Synthesis of novel angular heterocyclic lignans by an InCl 3-catalyzed Friedel-Crafts-type cyclization

Article abstract of DOI:10.1002/ejoc.200701027

The synthesis of a 1-aryltetralin privileged structure-based library of novel angular heterocyclic lignans is described. Indolotetralins 3, tetrahydroquinolinotetralins 4, and thiochromanotetralins 5 were obtained from the methyl ester of thuriferic acid

Full text of DOI:10.1002/ejoc.200701027

FULL PAPER
DOI: 10.1002/ejoc.200701027
Synthesis of Novel Angular Heterocyclic Lignans by an InCl3-Catalyzed
Friedel–Crafts-Type Cyclization
Matthieu Dorbec,[a,b] Jean-Claude Florent,*[a,b] Claude Monneret,[a,b] Marie-Noëlle Rager,[c]
Céline Fosse,[d] and Emmanuel Bertounesque*[a,b]
Keywords: Friedel–Crafts cyclization / Heterocyclic lignans / Indium / Michael addition / Privileged structures
The synthesis of a 1-aryltetralin privileged structure-based
library of novel angular heterocyclic lignans is described. In-
dolotetralins 3, tetrahydroquinolinotetralins 4, and thiochro-
manotetralins 5 were obtained from the methyl ester of thuri-
feric acid 2 according to a three-step procedure involving an
InCl3-catalyzed Friedel–Crafts-type cyclization as the key
step.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
tively enrich a screening compound collection. It is note-
worthy that natural compounds encompass privileged struc-
tures as their biosynthesis involves different proteins and
they may bind to other proteins as well.[6] The evolution
of this concept has been pursued for privileged structures
associated with a target receptor family[1d] (e.g., 5,5-trans-
fused lactams for serine protease, reverse turn mimic for G
protein-coupled receptor). However, Schnur et al.[7] refute
the so-called target family privileged structures having ana-
lyzed target family ligands in the MDDR database which
contains compounds targeted and tested for potential
therapeutic value that were compiled from literature data
and confirm even more the definition of the original con-
cept of privileged structures by Evans et al.[2]
The 1-aryltetralin system 1 is a privileged structure found
in natural cyclolignans and synthetic derivatives which pres-
ent a wide range of biological activities,[8–10] such as the
inhibition of tubulin polymerization and DNA topoisomer-
ase II, and immunosuppressive, anti-HIV, and antidepres-
sant activities. Recently, cyclolignans have been reported as
inhibitors of the insulin-like growth factor receptor (IGF-
1R).[11,12] To the best of our knowledge there have been
only a few reports on the synthesis of angular lignans pos-
sessing the 1-aryltetralin scaffold 1: The synthesis of pyr-
azolignans[13] and isoxazolines[14] from 7-ketolignanolides
with hydrazine and oxime derivatives, respectively. As an
extension to our previous work,[15] we describe herein the
synthesis of novel angular heterocyclic lignans 3–5 from
methyl thuriferate 2, a derivative of the cyclolignan thuri-
feric acid[16] that possesses three independently addressable
functional groups, by using indium halides[17] as mild Lewis
acid catalysts (Figure 1). Thus, these compounds combine
the 1-aryltetralin privileged-structure 1 and heterocyclic
motifs found in many biologically important derivatives,
namely indole,[1b,18] tetrahydroquinoline[19] and thiochrom-
Introduction
The search for privileged structures is rapidly becoming
a crucial component of strategy in drug discovery as they
represent an ideal source of lead compounds with enhanced
drug-like properties.[1] The concept of “privileged struc-
tures” was introduced in 1988 by Evans et al.[2] when focus-
ing on the design of benzodiazepine-based CCK-A antago-
nists and has since received general acceptance.[1,3] A privi-
leged structure is a “single molecular scaffold able to pro-
vide ligands for diverse receptors” through judicious modi-
fication of functional groups. Some common molecular
frameworks can act on different gene families, indicating
that diverse protein targets can contain structurally com-
mon ligand binding sites.[4] Thus, the privileged structures
would form favorable noncovalent interactions with recep-
tors giving rise to a broad binding pattern, the side-chains
attached to the scaffold in a well-defined fashion being re-
sponsible for molecular recognition of the receptor. This
was supported by the study of Fesik and co-workers,[5] an
NMR-based screening of fragment binding against 11 pro-
tein targets which identified 12 recurring fragments (e.g.,
carboxylic acid, diphenylmethane and biphenyl above all).
This result suggests that the use of these preferred molecu-
lar motifs in a combinatorial library design should qualita-
[a] CNRS UMR 176,
26 rue d’Ulm, 75248 Paris Cedex 05, France
E-mail: emmanuel.bertounesque@curie.fr
[b] Institut Curie, Centre de Recherche,
26 rue d’Ulm, 75248 Paris Cedex 05, France
[c] Département de RMN, Ecole Nationale Supérieure de Chimie
de Paris,
11 rue P. et M. Curie, 75231 Paris Cedex 05, France
[d] Département de Spectrométrie de Masse, CNRS UMR 7573,
Ecole Nationale Supérieure de Chimie de Paris,
11 rue P. et M. Curie, 75231 Paris Cedex 05, France
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2008, 1723–1731
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1723

J.-C. Florent, E. Bertounesque et al.
FULL PAPER
ane[20] structures. The synthesis of 3–5 was accomplished by Scheme 2). The Michael addition of indoles to 2 was per-
an InCl3-catalyzed intramolecular Friedel–Crafts-type reac- formed[23,24] by using a catalytic amount of InBr3 (10 mol-
tion[21,22] as the key step.
%) at room temperature in DCM (Table 1, entries 1–5) or
at reflux in DCE for 5-nitroindole (Table 1, entry 6), afford-
ing the desired β-indolyl ketones 6a–f in good yields (83–
1
100%) and with dr Ͼ 95%, as judged by H NMR. The
2,3-trans stereochemistry was assigned on the basis of the
coupling constants J1,2 and J2,3 for compounds 6c (10.7 and
11.5 Hz), 6d (10.5 and 11.7 Hz), and 6f (10.9 and 12 Hz).
Stereoselective reduction of 6a–f with NaBH4 at 0 °C gave
the corresponding benzylic alcohols 7a–f in 82–96% yield
and with dr Ͼ 95% (Table 1, entries 1–6). The 3,4-trans
stereochemistry was deduced from the coupling constants
J2,3 and J3,4 for compounds 7c (10.7 and 8.6 Hz), 7d (10.7
and 8.3 Hz), and 7f (11 and 8 Hz).
Recently, direct carbon–carbon formation between allylic
and benzylic alcohols (i.e., diphenylmethanol and 1-phenyl-
ethanol) and active methylenes (i.e., diesters, keto esters,
and diketones), alkoxy ketones, and indoles catalyzed by
indium trichloride was demonstrated by Baba and co-
workers.[25] Two mechanisms for the activation of alcohols,
probably via the generation of a benzylic cation, have been
proposed for this reaction: Alkylation of indium-activated
alcohol and a two-step mechanism (i.e., dimerization of the
alcohol followed by alkylation), without forgetting a pos-
sible interaction between InCl3 and the active methylene.
Benzylic alcohols 7a–e underwent an InCl3-catalyzed intra-
molecular Friedel–Crafts-type cyclization[26] to give the in-
dolotetralin compounds 3a–e in 73–96% yields (Table 2, en-
tries 1–5). Note that these compounds exhibit a cis junction
(dr Ͼ 95%) at the fusion of the rings. This protocol was
much less effective for 3f due to the presence of the deacti-
vating nitro group on the indole ring (Table 2, entry 6). The
stereochemical assignment of 3 was established on the basis
of NOESY correlations of compounds 3b and 3c (3b: NMe/
5-H, 3-H/4-H, 1-H/3-H, 2-H/2Ј-H,6Ј-H; 3c: NH/5-H, 3-H/
4-H, 1-H/3-H, 2-H/2Ј-H,6Ј-H, Figure 2).[27]
Figure 1. Structures of indolotetralins 3, tetrahydroquinolinotetral-
ins 4 and thiochromenotetralins 5.
Results and Discussion
Indolotetralins 3, tetrahydroquinolinotetralins 4, and thio-
chromanotetralins 5 were obtained in three steps from the
methyl ester of thuriferic acid 2: Sequential stereoselective
Michael addition of the requisite nucleophile to 2, stereose-
The Michael additions of anilines[15a] in refluxing THF
lective reduction of the substituted tetralone derivative, and and thiophenols[28] in THF at room temperature were both
InCl3-catalyzed intramolecular Friedel–Crafts-type cycliza- catalyzed by Et3N and gave the corresponding β-amino
tion from the resulting benzyl alcohol (Scheme 1 and ketones 8a–e (Table 1, entries 7–11) and β-thioketones 9a–
Scheme 1. Synthesis of indolotetralins 3a–f. Reagents and conditions: (a) InBr3, indole, DCM, room temp.; (b) NaBH4, THF, MeOH,
0 °C to room temp.; (c) InCl3, DCE, reflux.
1724
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 1723–1731

Novel Angular Heterocyclic Lignans
Scheme 2. Syntheses of tetrahydroquinolino-tetralins 4a–e and thiochromano-tetralins 5a–d. Reagents and conditions: (a) Et3N, aniline
or thiophenol, THF; (b) NaBH4, THF, MeOH, 0 °C to room temp.; (c) InCl3, DCE, reflux.
either the lack of reactivity of 2 towards oxa-Michael ad-
dition or its tendency for aromatization. All experiments
were run with benzyl alcohol as a model substrate known
for its reactivity. Thus, tributylphosphane-catalyzed hydro-
alkoxylation[29] or the use of [Rh(cod)Cl2]2 in the presence
of K2CO3 in THF at reflux led to aromatization yielding
the corresponding arylnaphthalene, whereas the [Rh(cod)-
(OMe)]2-catalyzed reaction led to transfer hydrogenation
with the exo methylene of the coupling partner 2.[30] Other
methodologies applied {e.g., Tf2NH, Cu(OTf)2, InBr3,
InCl3, PdCl2, [PdCl2(MeCN)2]} were also ineffective.[31–33]
Cyclization of 10a–e using a catalytic amount of InCl3 in
refluxing DCE furnished tetrahydroquinolinotetralins 4a–e
Figure 2. Relevant NOESY correlations for 3b (R1 = Me, R2 = H)
and 3c (R1 = H, R2 = Br).
in 62–93% yields and with dr Ͼ 95% (Table 2, entries 7–
11). Interestingly, Yadav et al.[26] recently developed an
InCl3-catalyzed tandem Michael/Friedel–Crafts cyclization
that provides novel access to optically active tetra-
hydroquinolines from δ-hydroxy-α,β-unsaturated aldehydes
and arylamines. As for the synthesis of thiochromanotetral-
ins 5a–d, this reaction was applied with success when elec-
tron-donating groups were attached to the thioether ring,
giving rise to 5c (76%, dr Ͼ 95%) and 5d (86%, dr Ͼ 95%)
from 11c and 11d, respectively (Table 2, entries 14 and 15),
although sulfur is generally not a good substituent for elec-
trophilic aromatic substitutions.[20c] In the case of 11a and
11b, characterized by the presence of a deactivating group
on the thioether ring, we observed competition between in-
tramolecular cyclization and dehydration at position C-4,
leading to 5a and 5b, each one as an inseparable 1:1 mixture
with the resulting 1,2-dihydronaphthalene 12a and 12b,
d (Table 1, entries 12–15) in good-to-excellent yields (dr Ͼ
95%), respectively. In the latter case, no reaction with 4-
nitrothiophenol was observed even in the presence of an
excess of base (Table 1, entry 16).
Reduction of the Michael adducts 8a–e and 9a–d with
NaBH4 in MeOH at 0 °C gave 10a–e (83–100% yields, dr
Ͼ 95%) and 11a–d (82–95% yields, dr Ͼ 95%), respectively
(Table 1). The 2,3- and 3,4-trans stereochemistry of 10 was
deduced from the coupling constants J2,3 (10.9–11.4 Hz)
and J3,4 (9.2–9.5 Hz), and was further confirmed by
NOESY cross-peaks between 1-H/3-H, 2-H/4-H, and 2-H/
2Ј-H,6Ј-H for 10d. The coupling constants J2,3 (10.8–
10.9 Hz) and J3,4 (8.0–9.5 Hz) allowed the stereochemical
assignment of 11.
It is worth noting that all attempts to hydroalkoxylate
enone 2 were unsuccessful. With the aim of preparing chro- respectively. Use of InBr3 improved the yields of 5a and 5b
manotetralins, many attempts were made but all revealed slightly, as judged by 1H NMR (Table 2, entries 12 and 13).
Eur. J. Org. Chem. 2008, 1723–1731
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1725

J.-C. Florent, E. Bertounesque et al.
FULL PAPER
Table 1. Michael addition to methyl thuriferate 2 and reduction of the adducts (reagents and conditions are given in the footnotes).
[a] Indole (1.3 equiv.), InBr3 (10%), CH2Cl2, room temp., 2 h. [b] NaBH4 (1.5 equiv.), THF/MeOH (1:1), 0 °C to room temp., 2 h (β-OH
configuration). [c] 5-Nitroindole (1.3 equiv.), InBr3 (10%), DCE, reflux, 1 h. [d] Aniline (4 equiv.), Et3N (4 equiv.), THF, reflux, 24 h (see
ref.[27]). [e] NaBH4 (2 equiv.), THF/MeOH (1:1), 0 °C to room temp., 1 h (β-OH configuration). [f] Thiophenol (2 equiv.), Et3N (0.5 equiv.),
THF, room temp., 2.5 h. [g] 4-Nitrothiophenol (5 equiv.), Et3N (5 equiv.), THF, reflux, 48 h. [h] No reaction; Ar = 3,4,5-trimethoxyphenyl.
Cyclization of 11a was attempted with a catalytic amount
The relative stereochemistry of 4 was determined on the
of p-toluenesulfonic acid in refluxing toluene.[20c] This re- basis of the J values (J2,3 = 10.4–10.9 Hz, J3,4 = 3.7–4.2 Hz)
sulted in the exclusive formation of 12a. Treatment of 11a and NOESY data (4d: 1-H/4-H, 2-H/2Ј-H,6Ј-H, 3-H/4-H,
with TiCl4 (the Angle protocol)[34] afforded a mixture of 3ЈЈ-H/2Ј-H,6Ј-H). The coupling constants J2,3 (5c: 10.5 Hz;
11a and of its epimer after 1 h at –78 °C in DCM. The same 5d: 10.6 Hz) and J3,4 (5c: 4.6 Hz; 5d: 4.8 Hz) allowed the
reaction at room temperature gave 12a in quantitative yield. stereochemical assignment of compounds 5.
Cyclization of 12a into 5a by an intramolecular hydroaryl-
ation reaction with polyphosphoric acid[35–37] at 100 °C or Friedel–Crafts-type cyclization is presumably an electro-
with the mild catalyst[38] RuCl3/AgOTf were unsuccessful.
philic aromatic substitution. Indirect evidence of the in-
The mechanism for the InCl3-catalyzed intramolecular
1726
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 1723–1731

Novel Angular Heterocyclic Lignans
Table 2. InCl3-catalyzed intramolecular Friedel–Crafts-type cyclization (reagents and conditions are given in the footnotes).
[a] InCl3 (10%), DCE, reflux, 30 min. [b] InCl3 (10%), DCE, reflux, 20 min. [c] InBr3 (10%), DCE, reflux, 15 min. [d] Inseparable mixture
1
of 5a,b and 12a,b in a 1:1 ratio, as determined by H NMR spectroscopy. Ar = 3,4,5-trimethoxyphenyl.
volvement of the benzyl cation at C-4 has been provided by Cyclization of these C-4 α-OH isomers catalyzed by InCl3
additional experiments. It should be noted that this inter- (10 mol-%) led to the same products as those obtained from
mediate was stabilized by the methyleneoxy group in the the C-4 β-OH isomers (i.e., 3e and 4d) and with satisfying
para position. In this event, reduction of β-indolyl ketone yields, a result that apparently indicates the formation of
6e and amino ketone 8d with -selectride at –78 °C gave in the benzyl carbocation by activation of the benzyl alcohol
each case a separable mixture (1:1 ratio) of the correspond- under the influence of InCl3. In the case of the cyclization
ing α-OH (e.g., J3,4 = 2.5 Hz for the reduced product from of 7a–f, it is not certain whether indolotetralins 3a–f result
6e) and β-OH isomers at the C-4 position in good yields. from electrophilic substitution directly at the C-2 position
Eur. J. Org. Chem. 2008, 1723–1731
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1727

J.-C. Florent, E. Bertounesque et al.
FULL PAPER
DCM (5 mL) at room temperature. The reaction mixture was
stirred at reflux for 1 h at room temperature and subjected to evap-
oration under reduced pressure. Purification of the crude product
by flash chromatography on a silica gel column (cyclohexane/ethyl
acetate, 7:3) gave the corresponding 3-indol-3-ylmethyltetralone 6f.
Yellow solid (126.7 mg, 92% yield); m.p. 179–181 °C. [α]2D0 = –118.2
of the indole or from electrophilic substitution at C-3 fol-
lowed by rearrangement of an intermediate spiroindolenine
to C-2.[39]
Conclusions
(c = 1.02, CHCl ). IR (CHCl ): ν = 3469, 3019, 2975–2915, 1732,
˜
3
3
1671, 1593, 1506, 1480 cm–1. 1H NMR (300 MHz, CDCl3): δ =
8.64 (d, J = 1.9 Hz, 1 H, 4ЈЈ-H), 8.55 (br. s, 1 H, NH), 8.05 (dd, J
= 9.0, 1.9 Hz, 1 H, 6ЈЈ-H), 7.47 (s, 1 H, 5-H), 7.33 (d, J = 9.0 Hz,
1 H, 7ЈЈ-H), 7.25 (m, 1 H, 2ЈЈ-H), 6.28 (s, 2 H, 2Ј-H, 6Ј-H), 6.22 (s,
1 H, 8-H), 5.96 (s, 2 H, OCH2O), 4.34 (d, J = 10.9 Hz, 1 H, 1-H),
3.83 (s, 3 H, 4Ј-OMe), 3.76 (s, 6 H, 3Ј-OMe, 5Ј-OMe), 3.40 (s, 3 H,
CO2Me), 3.35 (m, 1 H, 3-H), 3.25 (m, 2 H, 11-H), 3.20 (dd, J =
12.0, 10.9 Hz, 1 H, 2-H) ppm. 13C NMR (75 MHz, CDCl3): δ =
195.3 (C-4), 172.8 (C-13), 153.4 (C-3Ј, C-5Ј), 152.5 (C-7), 147.4 (C-
6), 141.6 (C-5ЈЈ), 141.3 (C-1Ј), 138.8 (C-8ЈЈ), 137.2 (C-4Ј), 136.3 (C-
9), 127.3 (C-9ЈЈ), 127.0 (C-10), 126.9 (C-2ЈЈ), 117.5 (C-6ЈЈ), 116.6
(C-4ЈЈ), 115.6 (C-3ЈЈ), 111.0 (C-7ЈЈ), 108.4 (C-8), 106.1 (C-5, C-2Ј,
C-6Ј), 101.9 (OCH2O), 60.9 (4Ј-OMe), 56.2 (3Ј-OMe, 5Ј-OMe),
54.4 (C-2), 51.9 (CO2Me), 50.0 (C-3), 49.6 (C-1), 23.5 (C-11) ppm.
MS (ES+): m/z = 589 [M + H]+, 611 [M + Na]+. MS (ES–): m/z =
587 [M – H]–. HRMS (DCI/CH4): calcd. for C31H28N2O10·C2H5
617.2145; found 617.2135.
In conclusion, this account describes a mild and conve-
nient strategy for the stereoselective synthesis of a 1-aryl-
tetralin privileged structure-based library of novel angular
heterocyclic lignans such as indolotetralins 3, tetrahydro-
quinolinotetralins 4, and thiochromanotetralins 5 from the
methyl ester of thuriferic 2. The key reaction is an InCl3-
catalyzed Friedel–Crafts-type cyclization initiated by ben-
zylic carbocation formation. The ester group of 2 at the C-
2 position provides an opportunity for the further synthetic
development of these structures. A biological evaluation of
these compounds is currently under investigation.
Experimental Section
General Procedure for the Synthesis of 3-(Indol-3-ylmethyl)tet-
ralones 6a–e: Indium tribromide (8.7 mg, 10 mol-%) and the indole
(1.3 equiv.) were successively added to a solution of the methyl ester
of thuriferic acid 2 (105 mg, 0.246 mmol) in DCM (5 mL) at room
temperature. The reaction mixture was stirred for 2 h at room tem-
perature and subjected to evaporation under reduced pressure. Pu-
rification of the crude product by flash chromatography on a silica
gel column (cyclohexane/ethyl acetate, 7:3) gave the corresponding
3-(indol-3-ylmethyl)tetralones 6a–e.
General Procedure for the Synthesis of 3-(Phenylaminomethyl)-
tetralones 8a–e: Et3N (132 µL, 0.938 mmol) and the aniline
(0.938 mmol, 4 equiv.) were added to a solution of the methyl ester
of thuriferic acid 2 (100 mg, 0.234 mmol) in THF (4 mL) at room
temperature. The reaction mixture was then heated at 65 °C for
24 h, concentrated under reduced pressure, and the crude product
was purified by flash chromatography on silica gel (cyclohexane/
EtOAc, 5:2) to give the desired β-amino ketones 8a–e.
Compound 6a: Off-white solid (110 mg, 83% yield); m.p. 146–
149 °C. [α]2D0 = –72.6 (c = 0.14, CHCl3). 1H NMR (300 MHz,
CDCl3): δ = 8.03 (br. s, 1 H, NH), 7.66 (d, J = 7.4 Hz, 1 H, 4ЈЈ-
H), 7.48 (s, 1 H, 5-H), 7.30 (dd, J = 8.0, 0.8 Hz, 1 H, 7ЈЈ-H), 7.12
(m, 2 H, 5ЈЈ-H, 6ЈЈ-H), 7.02 (d, J = 2.0 Hz, 1 H, 2ЈЈ-H), 6.29 (s, 2
H, 2Ј-H, 6Ј-H), 6.24 (s, 1 H, 8-H), 5.96 (s, 2 H, OCH2O), 4.34 (d,
J = 10.6 Hz, 1 H, 1-H), 3.84 (s, 3 H, 4Ј-OMe), 3.76 (s, 6 H, 3Ј-
OMe, 5Ј-OMe), 3.32 (m, 3 H, 2-H, 3-H, 11a-H), 3.28 (s, 3 H,
CO2Me), 3.17 (m, 1 H, 11b-H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 195.7 (C-4), 172.9 (C-13), 153.3 (C-3Ј, C-5Ј), 152.3 (C-7), 147.3
(C-6), 141.1 (C-1Ј), 137.2 (C-4Ј), 136.6 (C-9), 135.9 (C-8ЈЈ), 127.7
(C-9ЈЈ), 127.2 (C-10), 123.6 (C-2ЈЈ), 121.8 (C-6ЈЈ), 119.2 (C-4ЈЈ, C-
5ЈЈ), 112.8 (C-3ЈЈ), 110.9 (C-7ЈЈ), 108.3 (C-8), 106.1 (C-5, C-2Ј, C-
6Ј), 101.8 (OCH2O), 60.9 (4Ј-OMe), 56.2 (3Ј-OMe, 5Ј-OMe), 54.2
(C-2), 51.5 (CO2Me), 49.8 (C-3), 49.4 (C-1), 24.0 (C-11) ppm. MS
(ES+): m/z = 566 [M + Na]+. HRMS (DCI/NH3): calcd. for
C31H29O8N 543.1893; found 543.1874.
Compound 8a: Off-white solid (131.6 mg, 94% yield); m.p. 162 °C.
[α]2D0 = –4.1 (c = 0.29, CHCl ). IR (CHCl ): ν = 3357, 2928, 1729,
˜
3
3
1670, 1593, 1506, 1480 cm–1. 1H NMR (300 MHz, CDCl3): δ =
7.45 (s, 1 H, 5-H), 7.25 (d, J = 8.8 Hz, 2 H, 3ЈЈ-H, 5ЈЈ-H), 6.55 (d,
J = 8.8 Hz, 2 H, 2ЈЈ-H, 6ЈЈ-H), 6.33 (s, 2 H, 2Ј-H, 6Ј-H), 6.26 (s, 1
H, 8-H), 6.00 (m, 2 H, OCH2O), 4.35 (d, J = 10.6 Hz, 1 H, 1-H),
3.86 (s, 3 H, 4Ј-OMe), 3.80 (s, 6 H, 3Ј-OMe, 5Ј-OMe), 3.50 (m, 1
H, 11a-H), 3.47 (s, 3 H, CO2Me), 3.39 (dd, J = 13.8, 3.7 Hz, 1 H,
11b-H), 3.24 (dd, J = 12.6, 10.6 Hz, 1 H, 2-H), 3.21 (m, 1 H, 3-
H) ppm. 13C NMR [75 MHz, (CD3)2CO]: δ = 195.5 (C-4), 173.3
(C-13), 154.6 (C-3Ј, C-6Ј), 153.5 (C-7), 148.9 (C-1ЈЈ), 148.4 (C-6),
143.0 (C-1Ј), 138.7 (C-4Ј), 137.8 (C-9), 132.5 (C-3ЈЈ, C-5ЈЈ), 127.7
(C-10), 115.4 (C-2ЈЈ, C-6ЈЈ), 109.2 (C-8), 108.5 (C-4ЈЈ), 107.7 (C-2Ј,
C-6Ј), 105.9 (C-5), 103.3 (OCH2O), 60.7 (4Ј-OMe), 56.6 (3Ј-OMe,
5Ј-OMe), 53.4 (C-2), 52.1 (CO2Me), 50.0 (C-1), 49.2 (C-3), 43.6 (C-
11) ppm. MS (DIC/NH3): m/z = 598, 600 [M + H]+. HRMS (DCI/
CH4): calcd. for C29H29NO8Br 598.1077, 600.1092; found
598.1071, 600.1101.
General Procedure for the Synthesis of 3-(Phenylthiomethyl)tet-
ralones 9a–d: Et3N (17 µL, 0.117 mmol) and the thiophenol
(0.468 mmol, 2 equiv.) were added to a solution of the methyl ester
of thuriferic acid 2 (100 mg, 0.234 mmol) in THF (2 mL) at room
temperature. The reaction mixture was stirred at room temperature
for 2.5 h, concentrated under reduced pressure, and the crude prod-
uct was purified by flash chromatography on silica gel (cyclohex-
ane/EtOAc, 5:2) to give the desired β-thioketones 9a–d.
Compound 9a: White solid (144 mg, 100% yield); m.p. 154 °C.
Compound 6f: Indium tribromide (8.3 mg, 10 mol-%) and 5-nitro-
indole (49.3 mg, 0.304 m) were added successively to a solution
of the methyl ester of thuriferic acid 2 (100 mg, 0.234 mmol) in
[α]2D0 = –78.5 (c = 0.35, CHCl ). IR (CHCl ): ν = 3013, 2975–2900,
˜
3
3
2943, 1730, 1673, 1593, 1505, 1480 cm–1. 1H NMR (300 MHz,
CDCl3): δ = 7.48 (s, 1 H, 5-H), 7.38 (d, J = 8.5 Hz, 2 H, 3ЈЈ-H,
1728
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 1723–1731

Novel Angular Heterocyclic Lignans
5ЈЈ-H), 7.24 (d, J = 8.5 Hz, 2 H, 2ЈЈ-H, 6ЈЈ-H), 6.33 (s, 2 H, 2Ј-H,
6Ј-H), 6.26 (s, 1 H, 8-H), 6.00 (m, 2 H, OCH2O), 4.33 (d, J =
10.9 Hz, 1 H, 1-H), 3.86 (s, 3 H, OMe), 3.80 (s, 6 H, OMe), 3.42
153.2 (C-3Ј, C-5Ј), 147.0 (C-7), 146.9 (C-1ЈЈ), 146.8 (C-6), 138.3 (C-
1Ј), 136.9 (C-4Ј), 132.0 (C-2ЈЈ, C-6ЈЈ), 131.7 (C-9), 131.1 (C-10),
115.2 (C-2ЈЈ, C-6ЈЈ), 110.2 (C-4ЈЈ), 108.4 (C-8), 106.1 (C-5), 105.8
(m, 2 H, 2-H, 11a-H), 3.40 (s, 3 H, CO2Me), 3.26 (m, 1 H, 11b- (C-2Ј, C-6Ј), 101.2 (OCH2O), 72.3 (C-4), 60.8 (4Ј-OMe), 56.1 (3Ј-
H), 3.21 (m, 1 H, 3-H) ppm. 13C NMR (75 MHz, CDCl3): δ =
OMe, 5Ј-OMe), 52.2 (CO2Me), 51.8 (C-2), 49.5 (C-11), 48.3 (C-
193.5 (C-4), 172.4 (C-13), 153.4 (C-3Ј, C-5Ј), 152.7 (C-7), 147.5 (C- 1), 45.0 (C-3) ppm. HRMS (DCI/CH4): calcd. for C29H31O8NBr
6), 141.4 (C-1Ј), 137.3 (C-4Ј), 136.2 (C-9), 135.8 (C-1ЈЈ), 131.9 (C- 600.1233, 602.1218; found 600.1228, 602.1207.
3ЈЈ, C-5ЈЈ), 131.4 (C-2ЈЈ, C-6ЈЈ), 126.5 (C-10), 120.2 (C-4ЈЈ), 108.5
(C-8), 106.2 (C-5), 106.1 (C-2Ј, C-6Ј), 102.0 (OCH2O), 60.9 (4Ј-
Compound 11a: White solid (100 mg, 90% yield); m.p. 162 °C.
[α]2D0 = –30.3 (c = 1.93, CHCl ). IR (CHCl ): ν = 3550–3300, 3012,
˜
3
3
OMe), 56.2 (3Ј-OMe, 5Ј-OMe), 53.4 (C-2), 52.0 (CO2Me), 49.3 (C-
3), 49.1 (C-1), 33.4 (C-11) ppm. MS (ES+): m/z = 615, 617 [M +
2974–2900, 1729, 1593, 1505, 1484 cm–1. 1H NMR (300 MHz,
CDCl3): δ = 7.39 (d, J = 8.5 Hz, 2 H, 3ЈЈ-H, 5ЈЈ-H), 7.25 (d, J =
8.5 Hz, 2 H, 2ЈЈ-H, 6ЈЈ-H), 7.02 (s, 1 H, 5-H), 6.25 (s, 2 H, 2Ј-H,
6Ј-H), 6.17 (s, 1 H, 8-H), 5.88 (m, 2 H, OCH2O), 4.81 (t, J =
8.2 Hz, 1 H, 4-H), 4.15 (d, J = 10.9 Hz, 1 H, 1-H), 3.83 (s, 3 H,
OMe), 3.78 (s, 6 H, OMe), 3.47 (s, 3 H, OMe), 3.27 (dd, J = 13.6,
4.6 Hz, 1 H, 11a-H), 3.11 (dd, J = 13.6, 4.8 Hz, 1 H, 11b-H), 2.93
(t, J = 10.9 Hz, 1 H, 2-H), 2.48 (d, J = 8.2 Hz, 1 H, OH), 2.37 (m,
1 H, 3-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 173.5 (C-13),
153.2 (C-3Ј, C-5Ј), 147.1 (C-7), 146.8 (C-6), 138.3 (C-1Ј), 136.9 (C-
4Ј), 135.3 (C-1ЈЈ), 132.1 (C-3ЈЈ, C-5ЈЈ) 131.6 (C-9), 131.2 (C-10),
131.0 (C-2ЈЈ, C-6ЈЈ), 120.3 (C-4ЈЈ), 108.5 (C-8), 106.4 (C-5), 105.9
(C-2Ј, C-6Ј), 101.1 (OCH2O), 71.5 (C-4), 60.9 (4Ј-OMe), 56.2 (3Ј-
OMe, 5Ј-OMe), 52.6 (C-2), 51.8 (CO2Me), 49.5 (C-1), 44.6 (C-3),
35.6 (C-11) ppm. MS (ES+): m/z = 639, 641 [M + Na]+. HRMS
(DCI/CH4): calcd. for C29H29BrNO8S·C2H5 645.1158, 647.1142;
found 645.1160, 647.1157.
H]+, 637, 639 [M
+
Na]+. HRMS (DCI/CH4): calcd. for
C29H27O8BrS·C2H5 643.1001, 645.0986; found 643.0977, 645.0984.
General Procedure for the Synthesis of 3-(Indol-3-ylmethyl)tetralols
7a–f: NaBH4 (1.5 equiv.) was added to a solution of 6a–f (100 mg)
in THF (3 mL) and MeOH (3 mL) cooled beforehand to 0 °C. The
reaction mixture was stirred for 2 h at 0 °C and then poured into
water (20 mL) and extracted with ethyl acetate (3ϫ10 mL). The
combined organic extracts were washed with brine (20 mL), dried
with MgSO4, and concentrated under reduced pressure. Purifica-
tion by flash chromatography on silica gel (cyclohexane/EtOAc,
3:2) afforded the desired alcohols 7a–f.
Compound 7a: White solid (82.3 mg, 82% yield); m.p. 146–149 °C.
[α]2D0 = +41.2 (c = 0.19, CHCl ). IR (CHCl ): ν = 3600–3450, 3479,
˜
3
3
3010, 2960–2900, 1729, 1593, 1504, 1484 cm–1. 1H NMR
(300 MHz, CDCl3): δ = 8.13 (s, 1 H, NH), 7.78 (d, J = 7.5 Hz, 1
H, 4ЈЈ-H), 7.35 (d, J = 7.3 Hz, 1 H, 7ЈЈ-H), 7.19 (m, 2 H, 5ЈЈ-H,
6ЈЈ-H), 7.11 (d, J = 2.2 Hz, 1 H, 2ЈЈ-H), 6.96 (s, 1 H, 5-H), 6.27 (s,
2 H, 2Ј-H, 6Ј-H), 6.17 (s, 1 H, 8-H), 5.86 (m, 2 H, OCH2O), 4.65
(m, 1 H, 4-H), 4.27 (d, J = 10.7 Hz, 1 H, 1-H), 3.84 (s, 3 H, 4Ј-
OMe), 3.77 (s, 6 H, 3Ј-OMe, 5Ј-OMe), 3.45 (s, 3 H, CO2Me), 3.18
(dd, J = 15.0, 4.6 Hz, 1 H, 11a-H), 2.87 (m, 2 H, 2-H, 11b-H), 2.83
(m, 1 H, 3-H), 2.06 (br. s, 1 H, OH) ppm. 13C NMR (75 MHz,
CDCl3): δ = 174.3 (C-13), 153.2 (C-3Ј, C-5Ј), 146.9 (C-7), 146.6 (C-
6), 138.8 (C-1Ј), 136.8 (C-4Ј), 136.2 (C-8ЈЈ), 132.1 (C-9), 131.4 (C-
10), 127.9 (C-9ЈЈ), 123.0 (C-2ЈЈ), 122.3 (C-6ЈЈ), 119.7 (C-5ЈЈ), 119.1
(C-4ЈЈ), 112.3 (C-3ЈЈ), 111.2 (C-7ЈЈ), 108.3 (C-8), 106.8 (C-5), 105.9
(C-2Ј, C-6Ј), 100.9 (OCH2O), 72.6 (C-4), 60.9 (4Ј-OMe), 56.1 (3Ј-
OMe, 5Ј-OMe), 53.8 (C-2), 51.5 (CO2Me), 49.6 (C-1), 45.3 (C-3),
27.0 (C-11) ppm. MS (ES+): m/z = 568 [M + Na]+. MS (ES–): m/z
= 544 [M – H]–. C31H31NO8 (545.58): calcd. C 68.25, H 5.73, N
2.57; found C 68.24, H 5.94, N 2.57.
General Procedure for the InCl3-Catalyzed Intramolecular Friedel–
Crafts Cyclization: A solution of alcohol 7a–f, 10a–e, or 11c,11d
(0.07 mmol) in DCE (2 mL) was heated at reflux, and indium tri-
chloride (1.5 mg, 0.007 mmol) was then added. The reaction mix-
ture was stirred for the indicated reaction time (see Table 2: 20 or
30 min), cooled to room temperature, and concentrated under re-
duced pressure. Purification by flash chromatography on silica gel
(cyclohexane/EtOAc, 5:1) gave the desired polycyclic compounds
3a–f, 4a–e, or 5c,5d.
Compound 3a: Off-white solid (23 mg, 73% yield); m.p. 220–222 °C.
[α]2D0 = –112.4 (c = 0.11, CHCl ). IR (CHCl ): ν = 3468, 3012,
˜
3
3
2975–2900, 1729, 1592, 1504, 1482 cm–1. 1H NMR (300 MHz,
CDCl3): δ = 7.96 (s, 1 H, NH), 7.46 (d, J = 6.5 Hz, 1 H, 4ЈЈ-H),
7.34 (dd, J = 8.3, 1.6 Hz, 1 H, 7ЈЈ-H), 7.13 (m, 2 H, 5ЈЈ-H, 6ЈЈ-H),
6.94 (s, 1 H, 5-H), 6.27 (s, 2 H, 2Ј-H, 6Ј-H), 6.24 (s, 1 H, 8-H), 5.94
(s, 2 H, OCH2O), 4.61 (d, J = 6.9 Hz, 1 H, 4-H), 4.06 (d, J =
11.1 Hz, 1 H, 1-H), 3.83 (s, 3 H, 4Ј-OMe), 3.73 (s, 6 H, 3Ј-OMe,
5Ј-OMe), 3.54 (m, 1 H, 3-H), 3.45 (s, 3 H, CO2Me), 3.11 (dd, J =
14.7, 6.5 Hz, 1 H, 11a-H), 2.97 (t, J = 11.1 Hz, 1 H, 2-H), 2.58 (d,
J = 14.7 Hz, 1 H, 11b-H) ppm. 13C NMR (75 MHz, CDCl3): δ =
175.2 (C-13), 153.1 (C-3Ј, C-5Ј), 146.7 (C-7), 146.3 (C-6), 144.0 (C-
2ЈЈ), 140.6 (C-8ЈЈ), 137.3 (C-1Ј), 136.7 (C-4Ј), 132.3 (C-9), 128.0 (C-
10), 125.1 (C-9ЈЈ), 121.1 (C-5ЈЈ), 120.0 (C-6ЈЈ), 118.9 (C-4ЈЈ), 116.7
General Procedure for the Synthesis of Alcohols 10a–e and 11a–d:
NaBH4 (13.6 mg, 0.360 mmol) was added to a solution of 8a–e
(or 9a–d) (0.180 mmol) in THF (3 mL) and MeOH (3 mL) cooled
beforehand to 0 °C. The reaction mixture was stirred for 2 h at 0 °C
and then poured into water (20 mL) and extracted with ethyl ace-
tate (3ϫ10 mL). The combined organic extracts were washed with
brine (20 mL), dried with MgSO4, and concentrated under reduced
pressure. Purification by flash chromatography on silica gel (cyclo-
hexane/EtOAc, 3:2) furnished the desired alcohols 10a–e (or 11a–
d).
Compound 10a: Off-white solid (108 mg, 100% yield); m.p. 178–
180 °C. [α]2D0 = –1.7 (c = 0.12, CHCl ). IR (CHCl ): ν = 3525–3300,
˜
3
3
3011, 2976–2900, 1732, 1594, 1505, 1484 cm–1. 1H NMR
(300 MHz, CDCl3): δ = 7.25 (d, J = 8.7 Hz, 2 H, 3ЈЈ-H, 5ЈЈ-H),
7.04 (s, 1 H, 5-H), 6.57 (d, J = 8.7 Hz, 2 H, 2ЈЈ-H, 6ЈЈ-H), 6.26 (s,
2 H, 2Ј-H, 6Ј-H), 6.16 (s, 1 H, 8-H), 5.89 (m, 2 H, OCH2O), 4.74
(d, J = 9.3 Hz, 1 H, 4-H), 4.17 (d, J = 11.2 Hz, 1 H, 1-H), 3.83 (s,
3 H, 4Ј-OMe), 3.78 (s, 6 H, 3Ј-OMe, 5Ј-OMe), 3.48 (s, 3 H,
CO2Me), 3.32 (m, 2 H, 11-H), 2.80 (t, J = 11.2 Hz, 1 H, 2-H), 2.29
(m, 1 H, 3-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 173.8 (C-13),
Eur. J. Org. Chem. 2008, 1723–1731
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1729

J.-C. Florent, E. Bertounesque et al.
FULL PAPER
(C-3ЈЈ), 111.7 (C-7ЈЈ), 109.3 (C-8), 107.1 (C-5), 106.1 (C-2Ј, C-6Ј),
101.1 (OCH2O), 60.9 (4Ј-OMe), 56.1 (3Ј-OMe, 5Ј-OMe), 51.8 (C-
2), 51.6 (CO2Me), 49.2 (C-1), 46.1 (C-3), 42.8 (C-4), 29.8 (C-
11) ppm. MS (ES+): m/z = 528 [M + H]+, 550 [M + Na]+. HRMS
(DCI/CH4): calcd. for C31H30NO7 528.2022; found 528.2018.
[1]
For reviews, see: a) A. A. Patchett, R. P. Nargund, Ann. Rep.
Med. Chem. 2000, 35, 289–298; b) D. A. Horton, G. T. Bourne,
M. L. Smythe, Chem. Rev. 2003, 103, 893–930; c) R. A. Good-
now Jr, W. Guba, W. Haap, Comb. Chem. High Throughput
Screening 2003, 6, 649–660; d) G. Müller, Drug Discov. Today
2003, 8, 681–691; e) R. W. DeSimone, K. S. Currie, S. A.
Mitchell, J. W. Darrow, D. A. Pippin, Comb. Chem. High
Throughput Screening 2004, 7, 473–493; f) L. Costantino, D.
Barlocco, Curr. Med. Chem. 2006, 13, 65–85.
B. E. Evans, K. E. Rittle, M. G. Bock, R. M. DiPardo, R. M.
Freidinger, W. L. Whitter, G. F. Lundell, D. F. Veber, P. S. An-
derson, R. S. L. Chang, V. J. Lotti, D. J. Cerino, T. B. Chen,
P. J. Kling, K. A. Kunkel, J. P. Springer, J. Hirshfield, J. Med.
Chem. 1988, 31, 2235–2246.
For the construction of a natural-product-like library based on
the 2,2-dimethylbenzopyran privileged structure, see: a) K. C.
Nicolaou, J. A. Pfefferkorn, A. J. Roecker, G.-Q. Cao, S. Bar-
luenga, H. J. Mitchell, J. Am. Chem. Soc. 2000, 122, 9939–9953;
b) K. C. Nicolaou, J. A. Pfefferkorn, H. J. Mitchell, A. J.
Roecker, S. Barluenga, G.-Q. Cao, R. L. Affleck, J. E. Lillig, J.
Am. Chem. Soc. 2000, 122, 9954–9967; c) K. C. Nicolaou, J. A.
Pfefferkorn, S. Barluenga, H. J. Mitchell, A. J. Roecker, G.-Q.
Cao, J. Am. Chem. Soc. 2000, 122, 9968–9976; for the design
of libraries of peptide-privileged structure hybrids, see: A. Pas-
ternak, Y. Pan, R. T. Mosley, S. P. Rohrer, E. T. Birzin, J.
Schaeffer, A. A. Patchett, L. Yang, Lett. Drug Des. Discovery
2004, 1, 121–125.
Compound 4a: Off-white solid (37.9 mg, 93% yield); m.p. 269 °C.
[α]2D0 = –61.6 (c = 0.50, CHCl ). IR (CHCl ): ν = 3011, 2975–2900,
˜
3
3
1728, 1593, 1504, 1484 cm–1. 1H NMR (300 MHz, CDCl3): δ =
7.15 (dd, J = 8.4, 1.9 Hz, 1 H, 5ЈЈ-H), 7.07 (d, J = 1.9 Hz, 1 H, 3ЈЈ-
H), 6.65 (s, 1 H, 5-H), 6.56 (d, J = 8.4 Hz, 1 H, 6ЈЈ-H), 6.37 (s, 1
H, 8-H), 6.05 (s, 2 H, 2Ј-H, 6Ј-H), 5.96 (m, 2 H, OCH2O), 4.26 (d,
J = 10.1 Hz, 1 H, 1-H), 4.08 (d, J = 3.8 Hz, 1 H, 4-H), 3.99 (s, 1
H, NH), 3.77 (s, 3 H, OMe), 3.64 (s, 6 H, OMe), 3.63 (m, 1 H,
11a-H), 3.62 (s, 3 H, CO2Me), 3.17 (dd, J = 12.5, 3.4 Hz, 1 H, 11b-
H), 2.76 (dd, J = 10.9, 10.1 Hz, 1 H, 2-H), 2.61 (m, 1 H, 3-H) ppm.
13C NMR (75 MHz, CDCl3): δ = 175.7 (C=O), 153.1 (C-3Ј, C-5Ј),
147.0 (C-7), 145.9 (C-6), 141.7 (C-1ЈЈ), 140.6 (C-1Ј), 136.3 (C-4Ј),
131.4 (C-3ЈЈ, C-9), 130.2 (C-5ЈЈ), 129.7 (C-10), 124.1 (C-2ЈЈ), 115.4
(C-6ЈЈ), 109.7 (C-5, C-8), 108.4 (C-4ЈЈ), 105.0 (C-2Ј, C-6Ј), 101.0
(OCH2O), 60.8 (4Ј-OMe), 56.0 (3Ј-OMe, 5Ј-OMe), 51.8 (CO2Me),
49.2 (C-2), 49.0 (C-1), 44.3 (C-11), 41.1 (C-4), 33.9 (C-3) ppm. MS
(ES+): m/z = 604, 606 [M + Na]+. HRMS (DCI/CH4): calcd. for
C29H29BrNO7 582.1127, 584.1112; found 582.1124, 584.1116.
[2]
[3]
[4]
[5]
[6]
[7]
[8]
P. D. Leeson, A. M. Davis, J. Steele, Drug Discov. Today: Tech-
nologies 2004, 1, 189–195.
P. J. Hajduk, M. Bures, J. Praestgaard, S. W. Fesik, J. Med.
Chem. 2000, 43, 3443–3447.
R. Breinbauer, I. R. Vetter, H. Waldmann, Angew. Chem. Int.
Ed. 2002, 41, 2878–2890.
D. M. Schnur, M. A. Hermsmeier, A. J. Tebben, J. Med. Chem.
2006, 49, 2000–2009.
For reviews on lignans and their biological activities, see: a)
R. S. Ward, Nat. Prod. Rep. 1995, 12, 183–205; b) R. S. Ward,
Nat. Prod. Rep. 1997, 14, 43–74; c) R. S. Ward, Nat. Prod. Rep.
1999, 16, 75–96.
Compound 5c: Off-white solid (29.3 mg, 76% yield); m.p. 210 °C.
[α]2D0 = –27.5 (c = 0.12, CHCl ). IR (CHCl ): ν = 3010, 2976–2900,
˜
3
3
[9]
[10]
M. Lautens, T. Rovis, Tetrahedron 1999, 55, 8967–8976.
E. C. Bucholtz, R. L. Brown, A. Tropsha, R. G. Booth, S. D.
Wyrick, J. Med. Chem. 1999, 42, 3041–3054.
1728, 1593, 1505, 1483 cm–1. 1H NMR (300 MHz, CDCl3): δ =
7.27 (d, J = 8.5 Hz, 1 H, 6ЈЈ-H), 6.73 (dd, J = 8.5, 2.5 Hz, 1 H, 5ЈЈ-
H), 6.55 (m, 2 H, 5-H, 3ЈЈ-H), 6.36 (s, 1 H, 8-H), 6.19 (s, 2 H, 2Ј-
H, 6Ј-H), 5.93 (m, 2 H, OCH2O), 4.19 (d, J = 10.6 Hz, 1 H, 1-H),
4.07 (d, J = 4.8 Hz, 1 H, 4-H), 3.80 (s, 3 H, 4Ј-OMe), 3.70 (s, 9 H,
3Ј-OMe, 5Ј-OMe, 4ЈЈ-OMe), 3.53 (s, 3 H, CO2Me), 3.16 (m, 1 H,
11a-H), 3.05 (m, 1 H, 3-H), 2.52 (t, J = 10.6 Hz, 1 H, 2-H), 2.44
(m, 1 H, 11b-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 175.1 (C-
13), 158.0 (C-4ЈЈ), 153.2 (C-3Ј, C-5Ј), 147.0 (C-7), 146.2 (C-6), 141.3
(C-2ЈЈ), 139.6 (C-1Ј), 136.7 (C-4Ј), 132.0 (C-9), 129.2 (C-10, C-6ЈЈ),
126.2 (C-1ЈЈ), 116.9 (C-3ЈЈ), 101.1 (C-5ЈЈ), 109.6 (C-5), 109.1 (C-8),
105.3 (C-2Ј, C-6Ј), 101.0 (OCH2O), 60.8 (4Ј-OMe), 55.8 (3Ј-OMe,
5Ј-OMe), 55.1 (4ЈЈ-OMe), 52.6 (C-2), 51.7 (CO2Me), 49.7 (C-1),
43.9 (C-4), 37.9 (C-3), 31.8 (C-11) ppm. HRMS (FAB+): calcd. for
C30H30NO8S 550.1661; found 550.1656. HRMS (DIC/NH3): calcd.
for C30H31NO8S 551.1740; found 551.1732.
[11]
a) A. Girnita, L. Girnita, F. del Prete, A. Bartolazzi, O. Lars-
son, M. Axelson, Cancer Res. 2004, 64, 236–242; b) D. Vasil-
canu, A. Girnita, L. Girnita, R. Vasilcanu, M. Axelson, O.
Larsson, Oncogene 2004, 23, 7854–7862; c) T. Stromberg, S.
Ekman, L. Girnita, L. Y. Dimberg, O. Larsson, M. Axelson, J.
Lennartsson, U. Hellman, K. Carlson, A. Osterborg, K. Vand-
erkerken, K. Nilsson, H. Jernberg-Wiklund, Blood 2006, 107,
669–678.
a) M. Axelson, O. Larsson, PCT WO 2002102805, 2002; b) M.
Axelson, O. Larsson, PCT WO 2004093781, 2004; c) M. Axel-
son, O. Larsson, PCT WO 2004054996, 2004.
M. Gordaliza, J. M. Miguel del Corral, M. A. Castro, M. L.
López-Vázquez, A. San Feliciano, M. D. García-Grávalos, A.
Carpy, Bioorg. Med. Chem. 1995, 3, 1203–1210.
a) J. M. Miguel del Corral, M. Gordaliza, M. A. Castro, M. D.
López-Vázquez, M. D. García-Grávalos, H. B. Broughton, A.
San Feliciano, Tetrahedron 1997, 53, 6555–6564; b) A. Castro,
J. M. Miguel del Coral, M. Gordaliza, C. Grande, A. Gómez-
Zurita, M. D. García-Grávalos, A. San Feliciano, Eur. J. Med.
Chem. 2003, 38, 65–74; c) M. A. Castro, J. M. Miguel del Cor-
ral, M. Gordaliza, M. A. Gómez-Zurita, M. L. de la Puente,
L. A. Betancur-Galvis, J. Sierra, A. San Feliciano, Eur. J. Med.
Chem. 2003, 38, 899–911.
a) M. Dorbec, J.-C. Florent, C. Monneret, M.-N. Rager, E.
Bertounesque, Synlett 2006, 591–594; b) M. Dorbec, J.-C. Flor-
ent, C. Monneret, M.-N. Rager, E. Bertounesque, Tetrahedron
2006, 62, 11766–11781.
[12]
[13]
[14]
Supporting Information (see also the footnote on the first page of
this article): General experimental procedures, 1H and 13C NMR
spectra, and HRMS (or elemental analysis) for compounds 6a–f,
8a–e, 9a–d, 7a–f, 9a–d, 10a–e, 11a–d, 3a–f, 4a–e, and 5c,5d.
Acknowledgments
[15]
We thank the Centre National de la Recherche Scientifique
(CNRS) and the Institut Curie for financial support. We thank
Sylvie Thirot for technical assistance.
1730
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 1723–1731

Novel Angular Heterocyclic Lignans
[16] For the isolation and synthesis of thuriferic acid, see: a) A.
San Feliciano, J. L. López, M. Medarde, J. M. Miguel del Cor-
ral, B. de Pascual-Teresa, P. Puebla, Tetrahedron 1988, 44,
7255–7260; b) P. H. Höfert, R. Matusch, Helv. Chim. Acta
1994, 77, 771–777; c) J. L. López-Pérez, E. del Olmo, B. de Pas-
cual-Teresa, M. Merino, S. Martín, A. San Feliciano, Tetrahe-
dron 1995, 51, 6343–6348; d) J. L. López-Pérez, E. del Olmo, B.
de Pascual-Teresa, M. Merino, A. San Feliciano, Tetrahedron
1996, 52, 4903–4910.
[17] For reviews on indium-mediated reactions, see: a) C. G. Frost,
K. K. Chauhan, J. Chem. Soc. Perkin Trans. 1 2000, 3015–
3019; b) B. C. Ranu, Eur. J. Org. Chem. 2000, 2347–2356; c) V.
Nair, S. Ros, C. N. Jayan, B. S. Pillai, Tetrahedron 2004, 60,
1959–1982; d) C. G. Frost, J. P. Hartley, Mini-Rev. Org. Chem.
2004, 1, 1–7; e) T.-P. Loh, G.-L. Chua, Chem. Commun. 2006,
2739–2749.
[18] For recent examples, see: a) N. Terzioglu, R. M. van Rijn,
R. A. Bakker, I. J. P. De Esch, R. Leurs, Bioorg. Med. Chem.
Lett. 2004, 14, 5251–5256; b) A. D. Napper, J. Hixon, T.
McDonagh, K. Keavey, J.-F. Pons, J. Barker, W. T. Yau, P. Am-
ouzegh, A. Flegg, E. Hamelin, R. J. Thomas, M. Kates, S.
Jones, M. A. Navia, J. O. Saunders, P. S. DiStefano, R. Curtis,
J. Med. Chem. 2005, 48, 8045–8054; c) M. Zheng, M. Zheng,
D. Ye, Y. Deng, S. Qiu, X. Luo, K. Chen, H. Liu, H. Jiang,
Bioorg. Med. Chem. Lett. 2007, 17, 2414–2420; d) J. C. Lanter,
J. J. Fiordeliso, W. Jiang, G. F. Allan, M.-T. Lai, O. Linton,
D. W. Hahn, S. G. Lundeen, Z. Sui, Bioorg. Med. Chem. Lett.
2007, 17, 123–126; e) S. Kher, K. Lake, I. Sircar, M. Pannala,
F. Bakir, J. Zapf, K. Xu, S.-H. Zhang, J. Liu, L. Morera, N.
Sakurai, R. Jack, J.-F. Cheng, Bioorg. Med. Chem. Lett. 2007,
17, 4442–4446.
[21] For examples of catalytic InIII salts used in Friedel–Crafts reac-
tions, see: a) G. Babu, N. Sridhar, P. T. Perumal, Synth. Com-
mun. 2000, 30, 1609–1614; b) C. J. Chapman, C. G. Frost, J. P.
Hartley, A. J. Whittle, Tetrahedron Lett. 2001, 42, 773–775; c)
R. Nagarajan, P. T. Perumal, Tetrahedron 2002, 58, 1229–1232;
d) C. G. Frost, J. P. Hartley, A. J. Whittle, Synlett 2001, 830–
832; e) C. G. Frost, J. P. Hartley, D. Griffin, Tetrahedron Lett.
2002, 43, 4789–4791; f) J. S. Yadav, S. Abraham, B. V. S. Reddy,
G. Sabitha, Synthesis 2001, 2165–2168; g) J. S. Yadav, S. Abra-
ham, B. V. S. Reddy, G. Sabitha, Tetrahedron Lett. 2001, 42,
8063–8065; h) M. Bandini, P. G. Cozzi, M. Giacomini, P. Mel-
chiorre, S. Selva, A. Umani-Ronchi, J. Org. Chem. 2002, 67,
5386–5389; i) M. Bandini, P. Melchiorre, A. Melloni, A. Um-
ani-Ronchi, Synthesis 2002, 1110–1114; j) R. Hayashi, G. R.
Cook, Org. Lett. 2007, 9, 1311–1314.
[22] For other work in this area, see: a) T. Tsuchimoto, T. Maeda,
E. Shirakawa, Y. Kawakami, Chem. Commun. 2000, 1573–
1574; b) J. S. Yadav, B. V. S. Reddy, S. Abraham, G. Sabitha,
Tetrahedron Lett. 2001, 42, 8067–8070; c) J. S. Yadav, B. V. S.
Reddy, G. Mahesh Kumar, C. Madan, Synlett 2001, 11, 1781–
1783; d) J. S. Yadav, B. V. S. Reddy, G. Parimala, Synlett 2002,
7, 1143–1145.
[23] a) M. Bandini, P. G. Cozzi, M. Giacomini, P. Melchiorre, S.
Selva, A. Umani-Ronchi, J. Org. Chem. 2002, 67, 3700–3704;
b) M. Agnusdei, M. Bandini, A. Melloni, A. Umani-Ronchi,
J. Org. Chem. 2003, 68, 7126–7129.
[24] Michael addition of indoles to enones catalyzed by InCl3 has
also been described, see: J. S. Yadav, S. Abraham, B. V. S.
Reddy, G. Sabitha, Synthesis 2001, 2165–2169.
[25] M. Yasuda, T. Somyo, A. Baba, Angew. Chem. Int. Ed. 2006,
45, 793–796.
[19] For the synthesis of tetrahydroquinolines and their biological
activities, see, for example: a) H. Togo, Y. Hoshina, T. Muraki,
H. Nakayama, M. Yokoyama, J. Org. Chem. 1998, 63, 5193–
5200; b) A. S. Kiselyov, L. Smith II, R. W. Armstrong, Tetrahe-
dron 1998, 54, 5089–5096; c) A. S. Kiselyov, L. Smith II, A.
Virgilio, R. W. Armstrong, Tetrahedron 1998, 54, 7987–7996,
and references cited therein; d) M. Takamura, K. Funabashi,
M. Kanai, M. Shibasaki, J. Am. Chem. Soc. 2000, 122, 6327–
6328; e) G. Sundararajan, N. Prabagaran, B. Varghese, Org.
Lett. 2001, 3, 1973–1976; f) O. B. Wallace, K. S. Lauwers, S. A.
Jones, J. A. Dodge, Bioorg. Med. Chem. Lett. 2003, 13, 1907–
[26] J. S. Yadav, B. V. S. Reddy, B. Padmavani, Synthesis 2004, 405–
408.
[27] See the Exptl. Sect. for the numerotation: compounds 6a, 3a
and 4a.
[28] R. Tamura, K.-i. Watabe, A. Kamimura, K. Hori, Y. Yoko-
mori, J. Org. Chem. 1992, 57, 4903–4905.
[29] I. C. Stewart, R. G. Bergman, F. D. Toste, J. Am. Chem. Soc.
2003, 125, 8696–8697.
[30] M. V. Farnworth, M. J. Cross, J. Louie, Tetrahedron Lett. 2004,
45, 7441–7443.
[31] T. C. Wabnitz, J. B. Spencer, Org. Lett. 2003, 5, 2141–2144.
1910; g) H. C. Smith, C. K. Cavanaugh, J. L. Friz, C. S. [32] M. Beller, J. Seayad, A. Tillack, H. Jiao, Angew. Chem. Int. Ed.
Thompson, J. A. Saggers, E. L. Michelotti, J. Garcia, C. M.
Tice, Bioorg. Med. Chem. Lett. 2003, 13, 1943–1946; h) Z. Li,
J. Zhang, C.-J. Li, Tetrahedron Lett. 2003, 44, 153–156, and
references cited therein; i) M. J. Fisher, R. T. Backer, S. Husain,
H. M. Hsiung, J. T. Mullaney, T. P. O’Brian, P. L. Ornstein,
R. R. Rothhaar, J. M. Zgombick, K. Briner, Bioorg. Med.
Chem. Lett. 2005, 15, 4459–4462.
2004, 43, 3368–3398.
[33] K. J. Miller, T. T. Kitagawa, M. M. Abu-Omar, Organometallics
2001, 20, 4403–4412.
[34] S. R. Angle, M. S. Louie, J. Org. Chem. 1991, 56, 2853–2866.
[35] a) M. Natarajan, V. T. Ramakrishnan, Ind. J. Chem., Sect. B
1984, 23, 720–727; b) P. R. Angibaud, M. G. Venet, W. Filliers,
R. Broeckx, Y. A. Ligny, P. Muller, V. S. Poncelet, D. W. End,
Eur. J. Org. Chem. 2004, 479–486.
[36] C. Deshayes, M. Chabannet, S. Gelin, Synthesis 1982, 1088–
1089.
[37] B. Chantegrel, A.-I. Nadi, S. Gelin, Synthesis 1983, 948–950.
[38] S. W. Youn, S. J. Pastine, D. Sames, Org. Lett. 2004, 6, 581–
584.
[39] W. A. Remers, R. K. Brown, Indoles Part I in The Chemistry
of Heterocyclic Compounds (Ed.: W. J. Houlihan), Wiley, New
York, 1972, pp. 90–94.
[20] For the synthesis of thiochromans and their biological activi-
ties, see: a) S. W. Schneller, Adv. Heterocycl. Chem. 1975, 18,
59–97; b) J. Cossy, F. Henin, C. Leblanc, Tetrahedron Lett.
1987, 28, 1417–1418; c) S. A. Fleming, J. Heterocycl. Chem.
2000, 37, 1527–1531; d) A. R. Katritzky, M. A. C. Button, J.
Org. Chem. 2001, 66, 5595–5600; e) S. Liu, C. W. Brown, K. D.
Berlin, A. Dhar, S. Guruswamy, D. Brown, G. J. Gardner, M. J.
Birrer, D. M. Benbrook, J. Med. Chem. 2004, 47, 999–1007; f)
S. Frigoli, C. Fuganti, L. Malpezzi, S. Serra, Org. Process Res.
Dev. 2005, 9, 646–650; g) L. Zu, J. Wang, H. Li, H. Xie, W.
Jiang, W. Wang, J. Am. Chem. Soc. 2007, 129, 1036–1037.
Received: October 30, 2007
Published Online: February 18, 2008
Eur. J. Org. Chem. 2008, 1723–1731
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1731