Convenient access to bis-indole alkaloids. Application to the synthesis of?topsentins

Article abstract of DOI:10.1016/j.tet.2008.04.045

Topsentins and related bis-indole alkaloids may be efficiently synthesized through an addition/oxidation sequence leading to 2-(3-indolylcarbonyl)-imidazole derivatives followed by a Pd-catalyzed heteroarylation with the appropriate 3-stannylindoles.

Full text of DOI:10.1016/j.tet.2008.04.045

Tetrahedron 64 (2008) 5904–5914
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journal homepage: www.elsevier.com/locate/tet
Convenient access to bis-indole alkaloids. Application to the synthesis
of topsentins
*
´
¨
Sajal K. Mal, Luis Bohe, Saıd Achab
Institut de Chimie des Substances Naturelles, CNRS, Avenue de la Terrasse, 91198 Gif sur Yvette Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Topsentins and related bis-indole alkaloids may be efficiently synthesized through an addition/oxidation
sequence leading to 2-(3-indolylcarbonyl)-imidazole derivatives followed by a Pd-catalyzed hetero-
arylation with the appropriate 3-stannylindoles.
Received 12 February 2008
Received in revised form 8 April 2008
Accepted 10 April 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Available online 15 April 2008
Keywords:
Topsentins
Bis-indole
Cross-coupling
Imidazole
1. Introduction
derivative (intermediate generated in situ from 3-bromoacetyl-
indole via an acetylhydrazinium derivative). It was developed
During the last two decades or so, a group of rare but structur-
ally related bis-(indolyl)imidazole metabolites known as the top-
sentins1 (Fig. 1) has established itself as a class of biologically
important natural products.
for the first synthesis of deoxytopsentin 13a (Fig.1), which appeared
soon after the first paper on isolation and characterization of
topsentin derivatives.1a Closely related self-1b,3b and cross-con-
densations1b have then been achieved by generating similar in-
termediates capable to condensate in situ. Accordingly, Rinehart
reported the first synthesis of topsentin 2 (Fig.1), albeit in low yield,
via the cross-condensation of the intermediates generated from the
action of ammonia on 3-glyoxalindole and 6-benzyloxy-3-glyox-
alindole.1b On the other hand, it was recently shown that the central
Since the first report, in 1987,1a relating on the isolation of this
class of compounds from marine sponges1 the study of their bi-
ological activities has attracted considerable interest. Accordingly,
remarkably diverse types of bioactivities such as antitumor,1b,f,g
antiviral,1b antifungal,1e antibacterial,1h and anti-inflammatory2
activities have been reported. Due to the important biological
properties featuring this class of natural products its members were
soon recognized as attractive candidates for studies aimed to
the potential development of a new class of pharmacologically ac-
tive agents, and therefore as interesting targets for synthetic de-
velopments. Among the strategies used for the few syntheses of this
class of compounds two categories appear. Indeed, the tricyclic core
has been built either through the construction of the central imid-
a-ketoimidazole unit of topsentins may be conveniently formed
by condensation between a 3-indolyl-a,b-diamiminoethane de-
rivative and a 3-indolyl-
a
-ketoimidate.3c,d The first synthesis of
H
O
N
N
n
R
R1
azole (or
or by the binding of two 3-indolyl derivatives to a preformed
imidazole (or
-ketoimidazole) moiety.4 Moreover, basically two
a
-ketoimidazole) unit from two 3-indolyl-derivatives1b,3
N
N
H
H
a
n = 1
1 R = R1 = H
Deoxytopsentin
Topsentin
Dibromodeoxytopsentin
Deoxybromotopsentin
Bromotopsentin
approaches have been developed within each category. For the
building of the central imidazole unit, the pioneering approach
2 R = OH, R1 = H
3 R = Br R1 = Br
4 R = H, R1 = Br
5 R = OH, R1 = Br
n = 0
involved the self-condensation of
a 3-indolyl-glyoxaldimine
6 R = R1 = H
Nortopsentin D
* Corresponding author. Tel.: þ33 (0) 1 69823092; fax: þ33 (0) 1 69823072.
E-mail address: achab@icsn.cnrs-gif.fr (S. Achab).
Figure 1.
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.04.045

S.K. Mal et al. / Tetrahedron 64 (2008) 5904–5914
5905
dibromodeoxytopsentin 33d (Fig. 1) along with other topsentin
2. Results and discussion
derivatives have been described in this way. Obviously this ap-
proach is more efficient for the synthesis of topsentin derivatives
involving two different indolyl moieties than the above one that
involves unselective cross-condensation reactions. With regard to
the strategy based on the binding of two 3-indolyl derivatives to
a preformed imidazole derivative, two similar approaches using
palladium-catalyzed couplings were shown to work efficiently.4
One was developed for both the first synthesis of nortopsentin D 64a
(Fig. 1) and the synthesis of topsentin 2.4b The synthesis of 2 made
use of the Suzuki reaction5 between the indolyl residue and the
imidazole unit. Then the indolylcarbonyl moiety was incorporated
via organometallic addition of the intermediate to a (3-indolyl)-
Weinreb amide. For the synthesis of 6, both indolyl residues were
linked to the imidazole unit by successive Suzuki couplings. The
other approach also involved the assembly of the topsentin
framework by successively forming two carbon–carbon bonds as
retrosynthetically depicted in Scheme 1, i.e., an aryl–aryl (5-imid-
azolyl, 3-indolyl) bond via a Stille coupling6 and a C–C(O) bond via
aldehyde-arylation followed by oxidation of the secondary alcohol.
The last two-step sequence may be performed starting from an
aldehyde situated either on the indole moiety or on the imidazole
ring, thus forming a 2-(imidazolyl)–carbonyl bond (option a1 in
Scheme 1) or a 3-(indolyl)–carbonyl bond (option a2 in Scheme 1),
respectively.
When the two approaches depicted in Scheme 1 were applied to
the synthesis of deoxytopsentin 1 that following route a1 proved
more efficient and led to 1 in higher overall yield. Indeed, com-
pound 1 was synthesized through route a1 in 50% yield from the
(indolyl)aldehyde 7a, whereas route a2 provided the target com-
pound in a satisfactory, but considerably lower, 30% yield from the
(imidazolyl)aldehyde 8c (Scheme 2). The secondary alcohol 9 was
the common product for the first step in each variant. In route a1
alcohol 9 was formed in 84% isolated yield from the attack of the
N-protected 2-lithioimidazole 8b on the N-protected indole-3-
carboxaldehyde 7a in THF at low temperature. Aldehyde 7a was
readily prepared in high yield from commercially available indole-
3-carboxaldehyde according to a known protocol8 and the orga-
nolithium reagent 8b was generated in situ as described in the
literature,9 by the action of n-butyllithium on the 4,5-diiodo-
N-protected imidazole derivative 8a at ꢀ78 ꢁC for 45 min. The
BOM
CHO
I
N
N
THF, –78 °C, 2 h
Y
+
R
85% (9)
Y = H
N
I
74% (13)
Y = OBn
SO2Ph
nBuLi
BOM
N
(R = H) 8a
7a Y = H
THF
7e Y = OBn
HO
–78 °C
45 min
(R = Li) [8b]
P
N
Bu3Sn
X
CHO
N
I
DMF, –78 °C to rt
72% (from 8a)
R1
through (a1):
R
Y
M
N
N
P
N
N
P
SO2Ph
BOM
X
THF, rt
9 Y = H
Stille coupling
overnight
13 Y = OBn
N
+
OHC
50% (9)
N
H
N
N
O
I
SO2Ph
8c
MnO2
, CH2Cl2
N
EtMgBr
THF
R
R1
rt, 3 h
7b, X = I
N
H
(Bu3Sn)2
(1.2 equiv)
Pd(PPh3)4
(5 mol%)
toluene
98% (10)
87% (14)
N
H
0 °C to rt
rt, 30min
7c, X = MgBr
or
a2
a1
aldehyde arylation/alcohol oxidation
I
reflux, 6 h
65%
N
O
N
BOM
P
N
PdCl2(PPh3)2 (8-10 mol%)
CuI (18-20 mol%)
DMF, 120 °C, 2 h
M
Bu3Sn
X
R
R1
through (a2):
N
SO2Ph
OHC
+
N
P
N
P
N
N
SO2Ph
75% (11)
79% (15)
Bu3Sn
Scheme 1. Retrosynthetic scheme.
Y
7d
10 Y = H
14 Y = OBn
1) aq KOH 10%
Some time ago, we have reported the syntheses of deoxytop-
sentin 1 and topsentin 2 through route a1, and the first syntheses of
deoxybromotopsentin 4 and bromotopsentin 5 (Fig. 1) following
the alternative route a2.4c Our approach is versatile allowing
a convenient access to all members of the topsentin family from
simple and easily available commercial starting materials providing
satisfactory yields, equivalent or even higher than those delivered
through different approaches. The upsurge of recent papers
devoted to the study of new syntheses and pharmacological
properties of topsentins1j,3c,d and related bis-indole alkaloids7 bear
witness to the current activity in the field. This prompt us to dis-
close the full experimental details associated with the preliminary
communicated synthesis of topsentins4c along with new related
approaches and results comprising the effect induced by changing
the protecting groups.
EtOH-THF (2:1), reflux, 3h
86% (12 Y = H)
97% (16 Y = OBn)
NH
SO2Ph
SO2Ph
N
2) 10% Pd/C, HCO2NH4
EtOH, reflux, 3h
96% (1 Y = H)
HN
O
N
BOM N
O
N
95% ( 2 Y = OBn)
Y = H
82% (2 steps)
NH
Y = OH 92% (2 steps)
N
Y
Y
11 Y = H
1 Y = H
2 Y = OH
15 Y = OBn
Scheme 2. Synthesis of deoxytopsentin 1 and topsentin 2.

5906
S.K. Mal et al. / Tetrahedron 64 (2008) 5904–5914
reaction time before addition of compound 7a must be strictly
controlled since it was shown9 that the 2-imidazolyllithium
derivative 8b is formed via acid/base equilibration of the 4-imida-
zolyllithium derivative (not shown in Scheme 2) initially produced.
The benzyloxymethyl (BOM) group plays a major role directing,
regiospecifically, the initial metal–halogen exchange to the vicinal
position through chelation of the oxygen atom to the 5-lithio
substituent. By the alternative route a2 alcohol 9 was isolated in
50% yield from the reaction of imidazole-2-carboxaldehyde 8c with
3-indolyl-magnesium bromide 7c. The Grignard reagent was gen-
erated in situ, as already described,10 by halogen–magnesium ex-
change of 3-iodoindole 7a11 with ethylmagnesium bromide.
Aldehyde 8c was easily prepared following a described procedure
from protected diiodoimidazole 8a, by quenching the organolithium
derivative 8b with dimethylformamide.9 The oxidation of the sec-
ondary alcohol 9 with excess manganese dioxide at rt led to the
corresponding carbonyl derivative 10 in high yield thus achieving
the formation of the desired aryl–carbonyl bond. The formation of
10 from 9 was characterized by the disappearance of the signals of
the CH and OH protons of the alcohol in the 1H NMR spectrum, at
6.2 ppm (br d, 1H, J¼5.5 Hz) and 5.85 ppm (br d, 1H, J¼5.5 Hz), re-
spectively, and also in the 13C NMR spectrum by the appearance of
the signal of the carbonyl carbon of 10 at 177.2 ppm with the con-
comitant disappearance of the signal of the carbon bearing the OH
of 9 at 63.8 ppm. The oxidation yield was obviously independent
of the way in which the alcohol was prepared. Therefore, on account
of the results for the arylation step, the formation of a 2-imidazolyl–
carbonyl bond should be preferred over the formation of 3-indolyl–
carbonyl bond so as to achieve improved yield.
The remaining 4-imidazolyl–3-indolyl bond, needed to complete
the assembly of the deoxytopsentin core, was built through palla-
dium-catalyzed cross-coupling between the iodo-imidazole moiety
of 10 and 3-stannylindole 7d, which was readily prepared from 3-
iodoindole 7b as described.12 This reaction, performed in DMF at
120 ꢁC for 2 h and using copper iodide as co-catalyst,13 led to the
fully protected deoxytopsentin derivative 11 in 76% yield from 10,
thus amounting a 63% overall yield from indole 7a according to route
a1, or a 37% overall yield from imidazole 8c according to route a2.
The N-protecting groups were smoothly removed in two steps
using standard conditions. Thus alkaline hydrolysis of 11 under
reflux, with ethanol and THF as co-solvents, deprotected the indolyl
moieties leading to intermediate 12 (N-BOM-imidazolyl derivative
not shown in Scheme 2) in 86% yield. Finally, the benzyloxymethyl
group was conveniently removed using ammonium formate as the
hydrogen donor and palladium on carbon as catalyst14 furnishing
the expected deoxytopsentin 1 in 96% yield from 12 (overall
deprotection yield of 82%). Spectroscopic data for compound 1 were
in agreement with those described for natural deoxytopsentin.1b
Route a1 was also applied to the synthesis of topsentin 2, which
was obtained in 47% yield from the known indole-3-carboxaldehyde
7e15 as summarized in Scheme 2. The arylation of aldehyde 7e by
the organolithium reagent 8b followed by oxidation of the corre-
sponding secondary alcohol 13 led to the 2-indolylcarbonyl-
4-iodoimidazole 14 in 64% yield from 7e. Subsequent Stille
cross-coupling with stannane 7d produced topsentin derivative 15 in
79% isolated yield from 14. This three-step sequence, carried out
undertheconditions alreadydescribedfor thesynthesis of1, afforded
protected topsentin 15 in 51% overall yield. Deprotection leading to
topsentin 2 was also performed as before, in two steps, since the
benzyl ether protection for the OH group was selected as to allow
smooth cleavage of the benzylether14 together with the imidazole
N-BOM group. Thus alkaline treatment of 15 under reflux for 3 h led
to the desulfonylated derivative, N-benzyloxymethyl-O-benzyl top-
sentin 16 (not shown in Scheme 2) and subsequent hydrogenolysis
afforded free topsentin 2 in 92% yield from 15. Spectroscopic data for
compound 2 were in agreement with those previously described for
natural topsentin.1b The formation of the cross-coupling product 15
from compound 14 can be monitored by the disappearance of the
signal of the carbon bearing the halogen of 14, at 83.1 ppm in the 13
C
NMR spectrum, and the downfield shift of the proton in position-2 of
the indolyl residue in the 1H NMR spectrum, from
9.1 ppm (s,1H) in
the substrate 14 to 9.6 ppm (s, 1H) in the product 15. A similar
d
d
deprotection for the signal of the proton in position 2 of the indolyl
moiety (which resonated at 9.27 ppm (s) in 10 and 9.6 ppm (s) in 11)
was associated with the coupling of the iodoketone 10 with stannane
7d leading to the protected deoxytopsentin derivative 11. Full
deprotection furnishing the target 2 was characterized by the split-
ting of the signals in the 1H and 13C NMR spectra in neutral solution
because of the formation of two isomers. As described,1a,b upon ad-
dition of a strong acid to the NMR solvent, both tautomers are pro-
tonated leading to the same salt thus suppressing the splitting of the
NMR signals. These spectral features and trends as well as those al-
ready pointed out for the transformation of 9 to 10 by alcohol oxi-
dation hold in all cases we examined. Therefore, they are valuable
tools for monitoring the progress of the entire process.
The synthesis of bromodeoxytopsentin 4 through pathways a1
and a2 is detailed in Scheme 3. Once again the first one (path a1)
Br
SEM
N
THF
0 °C, 30 min
rt, overnight
N
H
X
7f
+
OHC
N
53%
N
I
1) I2, KOH
SO2Ph
DMF, rt, 30 min
2) NaH, DMF
8d
t-BuLi
7b X = I
7i X = Li
PhSO2Cl
rt, 3 h
THF
SEM
–78 °C
10 min
95% (2 steps)
HO
N
N
I
I
7a + [8b]
Br
N
N
SO2Ph
19
2 steps
SO2Ph
(Scheme 1)
7g
82% (10)
(Bu3Sn)2
Pd(PPh3)4
(5 mol%)
toluene
reflux, 6 h
65%
MnO2
,
CH2Cl2
rt, 3 h, 93% (20)
I
PdCl2(PPh3)2
(8-10 mol%)
P
N
O
N
Br
CuI (14-20 ml%)
DMF, 120 °C, 2 h
+
SO2Ph
N
N
SO2Ph
73% (17)
51% (21)
Bu3Sn
10 P = BOM
20 P = SEM
7h
Br
Br
1) aq KOH 10%
EtOH-THF (2:1)
reflux, 3 h
90% (18 P = BOM)
89% (22 P = SEM)
2) 3N HCl-THF (2:1)
reflux,14 h
71% (P = BOM)
64% (P = SEM)
SO2Ph
SO2Ph
N
NH
P
N
O
N
HN
O
N
N
NH
P = BOM 64% (2 steps)
P = SEM
57% (2 steps)
17 P = BOM
21 P = SEM
4
Scheme 3. Synthesis of bromodeoxytopsentin 4.

S.K. Mal et al. / Tetrahedron 64 (2008) 5904–5914
5907
provided the target 4 in higher overall yield (39% from aldehyde 7a)
I
X
than the second (15% from aldehyde 8d). With regard to path a1, the
5-iodoimidazole derivative 10 already prepared (Scheme 2) was an
intermediate for the projected cross-coupling with bromoindolyl
stannane 7h en route to compound 17. The organostannane 7h was
obtained in 65% yield by palladium-catalyzed coupling of the pro-
tected 3-iodo-6-bromoindole 7g with hexabutylditin using a set of
reaction conditions already described in the literature for the
synthesis of other closely related indolylstannyl derivatives.16 The
starting iodide 7g could be conveniently prepared in high yield
from the commercially available 6-bromoindole 7f as shown in
Scheme 3, via the parent 3-iodo-6-bromoindole and subsequent
N-phenylsulfonylation of that intermediate. The Stille reaction of 10
with 7h, performed under the previously described conditions,
afforded the fully protected derivative 17 in 73% yield from 10.
The overall yield of the three-step sequence leading to 17 from
indole-3-carboxaldehyde 7a was thus 60%, the same figure as for
the transformation 7a to 11 (Scheme 2). These results underline
the synthetic utility of our approach, which allow an access to all
members of the topsentin family, including the brominated ones,
through a single set of standard reaction conditions. The key feature
is that the Stille coupling is iodide specific and tolerates an aryl
bromide. Thus, stannane 7h is an efficient reagent for the cross-
coupling step as the bromoaryl moiety is not affected. Needless to
say, besides the syntheses of bromotopsentins herein described
(Schemes 3 and 4), access to stannane 7h opened a way for its use
in the synthesis of other natural products containing the 6-bro-
moindolyl moiety.17 Although, the cross-coupling reactions of the
iodoimidazole 10 with the brominated stannylindole 7h (Scheme
3) or with the unsubstituted indolylstannylindole 7d (Scheme 2)
could be performed under the same conditions, the deprotection
protocol for compound 17 had to be modified since the use of
hydrogenolytic conditions should most probably result in con-
comitant dehalogenation.1b,18 As a consequence, after the initial
alkaline hydrolysis of compound 17 leading to the corresponding
desulfonylated N-BOM derivative 18 (not shown in Scheme 3) we
took advantage of the lability of the benzyloxymethyl group under
mildly acidic conditions.9,19 Thus the remaining BOM protecting
group was removed without affecting the bromoindole moiety
through acid hydrolysis, by refluxing compound 18 in a 3 N HCl/THF
mixture. The deprotection sequence afforded bromodeoxytop-
sentin 4 in 64% overall yield from the entirely protected precursor
17. Spectroscopic data for compound 4 were in agreement with
those described for natural bromodeoxytopsentin.1f
SO2Ph
N
N
P
N
+
CHO
OMOM
8d P = SEM
8c P = BOM
t-BuLi
THF
7i X = I
X = Li
–78 °C
30min .
7j
1) THF, –78 °C, 1.5 h
44% (23, P = SEM)
64% (27, P = BOM)
2) MnO2, CH2Cl2, rt, 3h
87% (24, P = SEM)
92% (28, P = BOM)
I
PdCl2(PPh3)2
(8-10 mol%)
CuI
P
N
O
N
(16-24 mol%)
DMF
120 °C, 2 h
+
SO2Ph
N
7h
(Scheme 3)
66% P = SEM
71% P = BOM
OMOM
38% (2 steps)
59% (2 steps)
24 P = SEM
28 P = BOM
Br
Br
1) aq KOH 10%
EtOH-THF (2:1)
reflux, 3 h
94% (26 P = SEM)
N
SO2Ph
NH
89% (30 P = BOM)
2) 3N HCl-THF (2: 1)
reflux,14 h
N
P
N
O
N
HN
71% (P = SEM)
68% (P = BOM)
67% (2 steps)
61% (2 steps)
P = SEM
SO2Ph P = BOM
O
N
NH
OMOM
OH
5
25 P = SEM
29 P = BOM
Another protecting group was tested in path a2, which started
by the arylation of the (imidazolyl)aldehyde 8d. We though that it
was wise to use the [2-(trimethylsilyl)ethoxy]methyl (SEM) pro-
tecting group for imidazole as this moiety may be easily removed
under acidic conditions.20 Moreover, as an ortho-directing group it
is well suited to induce a regiospecific metalation leading to 8d
from the parent 4,5-diiodoimidazolyl derivative. In this way, it
should behave similarly to the BOM moiety in the transformation of
8a into 8c (see Scheme 2). Thus, addition of the 3-lithioindole re-
agent 7f to aldehyde 8e led to the secondary alcohol 19 in 53% yield.
As we also observed an equivalent yield for the closely related
addition of the (indolyl)Grignard 7c to aldehyde 8c leading to
alcohol 9 (Scheme 2) it follows that the nature of the indolyl-
organometallic reagent plays a minor role in the outcome of these
reactions. Subsequent MnO2 oxidation of 19 in high yield and cross-
coupling of the corresponding carbonyl derivative 20 with stan-
nylindole 7h in 51% yield led to the fully protected compound 21 in
25% overall yield from 8d. Deprotection of compound 21 using the
two-step sequence previously described for the closely related
BOM derivative 17 led to bromodeoxytopsentin 4 in 57% overall
yield. Thus both the BOM and SEM moieties used in pathways a1
and a2 proved satisfactory for the final two-step deprotection.
Scheme 4. Synthesis of bromotopsentin 5.
Indeed, they avoided dehalogenation and displayed similar overall
efficiency. Nevertheless, BOM appeared as superior to SEM for the
Stille reaction with stannane 7h. The cross-coupling compound 17
was produced from iodoimidazole 10 in considerably higher yield
than the SEM-protected compound 21 from iodoimidazole 20.
The efficiency of these protecting groups was also evaluated in
the synthesis of bromotopsentin 5 through pathway a2 (Scheme 4).
With stannane 7h in hand, the 2-indolylcarbonyl-4-iodoimidazole
derivatives (24 and 28) needed as counterparts for the projected
cross-coupling leading to fully protected bromotopsentins (25 and
29) were prepared. Thus, compound 25 was obtained by the
organolithium-mediated addition of the (N,O-bisprotected)-6-hy-
droxy-3-iodoimidazole 7i to the imidazolylaldehyde 8e and com-
pound 26 was prepared by a similar organolithium addition to
aldehyde 8c.4b The iodoindole 7i was prepared from 4-OMOM-
benzaldehyde. The corresponding ethyl 2-indolylcarboxylate was
prepared according to Moody22 and then saponified. Subsequent
decarboxylation afforded 6-(methoxymethoxy)-1H-indole that was
iodinated and protected, by N-phenylsufonation, following

5908
S.K. Mal et al. / Tetrahedron 64 (2008) 5904–5914
standard procedures. For the O-protection of the starting organo-
lithium reagent 7j the methoxymethyl (MOM) group was preferred
to the benzyl group used in the synthesis of topsentin 2 (Scheme 2).
The MOM moiety may be removed under acidic treatment,21 and
thus concomitantly with the imidazole protecting groups (SEM or
BOM). Hence, an alkaline–acidic deprotection sequence, similar to
that previously used (Scheme 3), afforded free bromotopsentin 5
from the N,O-protected precursors 25 and 29 without reductive
debromination. Spectroscopic data for the corresponding com-
pound 5 were in agreement with those described for natural bro-
motopsentin.1b Once more, BOM protection for the imidazolyl
moiety of the starting aldehyde afforded improved overall yield of
the target 5 (25% from aldehyde 8c vs 15% from aldehyde 8e), al-
though the decisive step that confirms the preference for BOM over
SEM was here the first one, leading to the corresponding secondary
alcohols, instead of the cross-coupling step as before (Scheme 3).
Indeed, whereas the arylation of the SEM-protected substrate 8d
led to the indolyl-imidazolyl carbinol 23 in 44% yield, under iden-
tical conditions alcohol 27 was obtained in 64% yield from aldehyde
8c displaying N-BOM protection for the imidazole ring. All sub-
sequent steps, from alcohol oxidation to the final acidic depro-
tection showed very close yields for the corresponding reactions
involving the SEM or the BOM moieties as N-protecting groups for
the imidazole residue. The silylated moiety showed enhanced la-
bility throughout organometallic reactions (Schemes 3 and 4) as
well as throughout workup and purification processes. All of that
may account for the lower overall yields often encountered with N-
SEM-protected imidazole derivatives involved therein. But in any
case and as a matter of facts, the BOM protecting group proved
superior to the SEM in the sequences leading to topsentins fol-
lowing routes a1 and a2. It is also more versatile allowing conve-
nient removal either under neutral or acidic conditions and thus
may be widely used.
received, without further purification. When needed, solvents were
distilled and dried by standard methods. THF was distilled from
benzophenone ketyl; CH2Cl2 and toluene were distilled from CaH2.
All reactions were monitored by TLC using commercial silica gel
plates and visualization was accomplished by UV light and by
staining with PMA solution (5 g of phosphomolybdic acid in 100 mL
of EtOH) and heating. Flash chromatography was performed on
silica gel 60 Å (1% NEt3 in the mobile phase was used to deactivate
the solid phase when needed).
4.2. Synthesis of deoxytopsentin 1
(1-Benzenesulfonyl-1H-indol-3-yl)-(1-benzyloxymethyl-4-iodo-
1H-imidazol-2-yl)-methanol 9. (a) By addition of 2-Li-imidazole 8b
to 1-benzenesulfonyl-1H-indole-3-carboxaldehyde 7a: to a solu-
tion of compound 8a (886 mg, 2 mmol) in THF (20 mL) at ꢀ78 ꢁC
was added n-BuLi (1.6 M, 1.5 mL) and the reaction mixture was
stirred for 45 min at that temperature. To the solution of the cor-
responding imidazol-2-yllithium derivative 8b9 thus formed was
added dropwise a solution of aldehyde 7a (298 mg, 1.04 mmol) in
THF (6 mL) and then the reaction mixture was slowly warmed to
5 ꢁC (over 4 h). It was then diluted with CH2Cl2, washed (saturated
NH4Cl and brine), dried (MgSO4), and evaporated under reduced
pressure. Flash chromatography of the residue (eluting with
CH2Cl2/EtOAc 92:8) provided the secondary alcohol 9 (529 mg,
85%) as a white solid; mp 163–164 ꢁC. Rf 0.42 (CH2Cl2/EtOAc 9:1); IR
(KBr,
(300 MHz, CDCl3)
n )
cmꢀ1 3275–3037, 1448, 1375, 1182, 1080; 1H NMR
d
7.97 (d, 1H, J¼8.2 Hz), 7.85 (br d, 2H, J¼7.9 Hz),
7.7 (br s, 1H), 7.42 (m, 1H), 7.38–7.16 (m, 8H), 7.11 (m, 1H), 7.04–6.95
(m, 2H), 6.98 (s,1H), 6.2 (br d,1H, J¼5.5 Hz), 5.85 (br d,1H, J¼5.5 Hz,
exchangeable with D2O), 5.2 (d, 1H, JAB¼10.1 Hz), 5.07 (d, 1H,
JAB¼10.1 Hz), 4.07 (d, 1H, JAB¼12.4 Hz), 3.94 (d, 1H, JAB¼12.4 Hz);
13C NMR (CDCl3, 75 MHz)
d 150.4, 137.9, 135.9, 135.5, 133.9, 129.2,
128.5, 128.2, 128.1, 127.5, 126.7, 125.1, 123.6, 122.4, 120.2, 113.6, 79.7,
74.6, 70.5, 63.8; HRMS m/z 599.0381 calcd for C26H22N3O4SI; found
599.0375. Anal. Calcd for C26H22IN3O4S: C, 52.09; H, 3.77; N, 7.01.
Found: C, 52.18; H, 3.71; N, 6.89. (b) By addition of indole-Grignard
7c to aldehyde 8c: (b1) preparation of 1-benzyloxymethyl-4-iodo-
1H-imidazole-2-carboxaldehyde 8c: to a solution of imidazole (4 g,
58.8 mmol) in 2 M NaOH (360 mL) was slowly added a solution of I2
(28 g, 110 mmol) and KI (35 g, 105 mmol) in H2O (180 mL). The
mixture was stirred overnight at rt and then neutralized (with
AcOH). The precipitate was filtered. The solid was washed with H2O
and air-dried to furnish 4,5-diiodoimidazole23 (16.1 g, 85%) as
a white powder. To a solution of the latter (6 g, 18.6 mmol) in DMF
(50 mL) at rt was added K2CO3 (26 g, 188 mmol) and then benzyl-
oxymethylchloride BOMCl (4 mL, 28 mmol). The reaction mixture
was stirred at rt overnight, then filtered and the filtrate was
evaporated under vacuum. Flash chromatography (CH2Cl2) of the
oily residue led to 1-benzyloxymethyl-4,5-diiodo-1H-imidazole
8a9 (5.1 g, 62%). To a solution of compound 8a (1.2 g, 2.7 mmol) in
THF (25 mL) at ꢀ78 ꢁC was added n-BuLi (1.6 M, 2 mL) and the
solution was stirred at that temperature for 45 min. It was then
quenched by addition of dry DMF (1.5 mL) and stirred for a further
10 min. Then the mixture was slowly warmed to rt and then treated
with a saturated aqueous solution of NH4Cl and EtOAc. The organic
layer was washed (H2O and brine), dried (MgSO4), and evaporated
under reduced pressure. Flash chromatography of the residue
(eluting with hexane/EtOAc 3:1) furnished the aldehyde 8c9
(675 mg, 72%) as an essentially white solid. (b2) To a solution of 3-
iodoindole 7b11 (200 mg, 0.52 mmol) in dry THF (4 mL) at 0 ꢁC was
added a diethyl ether solution of EtMgBr (3 M, 0.21 mL) at 0 ꢁC and
then the reaction mixture was allowed to warm to rt and stirred
for 30 min. To the resulting Grignard derivative 7c10 was added a
solution of aldehyde 8c (178 mg, 0.52 mmol) in THF (2 mL).
The reaction mixture was allowed to warm to rt and then stirred
3. Conclusion
In summary, we developed effective procedures for the synthesis
of several bioactive marine bis-indole alkaloids belonging to the
topsentin family using commercially available and inexpensive
starting materials. Our strategy is simple and compares favorably
with other procedures. It calls for an aldehyde-arylation/alcohol-
oxidation sequence leading to 2-(3-indolyl)carbonyl-5-iodo-
imidazole derivatives followed by the transition metal-catalyzed
heteroarylation of those intermediates with the appropriate 3-
stannylindole. The syntheses may be started either with a 3-indolyl-
carboxaldehyde or 2-imidazolyl-carboxaldehyde as the substrate.
Experimental evidence suggested that arylation of 3-indolyl-alde-
hydesby2-imidazolyl-organometallic reagentsin thefirststepis the
most convenient pathway when both starting materials are avail-
able. This methodology offers, we believe, a valuable alternative for
a general access to topsentin derivatives and moreover its scope
should be easily extended for the synthesis of other bis-indolyl
alkaloids and related analogs.
4. Experimental section
4.1. General information
NMR spectra were recorded at 300 MHz for 1H and 75 MHz for
13C. Chemical shifts (
d) are given in parts per million relative to TMS
or to the solvent signal and coupling constants (J) are given in hertz.
Mass spectra and HRMS were obtained using EI as ion sources. IR
spectra were recorded as KBr pellets or neat. Elemental analyses
were performed at the microanalytical laboratory of ICSN-CNRS.
Melting points were not corrected. UV spectra were recorded
in EtOH solution. Commercially available compounds were used as

S.K. Mal et al. / Tetrahedron 64 (2008) 5904–5914
5909
overnight. It was then diluted with CH2Cl2 and washed (saturated
NH4Cl and brine), dried (MgSO4), and evaporated under reduced
pressure. Flash chromatography of the residue (eluting with
CH2Cl2/EtOAc 92:8) led to the alcohol 9 (155 mg, 50%) as a white
calcd for C28H22N4O2; found 446.1742. Anal. Calcd for C28H22N4O2
1/2H2O: C, 73.83; H, 5.09; N, 12.30. Found: C, 73.78; H, 5.06; N,
12.33. Deoxytopsentin 1. A solution of compound 12 (90 mg,
0.2 mmol) in EtOH (15 mL) containing 10% Pd/C (40 mg) and am-
monium formate14 (170 mg, 2.6 mmol) was refluxed for 3 h. The
reaction mixture was then cooled to rt and filtered through a pad
of Celite (rinsing with CH2Cl2 and EtOAc). The filtrate was evapo-
rated under reduced pressure to provide deoxytopsentin 1 (63 mg,
solid.
(1-Benzenesulfonyl-1H-indol-3-yl)-(1-benzyloxymethyl-4-
iodo-1H-imidazol-2-yl)-methanone 10. To a solution of the second-
ary alcohol 9 (380 mg, 0.63 mmol) in CH2Cl2 (20 mL) was added
MnO2 (1.4 g) and the resulting suspension was stirred for 3 h at rt.
The reaction mixture was filtered (rinsing with CH2Cl2) and the
filtrate was evaporated leading to compound 10 (370 mg, 98%) as an
oil, which solidified on standing in the refrigerator. Rf 0.67 (CH2Cl2);
96%) as a yellow solid; Rf 0.36 (CH2Cl2:MeOH 19:1); IR (KBr,
n
cmꢀ1) 3366–3283, 2926, 1582, 1527, 1458, 1429, 1238, 1105; UV
(EtOH, lmax nm) 208, 230, 253, 273, 375; 1H NMR (300 MHz, 1%
IR (KBr,
1080, 979; 1H NMR (300 MHz, CDCl3)
8.05–7.95 (m, 3H), 7.57 (m, 1H), 7.49 (m, 2H), 7.41 (s, 1H), 7.39–7.25
(m, 7H), 5.92 (s, 2H), 4.61 (s, 2H); 13C NMR (75 MHz, CDCl3)
177.2,
n
cmꢀ1) 3151, 3128, 2876, 1630, 1529, 1450, 1377, 1192, 1178,
9.27 (s, 1H), 8.43 (m, 1H),
TFA in DMSO-d6) d 12.38 (br s, 1H), 11.56 (br s, 1H), 9.05 (d, 1H,
d
J¼2.5 Hz), 8.38 (m, 1H), 8.08 (br d, 1H, J¼2.7 Hz), 8.04 (br d, 1H,
J¼7.6 Hz), 7.91 (s, 1H), 7.60 (m, 1H), 7.51 (br d, 1H, J¼7.4 Hz), 7.30
(m, 2H), 7.26–7.15 (m, 4H); 13C NMR (75 MHz, 1% TFA in DMSO-d6)
d
144.6, 137.6, 136.3, 134.43, 134.37, 129.5, 128.5, 128.3, 128.2, 127.8,
127.2, 125.6, 124.8, 122.9, 118.7, 113.1, 83.1, 76.7, 71.7; HRMS m/z
597.0221 calcd for C26H20IN3O4S; found 597.0219. Anal. Calcd for
d 175.2, 144.3, 137.7, 136.8, 136.7, 133.7, 126.6, 124.9, 124.5,
123.6, 122.5, 122.1, 121.9, 120.2, 120.0, 119.8, 119.7, 114.0, 112.8,
112.3, 106.2; HRMS m/z 326.1167 calcd for C20H14N4O; found
326.1169.
C
26H20IN3O4S: C, 52.27; H, 3.37; N, 7.03. Found: C, 52.19; H, 3.53; N,
6.78. 1-Benzenesulfonyl-3-tributylstannyl-1H-indole 7d. To a solution
of 3-iodoindole 7b (1 g, 2.6 mmol) in toluene (25 mL) was added
hexabutylditin (1.6 mL, 3.17 mmol) and Pd(PPh3)4 (150 mg,
0.13 mmol). The reaction mixture was refluxed for 6 h under argon,
cooled to rt, and evaporated to dryness affording an oily residue
(3.05 g), which was purified by column chromatography (eluting
with hexane/Et2O/Et3N 94:5:1) to give stannane 7d12 (927 mg,
65%). (1-Benzenesulfonyl-1H-indol-3-yl)-[4-(1-benzenesulfonyl-1H-
indol-3-yl)-1-benzyloxymethyl-1H-imidazol-2-yl]-methanone 11. To
a solution of compound 10 (230 mg, 0.38 mmol) in DMF (5 mL)
under argon was added Pd(PPh3)2Cl2 (30 mg, 0.04 mmol), CuI
(15 mg, 0.08 mmol), and a solution of the stannane 7d (280 mg,
0.51 mmol) in DMF (3 mL). The reaction mixture was warmed at
120 ꢁC under argon and stirred at the same temperature for 2 h.
Then the reaction mixture was cooled to rt, diluted with CH2Cl2,
washed (15% ammonia and brine), dried (MgSO4), and evaporated
under reduced pressure. Flash chromatography of the residue
(eluting with CH2Cl2/hexane 4:1) gave compound 11 (211 mg, 75%)
4.3. Synthesis of topsentin 2
1-Benzenesulfonyl-6-benzyloxy-1H-indole-3-carboxaldehyde 7e.
A solution of 6-benzyloxy-1H-indole-3-carboxaldehyde15 (680 mg,
2.7 mmol) in DMF (8 mL) was slowly added to a suspension of NaH
(60%, 150 mg, 3.7 mmol) in THF (25 mL) at 0 ꢁC. The reaction mix-
ture was stirred for 30 min and PhSO2Cl (0.5 mL, 3.3 mmol) was
added. After that, the cooling bath was removed and the reaction
mixture was stirred overnight at rt. It was then diluted with CH2Cl2,
washed (saturated NaHCO3 and brine), dried (MgSO4), and evapo-
rated under reduced pressure. Purification of the residue by flash
chromatography (eluting with CH2Cl2/hexane 9:1) led to aldehyde
7e (985 mg, 93%) as a white solid. Rf 0.51 (CH2Cl2/hexane 9:1); IR
(KBr,
NMR (300 MHz, CDCl3)
1H), 7.78 (d, 2H, J¼8.2 Hz), 7.6–7.3 (m, 9H), 7.06 (dd, 1H, J¼8.2,
2.0 Hz), 5.1 (s, 2H); 13C NMR (75 MHz, CDCl3)
185.2, 157.9, 137.3,
n
cmꢀ1) 3134–3070, 2824, 2739, 1682, 1217–1186, 738, 729; 1H
10.02 (s, 1H), 8.1 (d, 1H, J¼8.2 Hz), 8.09 (s,
d
d
as a colored thick syrup. Rf 0.33 (CH2Cl2/hexane 4:1); IR (KBr,
cmꢀ1) 3159, 3065, 2928, 1635, 1533, 1446, 1375, 1184, 1132, 1097,
976; 1H NMR (300 MHz, CDCl3)
n
136.7, 136.3, 135.1, 134.6, 129.6, 129.2, 128.7, 128.0, 127.3, 127.0,
123.2, 122.7, 120.0, 115.0, 98.7, 70.5; MS m/z 391 (Mþ, 70%), 300
(MþꢀBn, 10%). (1-Benzenesulfonyl-6-benzyloxy-1H-indol-3-yl)-(1-
benzyloxymethyl-4-iodo-1H-imidazol-2-yl)-methanol 13. To a solu-
tion of compound 8a (1 g, 2.27 mmol) in THF (20 mL) at ꢀ78 ꢁC was
added n-BuLi (1.6 M, 1.6 mL) and the reaction mixture was stirred
for 45 min at that temperature. Then, to the resulting solution of
the imidazol-2-yllithium derivative 8b was added a solution of
aldehyde 7e (300 mg, 0.77 mmol) in THF (5 mL) and the reaction
mixture was slowly warmed to 0 ꢁC. It was then treated with sat-
urated NH4Cl and extracted with CH2Cl2. The organic layer was
washed (H2O and brine), dried (MgSO4), and evaporated under
reduced pressure. Flash chromatography of the residue (eluting
with CH2Cl2/EtOAc 9:1) provided the alcohol 13 (400 mg, 74%) as
a thick syrup, which solidified upon cooling; mp 145–146 ꢁC. Rf 0.22
d
9.6 (s, 1H), 8.47 (dd, 1H, J¼8.3,
2.3 Hz), 8.27 (d, 1H, J¼7.3 Hz), 8.09 (d, 1H, J¼8 Hz), 8.02 (d, 2H,
J¼8.2 Hz), 8.0 (s, 1H), 7.94 (d, 2H, J¼7.3 Hz), 7.62 (s, 1H), 7.56–7.15
(m,16H), 6.02 (s, 2H), 4.65 (s, 2H); 13C NMR (75 MHz, CDCl3)
d 178.0,
142.5, 137.9, 137.6, 136.6, 135.4, 134.5, 134.4, 133.9, 129.6, 129.3,
128.6, 128.5, 128.1, 127.8, 127.1, 126.8, 125.6, 125.2, 124.8, 123.9,
122.9, 122.7, 121.5, 120.8, 119.0, 116.4, 113.7, 113.0, 76.9, 71.5; HRMS
m/z 726.1658 calcd for C40H30N4O6S2; found 726.1606. Anal. Calcd
for C40H30N4O6S2: C, 66.10; H, 4.16; N, 7.71. Found: C, 65.88; H, 4.29;
N, 7.42. [1-Benzyloxymethyl-4-(1H-indol-3-yl)-1H-imidazol-2-yl]-
(1H-indol-3-yl)-methanone 12. To a solution of compound 11
(180 mg, 0.248 mmol) in EtOH/THF (15 mL:4 mL) was added a 10%
aqueous KOH solution (5 mL). The reaction mixture was stirred at
reflux temperature for 2 h and then cooled to rt and concentrated
under vacuum. The residue was diluted with EtOAc, washed (H2O
and brine), dried (MgSO4) and evaporated under reduced pressure.
Flash chromatography of the residue (eluting with CH2Cl2:EtOAc
9:1) furnished compound 12 (95 mg, 86%) as a pale yellow pow-
(CH2Cl2/EtOAc 9:1); IR (KBr,
n
cmꢀ1) 3144–3040, 1618, 1489, 1209,
1174, 1105; 1H NMR (300 MHz, CDCl3)
d
7.7 (br d, 2H, J¼7.4 Hz), 7.55
(d, 1H, J¼2.15 Hz), 7.5–7.2 (m, 13H), 7.15 (d, 1H, J¼8.7 Hz), 7.1 (br dd,
2H, J¼7.3, 3.5 Hz), 7.01 (s, 1H), 6.85 (dd, 1H, J¼8.7, 2.3 Hz), 5.13 (s,
2H), 5.10 (d, 1H, J¼10.7 Hz), 4.97 (d, 1H, J¼10.7 Hz), 4.18 (d, 1H,
der; mp 173–175 ꢁC; Rf 0.4 (CH2Cl2:EtOAc 9:1); IR (KBr,
3402–3343, 1605, 1521, 1468, 1375, 1431, 1076; 1H NMR (300 MHz,
DMSO-d6)
n
cmꢀ1
)
J¼11.8 Hz), 4.07 (d, 1H, J¼11.8 Hz); 13C NMR (75 MHz, CDCl3)
d 157.1,
150.4, 137.9, 136.8, 136.4, 136.0, 133.7, 129.1, 128.6, 128.4, 128.0,
127.9, 127.5, 127.3, 126.6, 126.3, 122.53, 122.46, 122.1, 120.8, 113.5,
99.2, 79.6, 74.6, 70.4, 70.3, 63.8; HRMS m/z 705.0768 calcd for
d
12.2 (br s, 1H), 11.4 (br s, 1H), 9.22 (d, 1H, J¼3.0 Hz), 8.5
(br dd, 1H, J¼5.9, 3.2 Hz), 8.2 (br d, 1H, J¼7.2 Hz), 8.05 (s, 1H), 7.95
(d, 1H, J¼2.4 Hz), 7.62 (br dd, 1H, J¼5.9, 3.2 Hz), 7.53 (br d, 1H,
J¼7.3 Hz), 7.40–7.15 (m, 9H), 6.08 (s, 2H), 4.7 (s, 2H); 13C NMR
C
33H28IN3O5S; found 705.0794. (1-Benzenesulfonyl-6-benzyloxy-
1H-indol-3-yl)-(1-benzyloxymethyl-4-iodo-1H-imidazol-2-yl)-meth-
anone 14. To solution of secondary alcohol 13 (600 mg,
(75 MHz, DMSO-d6)
d
178.0, 142.8, 137.8, 137.7, 137.0, 136.8, 136.5,
a
128.4, 127.8, 127.0, 125.1, 123.3, 123.2, 122.3, 121.9, 121.7, 120.2,
119.8, 119.6, 115.1, 112.5, 112.0, 109.6, 76.6, 70.6; HRMS m/z 446.1716
0.85 mmol) in CH2Cl2 (70 mL) was added MnO2 (1.7 g, 19.5 mmol).
The reaction mixture was stirred at rt for 3 h and then filtered. The

5910
S.K. Mal et al. / Tetrahedron 64 (2008) 5904–5914
solid residue was rinsed (CH2Cl2, Et2O). The filtrate was evaporated
under reduced pressure to provide ketone 14 (520 mg, 87%) as
a colored syrup. An analytical sample was prepared by filtering on
J¼1.9 Hz), 6.86 (dd, 1H, J¼8.5, 2.0 Hz); 13C NMR (75 MHz, 1% TFA in
DMSO-d6)
d 174.6, 154.6, 144.0, 137.8, 136.6, 136.4, 133.4, 124.7,
124.2, 122.2, 122.0, 120.0, 119.8, 119.4, 119.0, 114.0, 112.4, 112.1, 106.1,
97.7; HRMS m/z 342.1110 calcd for C20H14N4O2; found 342.1116.
silica gel. Rf 0.83 (CH2Cl2/EtOAc 9:1); IR (KBr,
n
cmꢀ1): 3144–3040,
9.1 (s, 1H),
1618, 1489, 1209, 1174, 1105; 1H NMR (300 MHz, CDCl3)
d
8.36 (d, 1H, J¼8.9 Hz), 7.85 (d, 1H, J¼8.8 Hz), 7.83 (s, 1H), 7.56 (d, 1H,
J¼2.2 Hz), 7.54–7.35 (m, 9H), 7.3–7.2 (m, 5H), 7.1 (dd, 1H, J¼8.9,
2.4 Hz), 5.89 (s, 2H), 5.17 (s, 2H), 4.59 (s, 2H); 13C NMR (75 MHz,
4.4. Synthesis of bromodeoxytopsentin 4
4.4.1. Using the BOM protecting group for the imidazole moiety
1-Benzenesulfonyl-6-bromo-3-tributylstannyl-1H-indole 7h. To
a solution of 6-bromo-indole 7f (1.8 g, 9.18 mmol) in dry DMF
(30 mL) was added KOH (1.4 g, 25 mmol) and then a solution of I2
(2.4 g, 9.45 mmol) in DMF (30 mL) was added dropwise. The re-
action mixture was stirred at rt for 30 min and then poured onto
ice. The resulting mixture was extracted with EtOAc. The organic
extract was washed (diluted aq NaSO3H, H2O, brine), dried
(MgSO4), and evaporated to afford crude 6-bromo-3-iodoindole,
which was used for the next step without further purification. To
a solution of the later (2.94 g, 9.1 mmol) in dry DMF (40 mL) was
added NaH (60%, 480 mg, 12 mmol) at 0 ꢁC. The reaction mixture
was stirred at that temperature for 30 min and then a solution of
PhSO2Cl (1.6 mL, 10.6 mmol) in DMF (10 mL) was added. The re-
action mixture was allowed to warm to rt and stirred for 3 h. It was
then poured into cold H2O, extracted with EtOAc, washed (H2O,
brine), dried (MgSO4), and evaporated under reduced pressure.
Flash chromatography of the residue (eluting with hexane/EtOAc
9:1) furnished 1-benzenesulfonyl-6-bromo-3-iodo-1H-indole 7g
(4.05 g, 95%) as a pale yellow solid. Rf 0.37 (hexane/AcOEt 9:1);
CDCl3)
d 177.1, 157.4, 144.6, 137.5, 136.8, 136.3, 135.3, 134.3, 129.5,
128.6, 128.5, 128.2, 128.0, 127.7, 127.3, 127.1, 123.5, 122.3, 118.9,
114.6, 98.7, 83.1, 76.8, 71.6, 70.4; HRMS m/z 703.0675 calcd
for C33H26IN3O5S; found 703.0638. (1-Benzenesulfonyl-6-benzyl-
oxy-1H-indol-3-yl)-[4-(1-benzenesulfonyl-1H-indol-3-yl)-1-benzyl-
oxymethyl-1H-imidazol-2-yl]-methanone 15. To a solution of com-
pound 14 (400 mg, 0.57 mmol) in DMF (10 mL), under argon, were
successively added Pd(PPh3)2Cl2 (32 mg, 0.011 mmol), CuI (20 mg,
0.1 mmol), and then a solution of the stannane 7d (280 mg,
0.51 mmol) in DMF (3 mL). The reaction mixture was heated and
stirred under argon at 120 ꢁC for 2 h. After cooling to rt, the reaction
mixture was concentrated, taken up in CH2Cl2, filtered through
Celite, washed (15% NH4OH and brine), dried (MgSO4), and evap-
orated under reduced pressure. Flash chromatography of the resi-
due (eluting with CH2Cl2/hexane 4:1) afforded compound 15
(375 mg, 79%) as a yellow fluffy solid. Rf 0.44 (CH2Cl2/hexane 4:1);
IR (KBr,
n
cmꢀ1) 3151–3067, 2924, 1628, 1531, 1448, 1375, 1182,
1093; 1H NMR (300 MHz, CDCl3)
d
9.4 (s, 1H), 8.31 (d, 1H, J¼8.8 Hz),
8.24 (d, 1H, J¼8.2 Hz), 8.07 (d, 1H, J¼8.6 Hz), 7.98 (s, 1H), 7.95 (d, 2H,
J¼7.4 Hz), 7.88 (d, 2H, J¼7.8 Hz), 7.62 (s, 1H), 7.6–7.2 (m, 19H), 7.07
(dd, 1H, J¼2.0, 8.7 Hz), 5.99 (s, 2H), 5.18 (s, 2H), 4.65 (s, 2H); 13C
mp 173–174 ꢁC; IR (KBr,
n
cmꢀ1) 3140–3126, 1585, 1421, 1367, 1176;
8.16 (d, 1H, J¼1.5 Hz), 7.89 (br d, 2H,
1H NMR (300 MHz, CDCl3)
d
NMR (75 MHz, CDCl3)
d
178.0, 157.4, 142.5, 138.0, 137.7, 136.8, 136.6,
J¼7.3 Hz), 7.65 (s, 1H), 7.58 (m, 1H), 7.48 (m, 2H), 7.41 (dd, 1H, J¼8.4,
135.5, 135.4, 134.3, 133.9, 129.6, 129.3, 128.6, 128.5, 128.1, 120.0,
127.8, 127.4, 127.0, 126.8, 125.2, 123.9, 123.5, 122.7, 122.4, 121.5,
120.7, 119.2, 116.5, 114.5, 113.7, 98.6, 76.9, 71.5, 70.4; HRMS m/z
832.2035 calcd for C47H36N4O7S2; found 832.2025. Anal. Calcd for
1.5 Hz), 7.21 (d, 1H, J¼8.4 Hz); 13C NMR (75 MHz, CDCl3)
d 137.6,
134.8, 134.4, 131.4, 130.1, 129.6, 127.4, 126.8, 123.2, 119.6, 116.3, 66.5;
79
HRMS m/z 460.8582 calcd for C
m/z 462.8561 calcd for C
H BrINO2S; found 462.8584,
9
14
81
H BrINO2S; found 462.8591. To a solu-
9
14
C
47H36N4O7S2$1/4H2O: C, 67.41; H, 4.39; N, 6.69. Found: C, 67.29; H,
tion of compound 7g (600 mg, 1.3 mmol) in DMF (15 mL) was
added dichlorobis(triphenylphosphine)palladium(II), PdCl2(PPh3)2
(76 mg, 0.11 mmol), and then hexabutylditin, (Bu3Sn)2 (1 mL,
2 mmol). The reaction mixture was warmed to 100 ꢁC and stirred at
that temperature for 30 min. Then the reaction mixture was cooled
to rt, diluted with Et2O, washed (H2O, brine), dried (MgSO4), and
evaporated to provide the crude stannane (1.9 g) as a colored oil,
which upon flash chromatography (eluting with hexane/EtOAc/
Et3N 94:5:1) afforded pure stannane 7h (526 mg, 64%) as a colorless
4.45; N, 6.56. (6-Benzyloxy-1H-indol-3-yl)-[1-benzyloxymethyl-4-
(1H-indol-3-yl)-1H-imidazol-2-yl]-methanone 16. To a solution of
compound 15 (330 mg, 0.396 mmol) in EtOH/THF (4:1, 25 mL) was
added a 10% aqueous KOH solution (10 mL). The reaction mixture
was stirred under reflux for 2 h, then cooled to rt and concentrated
under vacuum. The residue was diluted with EtOAc. The organic
layer was washed (H2O, brine), dried (MgSO4), and evaporated
under reduced pressure. Flash chromatography of the residue
(eluting with CH2Cl2/EtOAc 9:1) afforded compound 16 (212 mg,
oil. Rf 0.58 (hexane/AcOEt 9:1); IR (KBr,
1592, 1446, 1417, 1373, 1184, 1130, 1091; 1H NMR (300 MHz, CDCl3)
8.19 (br s, 1H), 7.88 (br d, 2H, J¼7.6 Hz), 7.52 (m, 1H), 7.43 (m, 2H),
n
cmꢀ1) 2957–2928, 2852,
97%) as a yellow solid. Rf 0.41 (CH2Cl2/EtOAc 9:1); IR (KBr,
n
cmꢀ1
10.1
)
3397, 1608, 1506, 1452, 1080, 874; 1H NMR (300 MHz, CDCl3)
d
d
(br s, 1H), 8.57 (d, 1H, J¼3 Hz), 8.41 (d, 1H, J¼8.7 Hz), 8.04 (br s, 1H),
7.8 (d, 1H, J¼7.5 Hz), 7.49 (s, 1H), 7.15 (m, 13H), 7.0 (d, 1H, J¼7.5 Hz),
6.9 (dd, 1H, J¼2.1, 8.7 Hz), 6.09 (br s, 1H), 5.87 (s, 2H), 4.56 (s, 2H),
7.38 (s, 1H), 7.31 (br s, 2H), 1.51 (m, 6H), 1.31 (m, 6H), 1.13 (m, 6H),
0.86 (t, 9H, J¼7 Hz); 13C NMR (75 MHz, CDCl3)
d 138.2, 136.5, 135.9,
133.8, 131.9, 129.3, 126.6, 126.4, 123.8, 117.9, 117.1, 116.5, 29.0, 27.1
4.16 (s, 2H); 13C NMR (75 MHz, CDCl3)
d
178.4, 156.1, 143.3, 137.0,
(satellites at 27.5 and 26.7), 13.6, 9.9 (satellites at 12.1 and
79
136.8, 136.6, 136.5, 136.3, 128.3, 128.0, 127.9, 127.8, 123.0, 122.7,
122.1, 120.7, 120.1, 119.5, 118.3, 115.8, 113.2, 112.0, 109.7, 95.7, 76.4,
71.1, 69.7; HRMS m/z 552.2137 calcd for C35H28N4O3; found
7.5); HRMS m/z 625.0672 calcd for C
H
H
BrNO2S120Sn; found
26 36
81
625.0666, m/z 627.0651 calcd for
C
BrNO2S120Sn; found
26 36
627.0784. [4-(1-Benzenesulfonyl-6-bromo-1H-indol-3-yl)-1-benzyl-
oxymethyl-1H-imidazol-2-yl]-(1-benzenesulfonyl-1H-indol-3-yl)-
methanone 17. To a solution of the iodoimidazole 10 (125 mg,
0.21 mmol) in DMF (4 mL) at rt was added PdCl2(PPh3)2 (12 mg,
0.017 mmol) and CuI (6 mg, 0.03 mmol). The reaction mixture was
552.2161. Topsentin 2.
A solution of compound 16 (140 mg,
0.25 mmol) in EtOH (20 mL) containing 10% Pd/C (50 mg) and
ammonium formate (210 mg, 3.3 mmol) was refluxed for 3 h. The
reaction mixture was then cooled to rt and filtered through a pad of
Celite (rinsing with CH2Cl2 and EtOAc). The filtrate was evaporated
under reduced pressure. Flash chromatography of the residue
(eluting with CH2Cl2/MeOH 94:6) provided topsentin 2 (83 mg,
heated 120 ꢁC and
a solution of the stannane 7h (160 mg,
0.256 mmol) in DMF (1 mL) was added. The reaction mixture was
stirred at 120 ꢁC for 2 h and then allowed to return to rt. It was
filtered through a pad of Celite and concentrated under vacuum.
The residue was purified by flash chromatography (eluting with
CH2Cl2/hexane 7:3) to afford compound 17 (124 mg, 73%). Rf 0.28
95%) as a yellow powder. Rf 0.24 (CH2Cl2/MeOH 95:5); IR (KBr,
n
cmꢀ1) 3366–3283, 2926, 1582, 1527, 1458, 1429, 1238, 1105; UV
(EtOH, lmax nm) 208, 230, 253, 273, 375; 1H NMR (300 MHz, 1% TFA
in DMSO-d6)
d
12.15 (d, 1H, J¼2.6 Hz), 11.64 (br s, 1H), 8.84 (d, 1H,
(CH2Cl2/hexane 7:3); 1H NMR (300 MHz, CDCl3)
d 9.53 (s, 1H), 8.46
J¼2.9 Hz), 8.15 (d, 1H, J¼8.5 Hz), 8.11 (d, 1H, J¼2.6 Hz), 8.05 (d, 2H,
J¼7.5 Hz), 7.96 (s, 1H), 7.53 (d, 1H, J¼7.2 Hz), 7.22 (m, 2H), 7.0 (d, 1H,
(m, 1H), 8.16 (d, 1H, J¼8.5 Hz), 8.05–7.97 (m, 3H), 7.95 (d, 1H,
J¼7.7 Hz), 7.61 (s, 1H), 7.60–7.45 (m, 7H), 7.38 (m, 2H), 7.29 (m, 5H);

S.K. Mal et al. / Tetrahedron 64 (2008) 5904–5914
5911
13C NMR (75 MHz, CDCl3)
136.1, 134.9, 134.5, 134.4, 134.2, 129.6, 129.5, 128.6, 128.5, 128.1,
127.8,127.4,127.3,127.2,127.1,126.8,125.6,124.9,122.9,122.7,120.8,
d
177.9, 142.6, 137.8, 137.7, 136.9, 136.6,
under reduced pressure. Flash chromatography of the residue
(eluting with CH2Cl2/EtOAc 98:2/94:6) afforded the secondary
alcohol 19 (440 mg, 53%) as a colorless oil. Rf 0.16 (CH2Cl2/AcOEt
119.0, 118.9, 116.7, 116.3, 115.1, 71.6; HRMS m/z 804.0712 calcd
97.5:2.5); IR (KBr,
n
cmꢀ1) 3400–3100, 2953–2895, 2361, 2341,1599,
79
for C
H
BrN4O6S2; found 804.0700, m/z 806.0691 calcd for
1448,1373,1176,1118,1099; 1H NMR (300 MHz, CDCl3)
d 7.97 (d,1H,
40 29
81
C
H
40 29
BrN4O6S2; found 806.0626. Bromodeoxytopsentin 4. To a so-
J¼6.3 Hz), 7.9 (d, 2H, J¼7.5 Hz), 7.71 (br d, 1H, J¼1.0 Hz), 7.53 (m,
1H), 7.41 (m, 2H), 7.28 (m, 2H), 7.13 (br t, 1H, J¼7.5 Hz), 7.01 (s, 1H),
6.16 (br d, 1H, J¼2 Hz), 5.62 (br d, 1H, J¼5.2 Hz), 5.11 (d, 1H,
J¼10.5 Hz), 5.04 (d, 1H, J¼10.5 Hz), 3.11 (m, 2H), 0.63 (m, 2H), ꢀ0.12
lution of compound 17 (120 mg, 0.15 mmol) in EtOH/THF (10:2 mL)
was added 10% aqueous KOH (4 mL). The reaction mixture was
refluxed for 3 h and then it was allowed to return to rt, diluted with
CH2Cl2, and washed (H2O and brine). The organic phase was dried
(MgSO4) and evaporated to dryness leaving crude 18 as an oil
(62 mg, 90%). Compound 18 was dissolved in a mixture of 3 N HCl/
THF (2:1, 9 mL). The solution was stirred overnight under reflux,
then cooled to rt and made basic by slow addition of 10% aqueous
NaOH and extracted with EtOAc. The organic phase was washed
(H2O and brine), dried (MgSO4), and evaporated under reduced
pressure. Flash chromatography of the residue (eluting with
CH2Cl2/EtOAc 9:1/4:1) led to bromodeoxytopsentin 4 (39 mg,
71%; 64% from 17). Rf 0.33 (CH2Cl2/EtOAc 4:1); 1H NMR (300 MHz,
(s, 9H); 13C NMR (75 MHz, CDCl3)
d 150.1, 138.0, 135.5, 133.9, 129.3,
128.3, 126.6, 126.3, 125.1, 123.8, 123.6, 122.4, 120.2, 113.6, 79.5, 75.2,
66.8, 63.8, 17.6, ꢀ1.6; HRMS m/z 609.0614 calcd for C24H28IN3O4SSi;
found 609.0628. (1-Benzenesulfonyl-1H-indol-3-yl)-[4-iodo-1-(2-
trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-methanone 20. To
a solution of alcohol 19 (385 mg, 0.63 mmol) in CH2Cl2 (30 mL) was
added MnO2 (1.1 g, 12 mmol) and the resulting suspension was
stirred for 3 h at rt. The reaction mixture was filtered (rinsing with
CH2Cl2) and the filtrate was evaporated leading to essentially pure
compound 20 (357 mg, 93%) as colorless oil. Rf 0.48 (CH2Cl2/hexane
2% TFA in DMSO-d6)
d
11.0 (br s, 1H), 10.3 (br s, 1H), 8.99 (d, 2H,
4:1); IR (KBr,
n
cmꢀ1) 1634, 1530, 1446, 1383, 1176, 1099, 976, 1176,
9.28 (s, 1H), 8.42 (m, 1H), 8.02 (m,
J¼3.1 Hz), 8.36 (m, 1H), 8.08 (d, 1H, J¼2.6 Hz), 8.02 (d, 1H, J¼8.5 Hz),
858; 1H NMR (300 MHz, CDCl3)
d
7.96 (s, 1H), 7.70 (d, 2H, J¼1.8 Hz), 7.60 (m, 1H), 7.36–7.25 (m, 3H);
3H), 7.6 (m, 1H), 7.53 (m, 2H), 7.51 (s, 1H), 7.38 (m, 2H), 5.84 (s, 2H),
13C NMR (75 MHz, 2% TFA in DMSO-d6)
d
173.0, 142.3, 138.8, 137.8,
3.65 (m, 2H), 0.97 (m, 2H), ꢀ0.03 (s, 9H); 13C NMR (75 MHz, CDCl3)
137.2, 131.6, 126.6, 126.4, 124.4, 123.7, 123.5, 123.2, 121.76, 121.70,
d 177.2, 144.6, 137.6, 134.4, 129.5, 128.6, 127.2, 125.6, 124.8, 122.8,
117.4, 115.4, 115.2, 114.0, 113.1, 104.4; HRMS m/z 404.02907 calcd for
118.8, 113.1, 83.0, 77.4, 67.5, 17.8, ꢀ1.5; HRMS m/z 607.0458 calcd for
79
C
C
H
H
20 13
BrN4O; found 404.02727, m/z 406.02522 calcd for
BrN4O; found 406.01652.
C24H26IN3O4SSi; found 607.0458. [4-(1-Benzenesulfonyl-6-bromo-
20 13
81
1H-indol-3-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-
yl]-(1-benzenesulfonyl-1H-indol-3-yl)-methanone 21. To a solution
of the iodo-imidazole 20 (315 mg, 0.52 mmol) in DMF (12 mL) were
added, under argon, PdCl2(PPh3)2 (42 mg, 0.06 mmol) and CuI
(20 mg, 0.1 mmol). Then a solution of the stannane 7h (525 mg,
0.84 mmol) in DMF (3 mL) was added dropwise. The reaction
mixture was heated under argon and stirred at 120 ꢁC for 2 h, then
it was allowed to return to rt and filtered through a pad of Celite
(rinsing with CH2Cl2). The filtrate was concentrated under reduced
pressure. Flash chromatography of the residue (eluting with
CH2Cl2/hexane 3:1) afforded compound 21 (217 mg, 51%) as a pale
4.4.2. Using a SEM protecting group for the imidazole moiety
4-Iodo-[2-(trimethylsilyl)ethoxy]methyl-1H-imidazole-2-carbox-
aldehyde 8d. To
a solution of 4,5-diiodoimidazole (500 mg,
1.56 mmol) in DMF (20 mL) at 0 ꢁC was added NaH (60%, 100 mg,
2.5 mmol) in small portions. After stirring at that temperature for
30 min, 2-(trimethylsilyl)ethoxymethylchloride SEMCl (0.4 mL,
2.3 mmol) was added dropwise. The reaction mixture was allowed
to warm slowly to rt and stirred for 3 h. It was then diluted with
Et2O and washed (saturated NaCO3H, H2O and brine), dried
(MgSO4), and evaporated under reduced pressure to provide an oily
residue (711 mg). Flash chromatography of the oily residue (eluting
with CH2Cl2/EtOAc 97:3) led to 4,5-diiodo-1-(2-trimethylsilanyl-
ethoxymethyl)-1H-imidazole4b (510 mg, 72%). To a solution of that
SEM-protected imidazole derivative (2 g, 4.4 mmol) in THF (25 mL)
at ꢀ78 ꢁC was added n-BuLi (2.5 M, 2.2 mL). The solution was
stirred at that temperature for 45 min and the lithium derivative
thus formed was quenched by addition of DMF (2 mL). The reaction
mixture was allowed to warm to rt and then treated with a satu-
rated NH4Cl aqueous solution and EtOAc. The organic layer was
washed (H2O and brine), dried (MgSO4), and evaporated under
reduced pressure. Flash chromatography of the residue (eluting
with CH2Cl2/EtOAc 97.5:2.5) furnished the aldehyde 8d (710 mg,
yellow syrup. Rf 0.34 (CH2Cl2/hexane 3:1); IR (KBr,
1448, 1377, 1184, 1136, 1091, 976, 1176, 858; 1H NMR (300 MHz,
CDCl3)
n
cmꢀ1) 1633,
d
9.6 (s, 1H), 8.48 (m, 1H), 8.29 (d, 1H, J¼1.6 Hz), 8.22 (d, 1H,
J¼8.5 Hz), 8.2–7.95 (m, 6H), 7.69 (s, 1H), 7.65–7.45 (m, 7H), 7.40 (m,
2H), 5.97 (s, 2H), 3.71 (m, 2H), 1.02 (m, 2H), ꢀ0.07 (s, 9H); 13C NMR
(75 MHz, CDCl3) d 177.9, 142.5, 137.8, 137.7, 136.1, 134.9, 134.5, 134.4,
134.2, 129.6, 129.5, 128.7, 127.5, 127.3, 127.1, 126.6, 125.6, 124.8,
122.9, 120.5, 119.0, 116.7, 116.4, 113.0, 77.3, 67.3, 17.9, ꢀ1.4; HRMS
79
m/z 814.0950 calcd for C
H BrN4O6S2Si; found 814.0924, m/z
38 35
81
816.0930 calcd for C
H BrN4O6S2Si; found 816.0831. [4-(6-Bromo-
38 35
1H-indol-3-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-
yl]-(1H-indol-3-yl)-methanone 22. To a solution of compound 21
(180 mg, 0.22 mmol) in EtOH/THF (10 mL:2 mL) was added 10%
aqueous KOH (4 mL). The reaction mixture was refluxed for 2.5 h,
cooled back to rt, diluted with EtOAc, and washed (H2O and brine).
The organic phase was dried (MgSO4) and evaporated under
reduced pressure. Flash chromatography of the residue (eluting
with CH2Cl2/EtOAc 9:1) furnished compound 22 (105 mg, 89%) as
45%) as a pale yellow oil. IR (KBr,
943, 860, 837; 1H NMR (300 MHz, CDCl3)
5.68 (s, 2H), 3.51 (t, 2H, J¼9 Hz), 0.86 (t, 2H, J¼9 Hz), ꢀ0.07 (s, 9H);
13C NMR (75 MHz, CDCl3)
180.9, 144.9, 130.6, 85.3, 75.8, 67.2, 17.6,
n
cmꢀ1) 1689, 1402, 1250, 1097,
9.68 (s, 1H), 7.4 (s 1H),
d
d
–1.6; HRMS m/z 352.0104 calcd for C14H8IN2O2Si; found 352.0096.
(1-Benzenesulfonyl-1H-indol-3-yl)-[4-iodo-1-(2-trimethylsilanyl-
ethoxymethyl)-1H-imidazol-2-yl]-methanol 19. To a solution of 1-
benzenesulfonyl-3-iodo-1H-indole 7b (1 g, 2.6 mmol) in dry THF
(24 mL) under argon at ꢀ90 ꢁC (liquid nitrogen/MeOH) was added
tBuLi (1.7 M in pentane, 3.6 mL) and the reaction mixture was
stirred at that temperature for 5 min. To the resulting solution of 3-
lithio-derivative 7i was added a solution of aldehyde 8d (480 mg,
1.36 mmol) in THF (6 mL). The reaction mixture was slowly warmed
to ꢀ20 ꢁC (over 2 h), quenched at that temperature with saturated
aqueous NH4Cl, and then extracted at rt with CH2Cl2. The organic
layer was washed (H2O and brine), dried (MgSO4), and evaporated
a yellow syrup; IR (KBr,
n
cmꢀ1) 3395–3308, 1597, 1518, 1452, 1425,
9.16 (br s, 1H),
1095, 1078, 858, 744; 1H NMR (300 MHz, CDCl3)
d
8.71 (m, 1H), 8.60–8.53 (m, 2H), 7.83 (d, 1H, J¼8.5 Hz), 7.49 (s, 1H),
7.36–7.11 (m, 6H), 5.92 (s, 2H), 3.70 (m, 2H), 0.98 (m, 2), ꢀ0.04 (s,
9H); 13C NMR (75 MHz, CDCl3)
d 178.7, 143.6, 137.3, 136.9, 136.3,
136.1, 126.8, 124.1, 123.9, 123.7, 123.1, 123.0, 122.5, 121.2, 118.8, 116.3,
116.0, 114.7, 111.9, 110.8, 77.0, 67.2, 18.1, ꢀ1.3; HRMS m/z 534.1086
79
calcd for C
H BrN4O2Si; found 534.1089, m/z 536.1066 calcd
26 27
81
for C
H BrN4O2Si; found 536.1077. Deoxybromotopsentin 4. The
26 27
SEM-protected compound 22 (87 mg, 0.16 mmol) was dissolved in
a mixture of 3 N HCl/THF (2:1, 9 mL). The reaction mixture was

5912
S.K. Mal et al. / Tetrahedron 64 (2008) 5904–5914
stirred overnight under reflux, then cooled to rt and made basic by
slow addition of 10% aqueous NaOH. The alkaline reaction mixture
was extracted with EtOAc. The organic layer was washed (H2O and
brine), dried (MgSO4), and evaporated under reduced pressure.
Flash chromatography of the residue (eluting with CH2Cl2/EtOAc
9:1/4:1) led to bromodeoxytopsentin 4 (42 mg, 64%, already
described).
(saturated NaCO3H, H2O, brine), dried (MgSO4), and evaporated
under reduced pressure. Flash chromatography of the residue
(eluting with hexane/EtOAc 4:1) furnished compound 7i (1.5 g, 71%)
as a thick oil. Rf 0.38 (hexane/EtOAc 4:1); IR (KBr,
n
cmꢀ1) 3142,1612,
7.90
1579, 1487, 1184, 1446, 1371, 1176; 1H NMR (300 MHz, CDCl3)
d
(m, 2H), 7.68 (d, 1H, J¼2.0 Hz), 7.6 (s, 1H), 7.56 (m, 1H), 7.45 (m, 2H),
7.24 (d, 1H, J¼8.6 Hz), 7.03 (dd, 1H, J¼8.6, 2.1 Hz), 5.24 (s, 2H), 3.5 (s,
3H); 13C NMR (75 MHz, CDCl3)
d 156.1, 137.5, 134.8, 134.0, 129.2,
4.5. Synthesis of bromotopsentin 5
127.1, 126.9, 122.5, 114.4, 100.8, 95.0, 66.7, 56.0; HRMS m/z 442.9688
calcd for C16H14INO4S; found 442.9689.
4.5.1. 1-Benzenesulfonyl-3-iodo-6-methoxymethoxy-1H-indole 7i
To a solution of 4-hydroxybenzaldehyde (6 g, 49 mmol) in
CH2Cl2 (50 mL) maintained around 0 ꢁC in a cooling bath were
added iPr2NEt (19 mL, 110 mmol) and methoxymethylchloride,
MOMCl (5 mL, 65 mmol). The reaction mixture was allowed to
warm and stirred at rt for 1.5 h and then diluted with CH2Cl2,
washed (1 N HCl, saturated NaHCO3, H2O, and brine), and evapo-
rated under reduced pressure. Purification of the residue by flash
chromatography (eluting with CH2Cl2/EtOAc 95:5) led to 4-
(methoxymethyl)oxy-benzaldehyde (7.7 g, 94%). A mixture of eth-
ylazidoacetate (9.7 g, 75 mmol) and 4-OMOM-aldehyde (3 g,
18 mmol) in EtOH (18 mL) was added slowly (over 1.5 h) to a solu-
tion of NaOEt in EtOH (2.5 N, 30 mL) at ꢀ10 ꢁC. Then, the reaction
mixture was warmed to rt, most of the solvent was evaporated
under reduced pressure, and the residue was diluted with EtOAc.
The resulting solution was washed (H2O, brine), dried (MgSO4), and
evaporated under reduced pressure. The residue was dissolved in
xylene (60 mL) and the solution was refluxed for 1 h. The reaction
mixture was cooled to rt. Evaporation of the solvent under reduced
pressure led to 6-(methoxymethoxy)-1H-indole-2-carboxylic acid
ethyl ester (2.58 g, 57%) as a pale yellow solid. To a solution of this
ester (2.38 g, 9.6 mmol) in THF/H2O/MeOH (4:3:2, 90 mL) was
added a large excess of LiOH$H2O (6 g). The reaction mixture was
stirred at rt for 4 h and then most of the organic solvents were re-
moved under reduced pressure. The essentially aqueous residue
was cooled to 0 ꢁC, acidified to pH w3 (with 5 N HCl), and extracted
with EtOAc. The organic extracts were combined, washed (H2O,
brine), dried (MgSO4), and evaporated under reduced pressure to
provide the corresponding acid (2.1 g) as a powder. The crude acid
was treated with Cu (1.4 g) in quinoline (30 mL) at reflux for 2 h. The
reaction mixture was then cooled to rt, diluted with EtOAc, and
filtered through Celite. The filtrate was acidified to pH w4 with 5 N
HCl (cooling by addition of ice). The organic phase was washed
(saturated NaCO3H and brine), dried (MgSO4), and evaporated un-
der reduced pressure. The residue was diluted with Et2O, washed
(1 N aqueous HCl, saturated NaCO3H, and brine), dried (MgSO4), and
evaporated to dryness under reduced pressure. Flash chromatog-
raphy of the residue (eluting with hexane/EtOAc 4:1) furnished the
expected 6-methoxymethoxy-1H-indole (952 mg, 56%) as a pale
yellow oil. Rf 0.33 (hexane/EtOAc 4:1); 1H NMR (300 MHz, CDCl3)
4.5.2. Synthesis of 5 using the SEM protecting group for the
imidazole moiety
(1-Benzenesulfonyl-6-methoxymethoxy-1H-indol-3-yl)-[4-iodo-
1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-methanol 23.
To a solution of indole 7i (1 g, 2.26 mmol) in dry THF (25 mL) under
argon at ꢀ78 ꢁC was added tBuLi (1.7 M in pentane, 1.5 mL) and the
reaction mixture was stirred at that temperature for 30 min. To the
resulting solution of 3-lithio-indole 7j was added a solution of al-
dehyde 8d (740 mg, 2.1 mmol) in THF (6 mL). The mixture was
slowly warmed to 0 ꢁC (over 3 h), quenched by addition of satu-
rated aqueous NH4Cl, and diluted with CH2Cl2. The organic layer
was washed (H2O and brine), dried (MgSO4), and evaporated under
reduced pressure. Flash chromatography of the residue (1.63 g,
eluting with hexane/EtOAc 6:4) afforded the secondary alcohol 23
(625 mg, 44%) as a colorless oil. Rf 0.29 (hexane/EtOAc 6:4); IR (KBr,
n
cmꢀ1) 3134–2953,1614,1485,1373,1184,1101; 1H NMR (300 MHz,
CDCl3)
d
7.93 (br d, 2H, J¼7.3 Hz), 7.70 (d, 1H, J¼2.1 Hz), 7.64 (d, 1H,
J¼1.2 Hz), 7.56 (m, 1H), 7.45 (m, 2H), 7.14 (d, 1H, J¼8.7 Hz), 7.04 (s,
1H), 6.88 (dd, 1H, J¼8.7, 2.1 Hz), 6.15 (br s, 1H), 5.77 (m, 1H, ex-
changeable with D2O), 5.23 (d, 1H, J¼6.7 Hz), 5.20 (d, 1H, J¼6.7 Hz),
5.15 (d, 1H, J¼10.5 Hz), 5.08 (d, 1H, J¼10.5 Hz), 3.51 (s, 3H), 3.14 (m,
2H), 0.69 (m, 2H), ꢀ0.09 (s, 9H); 13C NMR (75 MHz, CDCl3)
d
155.4, 150.1, 137.8, 136.2, 133.8, 129.2, 126.9, 123.0, 122.2,
120.7, 113.9, 101.4, 94.9, 79.3, 75.1, 66.6, 63.7, 55.9, 17.6, ꢀ1.6; HRMS
m/z 669.0825 calcd for C26H32IN3O6SSi; found 669.0808. (1-Benz-
enesulfonyl-6-methoxymethoxy-1H-indol-3-yl)-[4-iodo-1-(2-trimeth-
ylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-methanone 24. To
a
solution of alcohol 23 (500 mg, 0.75 mmol) in CH2Cl2 (75 mL) was
added MnO2 (1.5 g, 17 mmol) and the resulting suspension was
stirred for 3 h at rt. The reaction mixture was filtered (rinsing with
CH2Cl2) and the filtrate was evaporated under reduced pressure
leading to essentially pure compound 24 (432 mg, 87%) as a color-
less syrup. Rf 0.59 (hexane/EtOAc 6:4); IR (neat,
n
cmꢀ1): 1630,1529,
9.2 (s, 1H),
1448, 1383, 1186, 1099, 985; 1H NMR (300 MHz, CDCl3)
d
8.28 (d,1H, J¼8.8 Hz), 8.03 (br d, 2H, J¼7.5 Hz), 7.69 (d,1H, J¼2.1 Hz),
7.59 (m,1H), 7.50 (m, 2H), 7.45 (s,1H), 7.1 (dd,1H, J¼8.8, 2.2 Hz), 5.83
(s, 2H), 5.24 (s, 2H), 3.64 (t, 2H), 3.5 (s, 3H), 1.07 (m, 2H), ꢀ0.03 (s,
9H); 13C NMR (75 MHz, CDCl3)
d 177.1,155.8,144.5,137.4,135.1,134.4,
129.5,127.3,123.4,123.1,116.7,115.0,100.7, 94.9, 82.9, 77.3, 67.4, 56.0,
17.8, ꢀ1.5; HRMS m/z 667.0669 calcd for C26H30IN3O6SSi; found
667.0655. [4-(1-Benzenesulfonyl-6-bromo-1H-indol-3-yl)-1-(2-tri-
methylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-(1-benzenesulfonyl-
6-methoxymethoxy-1H-indol-3-yl)-methanone 25. To a solution of
the iodo-imidazole 24 (290 mg, 0.43 mmol) in DMF (12 mL) were
added, under argon, PdCl2(PPh3)2 (30 mg, 0.04 mmol) and CuI
(20 mg, 0.1 mmol). Then a solution of the stannane 7h (320 mg,
0.51 mmol) in DMF (3 mL) was added dropwise. The reaction mix-
ture was heated at 120 ꢁC under argon and stirred at the same
temperature for 2 h, then allowed to return to rt and filtered through
a pad of Celite (rinsing with CH2Cl2). The filtrate was concentrated
under reduced pressure. Flash chromatography of the residue
(eluting with hexane/EtOAc 7:3) afforded compound 25 (250 mg,
d
8.04 (br s,1H), 7.5 (d,1H, J¼8.6 Hz), 7.02–6.98 (m, 2H), 6.87 (dd,1H,
J¼8.6, 2.2 Hz), 6.45 (m,1H), 5.2 (s, 2H), 3.5 (s, 3H); 13C NMR (75 MHz,
CDCl3) d 153.5, 136.2, 123.6, 123.1, 121.0, 111.2, 102.1, 98.1, 95.3, 55.8.
To a solution of indole (860 mg, 4.86 mmol) in dry DMF (8 mL) was
added KOH (700 mg, 12.5 mmol) and, after 5 min of stirring at rt,
a solution of I2 (1.3 g, 5.1 mmol) in DMF (25 mL) was added drop-
wise. The reaction mixture was stirred at rt for 30 min and then
poured into cold H2O and extracted with EtOAc. The organic extract
was washed (diluted aq NaSO3H, H2O, brine), dried (MgSO4), and
evaporated under reduced pressure. To a solution of the crude 6-
(methoxymethyl)oxy-3-iodoindole (1.1 g) in dry THF/DMF (35 mL,
2.5:1) was added NaH (60%, 190 mg, 4.7 mmol) at 0 ꢁC. The reaction
mixture was stirred at that temperature for 10 min and then a so-
lution of PhSO2Cl (0.7 mL, 4.6 mmol) in THF (5 mL) was added. The
reaction mixture was allowed to warm to rt and stirred for 2 h. It
was then poured into cold H2O, extracted with CH2Cl2, washed
66%) as a yellow powder. Rf 0.35 (CH2Cl2/hexane 3:1); IR (KBr,
cmꢀ1) 1626, 1377, 1448, 1178, 1091, 985; 1H NMR (300 MHz, CDCl3)
9.5 (s, 1H), 8.34 (d,1H, J¼8.8 Hz), 8.27 (d,1H, J¼1.6 Hz), 8.22 (d,1H,
n
d

S.K. Mal et al. / Tetrahedron 64 (2008) 5904–5914
5913
J¼8.5 Hz), 8.05 (d, 2H, J¼7.7 Hz), 7.97 (d, 2H, J¼7.7 Hz), 7.96 (s, 1H),
7.74 (d, 1H, J¼2.1 Hz), 7.71 (s, 1H), 7.62–7.43 (m, 7H), 7.11 (dd, 1H,
J¼8.8, 2.1 Hz), 5.94 (s, 2H), 5.27 (s, 2H), 3.72 (m, 2H), 3.52 (s, 3H),1.02
and the resulting suspension was stirred for 3 h at rt. The reaction
mixture was filtered (rinsing with CH2Cl2) and the filtrate was
evaporated under reduced pressure leading to essentially pure
compound 28 (386 mg, 92%) as a colorless syrup. Rf 0.28 (CH2Cl2);
(m, 2H), 0.08 (s, 9H); 13C NMR (75 MHz, CDCl3)
d 177.7, 155.7,
142.3, 137.7, 137.4, 136.01, 135.96, 135.0, 134.7, 134.5, 134.1, 129.5,
129.4, 127.2, 127.0, 126.5, 123.3, 123.0, 122.7, 122.5, 120.4, 118.9,
IR (KBr,
CDCl3)
n
cmꢀ1) 1630, 1377, 1184, 1099, 983; 1H NMR (300 MHz,
d
9.28 (s, 1H), 8.27 (d, 2H, J¼8.8 Hz), 8.02 (d, 1H, J¼7.8 Hz),
116.3, 116.2, 114.7, 100.6, 94.9, 77.2, 67.1, 55.9, 17.8, ꢀ1.5; HRMS m/
7.69 (d, 1H, J¼2.2 Hz), 7.58 (m, 1H), 7.49 (m, 2H), 7.41 (s, 1H), 7.35–
7.22 (m, 5H), 7.07 (dd, 1H, J¼8.8, 2.2 Hz), 5.80 (s, 2H), 5.22 (s, 2H),
79
z 874.1162 calcd for C
H BrN4O8S2Si; found 874.1166. Anal. Calcd
40 39
for C40H39BrN4O8S2Si: C, 54.85; H, 4.49; N, 6.40. Found: C, 54.87;
H, 4.41; N, 6.29. [4-(6-Bromo-1H-indol-3-yl)-1-(2-trimethylsilanyl-
ethoxymethyl)-1H-imidazol-2-yl]-(6-methoxymethoxy-1H-indol-3-
4.60 (s, 2H), 3.50 (s, 3H); 13C NMR (75 MHz, CDCl3)
d 177.1, 155.8,
144.6,137.4,136.3,136.1, 135.1,134.4,129.7, 129.5,128.5,128.2,127.7,
127.3, 123.4, 123.1, 118.7, 115.0, 100.7, 94.9, 83.1, 76.8, 71.6, 56.0;
HRMS m/z 657.0430 calcd for C28H24IN3O6S; found 657.0436. [4-
(1-Benzenesulfonyl-6-bromo-1H-indol-3-yl)-1-benzyloxymethyl-1H-
imidazol-2-yl]-(1-benzenesulfonyl-6-methoxymethoxy-1H-indol-3-
yl)-methanone 29. To a solution of the iodo-imidazole 28 (342 mg,
0.52 mmol) in DMF (16 mL) were added, under argon, PdCl2(PPh3)2
(36 mg, 0.05 mmol) and CuI (19 mg, 0.1 mmol). Then a solution of
the stannane 7h (500 mg, 0.8 mmol) in DMF (4 mL) was added
dropwise. The reaction mixture was heated at 120 ꢁC under argon
and stirred at the same temperature for 2 h, then allowed to return
to rt and filtered through a pad of Celite (rinsing with CH2Cl2). The
filtrate was concentrated under reduced pressure. Flash chroma-
tography of the residue (eluting with CH2Cl2/hexane 9:1) afforded
yl)-methanone 26. To
a solution of compound 25 (170 mg,
0.194 mmol) in EtOH/THF (10:3,13 mL) was added 10% aqueous KOH
(5 mL). The reaction mixture was refluxed for 2.5 h, cooled to rt, and
diluted with EtOAc. The organic phase was washed (H2O and brine),
dried (MgSO4), and evaporated under reduced pressure. Flash
chromatography of the residue (eluting with CH2Cl2/EtOAc 85:15)
furnished compound 26 (109 mg, 95%) as a yellow fluffy powder. Rf
0.14 (CH2Cl2/EtOAc 9:1); IR (neat,
n
cmꢀ1) 2953–2893, 1597, 1518,
9.86 (br s,1H), 9.14 (br
1448, 1151, 1072; 1H NMR (300 MHz, CDCl3)
d
s, 1H), 8.47–8.38 (m, 3H), 7.69 (br d, 1H, J¼8.5 Hz), 7.45 (s, 1H), 7.23
(br d, 1H, J¼8.5 Hz), 7.08–6.99 (m, 3H), 6.82 (br s, 1H), 5.86 (s, 2H),
5.08 (s, 2H), 3.66 (m, 2H), 3.48 (s, 3H), 0.95 (m, 2H), ꢀ0.08 (s, 9H); 13
C
NMR (75 MHz, CDCl3)
d
178.2, 154.4, 143.3, 137.1, 136.8, 136.4, 136.0,
compound 29 (322 mg, 71%) as a syrup. Rf 0.36 (CH2Cl2); IR (KBr,
n
123.7, 123.2, 123.0, 121.6, 120.6, 118.6, 115.9, 115.6, 114.7, 113.9, 109.9,
cmꢀ1) 1597, 1520, 1448, 1149, 1070, 873; 1H NMR (300 MHz, CDCl3)
98.5, 94.9, 76.7, 67.0, 56.0, 17.8, ꢀ1.6; HRMS m/z 594.1297 calcd
d
9.45 (s,1H), 8.31 (d,1H, J¼8.8 Hz), 8.24 (d,1H, J¼1.5 Hz), 8.16 (d,1H,
79
for
C
C
H
BrN4O4Si; found 594.1202, m/z 596.1277 calcd for
J¼8.5 Hz), 8.02 (d, 2H, J¼7.6 Hz), 7.94 (d, 2H, J¼7.3 Hz), 7.90 (s, 1H),
7.71 (d, 1H, J¼2.1 Hz), 7.59 (s, 1H), 7.57–7.40 (m, 7H), 7.32–7.22 (m,
5H), 7.08 (dd,1H, J¼8.8, 2.1 Hz), 6.00 (s, 2H), 5.23 (s, 2H), 4.63 (s, 2H),
28 31
81
H
BrN4O4Si; found 596.1143. Anal. Calcd for C28H31BrN4O4Si: C,
28 31
56.47; H, 5.25; N, 9.41. Found: C, 56.37; H, 5.21; N, 9.24. Bromotop-
sentin 5. Compound 26 (92 mg, 0.15 mmol) was dissolved in a mix-
ture of 3 N HCl/EtOH (1:1, 10 mL). The reaction mixture was stirred
overnight under reflux, then cooled to rt and made basic by slow
addition of saturated aqueous Na2CO3. The alkaline reaction mixture
was extracted with EtOAc. The organic layer was washed (H2O and
brine), dried (MgSO4), and evaporated under reduced pressure.
Flash chromatography of the residue (eluting with CH2Cl2/MeOH
92:8) led to bromotopsentin 5 (45 mg, 69%). Rf 0.27 (CH2Cl2/MeOH
3.50 (s, 3H); 13C NMR (75 MHz, CDCl3)
d 177.8, 155.8, 142.4, 137.7,
137.5,136.6,136.0,135.1,134.9,134.5,134.1,129.6,129.5,128.4,128.0,
127.7, 127.4, 127.2, 126.8, 123.5, 123.2, 122.9, 122.85, 120.8, 119.0,
118.9, 116.6, 116.3, 114.9, 100.7, 94.9, 77.0, 71.5, 56.0; HRMS m/z
864.0929 calcd for C
calcd for C
4-(6-bromo-1H-indol-3-yl)-1H-imidazol-2-yl]-(6-methoxymethoxy-
1H-indol-3-yl)-methanone 30. To a solution of compound 29
(280 mg, 0.32 mmol) in EtOH/THF (10:3, 13 mL) was added 10%
aqueous KOH (5 mL). The reaction mixture was refluxed for 2.5 h,
cooled to rt, and diluted with EtOAc. The organic phase was washed
(H2O and brine), dried (MgSO4), and evaporated under reduced
pressure. Flash chromatography of the residue (eluting with CH2Cl2/
MeOH 97:3) furnished compound 30 (168 mg, 89%) as a yellowsolid.
79
H BrN4O8S2; found 864.0923; m/z 866.0903
H BrN4O8S2; found 866.0936. [1-Benzyloxymethyl-
42 33
81
42 33
9:1). UV (EtOH, lmax nm) 238, 287, 378; IR (neat,
1712,1633,1595,1527,1458,1157,1109; 1H NMR (300 MHz,1% TFA in
DMSO-d6)
n
cmꢀ1) 3447–3180,
d
12.21 (br s, 1H), 11.78 (br s, IH), 8.63 (d, 1H, J¼3.1 Hz),
8.13 (d, 1H, J¼2.6 Hz), 8.1 (d, 1H, J¼8.5 Hz), 8.08 (s, 1H), 8.0 (d, 1H,
J¼8.6 Hz), 7.74 (d, 1H, J¼1.5 Hz), 7.32 (dd, 1H, J¼8.6, 1.5 Hz), 6.97 (d,
1H, J¼2 Hz), 6.85 (dd, 1H, J¼8.5, 2 Hz); 13C NMR (75 MHz, 1% TFA in
DMSO-d6)
d
172.7,155.2,142.4,138.3,137.6,137.5,131.5,126.3,123.61,
Rf 0.25 (CH2Cl2/MeOH 98:2); IR (neat,
n
cmꢀ1) 1597,1520,1448,1149,
9.63 (br s,1H), 8.93 (br s,1H),
123.2, 122.2, 121.5, 119.0, 117.2, 115.1, 115.0, 114.2, 113.0, 104.5, 98.1;
1070, 873; 1H NMR (300 MHz, CDCl3)
d
79
HRMS m/z 420.0208 calcd for C
422.0185 calcd for C
H
BrN4O2; found 420.0221, m/z
8.43 (d,1H, J¼3 Hz), 8.38 (d,1H, J¼8.7 Hz), 7.64 (d,1H, J¼8.5 Hz), 7.35
(s, 1H), 7.26–7.14 (m, 6H), 7.06 (m, 2H), 7.00 (dd, 1H, J¼8.7, 2.1 Hz),
6.78 (d, 1H, J¼2.1 Hz), 5.77 (s, 2H), 5.02 (s, 2H), 4.78 (m, 2H), 3.43 (s,
20 13
81
H BrN4O2; found 422.0201.
20 13
4.5.3. Synthesis of 5 using the BOM protecting group for the
imidazole moiety
3H); 13C NMR (75 MHz, CDCl3)
d 178.1,154.4,143.3,137.1,136.7,136.6,
136.5,136.1,128.4,128.9,127.8,123.7,123.3,123.2,123.0,121.7,120.7,
(1-Benzenesulfonyl-6-methoxymethoxy-1H-indol-3-yl)-(1-benzyl-
oxymethyl-4-iodo-1H-imidazol-2-yl)-methanol 27. To a solution of
indole 7i (720 mg, 1.62 mmol) in dry THF (20 mL) under argon at
118.8, 115.9, 115.6, 114.6, 113.9, 110.0, 98.6, 94.9, 76.5, 71.2, 67, 56.0;
79
HRMS m/z 584.1059 calcd for C
H BrN4O4Si; found 584.1061; m/z
30 25
81
586.1039 calcd for C H BrN4O4Si; found 586.1000. Bromotopsentin
28 31
t
ꢀ78 ꢁC was added BuLi (1.7 M in cyclohexane, 2.2 mL) and the
5. Compound 30 (148 mg, 0.25 mmol) was dissolved in a mixture of
3 N HCl/EtOH (1:1, 10 mL). The reaction mixture was stirred over-
night under reflux, then cooled to rt and made basic byslowaddition
of saturated aqueous Na2CO3. The alkaline reaction mixture was
extracted with EtOAc. The organic layer was washed (H2O and
brine), dried (MgSO4), and evaporated under reduced pressure.
Flash chromatography of the residue (eluting with CH2Cl2/MeOH
92:8) led to bromotopsentin 5 (72 mg, 68%, already described).
reaction mixture was stirred at that temperature for 10 min. A so-
lution of aldehyde 8c (440 mg, 1.28 mmol) in THF (8 mL) was then
added to the reaction mixture (solution of 3-lithio-indole 7k).
The mixture was slowly warmed to 0 ꢁC (over 3 h), quenched by
addition of saturated aqueous NH4Cl, and diluted with CH2Cl2. The
organic layer was washed (H2O and brine), dried (MgSO4), and
evaporated under reduced pressure. Flash chromatography of the
residue (eluting with CH2Cl2/EtOAc 92:8) afforded the secondary
alcohol 27 (542 mg, 64%) as a colorless oil. (1-Benzenesulfonyl-
6-methoxymethoxy-1H-indol-3-yl)-(1-benzyloxymethyl-4-iodo-1H-
imidazol-2-yl)-methanone 28. To a solution of alcohol 27 (420 mg,
0.64 mmol) in CH2Cl2 (50 mL) was added MnO2 (700 mg, 8 mmol)
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