 ),
0
109.3 (C8), 105.6 (C2 , C6 , C5), 101.1 (OCH2O), 70.1 (C4),
0
0
0
(OMe(3 ,5 )), 50.3 (C11), 49.0 (C2), 44.3 (C1), 38.9 (C3);
MS (ES+): m/z¼558 [M+H]+.
0
0
0
60.9 (OMe(4 )), 56.2 (OMe(3 ,5 )), 50.3 (C11), 49.0 (C2), 44.2
(C1), 38.8 (C3); MS (ES+): m/z¼584 [M+H]+.
4.6.7. (1R,2S,3R,4R)-N-(40-Methoxybiphenyl)-picro-
podophyllin-cis-g-lactam 4ah.
4.6.5. (1R,2S,3R,4R)-N-(40-Fluorobiphenyl)-picropodo-
phyllin-cis-g-lactam 4ae.
OH
OH
O
N
OMe
O
O
N
F
O
O
O
MeO
OMe
MeO
OMe
OMe
OMe
White solid; 30.0 mg, yield: 95%; mp: 227 ꢁC; [a]D20 ꢂ91 (c
White solid; 28.4 mg; yield: 92%; mp: 209–212 ꢁC; [a]D20
ꢂ77 (c 0.35, CHCl3); IR (CHCl3) 3500–3300, 3005, 2960–
0.42, CHCl3); IR (CHCl3) 3500–3300, 3021, 3008, 2960,
1697, 1592, 1502, 1482 cmꢂ1
;
1H NMR (300 MHz,
2900, 1695, 1593, 1500, 1482 cmꢂ1; H NMR (300 MHz,
1
00
00
CDCl3): d 7.68 (d, J¼8.6 Hz, 2H, H2 , H6 ), 7.51 (d,
00
00
000
000
J¼8.6 Hz, 2H, H3 , H5 ), 7.49 (d, J¼8.6 Hz, 2H, H2 , H6 ),
00
00
CDCl3): d 7.72 (d, J¼8.7 Hz, 2H, H2 , H6 ), 7.52 (d,
000
000
7.06 (s, 1H, H5), 6.95 (d, J¼8.6 Hz, 2H, H3 , H5 ), 6.49 (s,
000
000
00
00
J¼8.7 Hz, 2H, H2 , H6 ), 7.50 (d, J¼8.7 Hz, 2H, H3 , H5 ),
0
0
2H, H2 , H6 ), 6.36 (s, 1H, H8), 5.92 (m, 2H, OCH2O), 4.48
(t, J¼7.1 Hz, 1H, H4), 4.21 (d, J¼4.9 Hz, 1H, H1), 4.00 (m,
2H, H11), 3.85 (s, 3H, OMe), 3.84 (s, 3H, OMe), 3.82 (s,
000
000
7.11 (t, 2H, J¼8.7 Hz, H3 , H5 ), 7.05 (s, 1H, H5), 6.49 (s,
0
2H, H2 , H6 ), 6.40 (s, 1H, H8), 5.93 (m, 2H, OCH2O), 4.53
0
(t, J¼7.7 Hz, 1H, H4), 4.25 (d, J¼4.8 Hz, 1H, H1), 4.04 (m,
0
0
6H, OMe(3 ,5 )), 3.36 (dd, J¼9.0, 4.9 Hz, 1H, H2), 2.68 (m,
0
0
0
2H, H11), 3.85 (s, 3H, OMe(4 )), 3.83 (s, 6H, OMe(3 ,5 )),
3.38(dd, J¼9.2, 4.8 Hz, 1H, H2), 2.72(m, 1H, H3), 2.17(d,J¼
7.7 Hz, 1H, OH); 13C NMR (75 MHz, CDCl3): d 174.0 (C13),
1H, H3), 2.54 (br s, 1H, OH); 13C NMR (75 MHz, CDCl3):
000
d 174.0 (C13), 159.1 (C4 ), 153.5 (C3 , C5 ), 147.2 (C7),
0
0
0
146.8 (C6), 140.4 (C1 ), 137.8 (C1 ), 137.2 (C4 ), 136.7
00
00
000
0
0
162.5 (d, J¼226.4 Hz, C4 ), 153.5 (C3 , C5 ), 147.2 (C7),
0
000
000
(C4 ), 132.8 (C1 ), 132.3 (C9), 131.2 (C10), 129.9 (C2 ,
0
146.8 (C6), 140.3 (C1 ), 138.4 (C1 ), 136.7 (C4 ), 136.5 (C4 ,
00
0
00
000
00
00
00
00
000
000
C6 ), 127.0 (C3 , C5 ), 120.0 (C2 , C6 ), 114.2 (C3 , C5 ),
000
000
C1 ), 132.2 (C9), 131.2 (C10), 128.4 (d, J¼7.9 Hz, C2 ,
0
109.4 (C8), 105.6 (C2 , C6 ), 105.4 (C5), 101.1 (OCH2O),
0
000
00
00
00
00
C6 ), 127.3 (C3 , C5 ), 120.0 (C2 , C6 ), 115.6 (d, J¼
0
0
70.2 (C4), 60.9 (OMe), 56.1 (OMe(3 ,5 )), 55.3 (OMe), 50.4
(C11), 49.0 (C2), 44.2 (C1), 38.8 (C3); HRMS (DCI/NH3):
calcd for C35H34NO8 596.2284, found 596.2272.
000
21.3 Hz, C3 , C5 ), 109.4 (C8), 105.5 (C2 , C6 ), 105.4 (C5),
000
0
0
0
0
101.1 (OCH2O), 70.4 (C4), 60.9 (OMe), 56.1 (OMe(3 ,5 )),
50.4 (C11), 49.0 (C2), 44.2 (C1), 38.8 (C3); HRMS (DCI/
NH3): calcd for C34H31FNO7 584.2085, found 584.2075.
4.6.8. (1R,2S,3R,4R)-N-(20,30,40-Trimethoxybiphenyl)-
picropodophyllin-cis-g-lactam 4ai.
4.6.6. (1R,2S,3R,4R)-N-(40-Trifluoromethylbiphenyl)-
picropodophyllin-cis-g-lactam 4af.
OH
MeO
OMe
OMe
OH
O
O
N
O
N
CF3
O
O
O
MeO
OMe
OMe
MeO
OMe
OMe
Off-white solid; 22.9 mg; yield: 66%; mp: 148–153 ꢁC; [a]D20
ꢂ56 (c 0.17, CHCl3); IR (CHCl3) 3500–3300, 2970–2900,
White gum; 28.5 mg; yield: 85%; [a]2D0 ꢂ26 (c 0.13,
CHCl3); IR (CHCl3) 3500–3300, 3029, 3012, 2975–2900,
;
1693, 1594, 1504, 1488 cmꢂ1 1H NMR (300 MHz,
;
1697, 1592, 1504, 1482 cmꢂ1
1H NMR (300 MHz,
CDCl3): d 7.68 (d, J¼8.7 Hz, 2H, H2 , H6 ), 7.51 (d, J¼
00
00
00
00
00 00
CDCl3): d 7.78 (d, J¼8.7 Hz, 2H, H2 , H6 ), 7.67 (m, 4H,
8.7 Hz, 2H, H3 , H5 ), 7.04 (s, 1H, H5), 7.00 (d, J¼8.6 Hz,
000 000 0
000
000
000
000
00
00
H2 , H3 , H5 , H6 ), 7.60 (d, J¼8.7 Hz, 2H, H3 , H5 ),
1H, H6 ), 6.72 (d, J¼8.6 Hz, 1H, H5 ), 6.50 (s, 2H, H2 ,
0
0
7.05 (s, 1H, H5), 6.50 (s, 2H, H2 , H6 ), 6.40 (s, 1H, H8),
0
H6 ), 6.41 (s, 1H, H8), 5.93 (m, 2H, OCH2O), 4.54 (t,

11778
M. Dorbec et al. / Tetrahedron 62 (2006) 11766–11781
J¼8.5 Hz, 1H, H4), 4.27 (d, J¼4.7 Hz, 1H, H1), 4.03 (m, 2H,
H11), 3.92(s, 3H, OMe), 3.89(s, 3H, OMe), 3.85(s, 3H, OMe),
3.83(s, 6H, OMe), 3.65(s, 3H, OMe), 3.38(dd, J¼9.2, 4.7 Hz,
1H, H2), 2.73 (m, 1H, H3), 2.17 (br s, 1H, OH); 13C NMR
J¼4.5 Hz, 1H, H4), 4.59 (d, J¼2.3 Hz, 1H, H1), 3.84 (m,
0 0 0
1H, H11a), 3.82 (s, 3H, OMe(4 )), 3.77 (s, 6H, OMe(3 ,5 )),
3.72 (m, 1H, H11b), 3.64 (dd, J¼10.7, 2.3 Hz, 1H, H2),
3.22 (m, 1H, H3), 2.36 (d, J¼4.5 Hz, 1H, OH); 13C NMR
(75 MHz, CDCl3): d 174.5 (C13), 159.7 (d, J¼246.1 Hz,
0
(75 MHz, CDCl3): d 173.9 (C13), 153.5 (C3 , C5 ), 153.2
0
000
000
000
(C4 ), 151.5 (C2 ), 147.2 (C7), 146.8 (C6), 142.1 (C3 ),
000 0 0 00
C2 ), 153.2 (C3 , C5 ), 147.2 (C6, C7), 138.5 (C1 ), 138.2
0
140.4 (C1 ), 137.8 (C1 ), 136.8 (C4 ), 134.8 (C4 ), 132.2 (C9),
00
0
00
0 0 000 00
(C1 ), 136.6 (C4 ), 131.9 (C9), 131.6 (C6 ), 130.5 (C4 ),
00
00
000
000
131.2 (C10), 129.5 (C3 , C5 ), 128.0 (C1 ), 124.6 (C6 ),
00
00
000
129.7 (C10), 129.3 (C3 , C5 ), 128.9 (d, J¼8.2 Hz, C4 ),
00
119.4 (C2 , C6 ), 109.5 (C8), 107.5 (C5 ), 105.5 (C5, C2 ,
0
C6 ), 101.1 (O–CH2–O), 70.4 (C4), 60.9 (OMe), 56.2 (OMe),
50.4 (C11), 49.0 (C2), 44.2 (C1), 38.8 (C3); HRMS (DCI/
NH3): calcd for C37H38NO10 656.2496, found 656.2493.
00
000
0
0
0
0
0
0
0
128.3 (d, J¼13.3 Hz, C1 ), 124.4 (d, J¼3.5 Hz, C5 ),
0
0
0
0
0
0
119.7 (C2 , C6 ), 116.1 (d, J¼22.6 Hz, C3 ), 109.9 (C8),
0 0
105.7 (C5), 104.7 (C2 , C6 ), 101.1 (OCH2O), 67.7 (C4),
0
0
0
60.9 (OMe(4 )), 56.2 (OMe(3 ,5 )), 48.8 (C2), 48.2 (C11), 45.8
(C1), 35.5 (C3); MS (ES+): m/z¼584 [M+H]+, 606 [M+Na]+.
4.6.9. (1R,2S,3R,4S)-N-(30-Chlorobiphenyl)-epipicro-
podophyllin-cis-g-lactam 4ba.
4.6.11. (1R,2S,3R,4S)-N-(40-Methoxybiphenyl)-epipicro-
podophyllin-cis-g-lactam 4bc.
OH
Cl
OH
O
N
O
O
N
OMe
O
O
O
MeO
OMe
OMe
MeO
OMe
OMe
White solid; 22.3 mg; yield: 70%; mp: 168–173 ꢁC; [a]D20 +35
(c 0.48, CHCl3); IR (CHCl3) 3500–3300, 3010, 2970–2900,
1690, 1591, 1505, 1483 cmꢂ1; 1H NMR (300 MHz, CDCl3):
Whitesolid; 25.6 mg;yield:81%;mp:148–150 ꢁC;[a]D20 +43
(c 0.48, CHCl3); IR (CHCl3) 3500–3300, 3020, 3008, 2960–
2900, 1688, 1590, 1502, 1484 cmꢂ1; H NMR (300 MHz,
1
00
00
00
00
d 7.63 (d, J¼8.7 Hz, 2H, H2 , H6 ), 7.49 (m, 3H, H3 , H5 ,
00
00
CDCl3): d 7.59 (d, J¼8.7 Hz, 2H, H2 , H6 ), 7.48 (d,
000
000
000
000
H2 ), 7.33 (m, 3H, H4 , H5 , H6 ), 7.10 (s, 1H, H5), 6.67
00
00
000
000
J¼8.7 Hz, 2H, H3 , H5 ), 7.43 (d, J¼8.8 Hz, 2H, H2 , H6 ),
0
(s, 1H, H8), 6.35 (s, 2H, H2 , H6 ), 5.94 (m, 2H, OCH2O),
0
000
000
7.10 (s, 1H, H5), 6.94 (d, J¼8.8 Hz, 2H, H3 , H5 ), 6.69 (s,
4.91 (t, J¼4.1 Hz, 1H, H4), 4.59 (d, 1H, J¼2.4 Hz, H1),
0
0
1H, H8), 6.36 (s, 2H, H2 , H6 ), 5.94 (m, 2H, OCH2O), 4.91
(t, J¼4.3 Hz, 1H, H4), 4.59 (d, J¼2.2 Hz, 1H, H1), 3.84 (m,
1H, H11a), 3.83 (s, 3H, OMe), 3.82 (s, 3H, OMe), 3.77 (s,
0
3.84 (m, 1H, H11a), 3.82 (s, 3H, OMe(4 )), 3.76 (s, 6H,
0
0
OMe(3 ,5 )), 3.72 (m, 1H, H11b), 3.63 (dd, J¼10.7, 2.4 Hz,
13
1H, H2), 3.22 (m, 1H, H3), 2.44 (d, J¼4.1 Hz, 1H, OH);
0
0
6H, OMe(3 ,5 )), 3.72 (m, 1H, H11b), 3.63 (dd, J¼10.7,
2.2 Hz, 1H, H2), 3.22 (m, 1H, H3), 2.29 (d, J¼4.3 Hz, 1H,
OH); 13C NMR (75 MHz, CDCl3): d 174.3 (C13), 159.1
0
C NMR (75 MHz, CDCl3): d 174.6 (C13), 153.2 (C3 ,
0
C5 ), 147.1 (C7, C6), 142.2 (C3 ), 138.8 (C1 ), 138.2 (C1 ),
000
00
0
0
136.6 (C4 ), 135.9 (C1 ), 134.7 (C4 ), 131.7 (C9), 130.0
000
00
000
0
0
0
(C4 ), 153.2 (C3 , C5 ), 147.1 (C6, C7), 138.2 (C1 ), 137.7
000
(C5 ), 129.8 (C10), 127.4 (C3 , C5 ), 127.3 (C4 ), 127.2
00
00
000
00
(C1 ), 137.1 (C4 ), 136.7 (C4 ), 132.9 (C1 ), 131.6 (C9),
000
129.8 (C10), 127.9 (C2 , C6 ), 126.9 (C3 , C5 ), 120.2 (C2 ,
00
0
000
000
(C2 ), 125.4 (C6 ), 121.4 (C2 , C6 ), 109.9 (C8), 105.7 (C5),
000
00
00
000
00
00
00
0
0
0
104.7 (C2 , C6 ), 101.1 (OCH2O), 67.6 (C4), 60.9 (OMe(4 )),
00
C6 ), 114.2 (C3 , C5 ), 110.0 (C8), 105.6 (C5), 104.7 (C2 ,
000
000
0
0
0
56.2 (OMe(3 ,5 )), 48.8 (C2), 48.2 (C11), 45.8 (C1), 35.5
(C3); MS (ES+): m/z¼600, 602 [M+H]+, 622, 624 [M+Na]+.
0
C6 ), 101.0 (OCH2O), 67.6 (C4), 60.9 (OMe(4 )), 56.2
0
0
0
000
(OMe(3 ,5 )), 55.3 (OMe (4 )), 48.8 (C2), 48.2 (C11), 45.8
(C1), 35.5 (C3); MS (ES+): m/z¼596 [M+H]+, 618 [M+Na]+.
4.6.10. (1R,2S,3R,4S)-N-(20-Fluorobiphenyl)-epipicro-
podophyllin-cis-g-lactam 4bb.
4.6.12. (1R,2S,3R,4S)-N-(20,30,40-Trimethoxybiphenyl)-
epipicropodophyllin-cis-g-lactam 4bd.
OH
OH
O
N
O
MeO
OMe
OMe
O
O
N
F
O
O
MeO
OMe
OMe
MeO
OMe
OMe
White solid; 24.2 mg; yield: 79%; mp: 146–148 ꢁC; [a]D20
+49 (c 0.61, CHCl3); IR (CHCl3) 3500–3300, 3025, 3018,
Off-white solid; 23.3 mg; yield: 67%; mp: 136–139 ꢁC;
2960–2900, 1686, 1590, 1506, 1485 cmꢂ1
;
1H NMR
[a]2D0 +42 (c 0.59, CHCl3); IR (CHCl3) 3500–3300, 3018,
00
00
(300 MHz, CDCl3): d 7.64 (d, J¼8.8 Hz, 2H, H2 , H6 ),
2980–2900, 1690, 1591, 1504, 1485 cmꢂ1 1H NMR
;
00
00
00
00
7.49 (dd, J¼8.8, 1.3 Hz, 2H, H3 , H5 ), 7.37 (dt, J¼7.7,
(300 MHz, CDCl3): d 7.59 (d, J¼8.8 Hz, 2H, H2 , H6 ),
000
000
00 00
1.8 Hz, 1H, H6 ), 7.28 (m, 1H, H4 ), 7.17 (dt, J¼7.7,
7.43 (d, J¼8.8 Hz, 2H, H3 , H5 ), 7.12 (s, 1H, H5), 6.97 (d,
000
1.2 Hz, 1H, H5 ), 7.10 (m, 2H, H5, H3 ), 6.68 (s, 1H, H8),
000
0
0
0
0
0
0
J¼8.6 Hz, 2H, H6 ), 6.70 (d, J¼8.6 Hz, 2H, H5 ), 6.69 (s,
0 0
0
6.36 (s, 2H, H2 , H6 ), 5.94 (m, 2H, OCH2O), 4.91 (t,
0
1H, H8), 6.35 (s, 2H, H2 , H6 ), 5.94 (m, 2H, OCH2O), 4.91

M. Dorbec et al. / Tetrahedron 62 (2006) 11766–11781
11779
00
00
(t, J¼4.5 Hz, 1H, H4), 4.59 (d, J¼2.1 Hz, 1H, H1), 3.90 (s,
J¼7.8 Hz, 1H, H5 ), 7.28 (m, 1H, H4 ), 7.03 (s, 1H, H5),
000
000
3H, OMe), 3.87 (s, 3H, OMe), 3.86 (m, 1H, H11a), 3.81 (s,
7.02 (d, J¼9.4 Hz, 1H, H6 ), 6.71 (d, J¼9.4 Hz, 1H, H5 ),
0
0
0 0
3H, OMe), 3.76 (s, 6H, OMe(3 ,5 )), 3.75 (m, 1H, H11b),
3.65 (s, 3H, OMe), 3.62 (m, 1H, H2), 3.22 (m, 1H, H3),
2.55 (br s, 1H, OH); 13C NMR (75 MHz, CDCl3): d 174.4
6.49 (s, 2H, H2 , H6 ), 6.39 (s, 1H, H8), 5.92 (m, 2H,
OCH2O), 4.52 (d, J¼8.0 Hz, 1H, H4), 4.26 (d, J¼4.8 Hz,
1H, H1), 4.01 (m, 2H, H11), 3.92 (s, 3H, OMe), 3.89 (s, 3H,
0
(C13), 153.2 (C3 , C5 ), 153.1 (C4 ), 151.3 (C2 ), 147.2
0
000
000
0
0
0
OMe), 3.84 (s, 3H, OMe(4 )), 3.82 (s, 6H, OMe(3 ,5 )), 3.67
(s, 3H, OMe), 3.36 (dd, J¼9.0, 4.8 Hz, 1H, H2), 2.71 (m,
1H, H3); 13C NMR (75 MHz, CDCl3): d 173.9 (C13), 153.4
000
0
00
(C7), 147.0 (C6), 142.5 (C3 ), 138.3 (C1 ), 137.7 (C1 ),
0
136.6 (C4 ), 134.5 (C4 ), 131.8 (C9), 129.7 (C10), 129.4
00
00
00
000
000
00
(C3 , C5 ), 127.8 (C1 ), 124.6 (C6 ), 119.6 (C2 , C6 ),
00
0 0 000 000
(C3 , C5 ), 153.3 (C4 ), 151.3 (C2 ), 147.2 (C7), 146.8 (C6),
000
0
0
000 0 00 00 0
142.5 (C3 ), 140.5 (C1 ), 139.0 (C1 , C3 ), 136.7 (C4 ),
109.9 (C8), 107.5 (C5 ), 105.7 (C5), 104.8 (C2 , C6 ), 101.0
(OCH2O), 67.5 (C4), 61.0 (OMe), 60.9 (OMe), 56.2
(OMe), 56.0 (OMe), 48.9 (C2), 48.2 (C11), 45.9 (C1), 35.5
(C3); MS (ES+): m/z¼656 [M+H]+, 678 [M+Na]+.
00
132.2 (C9), 131.2 (C10), 128.5 (C5 ), 128.1 (C1 ), 125.6
000
00
000
00
00
(C4 ), 124.9 (C6 ), 120.5 (C2 ), 118.4 (C6 ), 109.4 (C8),
000
107.5 (C5 ), 105.7 (C5, C2 , C6 ), 101.1 (OCH2O), 70.3
0
0
0
0
(C4), 61.1 (OMe), 61.0 (OMe), 60.9 (OMe), 56.2 (OMe(3 ,5 )),
56.1 (OMe), 50.6 (C11), 49.0 (C2), 44.2 (C1), 38.8 (C3); MS
(ES+): m/z¼656 [M+H]+, 678 [M+Na]+.
4.6.13. (1R,2S,3R,4R)-N-(40-Methoxybiphen-2-yl)-picro-
podophyllin-cis-g-lactam 4ca.
OMe
4.6.15. (1R,2S,3R,4S)-N-(40-Methoxybiphen-2-yl)-epi-
picropodophyllin-cis-g-lactam 4da.
OH
O
N
O
OMe
O
OH
O
N
O
MeO
OMe
OMe
O
White solid; 22.7 mg; yield: 72%; mp: 220–223 ꢁC; [a]D20
ꢂ73 (c 0.34, CHCl3); IR (CHCl3) 3500–3200, 2980–2900,
MeO
OMe
1697, 1591, 1482 cmꢂ1
;
d 7.85 (s, 1H, H2 ), 7.49 (m, 3H, H6 , H2 , H6 ),7.35 (m,
1H NMR (300 MHz, CDCl3):
OMe
00
00
000
000
White solid; 23.7 mg; yield: 75%; mp: 147–152 ꢁC; [a]D20
+28 (c 0.49, CHCl3); IR (CHCl3) 3500–3300, 3020, 3010,
00
00
000
2H, H4 , H5 ), 7.04 (s, 1H, H5), 6.94 (d, J¼8.4 Hz, 2H, H3 ,
000
0
0
H5 ), 6.49 (s, 2H, H2 , H6 ), 6.37 (s, 1H, H8), 5.91 (m, 2H,
OCH2O), 4.50 (t, J¼7.7 Hz, 1H, H4), 4.23 (d, J¼5.0 Hz,
1H, H1), 4.03 (m, 2H, H11), 3.85 (s, 3H, OMe), 3.84 (s, 3H,
2960–2900, 1689, 1590, 1504, 1484 cmꢂ1
;
(300 MHz, CDCl3): d 7.74 (s, 1H, H2 ), 7.46 (m, 3H, H6 ,
1H NMR
00
00
000
000
00
00
H2 , H6 ),7.31 (m, 2H, H4 , H5 ), 7.11 (s, 1H, H5), 6.93
0
0
OMe), 3.82 (s, 6H, OMe(3 ,5 )), 3.35 (dd, J¼9.2, 5.0 Hz, 1H,
H2), 2.68 (m, 1H, H3), 2.26 (d, J¼7.7 Hz, 1H, OH); 13C
000
000
(d, 2H, J¼8.4 Hz, H3 , H5 ), 6.68 (s, 1H, H8), 6.34 (s, 2H,
0
H2 , H6 ), 5.93 (m, 2H, OCH2O), 4.90 (m, 1H, H4), 4.59 (d,
0
000
NMR (75 MHz, CDCl3): d 174.0 (C13), 159.3 (C4 ), 153.5
J¼2.1 Hz, 1H, H1), 3.85 (m, 1H, H11a), 3.83 (s, 3H, OMe),
0
(C3 , C5 ), 147.2 (C7), 146.7 (C6), 141.7 (C3 ), 140.5 (C1 ),
0
00
0
0
0
3.82 (s, 3H, OMe), 3.75 (s, 6H, OMe(3 ,5 )), 3.74 (m, 1H,
H11b), 3.62 (dd, 1H, J¼10.7, 2.1 Hz, H2), 3.21 (m, 1H,
H3), 2.54 (br s, 1H, OH); 13C NMR (75 MHz, CDCl3):
00
0
000
139.6 (C1 ), 136.7 (C4 ), 133.2 (C1 ), 132.3 (C9), 131.1
00
(C10), 129.2 (C5 ), 128.3 (C2 , C6 ), 123.1 (C4 ), 118.3
000
000
00
00
00
000
000
(C2 ), 118.0 (C6 ), 114.2 (C3 , C5 ), 109.4 (C8), 105.6 (C2 ,
0
000
d 174.6 (C13), 159.3 (C4 ), 153.2 (C3 , C5 ), 147.2 (C7),
000
147.0 (C6), 141.5 (C3 ), 139.4 (C1 ), 138.3 (C1 ), 136.5
0
0
0
C6 ), 105.4 (C5), 101.1 (OCH2O), 70.2 (C4), 60.8 (OMe),
0
00
0
0
56.2 (OMe(3 ,5 )), 55.3 (OMe), 50.5 (C11), 49.1 (C2), 44.2
(C1), 38.8 (C3); MS (ES+): m/z¼618 [M+Na]+.
0
(C4 ), 133.2 (C1 ), 131.7 (C9), 129.7 (C10), 129.1 (C5 ),
000
00
000
000
00
00
128.3 (C2 , C6 ), 123.1 (C4 ), 118.5 (C2 ), 118.2 (C6 ),
000
114.1 (C3 , C5 ), 109.9 (C8), 105.7 (C5), 104.6 (C2 , C6 ),
0
101.0 (OCH2O), 67.5 (C4), 60.9 (OMe(4 )), 56.2 (OMe(3 ,5 )),
00
4.6.14. (1R,2S,3R,4R)-N-(20,30,40-Trimethoxybiphen-2-
yl)-picropodophyllin-cis-g-lactam 4cb.
000
0
0
0
0
000
55.3 (OMe(4 )), 49.0 (C2), 48.4 (C11), 45.9 (C1), 35.5 (C3);
MS (ES+): m/z¼596 [M+H]+, 618 [M+Na]+.
OMe
OMe
OMe
4.6.16. (1R,2S,3R,4S)-N-(20,30,40-Trimethoxybiphen-2-
yl)-epipicropodophyllin-cis-g-lactam 4db.
OH
O
O
N
OMe
O
OMe
OMe
OH
MeO
OMe
O
O
OMe
N
White solid; 10 mg; yield: 29%; mp: 203–208 ꢁC; [a]D20 ꢂ69
(c 0.33, CHCl3); IR (CHCl3) 3500–3300, 3009, 2980–2900,
1695, 1592, 1504, 1483 cmꢂ1; 1H NMR (300 MHz, CDCl3):
O
MeO
OMe
OMe
00
00
d 7.71 (s, 1H, H2 ), 7.66 (d, J¼7.8 Hz, 1H, H6 ), 7.37 (t,

11780
M. Dorbec et al. / Tetrahedron 62 (2006) 11766–11781
Off-white solid; 20.5 mg; yield: 59%; mp: 147–150 ꢁC;
Nilsson, K.; Van Camp, B.; Vanderkerken, K. Blood
2006, 107, 655–660.
17. Stromberg, T.; Ekman, S.; Girnita, L.; Dimberg, L. Y.; Larsson,
O.; Axelson, M.; Lennartsson, J.; Hellman, U.; Carlson, K.;
Osterborg, A.; Vanderkerken, K.; Nilsson, K.; Jernberg-
Wiklund, H. Blood 2006, 107, 669–678.
18. Axelson, M.; Larsson, O. PCT WO 2004093781 (04.11.2004).
19. Axelson, M.; Larsson, O. PCT WO 2004054996 (01.07.2004).
20. Axelson, M.; Larsson, O. PCT WO 02102805 (27.12.2002).
21. Hajduk, P. J.; Bures, M.; Praestgaard, J.; Fesik, S. W. J. Med.
Chem. 2000, 43, 3443–3447.
[a]2D0 +24 (c 0.57, CHCl3); IR (CHCl3) 3500–3300, 3023,
1
3007, 2974–2900, 1689, 1590, 1504, 1483 cmꢂ1; H NMR
00
(300 MHz, CDCl3): d 7.61 (s, 1H, H2 ), 7.54 (d, J¼8.0 Hz,
00
00
00
1H, H6 ), 7.32 (t, J¼8.0 Hz, 1H, H5 ), 7.24 (m, 1H, H4 ),
000
7.01 (s, 1H, H5), 6.99 (d, J¼8.6 Hz, 1H, H6 ), 6.70 (d,
000
0
J¼8.6 Hz, 1H, H5 ), 6.67 (s, 1H, H8), 6.34 (s, 2H, H2 ,
0
H6 ), 5.93 (m, 2H, OCH2O), 4.90 (t, J¼4.1 Hz, 1H, H4),
4.58 (d, J¼2.0 Hz, 1H, H1), 3.90 (s, 3H, OMe), 3.87 (s,
0
3H, OMe), 3.84 (m, 1H, H11a), 3.81 (s, 3H, OMe(4 )), 3.75
0
0
(s, 6H, OMe(3 ,5 )), 3.72 (m, 1H, H11b), 3.67 (s, 3H, OMe),
3.62 (dd, J¼10.5, 2.0 Hz, 1H, H2), 3.22 (m, 1H, H3), 2.57
(br s, 1H, OH); 13C NMR (75 MHz, CDCl3): d 174.4
22. Kadow, J. F.; Vyas, D. M.; Doyle, T. W. Tetrahedron Lett. 1989,
30, 3299–3302.
0
(C13), 153.2 (C3 , C5 , C4 ), 151.3 (C2 ), 147.2 (C7), 147.0
0
000
000
23. Poli, G.; Giambastiani, G. J. Org. Chem. 2002, 67, 9456–9459.
24. Dorbec, M.; Florent, J.-C.; Monneret, C.; Rager, M.-N.;
Bertounesque, E. Synlett 2006, 591–594.
000
(C6), 142.4 (C3 ), 138.9 (C1 ), 138.8 (C1 ), 138.3 (C3 ),
0
00
00
0
136.6 (C4 ), 131.8 (C9), 129.7 (C10), 128.4 (C5 ), 128.1
00
000
00
000
00
00
(C1 ), 125.6 (C4 ), 124.9 (C6 ), 120.8 (C2 ), 118.6 (C6 ),
25. Lopez-Perez, J.; del Olmo, E.; de Pascual-Teresa, B.; Merino,
M.; Martin, S.; San Feliciano, A. Tetrahedron 1995, 51, 6343–
6348.
000
0
0
110.0 (C8), 107.4 (C5 ), 105.6 (C5), 104.6 (C2 , C6 ), 101.0
(OCH2O), 67.5 (C4), 61.1 (OMe), 61.0 (OMe), 60.9
0
0
26. Lopez-Perez, J.; del Olmo, E.; de Pascual-Teresa, B.; Merino,
M.; San Feliciano, A. Tetrahedron 1996, 52, 4903–4910.
27. Madrigal, B.; Puebla, P.; Ramos, A.; Pelaez, R.; Gravalos, D.;
Caballero, E.; Medarde, M. Bioorg. Med. Chem. 2002, 10,
303–312.
(OMe), 56.2 (OMe(3 ,5 )), 56.0 (OMe), 48.9 (C2), 48.4
(C11), 45.8 (C1), 35.5 (C3); MS (ES+): m/z¼656 [M+H]+,
678 [M+Na]+.
28. Pohmakotr, M.; Komutkul, T.; Tuchinda, P.; Prabpai, S.;
Kongsaeree, P.; Reutrakul, V. Tetrahedron 2005, 61, 5311–
5321.
Acknowledgements
This work was financially supported by the Centre National
de la Recherche Scientifique, the Institut Curie, and the
Ligue Nationale contre le Cancer.
€
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