Organic Letters
Letter
these molecules because of their intriguing structures, which are
fascinating from both topological and biosynthetic perspectives.
As described previously, biosynthetically a Friedel−Crafts
reaction may be responsible for the indole C-4 alkylation.
However, the selective functionalization of the less nucleophilic
C-4 position of 3-substituted indole is extremely difficult since
most electrophiles prefer to attack the C-2 position. Unlike
indole, there are some previous reports where direct C-4
disappointment, it did not provide the desired cyclization
product, and the starting material was recovered (Table 1, entry
Table 1. Optimization Table for Lewis Acid Catalyzed
Friedel−Crafts C-4 Cyclization Reaction of indole
9
cyclization on indoline derivatives have been reported. There
is one report in the literature where intramolecular direct C-4
cyclization on indole was carried out in Michael fashion using
10
molten NaCl−AlCl . This method was further applied to the
3
total synthesis of bruceolline and hapalindoles by Badenock et
entry
catalyst
equiv
solvent
yield (%)
11a
11b
a
al. and Johnston et al., respectively. Although functional-
ization at the C-4 position of indole has been studied for a long
time, no successful method except the Witkop photocyclization
1
BF ·OEt2
3
CH Cl2
NR
3
2
b
a
2
pTSA
3
CH Cl2
NR
2
a
3
Cu(OTf)2
Bi(OTf)3
Fe(OTf)3
SnCl4
0.1
0.1
0.1
1
CH Cl2
NR
2
1
2
a
has been reported. Reductive Heck reaction using 4-
bromoindole is another alternative for the synthesis of 4-
4
CH Cl2
NR
2
a
5
CH Cl2
NR
2
1
3
substituted indole. Both of these strategies are nontrivial in
case of mycoleptodiscin A (1). Our synthetic strategy was
guided by speculations concerning biosynthesis of these natural
products, i. e. selective inter and intramolecular Friedel−Crafts
alkylation of indole derivative at C-3 and C-4 positions,
respectively. It was envisioned that intermolecular Friedel−
Crafts alkylation at C-3 position of indole could be achieved
without much difficulty but as discussed earlier, the major
challenge is activation of C-4 of indole in the presence of C-2.
For this, we resorted to electrophilic aromatic substitution
reaction and effect of EWG/EDG on indole. It was
6
CH Cl2
30
35
2
7
AlCl3
1
CH Cl2
2
a
8
SnCl
AlCl
2
toluene
toluene
NR
4
a
9
2
NR
3
10
11
TMSOTf
1
CH
CH
Cl
Cl
45
63
2
2
2
TMSOTf
1.5
2
a
b
NR = no reaction. Toluene was also used for the same reaction.
1). Similar results were obtained when 3 equiv of pTSA was
used in CH Cl or toluene at room temperature (Table 1, entry
). Among the catalysts tested Cu(OTf) , Bi(OTf) , and
contemplated that EWG group such as − SO Ph on nitrogen
2
2
2
2
of 7-methoxyindole (10) would deactivate both C-2 and C-3
positions of indole and in turn C-4 would become most
nucleophilic position due to the resonance effect of methoxy
group at C-7 of indole, hence generating the 4-alkylation
product under Friedel−Crafts reaction conditions. To explore
whether this proposed biosynthetic pathway could be achieved
in absence of enzymatic catalysis, model studies were
conducted. Lewis acid catalyzed Friedel−Crafts reaction of 7-
methoxyindole (10) and cyclogeraniol (11) was attempted.
After screening various Lewis and Bronsted acids, mixture of 7-
methoxyindole (10) and cyclogeraniol (11) on treatment with
BF ·OEt in CH Cl at room temperature for 1 h afforded
2
3
Fe(OTf) in CH Cl failed to generate cyclization product, and
3
2
2
the starting material was recovered in each case (Table 1,
entries 3−5). Finally, compound 13, on treatment with 1 equiv
of SnCl in CH Cl , afforded cyclization product (confirmed by
4
2
2
1
H NMR of the crude sample) which after desulfonylation by
using Na−Hg in a MeOH/THF mixture afforded the C-4-
cyclized indole 14 as a single diastereomer in 30% overall yield
(Table 1, entry 6). Although the yield was moderate, this was
the first time the desired tetracyclic ring system was observed,
and thus, further optimization of the reaction was carried out.
Treatment of the compound 13 with 1 equiv of AlCl also
3
3
2
2
2
resulted in the formation of C-4-cyclized product with 35%
overall yield after desulfonylation (Table 1, entry 7). To our
delight, treatment of compound 13 with 1.5 equiv of TMSOTf
followed by desulfonylation afforded the desired compound 14
in 63% overall yield (Table 1, entry 11). To further check the
scope and generality of the intramolecular Friedel−Crafts
reaction, several diverse examples were carried out. First,
tion). As shown in Scheme 3, compounds 15a−d having
different substituents underwent smooth intramolecular
Friedel−Crafts cyclization at C-4 to provide 16a−d with
moderate to good yields. Further, compounds 15e−h also
reacted efficiently to generate C-4 cyclization product 16e−h in
highly diastereoselective fashion. The trans diequatorial
conformation of phenyl and methyl groups of the cyclization
coupling product 12 with 81% yield in highly regioselective
manner. Next, to effect the intramolecular Friedel−Crafts
reaction by activation of C-4 position of indole, nitrogen of
indole derivative 12 was converted to corresponding
sulfonamide 13 by treatment with benzenesulfonyl chloride
under basic conditions (Scheme 2). Various Lewis acids were
screened for intramolecular Friedel−Crafts reaction to form
C−C bond between C-4 of indole moiety with olefin in
cyclohexene ring. The compound 13 was treated with 3 equiv
of BF ·OEt in CH Cl as solvent at room temperature. To our
3
2
2
2
Scheme 2. Synthesis of C-4 Cyclization Precursor
1
product 16g was established by H NOE experiments as a
strong NOE interaction was observed between the H proton
a
and C-11 proton. A more general substrate 17 also underwent
smooth cyclization, which on subsequent desulfonylation
afforded compound 18 in 68% overall yield.
B
Org. Lett. XXXX, XXX, XXX−XXX