Evaluation of alternative approaches for the synthesis of macrocyclic bisindolylmaleimides

Article abstract of DOI:10.1039/b405010j

Approaches for the synthesis of macrocyclic bisindolylmaleimides, in which the indole nitrogens are linked with a tether, are described. Two alternative approaches were investigated: macrocyclisation in either the southern (by adding the tether to the bisindolylmaleimide ring system) or the northern district. With two-, three-and four-atom tethers, both of these approaches were unsuccessful for a wide range of attempted macrocyclisation reactions (palladium-catalysed π-allyl substitution, ring-closing metathesis, McMurry reaction, iodocyclisation, formation of a silylene derivative, substitution of an α,ω-disubstituted electrophile). The failure of all of these reactions was ascribed to the strained nature of the target ring system. However, with longer tethers (six to ten atoms), the macrocycles could prepared using either a ring-closing metathesis reaction or by substitution of an α,ω-dibromide). Fourteen successful macrocyclisation reactions are described; deprotection gave eleven macrocyclic bisindolylmaleimides in which an imide substituent had been removed.

Full text of DOI:10.1039/b405010j

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A R T I C L E
Evaluation of alternative approaches for the synthesis of macrocyclic
bisindolylmaleimides†
Stephen Bartletta and Adam Nelson*a,b
a
School of Chemistry, University of Leeds, Leeds, UK LS2 9JT
Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, UK LS2 9JT
b
Received 5th April 2004, Accepted 10th August 2004
First published as an Advance Article on the web 10th September 2004
Approaches for the synthesis of macrocyclic bisindolylmaleimides, in which the indole nitrogens are linked with
a tether, are described. Two alternative approaches were investigated: macrocyclisation in either the ‘southern’
(by adding the tether to the bisindolylmaleimide ring system) or the ‘northern’ district. With two-, three- and
four-atom tethers, both of these approaches were unsuccessful for a wide range of attempted macrocyclisation
reactions (palladium-catalysed p-allyl substitution, ring-closing metathesis, McMurry reaction, iodocyclisation,
formation of a silylene derivative, substitution of an a,x-disubstituted electrophile). The failure of all of these
reactions was ascribed to the strained nature of the target ring system. However, with longer tethers (six to ten
atoms), the macrocycles could prepared using either a ring-closing metathesis reaction or by substitution of an
a,x-dibromide). Fourteen successful macrocyclisation reactions are described; deprotection gave eleven macrocyclic
bisindolylmaleimides in which an imide substituent had been removed.
We are interested in how the conformation of macrocyclic
Introduction
bisindolylmaleimides 4, including cyclopentene analogues
(e.g. 4a) of K252a (2), may be exploited in biology and
chemistry. Some bis(benzothiophenyl)maleimides, which are
structurally related to bisindolylmaleimides, are photochromic
compounds which may be exploited in optical switching
devices.4 Two alternative approaches for the synthesis of
macrocyclic bisindolylmaleimides of general structure 4 may
be envisaged (Strategies A and B, Scheme 1).5 Strategy A
would involve the substitution of a bifunctional electrophile
7 with two indole molecules (→5); the macrocycle would
then be formed through the formation of the ‘northern’ dis-
trict to give a bisindolylmaleimide 4. Alternatively, an intact
bisindolylmaleimide could be reacted directly with an electro-
phile 7 to give an acyclic intermediate 6 (Strategy B); closure of
the ring in the ‘southern’ district would then yield the required
macrocycle 4. In this paper, we describe the potential of a range
of different reactions in the synthesis of macrocyclic bisindolyl-
maleimides. The relative merits of the two alternative strategies,
and the scope and limitations of each cyclisation reaction, are
discussed.
The indolocarbazole alkaloids, such as staurosporine (1) and
K252a (2) are potent, broad spectrum inhibitors of many
protein kinases.1 The lack of specificity of staurosporine
renders it a rather blunt tool for studying protein kinases.
Nonetheless, the indolocarbazoles have proved to be useful
leads in the discovery of selective inhibitors of specific protein
kinases. A fruitful strategy has been to disrupt the planarity of
the indolocarbazole ring system to give bisindolylmaleimides.2
The selectivity and potency of inhibition has been refined
through the formation of macrocyclic bisindolylmaleimide
analogues; for example, the bisindolylmaleimide LY333531 (3)
selectively inhibits the b isoforms of protein kinase C (PKCb)
(IC50 = 4.7 nM for PKCbI and 5.9 nM for PKCbII).2c,d PKCb
is selectively activated by elevated glucose in many vascular
tissues, and the bisindolylmaleimide 3 can produce significant
improvements in diabetic retinopathy, nephropathy, neuropathy
and cardiac dysfunction.3
Strategy A: preparation of intermediates for macrocyclisation in
the ‘northern’ district
One approach to the synthesis of bisindoles 5 would involve
the palladium-catalysed substitution of allylically substituted
cyclopentenes with indole nucleophiles6 (see Scheme 2 and
Table 1).‡ The Pd2(dba)3-catalysed reactions between the
racemic allylic acetate§ 14 and the anions of the indoles 15 and
17 were efficient, and gave the corresponding products 16 and
‡ An alternative approach, which was briefly investigated, would have
involved elaboration of a bisaniline (ref. 7). The dibromocyclopentene
8 (ref. 8) was substituted with aniline; however, the reaction was
not stereospecific, and the bisaniline 9 was obtained as a 65:35
cis:trans mixture of diastereoisomers (77% yield). The more hindered
nucleophile, 2-iodoaniline, was unreactive, and only the monosubstituted
cyclopentene 10 was obtained in 15% yield.
† Electronic supplementary information (ESI) available: synthesis and
characterisation for all compounds not mentioned in the Experimental;
results of molecular modelling of macrocycles 60 (n = 5, 6, 7); crystal
structure data for 20. See http://www.rsc.org/suppdata/ob/b4/b405010j/
§ The allylic acetate 14 was prepared in four steps from furyl alcohol
using a known reaction sequence (ref. 9).
2 8 7 4
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 8 7 4 – 2 8 8 3
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4

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Scheme 1 Closure of macrocycle in the ‘northern’ (Strategy A) and ‘southern’ districts (Strategy B).
Table 1 Palladium-catalysed substitution reactions with indole nucleophiles
Entry
Indole
Electrophile
Conditions
Product
Yielda (%)
b
b
b
b
1
2
3
4
5
6
7
11
12
15
12
15
17
17
13
13
13
14
14
14
19
NaH, DMF, cat. Pd(PPh3)4
NaH, DMF, cat. Pd(PPh3)4
NaH, DMF, cat. Pd(PPh3)4
15 mol% Pd2(dba)3, NaH, LiCl, DPPE, DMF
15 mol% Pd2(dba)3, NaH, LiCl, DPPE, DMF
15 mol% Pd2(dba)3, NaH, LiCl, DPPE, DMF
5 mol% Pd2(dba)3, NaH, LiCl, DPPE, DMF
—
—
—
—
90
92
45
16
18
20
a Yield of purified product. b No reaction.
18 in >90% yield (entries 5–6, Table 1). In contrast, attempted
two-directional10 reactions involving the biscarbonate 13 were
unsuccessful (entries 1–3).
(Fig. 2) and by the diastereotopicity of its methylene protons
(2-CHAHB) which was revealed by 1H NMR spectroscopy. The
dialdehyde 20 was converted into the diene 21 using a Wittig
homologation (Scheme 3).
The bisindole 22 with its unsubstituted butane-1,4-diyl linker
was prepared in excellent yield by reaction of the sodium anion
Fig. 1 Diagnostic NOE measurements for 19.
Fig. 2
Scheme 2
Desilylation of 18, and acetylation, gave the allylic acetate10
19 (Scheme 2) whose relative configuration was confirmed by
the observation of diagnostic NOE measurements (Fig. 1);
the allylic acetate 19 underwent smooth palladium-catalysed
substitution with the indole-3-carboxyaldehyde (17) to give
the required meso bisindole 20 (entry 7, Table 1). The relative
configuration of 20 was confirmed by X-ray crystallography
Scheme 3
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 8 7 4 – 2 8 8 3
2 8 7 5

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Scheme 4
of indole with 1,4-dibromobutane (Scheme 4).¶ The indole rings
of 22 were functionalised in a two-directional sense. Hence,
reaction with oxalyl chloride, and methanolysis of the resulting
glyoxylyl chloride,12 gave the bisglyoxylate ester 23. Similarly,
Vilsmeier carbonylation13 of 22 gave the required dialdehyde 24;
the dialdehyde 24 was reduced to give the corresponding diol 25
which, after acetylation, gave the diacetate 26.
Strategy B: preparation of intermediates for macrocyclisation in
the ‘southern’ district
The bisindolylmaleimides 29, 30 and 32 were prepared from the
3,4-dihalomaleimides14 28 and 31 (Scheme 5). Hence, treatment
of indole and 2-methylindole with EtMgBr in THF–Et2O–
toluene gave the corresponding indolyl anions which were
reacted with either 28 or 31; the required bisindolylmaleimides
could be obtained in high purity by direct precipitation from the
reaction mixture.15
Scheme 6
the monosubstituted bisindolylmaleimide 38e and recovered
starting material (29) (entries 5b–c).
Palladium-catalysed substitution of the bisindolylmaleimide
ring system was also investigated. Initially, we studied the
Pd2(dba)3-catalysed reaction of the sodium dianion derived
from 29 with the racemic allyl acetate 14 (entry 1, Table 3). An
essentially statistical mixture of products was obtained: the
required monosubstituted bisindolylmaleimide 42 (48%) and
the disubstituted product 43 (20%), presumably as a mixture of
diastereoisomers, were obtained.
However, when one of the indolyl nitrogens was blocked,
good yields of substitution products could be obtained: the
reactionof thecyclopent-3-enyl-substitutedbisindolylmaleimide
38e gave the substitution product 44 in 65% yield (entry 2,
Table 3). Similarly, the SEM-protected bisindolylmaleimide18,||
39 reacted smoothly, to give the bisindolylmaleimide 45 in 57%
yield (Scheme 7 and entry 3, Table 3).
Scheme 5
The alkylation of the bisindolylmaleimide 29 was studied with
a range of simple electrophiles (Scheme 6 and Table 2). Although
most alkylations of 29 were routine (entries 1–4, Table 2),
cyclopent-3-enylation16,17 required considerable optimisation:
reaction of 29 with either the mesylate 36 or the tosylate 37
under optimised conditions (Cs2CO3, DMF, 50 mol% Bu4NI)
gave similar yields of the disubstituted bisindolylmaleimide 33e,
¶ The corresponding bisindole with a hexane-1,6-diyl linker has been
prepared in an analogous manner (ref. 11). The corresponding reaction
with 1,3-dibromopropane, however, resulted in E2 elimination to give
N-allyl indole 27 (92%).
|| The required SEM-protected bisindolylmaleimide 39 was prepared in
two alternative ways: (a) by protection of the bisindolylmaleimide 29
(reaction with 1.0 equivalent of SEMCl gave a roughly statistical mixture
of 39, 52%, and 40, 23%), or (b) by the following reaction sequence:
monosubstitution of the 3,4-dichloromaleimide 28 and SEM protection
(→41), followed by a second substitution by indole (→39) (ref. 14).
2 8 7 6
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 8 7 4 – 2 8 8 3

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Table 2 Substitution reactions of bisindolylmaleimides
Entry
Reagent
Conditions
Product
Yielda (%)
Product
Yielda (%)
1
2
MeIb
allyl bromideb
iPrIb
iPrIb
iPrIb
iPrIb
iPrIb
iPrIb
34
NaH, DMF, 23 °C, 18 h
NaH, DMF, 23 °C, 72 h
NaH, THF, 23 °C, 84 h
NaH, DMF, 23 °C, 84 h
K2CO3, DMF, 23 °C, 84 h
K2CO3, DMF, 52 °C, 84 h
Cs2CO3, DMF, 23 °C, 84 h
Cs2CO3, DMF, 52 °C, 84 h
33a
90
84
—
86
47
73
64
95
79
—
30f
31f
—
—
—
—
—
—
—
—
—
—
38
38
—
—
—
—
—
—
—
—
—
—
37
36
33b
c
3a
3b
3c
3d
3e
3f
4
5a
5b
5c
33c
33c
33c
33c
33c
NaH, DMF, 23 °C, 24 h
33d
c,e
35d
Cs2CO3, 50 mol% Bu4NI, DMF, 52 °C, 96 h
Cs2CO3, 50 mol% Bu4NI, DMF, 52 °C, 96 h
Cs2CO3, 50 mol% Bu4NI, DMF, 52 °C, 96 h
36d
33e
33e
37d
a Yield of purified product. b 2.6 equivalents. c No reaction. d 1.1 equivalents. e 29 was recovered (>98%). f 29 was recovered (33%).
Table 3 Palladium-catalysed substitution of bisindolylmaleimides
Entry
Starting material
Conditions
Product
Yielda (%)
1
2
3
29
38
39
15 mol% Pd2(dba)3, 14, NaH, LiCl, DPPE, DMF
5 mol% Pd2(dba)3, 14, NaH, LiCl, DPPE, DMF
5 mol% Pd2(dba)3, 14, NaH, LiCl, DPPE, DMF
42b
44
45
48
65
57
a Yield of purified product. b The bisindolylmaleimides 43a and 43b were also isolated in a combined yield of 20%.
Treatment of the TBS ether 45 with PPTS in methanol
gave the required SEM-protected bisindolylmaleimide 46 in
88% yield, which was acetylated to give 47. Clean removal
of the SEM group from 47 was problematic: treatment
of 47 with THF–water–acetic acid resulted in fragmenta-
tion of the SEM group to give the hydroxymethyl-substi-
tuted bisindolyl-maleimide 49 (62%) as well as the required
product 48 (12%). However, removal of the SEM group
was much more efficient using TASF19 in THF, and gave the
bisindolylmaleimide 48 without competing deacetylation or
acyl transfer.
Strategy A: studies towards the closure of the macrocycle in the
‘northern’ district
Our synthetic studies had provided a range of bisindoles
(20, 21 and 23–25) which were suitably functionalised for
macrocyclisation in the ‘northern’ district (see Strategy A,
Scheme 1). Possible reactions which might be exploited in the
macrocyclisation step are summarised in Fig. 3.
Unfortunately, none of these approaches proved fruitful.
Ring-closing metathesis (RCM), a method of choice for
the formation of macrocyclic rings,20 afforded none of the
required product. Similarly, the McMurry reaction, which
has been used to prepare a wide range of strained cyclic
molecules,21 was also unsuccessful: the cyclisation of 20, 23
and 24 was studied under a range of alternative reaction
conditions22 but macrocyclic products were never isolated.*
Finally, the attempted formation of a cyclic bis(di-tert-
butylsilylene) derivative from the diol 25 did not yield a
macrocyclic product.
* Less strained macrocyclic bisindolylmaleimides (with a six-atom
tether linking the indole rings) have previously been prepared using a
McMurry reaction (ref. 11).
Scheme 7
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 8 7 4 – 2 8 8 3
2 8 7 7

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Fig. 3 Attempted cyclisations in the ‘northern’ district.
Fig. 4 Possible methods for cyclisation in the ‘southern’ district.
Strategy B: studies towards the closure of the macrocycle in the
‘southern’ district
Strategy B involved cyclisation reactions in which the bisindolyl-
maleimide ring system was intact (Strategy B, Scheme 1), and
a number of potential cyclisation precursors (e.g. 29, 38 and
48) had been prepared. Possible methods for cyclisation in the
‘southern’ district are summarised in Fig. 4.
A particularly direct approach would involve the reaction
of a bisindolylmaleimide with a bifunctional electrophile (see
structure 29, Fig. 4). Indeed, this general approach has previ-
ously been applied in the synthesis of macrocyclic bisindolyl-
maleimides with a six atom tether linking the indole rings (as
in 3).2c,4 Macrocyclisation reactions were, therefore, investgated
using the 1,3- to 1,10- a,x-dibromoalkanes (see Scheme 8
and Table 4). The reactions of the bisindolylmaleimide 29
were perfomed in parallel under dilute conditions (0.025 M).
Good yields of the macrocyclic bisindolylmaleimides 50a–e,
which have six- to ten-atom tethers, were obtained (entries
1–5, Table 4). The procedure was amenable to automation
on a ChemSpeed automated synthetic workstation. However,
with the shorter a,x-dibromoalkanes, the results were less
promising. With 1,3-dibromopropane, alkylation was followed
by elimination, and the diallylated bisindolylmaleimide 33b
was obtained.†† Attempts to prepare macrocyclic bisindolyl-
maleimides 50 with four- and five-atom tethers (n = 4 and 5)
were also unsuccessful, which presumably reflects the strained
nature of these ring systems.
Scheme 8
Under the same conditions, the bis(2-methylindolyl)-
maleimides 51a–e and 52a–c were also prepared (Scheme 8).
The yields of the macrocyclic products 51 and 52 were generally
rather lower than those of the macrocycles 50, presumably
because the indolyl 2-methyl substituents increase the strain of
the macrocyclic ring system.
Ring-closing metathesis could also be exploited in the
cyclisation step (Scheme 9). In marked contrast to the attempted
cyclisation of the diene 21, the cyclisation of 33d with 5 mol%
Grubbs’second generation catalyst (58) proceeded smoothly: the
macrocycle 59 was obtained in 74% yield as a single geometric
isomer of unknown configuration. The length of the tether had
a critical impact on the outcome of the cyclisation step: the
diallylated bisindolylmaleimide 33c did not undergo RCM, and
was, instead, recovered from the reaction mixture.
All other attempts to promote macrocyclisation in the
‘southern’ district were unsuccessful.‡‡ Our success with
intermolecular palladium-catalysed substitution reactions (see
Scheme 8 and Table 3) led us to investigate an intramolecular
version too.25 Unfortunately, attempted macrocyclisation of 48
was unsuccessful with a range of palladium catalysts [Pd2(dba)3;
Pd(PPh3)4] and phosphine ligands (DPPE; DPPF) of varying
bite angle.
†† The bifunctional electrophiles 53, 54 and 55 were prepared from
commercially available cyclopentane-1,3-diol, which was available
(Aldrich) as
a >95:5 mixture of trans and cis diastereomers.
Alkylations of 29 were investigated in the presence of Bu4NI in the
hope of promoting a Walden inversion (ref. 23) which would allow
macrocyclisation to occur. Analysis of the crude reaction mixtures by
analytical HPLC revealed, with 53 and 54, only starting material was
present, suggesting that elimination may, in fact, be competitive with
even the first alkylation step. With the dibromide 55, low yields of the
substituted bisindolylmaleimides 56 (10%) and 57 (6%) were obtained.
‡‡ In addition, iodocyclisation (see refs. 18a and 24) of the cyclopent-
3-enyl substituted bisindolylmaleimide 38 was attempted under two
alternative reaction conditions (DBU, KI, I2, THF; KOtBu, I2, THF).
In both cases, trace quantities of a less polar dimeric compound (MH+,
m/z = 965) was observed by LC-MS.
2 8 7 8
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 8 7 4 – 2 8 8 3

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Table 4 Preparation of macrocyclic bisindolylmaleimides
Table 5 Deprotection of macrocyclic bisindolylmaleimides
Entry
Starting material
n
Product
Yielda (%)
Entry
Starting material
n
Methoda
Product
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
29
29
29
29
29
30
30
30
30
30
32
32
32
6
7
8
9
10
6
7
8
9
10
6
50a
50b
50c
50d
50e
51a
51b
51c
51d
51e
52a
52b
52c
69
73
62
74
71
44
76
62
53
63
35
44
54
1
2
3
4
5
6a
6b
7a
7b
8a
8b
9
50a
50b
50c
50d
50e
51a
52a
51b
52b
51c
52c
51d
51e
59
6
7
8
9
10
6
6
7
7
8
8
9
10
—
A
A
A
A
A
A
B
A
B
A
B
60a
60b
60c
60d
60e
61a
61a
61b
61b
61c
61c
61d
61e
62
74
69
78
59
62
c
16
c
14
c
22
68
51
63
7
8
A
A
A
10
11
a Yield of purified product.
a Method A: (i) 5 N KOH, THF–MeOH; (ii) NH4OAc; Method B: (i) H2,
Pd(OH)2, MeOH; (ii) NaOMe, MeOH. b Yield of purified product. c The
required product 61 was not isolated.
ring strain of the smaller homologues which may, for example,
preclude efficient anhydride formation at an intermediate
stage. The bisindolylmaleimides 61a–c could be prepared by
hydrogenolysis27 of the BOM-protected bisindolylmaleimides
52a–c (entries 6b, 7b and 8b). The yields were also low, perhaps
because the imides were susceptible to ring-opening.
Summary
Our attempts to prepare macrocyclic bisindolylmaleimides
4 were plagued by the strained nature of these compounds.
A wide range of reactions were investigated for preparation of
macrocycles 4 with three- and four-atom tethers, L (including
cyclopentene-bridged structures, 4a). In all cases, an alternative,
more favourable process (such as elimination) intervened, or no
reaction was observed at all. Even one of the most reliable of all
for the synthesis of strained rings—the McMurry reaction—was
spectacularly unsuccessful. We ascribe the problems encountered
to extremely unfavourable transannular steric effects.
As soon as the tether was lengthened, however, the problems
disappeared. Ring-closing metathesis, which had proved fruitless
with lower homologues, enabled the smooth preparation of the
macrocycle 59. Furthermore, macrocyclic bisindolylmaleimides
with six- to ten-atom tethers (e.g. 60a–e) were easily prepared
by a double alkylation protocol. The macrocycle ring strain
in the bisindolylmaleimides 60 was estimated using molecular
modeling: we estimate that the ring strain may increase from
about 15 kJ mol−1 with six- and seven-carbon linkers (60 with
n = 6 or 7) to over 20 kJ mol−1 with a five-carbon linker (60,
n = 5). In view of the increased strain energy of the smaller
macrocycles (n  5), these results are, perhaps, not surprising.
The addition of a 2-methyl substituent to each of indole rings
appears to increase the strain in the bisindolylmaleimide ring
system significantly. Although the macrocycles 51a–e could
still be prepared, the yields were lower and deprotection was
less routine. Applications which exploit the conformational
properties of macrocyclic bisindolylmaleimides will be reported
in due course.
Scheme 9
Deprotection of the macrocyclic bisindolylmaleimides
The macrocyclic bisindolylmaleimides 50 and 59 were
deprotected using
three-step protocol26 (Scheme 10):
a
alkaline hydrolysis gave, after acidification, the corresponding
anhydrides which, on heating with ammonium acetate, yielded
the required bisindolylmaleimides 60a–e and 62 (entries 1–5 and
11, Table 5). Deprotection of the bisindolylmaleimides 51a–e
was attempted in the same way (entries 6a, 7a, 8a, and 9–10).
With the larger macrocycles 51d and 51e (with n = 9 and 10),
good yields of the products 61d–e were observed. In contrast,
at best trace quantities of the smaller homologues 61a–c were
obtained. We suggest that the 2-methyl substituents increase the
Experimental
All non-aqueous reactions were performed under an
atmosphere of nitrogen. High pressure reactions were car-
ried out in a Parr hydrogenation reaction vessel. Solvents
were removed under reduced pressure using either a Büchi
rotary evaporator and a Vacuubrand diaphragm pump, or a
Genevac HT-4 evaporation system. Automated synthesis was
carried out on a Chemspeed ASW2000 synthetic workstation.
Flash column chromatography28 was carried out using silica
(35–70 lm particles). Thin layer chromatography was carried
out on commercially available pre-coated plates (Merck silica
Scheme 10
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 8 7 4 – 2 8 8 3
2 8 7 9

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Kieselgel 60F254). Analytical HPLC was performed using either
a Thermo Hypersil-Keystone achiral column (250 × 4.6 mm
8 l Hyperprep HSC18) or, an Ultron chiral column (150 ×
4.6 mm ES-OVM) with a Dionex P580 pump and a PDA-100
UV detector at 254 nm. Preparative HPLC was conducted
with a Waters 2525 binary gradient pump with detection by
a Micromass ZQ mass spectrometer; an XTerra® preparative
HPLC column (19 × 50 mm) was used.
which was purified by column chromatography, eluting with
0–20% EtOAc in petrol to yield the indole 18 (84 mg, 92%) as a
viscous oil, RF 0.28 (20% EtOAc in petrol); mmax/cm−1 (film) 3058,
2929, 2857, 1662 and 1531; dH (500 MHz; CDCl3) 9.97 (1H, s,
aldehyde–H), 8.34–8.31 (1H, m, indole 4-H), 7.95 (1H, s, indole
2-H), 7.52–7.49 (1H, m, indole 7-H), 7.33–7.29 (2H, m, indole
5-H and 6-H), 6.21 (1H, dt, J 3.6 and 2.1 Hz, cp 4-H or 5-H),
6.00 (1H, ddd, J 5.6, 2.1 and 0.8 Hz, cp 4-H or 5-H), 5.37–5.34
(1H, m, cp 1-H or 3-H), 4.91 (1H, ddt, J 7.1, 2.1 and 0.8 Hz, cp
1-H or 3-H), 2.93 (1H, ddd, J 14.3, 8.2 and 7.1 Hz, cp 2-Ha/Hb),
1.86 (1H, dt, J 14.3 and 3.7 Hz, cp 2-Ha/Hb), 0.91 (9H, s, tBu),
0.13 (3H, s, SiMe2) and 0.09 (3H, s, SiMe2) ppm; dC (125 MHz;
CDCl3) 184.7 (CHO), 139.3, 137.2, 131.0, 125.7, 122.3, 118.6,
110.1 (indole 7-C), 106.2 (indole 3-C), 75.4, 59.9 (cp 1-C or
3-C), 41.9 (cp 2-C), 30.9, 25.9, (tBu), 25.8, 18.1, −4.6 (SiMe)
and −4.7 (SiMe) ppm; m/z (ES) 364 (100%, MNa+); found
MNa+ 364.1703; C20H27NO2NaSi requires M+ 364.1709.
Proton and carbon NMR spectra were recorded on a Bruker
Avance 500 or Avance DPX300 spectrophotometer. Carbon
NMR spectra were recorded with composite pulse decoupling
using the waltz 16 pulse sequence. NMR spectra were recorded
at 300 K, unless otherwise stated. Variable temperature NMR
experiments were carried out on a Bruker Avance DRX500
spectrophotometer. Infra-red spectra were recorded using a
Perkin-Elmer Spectrum One FT-IR spectrophotometer. Melting
points were recorded on a Reichert hot stage microscope and
are uncorrected. Mass spectra were recorded either on a VG
autospec mass spectrometer, operating at 70 eV, using both
the electron impact and fast atom bombardment methods of
ionisation, or using a Micromass LCT-KA111 electrospray
mass spectrometer. Accurate molecular weights were generally
obtained using electrospray mass spectrometry using reserpine
as the lock mass and sodium iodide as the standard. X-Ray
crystal structures were recorded and solved by departmental
staff using a Nonius Kappa CCD area detector diffractometer.
Microanalyses were carried out by staff of the School of
Chemistry using a Carlo Erba 1106 automatic analyser.
(1R*)-[3(S*)-3-O-Acetyl]indole-3-carboxyaldehyde 19
Acetic acid (40 ml) was added to a solution of the aldehyde 18
(1.53 g, 4.48 mmol) in THF (15 ml) and water (15 ml), and the
mixture was heated at 70 °C for 4 h. EtOAc (30 ml) and water
(30 ml) were added and the organics separated, washed with
NaHCO3 solution (30 ml), brine (30 ml) and dried (MgSO4).
The solvent was evaporated under reduced pressure and the
crude reaction mixture dissolved in pyridine (25 ml) and acetic
anhydride (3 ml). The reaction mixture was stirred for 3 h, and
pyridine and acetic anhydride were removed under reduced
pressure to yield the acetate 19 (472 mg, 1.75 mmol, 40% over
2 steps) as colourless plates, m.p. 92–94 °C; dH (300 MHz;
CDCl3) 10.00 (1H, s, aldehyde–H), 8.32–8.28 (1H, m, indole
4-H), 7.79 (1H, s, indole 2-H), 7.50–7.43 (1H, m, indole 7-H),
7.36–7.30 (2H, m, indole 5-H and 6-H), 6.38–6.33 (1H, m, cp
4-H or 5-H), 6.23–6.20 (1H, m, cp 4-H or 5-H), 5.78–5.72 (1H,
m, cp 1-H or 3-H), 5.50–5.41 (1H, m, cp 1-H or 3-H), 3.15 (1H,
dt, J 14.9 and 7.9 Hz, cp 2-Ha/Hb), 2.07 (3H, s, COCH3) and
1.93 (1H, dt, J 14.9 and 4.0 Hz, cp 2-Ha/Hb) ppm; dC (75 MHz;
CDCl3) 185.0, 170.9, 137.4, 136.2, 136.1, 134.3, 134.2, 126.1,
124.5, 123.6, 122.7, 119.1, 110.5, 60.2, 38.9 and 21.5 ppm; m/z
(FAB) 270 (100%, MH+); found MNa+ 292.0945; C16H15NO3Na
requires M+ 292.0950.
(1R*)-[3(S*)-3-(tert-Butyldimethylsilyloxy)cyclopent-4-enyl]-
indole-3-carboxylic acid methyl ester 16
Indole-3-carboxylic acid methyl ester (43.8 mg, 0.25 mmol) in
dry DMF (2 ml) was added slowly to NaH (20 mg of a 60%
dispersion in oil, 0.5 mmol) in dry DMF (1.5 ml), and the
mixture was stirred at room temperature under nitrogen for 1 h.
To this mixture was added a solution of the allylic acetate10 14
(64 mg, 0.25 mmol), tris(dibenzylideneacetone)dipalladium(0)
(12 mg, 5 mol%, 12.5 lmol), bis(diphenylphosphino)ethane
(15 mg, 15 mol%, 37.5 lmol) and lithium chloride (cat.) in dry
DMF (2 ml). The resulting mixture was stirred for 24 h under
nitrogen, then diluted in EtOAc (10 ml) and washed with water
(2 × 10 ml) and brine (10 ml). The organics were separated and
dried (MgSO4) and evaporated under reduced pressure to leave
a crude product which was purified by column chromatography,
eluting with 0–20% EtOAc in petrol to yield the indole 16 (84 mg,
90%) as a viscous oil, RF 0.58 (20% EtOAc in petrol); mmax/cm−1
(film) 2952, 2856, 1705, 1533 and 1460; dH (300 MHz; CDCl3),
8.12–8.08 (1H, m, indole 4-H), 7.94 (1H, s, indole 2-H), 7.42
(1H, d, J 7.1 Hz, indole 7-H), 7.21 (1H, dd, J 7.1, indole 6-H),
7.17 (1H, dd, J 7.1 Hz, indole 5-H), 6.08 (1H, dt, J 5.5 and
1.9 Hz, cp 4-H or 5-H), 5.89 (1H, ddd, J 5.5, 2.1 and 1.0 Hz,
cp 4-H or 5-H), 5.27–5.21 (1H, m, cyclopentene, 1-H or 3-H),
4.84–4.79 (1H, m, cyclopentene, 1-H or 3-H), 3.80 (3H, s, OMe),
2.85 (1H, ddd, J 14.1, 8.1 and 7.2 Hz, cp 2-Ha/Hb), 1.75 (1H, dt,
J 14.1 and 4.2 Hz, cp 2-Ha/Hb), 0.81 (9H, s, t-Bu), 0.04 (3H, s,
SiMe) and 0.00 (3H, s, SiMe) ppm; dC (75 MHz; CDCl3) 165.8,
136.6, 133.1, 131.3, 129.2, 127.5, 122.9, 122.1, 110.6, 107.6, 75.8,
60.2, 51.3, 42.4, 31.4, 26.3, 18.5, −4.2 and −4.3 ppm; m/z (EI)
314 (100%, M − tBu); found M+ 371.1905; C21H29NO3Si requires
M+ 371.1917.
(1R*,3S*)-Bis(3-formylindolyl)cyclopent-4-ene 20
Indole-3-carboxyaldehyde (29 mg, 0.2 mmol) in dry DMF
(0.7 ml) was added slowly to NaH (12 mg of a 60% dispersion in
oil, 0.3 mmol) in dry DMF (0.8 ml), and the mixture was stirred
at room temperature under nitrogen for 1 h. To this mixture was
added a solution of the allylic acetate 19 (54 mg, 0.2 mmol),
tris(dibenzylideneacetone)dipalladium(0) (9 mg,
5 mol%,
0.01 mmol), bis(diphenylphosphino)ethane (12 mg, 15 mol%,
0.03 mmol) and lithium chloride (cat.) in dry DMF (1 ml).
The resulting mixture was stirred for 24 h under nitrogen, then
diluted in EtOAc (10 ml) and washed with water (2 × 10 ml) and
brine (10 ml). The organics were separated and dried (MgSO4)
and evaporated under reduced pressure to leave a crude product
which was purified by column chromatography, eluting with
0–60% EtOAc in petrol to yield the bisindole 20 (32 mg, 45%) as
colourless plates, RF 0.2 (60% EtOAc in petrol); dH (300 MHz;
CDCl3) 9.98 (2H, s, aldehyde–H), 8.51 (2H, s, indole 2-H), 8.15
(2H, d, J 8.1, indole 4-H), 7.79 (2H, d, J 7.6 Hz, indole 7-H),
7.37 (2H, dt, J 7.6 and 7.1 Hz, indole 6-H), 7.30 (2H, dt, J 8.1
and 7.1 Hz, indole 5-H), 6.63 (2H, s, cp, 4-H and 5-H), 5.92 (2H,
t, J 7.1 Hz, cp, 1-H and 3-H), 3.59 (2H, dt, J 13.4 and 7.1 Hz,
cp 2-Ha/Hb), 1.86 (2H, dt, J 13.4 and 7.1 Hz, cp 2-Ha/Hb) ppm;
dC (75 MHz; CDCl3) 185.2 (CO), 138.5 (indole 2-C), 137.2 (cp
4-C and 5-C), 134.8, 125.1 (indole 4-C), 124.1, 123.1, 121.5,
118.1, 111.5 (indole 7-C), 105.4 (indole 3-C) and 60.42 ppm; m/z
(ES) 377 (100%, MNa+); found MNa+ 377.1273; C23H18N2O2Na
requires M+ 377.1266.
(1R*)-[3(S*)-3-(tert-Butyldimethylsilyloxy)cyclopent-4-enyl]-
indole-3-carboxyaldehyde 18
By the same general method, indole-3-carboxyaldehyde
(36.3 mg, 0.25 mmol), NaH (17 mg of a 60% dispersion in
oil), the allylic acetate10 14 (64 mg, 0.25 mmol), tris(dibenzyl-
ideneacetone)dipalladium (0) (12 mg, 5 mol%, 12.5 lmol),
bis(diphenylphosphino)ethane (15 mg, 15 mol%, 37.5 lmol)
and lithium chloride (cat.) gave a crude product after 24 h,
2 8 8 0
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 8 7 4 – 2 8 8 3

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Crystal data for 20
0.3 mmol) in dry DMF (1.5 ml), and the mixture was stirred at
ambient temperature under nitrogen for 1 h; a colour change
from red to blue was observed. To this mixture was added a
solution containing the allylic acetate10 14 (51 mg, 0.2 mmol),
tris(dibenzylideneacetone)dipalladium(0) (10 mg, 5 mol%,
0.01 mmol), bis(diphenylphosphino)ethane (12 mg, 15 mol%,
0.03 mmol) and lithium chloride (cat.) in dry DMF (4 ml).
The resulting mixture was stirred for 23 h under nitrogen, then
diluted with ethyl acetate (20 ml) and washed with water (3 ×
10 ml) and brine (10 ml). The organics were separated, dried
(MgSO4) and evaporated under reduced pressure to leave a crude
product, which was purified by column chromatography, eluting
with 20% EtOAc in petrol to yield the substituted indole 44 (89
mg, 65%) as a red film, RF 0.90 (40% EtOAc in petrol); (Found:
C, 75.1; H, 6.65; N, 5.7; C43H45N3O3Si requires C, 75.9; H, 6.65;
N, 6.1%); mmax/cm−1 (film) 3063, 2929, 2856, 1698, 1609, 1531 and
1462; dH (500 MHz; CDCl3) 7.69 (1H, s, indole 2-H or 2-H), 7.61
(1H, s, indole 2-H or 2-H), 7.48–7.42 (2H, m), 7.42–7.41 (1H,
m), 7.38–7.32 (1H, m), 7.10–6.98 (4H, m), 6.80–6.73 (2H, m),
6.06 (1H, dt, J 5.6 and 2.0 Hz, cp 2-H), 5.88 (1H, ddd, J 5.6, 2.0
and 3.0 Hz, cp 3-H), 5.76 (2H, s, cp 3-H and 4-H), 5.29–5.25
(1H, m, cp 1-H), 5.11 (1H, septet, J 4.2 Hz, cp 1-H), 4.87–4.84
(1H, m, cp 4-H), 4.83 (2H, s, CH2Ph), 2.99–2.90 (3H, m, cp 2-
Ha, 5-Ha and 5-Ha), 2.66–2.58 (2H, m, cp 2-Hb and 5-Hb), 1.81
(1H, dt, J 13.7 and 5.1 Hz, cp 5-Hb), 0.87 (9H, s, tBuSiMe2), 0.10
(3H, s, SiMe) and 0.06 (3H, s, SiMe) ppm; dC (500 MHz; CDCl3)
172.1 (CO), 172.0 (CO), 138.6, 137.2, 135.9, 135.7, 131.5,
130.1, 129.7, 129.0, 128.9, 128.6, 128.6, 128.4, 127.5, 126.3,
122.7, 122.5, 121.9, 120.1, 120.1, 110.0, 109.7, 106.2, 106.1, 75.5,
60.0 (cp 1-C), 54.7 (cp 1-C), 42.1 (CH2Ph), 41.8 (cp 2-C), 39.9
(cp 2-C and 5-C), 25.8 (tBuSiMe2), 18.1, −4.6 (SiMe) and −4.7
(SiMe) ppm; m/z (EI) 679 (65%, M+); found MNa+ 702.3117;
C43H45N3O3NaSi requires M+ 702.3128.
C23H18N2O2, M = 354.39, tetragonal, a = 12.05800(10) Å,
a = 90°, b = 12.05800(10) Å, b = 90°, c = 23.7500(2) Å, c = 90°,
U = 3453.14(5) Å3, T = 150(2) K, space group P41212, Z = 8,
l(Mo–Ka) = 0.088 mm−1, 58154 reflections measured, 2008
unique (Rint = 0.0657), which were used in all calculations. The
final wR (F2) was 0.1827 (all data). CCDC reference number
235422. See http://www.rsc.org/suppdata/ob/b4/b405010j/ for
crystallographic data in .cif format.
1-Benzyl-3-{1-[(1R*,4S*)-4-(tert-butyldimethylsilyloxy)-
cyclopent-2-enyl]-1H-indol-3-yl}-4-(1H-indol-3-yl)pyrrole-2,5-
dione 42 and 1-benzyl-3,4-bis{1-[(1R*,4S*)-4-tert-butyldimethyl-
silyloxy)cyclopent-2-enyl]-1H-indol-3-yl}pyrrole-2,5-dione 43
The bisindolylmaleimide 29 (84 mg, 0.2 mmol) in dry DMF
(1 ml) was added slowly to NaH (12 mg of 60% dispersion in
oil, 0.3 mmol) in dry DMF (1.5 ml), and the mixture was stirred
at ambient temperature under nitrogen for 1 h; a colour change
from red to blue was observed. To this mixture was added a
solution containing the allylic acetate10 14 (51 mg, 0.2 mmol),
tris(dibenzylideneacetone)dipalladium(0) (10 mg, 5 mol%,
0.01 mmol), bis(diphenylphosphino)ethane (12 mg, 15 mol%,
0.03 mmol) and lithium chloride (cat.) in dry DMF (4 ml).
The resulting mixture was stirred for 20 h under nitrogen, then
diluted with ethyl acetate (20 ml) and washed with water (3 ×
10 ml) and brine (10 ml). The organics were separated, dried
(MgSO4) and evaporated under reduced pressure to leave a crude
product which was purified by column chromatography, eluting
with 20–30% EtOAc in petrol to yield the monosubstituted indole
42 (59 mg, 48%) as a red film, RF 0.15 (20% EtOAc in petrol);
mmax/cm−1 (film) 3385, 2929, 2851, 1753, 1694, 1531 and 1461; dH
(500 MHz; CDCl3) 8.47 (1H, s, br NH), 7.72 (1H, d, J 2.8 Hz,
indole 2-H), 7.71 (1H, s, indole 2-H), 7.49–7.41 (3H, m), 7.34–
7.30 (4H, m), 7.08–7.01 (3H, m), 6.93 (1H, d, J 8.0), 6.76–6.71
(2H, m), 6.05 (1H, dt, J 5.5 and 2.0 Hz, cp 2-H or 3-H), 5.86 (1H,
dt, J 5.5 and 1.6 Hz, cp 2-H or 3-H), 5.29–5.25(1H, m, cp 1-H
or 4-H), 4.86–4.80 (1H, m, cp 1-H or 4-H), 4.84 (2H, s, CH2Ph),
2.91 (1H, dt, J 13.8 and 6.2 Hz, cp 5-Ha/b), 1.80 (1H, dt, J 13.8
and 5.2 Hz, cp 5-Ha/b), 0.87 (9H, s, tBuSiMe2), 0.09 (3H, s, SiMe)
and 0.06 (3H, s, SiMe) ppm; dC (125 MHz; CDCl3) 172.1, 171.9,
138.6, 137.1, 135.9, 135.8, 131.4, 130.3, 128.6, 128.2, 127.9,
127.6, 126.7, 126.6, 125.3, 122.6, 122.4, 122.2, 121.9, 120.3,
111.1 (indole 7-C or 7-C), 110.0 (indole 7-C or 7-C), 107.5
(indole 4-C or 4-C), 106.1 (indole 4-C or 4-C), 75.5, 60.0, 42.1,
41.8, 25.9, 25.8, 18.1, −4.6 and −4.7 ppm; m/z (EI) 613 (100%,
M+), 556 (20%, M+ − tBu), 417 (35%, M+ − cp).
1-Benzyl-3-{1-[(1R*,4S*)-4-(tert-butyldimethylsilyloxy)-
cyclopent-2-enyl]-1H-indol-3-yl}-4-{1-[2-(trimethylsilyl)-
ethoxymethyl]-1H-indol-3-yl}pyrrole-2,5-dione 45
The bisindolylmaleimide 39 (6.47 g, 11.8 mmol) in dry DMF
(24 ml) was added slowly to NaH (710 mg, of 60% dispersion
in oil, 17.8 mmol) in dry DMF (34 ml), and the mixture was
stirred at ambient temperature under nitrogen for 1 h; a colour
change from red to blue was observed. To this mixture was
added a solution of the allylic acetate10 14 (3.03 g, 11.8 mmol),
tris(dibenzylideneacetone)dipalladium(0) (542 mg, 5 mol%,
0.6 mmol), bis(diphenylphosphino)ethane (707 mg, 15 mol%,
1.8 mmol) and lithium chloride (cat.) in dry DMF (60 ml). The
resulting mixture was stirred for 20 h under nitrogen, then diluted
with ethyl acetate (400 ml) and washed with water (2 × 300 ml)
and brine (300 ml). The organics were separated, dried (MgSO4)
and evaporated under reduced pressure to leave a crude product
which was purified by column chromatography eluting with
10–20% EtOAc in petrol to yield the bisindolylmaleimide 45
(5.0 g, 57%) as a red foam, RF 0.64 (20% EtOAc in petrol); dH
(500 MHz; CDCl3) 7.80 (1H, s, indole 2-H), 7.78 (1H, s, indole
2-H), 7.54–7.45 (4H, m), 7.40–7.30 (3H, m), 7.16–7.03 (3H, m),
6.89 (1H, d, J 8.0 Hz), 6.78 (2H, t, J 7.7 Hz), 6.12–6.08 (1H, m,
cp 2-H or 3-H), 5.94–5.91 (1H, m, cp 2-H or 3-H), 5.52 (2H,
s, NCH2O), 5.38–5.30 (1H, m, cp 1-H or 4-H), 4.91–4.87 (1H,
m, cp 1-H or 4-H), 4.87 (2H, s, CH2Ph), 3.54 (2H, t, J 8.0 Hz,
OCH2CH2SiMe3), 3.02–2.91 (1H, m, cp 5-Ha/b), 1.78 (1H, m, cp
Also isolated was the disubstituted indole 43 (32 mg, 20%) as a
red film, RF 0.60 (20% EtOAc in petrol); dH (500 MHz; CDCl3)
7.71 (1H, s, indole 2-H), 7.69 (1H, s, indole 2-H), 7.62–7.58 (2H,
m), 7.42–7.30 (10H, m), 7.26–7.24 (4H, m), 6.99–6.85 (8H, m),
6.75–6.65 (4H, m), 5.96–5.93 (2H, m, cp 2-H or 3-H), 5.88–5.86
(2H, m, cp 2-H or 3-H), 5.26–5.21 (2H, m, cp 1-H or 4-H), 4.88–
4.84 (2H, m, cp 1-H or 4-H), 4.83 (2H, s, CH2Ph), 2.91–2.83
(2H, m, cp 5-Ha/b), 1.79–1.68 (2H, m, cp 5-Ha/b), 0.88 (9H, s,
tBuSiMe2), 0.87 (9H, s, BuSiMe2), 0.06 (3H, s, SiMe) and 0.06
t
(3H, s, SiMe) ppm; dC (125 MHz; CDCl3) 172.1 (CO), 143.3,
138.9, 138.6, 138.5, 137.2, 135.9, 131.5, 131.5, 131.2, 130.5,
130.2, 128.9, 128.6, 128.7, 127.5, 127.0, 126.9, 126.5, 126.5,
125.5, 122.5, 121.9, 120.1, 120.1, 110.1, 106.3, 75.5 (cp 1-H or
4-H), 60.1 (cp 1-H or 4-H), 42.0, 41.8, 25.9 (tBuSiMe2) and −4.6
(SiMe2) ppm; m/z (EI) 810 (100%, M+), 613 (20%, M+ − cp),
417 (20%, M+ − 2cp); found MNa+ 832.3897; C49H58N3O4NaSi2
requires M+ 832.3859.
t
5-Ha/b), 0.96–0.90 (11H, m, CH2SiMe3 and BuSi), 0.14 (3H, s,
SiMe), 0.11 (3H, s, SiMe) and 0.00 (9H, s, SiMe3) ppm; m/z (ES)
766 (100%, MNa+).
1-Benzyl-3-{1-[(1R*,4S*)-4-tert-butyldimethylsilyloxy)-
cyclopent-2-enyl]-1H-indol-3-yl}-4-(1-cyclopent-3-enyl-1H-
indol-3-yl)pyrrole-2,5-dione 44
1-Benzyl-3-[1-((1R*,4S*)-4-hydroxycyclopent-2-enyl)-1H-
indol-3-yl]-4-{1-[2-(trimethylsilyl)ethoxymethyl]-1H-indol-3-
yl}pyrrole-2,5-dione 46
Bisindolylmaleimide 38e (96 mg, 0.2 mmol) in dry DMF (1 ml)
was added slowly to NaH (12 mg of 60% dispersion in oil,
PPTS (904 mg, 3.6 mmol) was added in one portion to a stirred
solution of the silyl ether 45 (2.2 g, 3.0 mmol) in methanol
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 8 7 4 – 2 8 8 3
2 8 8 1

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(45 ml). The reaction mixture was stirred for 50 h at ambient
temperature under nitrogen. The solution was evaporated under
reduced pressure, the residue partitioned between ethyl acetate
(100 ml) and water (150 ml). The organics were separated,
washed with 5% aqueous NaHCO3 solution (100 ml), dried
(MgSO4) and evaporated under reduced pressure to leave a crude
product which was purified by column chromatography, eluting
with 40% EtOAc in petrol to yield the alcohol 46 (1.65 g, 88%)
as a red foam, RF 0.17 (30% EtOAc in petrol); (Found: C, 72.5;
H, 6.35; N, 6.3; C38H39N3O4Si requires C, 72.5; H, 6.2; N, 6.7%);
mmax/cm−1 (film) 3417 (br), 2954, 2873, 1697, 1610 and 1532; dH
(500 MHz; CDCl3) 7.82 (1H, s, indole 2-H or 2-H), 7.62 (1H,
s, indole 2-H or 2-H), 7.53–7.12 (10H, m), 6.85–6.80 (3H, m),
6.14 (1H, d, J 5.4 Hz, cp 2-H or 3-H), 5.97 (1H, d, J 5.4 Hz, cp
2-H or 3-H), 5.52 (2H, s, NCH2O), 5.36–5.32 (1H, m, cp 1-H or
4-H), 4.87 (2H, s, CH2Ph), 4.84–4.80 (1H, m, cp 1-H or 4-H),
3.54 (2H, t, J 8.0 Hz, OCH2CH2Si), 3.05 (1H, m, cp 5-Ha/b), 1.69
(2H, m, cp 5-Ha/b and OH (br)), 0.94 (2H, t, J 8.0 Hz, CH2SiMe3)
and 0.00 (9H, s, SiMe3) ppm; dC (75 MHz; CDCl3) 173.3, 173.2,
139.6, 138.4, 137.3, 133.7, 133.4, 130.8, 130.2, 130.0, 128.9,
127.5, 123.9, 123.9, 123.8, 123.6, 121.9, 121.9, 111.7, 111.0, 78.6,
77.5, 76.6, 67.5, 60.9, 43.2, 43.1, 40.1, 31.7, 30.2, 24.3, 19.1, 15.4
and −0.7 ppm; m/z (ES) 653 (100%, MNa+).
OCOCH3) and 1.95–1.87 (1H, m, cp 5-Ha/b) ppm; m/z (ES) 564
(50%, MNa+), 483 (100%, M − OAc); found MNa+ 564.1889;
C34H27N3O4Na requires M+ 564.1899.
19-Benzyl-6,7,10,11-tetrahydro-5,21:12,17-dimethenodibenzo[i,o]-
pyrrolo[3,4-l]-[1,8]diazacyclohexadecene-18,20(19H)-dione 59
Grubbs’ second generation catalyst 58 (7 mg, 5 mol%) was
added to a stirred solution of the diene 33d (86 mg, 0.16 mmol)
in CDCl3 (2 ml). The reaction mixture was stirred for 6 h and
followed by NMR spectroscopy. On completion the reaction
mixture was preabsorbed onto silica and the product isolated by
column chromatography, eluting with 0–30% EtOAc in petrol to
yield the macrocyclic compound 59 (60 mg, 74%) as a purple film
RF 0.25 (30% EtOAc in petrol); dH (500 MHz; CDCl3) 7.98 (2H,
d, J 7.3 Hz, indole 4-H), 7.53 (2H, d, J 7.0 Hz, o-Ph), 7.21–7.38
(9H, m, m-Ph, p-Ph, indole 7-H, indole 5-H and indole 6-H),
6.79 (2H, s, indole 2-H), 5.12 (2H, t, J 4.0 Hz, CHCH), 4.87
(2H, s, NCH2Ph), 4.06–4.02 (4H, m, NCH2CH2) and 2.48–2.45
(4H, m, NCH2CH2) ppm; dC (125 MHz; CDCl3) 171.2 (CO),
137.2, 135.7, 131.1, 130.2 (CHCH), 129.7 (indole 2-C),
128.8 (Ph-C), 128.6 (Ph-C), 127.6 (Ph-C), 127.1, 122.3 (indole
4-C), 122.2, 120.9, 109.1 (indole 7-C), 104.3 (indole 3-C), 45.8
(NCH2CH2), 41.7 (NCH2Ph) and 33.7 (NCH2CH2) ppm; m/z
(ES) 498 (100%, MH+); found MH+ 498.2162; C33H28N3O2
requires M+ 498.2182.
Acetic acid (1R*,4S*)-4-(3-{1-benzyl-2,5-dioxo-4-{1-[2-
(trimethylsilyl)ethoxymethyl]-1H-indol-3-yl}-2,5-dihydro-1H-
pyrrol-3-yl}indol-1-yl)cyclopent-2-enyl ester 47
Acknowledgements
Acetic anhydride (1.2 ml) was added to a solution of the alcohol
46 (1.62 g, 2.58 mmol), in pyridine (12 ml). The reaction mixture
was stirred at ambient temperature under nitrogen for 4 h. The
mixture was diluted with ether (50 ml), washed with HCl (3 M,
3 × 50 ml), saturated aqueous NaHCO3 solution (3 × 50 ml) and
brine (50 ml). The organics were dried (MgSO4) and evaporated
under reduced pressure to leave the acetate 47 (1.63 g, 94%) as
a red foam RF 0.8 (50% EtOAc in petrol); (Found: C, 70.8; H,
6.15; N, 6.2; C40H41N3O5Si requires C, 71.5; H, 6.15; N, 6.3%);
mmax/cm−1 (film) 3060, 2956, 1720, 1698, 1530 and 1398; dH
(500 MHz; CDCl3) 7.82 (1H, s, indole 2-H or 2-H), 7.74 (1H, s,
indole 2-H or 2-H), 7.52–7.28 (7H, m), 7.13–7.04 (3H, m), 6.86–
6.76 (3H, m), 6.23 (1H, d, J 5.4 Hz, cp 2-H or 3-H), 6.12 (1H,
d, J 5.4 Hz, cp 2-H or 3-H), 5.71–5.67 (1H, m, cp 1-H or 4-H),
5.53 (2H, s, NCH2O), 5.45 (1H, m, cp 1-H or 4-H), 4.88 (2H, s,
CH2Ph), 3.54 (2H, t, J 8.0 Hz, OCH2CH2SiMe3), 3.13 (1H, m,
cp 5-Ha/b), 2.10 (3H, s, OCOCH3), 1.92 (1H, m, cp 5-Ha/b), 0.94
(2H, t, J 8.0 Hz, CH2SiMe3) and 0.00 (9H, s, SiMe3) ppm; m/z
(ES) 694 (100%, MNa+); found MH+ 672.2910; C40H42N3O5Si
requires M+ 672.2894.
We thank EPSRC for a project studentship, Stuart Warriner
and Andrew Leach for helpful discussions, and Colin Kilner for
determining the structure of the bisindole 20.
References
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