Synthesis of new aza-analogs of staurosporine, K-252a and rebeccamycin by nucleophilic opening of C2-symmetric bis-aziridines

Article abstract of DOI:10.1039/b815737e

Stable, water-soluble aminosugar staurosporine, K-252a and rebeccamycin analogs have been prepared by nucleophilic opening of C₂-symmetric N-activated bis-aziridines by bis-indolylmaleimides. This divergent strategy allows the synthesis of unsymmetrical substituted derivatives and provides an easy access to the piperidine and pyrrolidine analogs.

Full text of DOI:10.1039/b815737e

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Synthesis of new aza-analogs of staurosporine, K-252a and rebeccamycin
by nucleophilic opening of C2-symmetric bis-aziridines†
Sandrine Delarue-Cochin‡ and Isabelle McCort-Tranchepain*
Received 9th September 2008, Accepted 5th November 2008
First published as an Advance Article on the web 17th December 2008
DOI: 10.1039/b815737e
Stable, water-soluble aminosugar staurosporine, K-252a and rebeccamycin analogs have been prepared
by nucleophilic opening of C2-symmetric N-activated bis-aziridines by bis-indolylmaleimides. This
divergent strategy allows the synthesis of unsymmetrical substituted derivatives and provides an easy
access to the piperidine and pyrrolidine analogs.
Introduction
Protein phosphorylation is one of the most fundamental mech-
anisms by which second messengers act to regulate a variety of
cellular processes. Protein kinase C (PKC) is a multigene family
of Ca2+/phospholipid-dependent protein kinases first identified
in 1977 that specifically phosphorylate serine and threonine
residues and are regulated by intracellular second messengers.1
The PKC family is of particular importance due to its fundamental
involvement in signal transduction, and it plays a key role in
numerous cellular processes including cell differentiation and
proliferation, apoptosis, exocytosis, membrane conductance and
transport, gene expression, smooth muscle contraction and activa-
tion of metabolic enzymes.2 Therefore, PKC is an actively exploited
target for the treatment of the associated diseases such as cancer,
rheumatoid arthritis, viral infection, diabetes, neurodegeneration,
renal failure, and depression.3
The broad spectrum of physiological and pathological processes
in which the different PKC isoforms are involved3,4 illustrates the
need to develop pharmacologically and therapeutically efficient
and selective PKC inhibitors.5
The majority of PKC inhibitors, such as the natural alkaloids
staurosporine 1 and K-252a 2 (Fig. 1), isolated from microbi-
ological sources, block the ATP binding site of the catalytic
domain.6 The structural basis of selectivity and potency has
Fig.
1
Structures of staurosporine, K-252a, aza analogs and
rebeccamycin.
now been clarified by the crystallization of a number of such
enzymes bound to inhibitors. There exist several known (and
probably still unknown) pockets and backbone residues that ATP
itself does not use, which can be targeted in order to introduce
specificity.7 Several structurally related molecules are currently
in clinical development;4 however, none of these inhibitors are
totally specific with respect to PKC isoforms and other families
of kinases, potentially causing adverse effects. Furthermore,
several show poor pharmacokinetic profiles as well as undesirable
physicochemical characteristics, such as low aqueous solubility.
It is noteworthy that the best isoform specificity (b) has been
obtained with a staurosporine analog modified on the aglycon,
but not on the bis-indolylmaleimide moiety (LY 333531).8,3b
Among the more novel disclosed PKC inhibitors are Schering-
Plough’s aza-analogs 3a of staurosporine and 3b of K-252a in
which the sugar moieties were replaced by non-functionalized
piperidine or pyrrolidine.9 These compounds are potent, water-
soluble but instable PKC inhibitors, and the alkyl group on the
piperidine nitrogen modulates both potency and selectivity. To
date, only simple non-functionalized analogs could be obtained
due to the lack of appropriate synthetic methodology.
In addition, rebeccamycin 4 (Fig. 1a), a DNA topoisomerase
inhibitor related to the structure of staurosporine, is a natural
antitumor antibiotic in which the sugar residue is only attached to
one indole nitrogen.10 Rebeccamycin and semi-synthetic analogs
inhibit the growth of many human tumoral and leukemic cell
Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques,
UMR 8601 CNRS, Universite´ Paris Descartes, 45 rue des Saints-Pe`res,
75270, Paris Cedex 06, France. E-mail: isabelle.mccort@parisdescartes.fr;
Fax: +33 (1) 42868387; Tel: +33 (1) 42862184
† Electronic supplementary information (ESI) available: Additional exper-
imental information. See DOI: 10.1039/b815737e
‡ Current address: BioCIS, UMR 8076 CNRS, Faculte´ de Pharmacie
de Chaˆtenay-Malabry, 5 rue Jean-Baptiste Cle´ment, 92290 Chaˆtenay-
Malabry, France.
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lines and are now undergoing clinical trials for cancer11 since
these nuclear enzymes catalyze topical rearrangement of DNA,
essential for transcription, replication and recombination.12 Both
the chemical nature and the isomeric form of the sugar residue
are essential for the interaction with DNA. Indeed, it has recently
been shown that replacing the glucose of a rebeccamycin residue
with a 2¢-amino glucose moiety can enhance both DNA-binding
affinity and sequence selectivity.13
11 and 12 which, to the best of our knowledge, has never been
reported to date.
Results and discussion
Synthesis of bis-indolylmaleimides 11 and indolocarbazoles 12
Based on these findings, we were interested in novel, stable,
water-soluble aminosugar staurosporine, K-252a and rebecca-
mycin derivatives with high potential with PKC isoform or
topoisomerase due to additional hydrogen bond donors and
acceptors (Fig. 2). As shown in the retrosynthetic scheme,
these structures incorporate a chiral, multisubstituted piperidine
or pyrrolidine connected to the indole nitrogens of indolocar-
bazole (5, 6) and bis-indolyl maleimide-type systems (7, 8), via
a methylene unit, obtained after deprotection of the various
functional groups. The fully protected polyfunctionalized com-
pounds resulted from a one-pot tandem alkylation-cyclization of
suitably protected functionalized N-activated bis-aziridines 9 and
10 by bis-indolylmaleimides 11. Indeed, our group has already
shown that in aprotic media regioselective opening by various
organometallic reagents or heteronucleophiles occurred at C-1 of
the C2-symmetric bis-aziridines 9 and 10 in the L-ido configuration,
followed by in situ heterocyclization leading to polysubstituted
piperidines in the L-ido configuration14 and pyrrolidines in the
D-gluco configuration.15 The regioselectivity of the intramolecular
heterocyclization is highly dependent on the flexibility of the
aziridine backbone at C-3 and C-4.15,16
Since our goal was to develop a general procedure to allow
the synthesis of unsymmetrical substituted derivatives, the bis-
indolylmaleimides 11a–c were prepared in a three-step sequence,
allowing the selective protection of one indolyl group, according
to the reported procedure17 (Scheme 1).
N–H Monomaleimides 15a,b were obtained by condensa-
tion of indole-MgBr 13a,b with 3,4-dichloro-N-methylmaleimide
14,18 easily obtained from the corresponding anhydride, fol-
lowed by standard protection of the N–H indole, either by
2-(trimethylsilyl)ethoxymethyl (SEM) or tert-butyloxycarbonyl
(Boc), to yield compounds 16a–c. C-3 alkylation of a second
indole-MgBr with N-protected monomaleimides 16a–c afforded
the bis-indolylmaleimides 11a and 11c in 72 and 78% yields re-
spectively, whereas the 5-fluoro bis-indolylmaleimide 11b was only
obtained in moderate yield (45%). On the oher hand, performing
the sucessive C-alkylations with lithium bis(trimethylsilyl)amide19
afforded the desired products 15a and 11a in only 48% and 32%
yields, respectively.
The bis-indolylmalimide 11a was oxidatively cyclized into
the correspon◦ding indolocarbazole 12a using Pd(OCOCF3)2 in
DMF at 90 C with 80% yield,20 while using either PdCl2
21
22
Here, we report our results concerning the access to new
polyfunctionalized aza-analogs of staurosporine, K-252a and
rebeccamycin. This target relies on the nucleophilic opening of N-
activated bis-aziridines 9 and 10 by N-heteroaromatic compounds
or Pd(OAc)2 led to 12a in 10–20% yield along with some
recovered starting material 11a (~20%). Bis-indolylmaleimide 11d
was synthesized in a straightforward fashion17 and converted into
the indolocarbazole 12b as described for 12a.
Fig. 2 Retrosynthetic analysis.
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Scheme 1 Reagents and conditions: i, a) 13a or 13b (2 eq), EtMgBr 3 M in Et2O (2 eq), THF, 60 ◦C, 1 h; b) 3,4-dichloro-N-methylmaleimide 14 (1 eq),
THF, rt, 2 h, 95% for 15a and 89% for 15b; ii, SEM-Cl (1.2 eq), NaH (1.5 eq), DMF, rt, 2 h, 77% for 16a and 74% for 16b; iii, Boc2O (1.2 eq), DMAP
(0.1 eq), THF, rt, 30 min, 76%; iv, a) 13a or 13b (2 eq), EtMgBr 3 M in Et2O (2 eq), THF, 60 ◦C, 1 h; b) From 16a or 16b: toluene, 65 ◦C, 1.5 h, 72% for
11a and 45% for 11b; From 16c: THF, reflux, 1 h, 78%; v, Pd(OCOCF3)2 (2.5 eq), DMF, 90 ◦C, 30 min, 76%.
Nucleophilic opening of N-activated bis-aziridines 9 and 10 by
N-SEM bis-indolylmaleimides 11
has been reported on N-alkylation of indole25 or heteroaromatic
derivatives26 by aziridines.
We first studied the access to bis-indolylmaleimide derivatives
(Scheme 2). Since only few examples of aziridine ring opening by
complex hindered nucleophiles have been reported so far,15b,25–27
we were delighted that nucleophilic ring-opening of bis-aziridines
9a,b,d and 10a–b by the sodium salt of the N-protected bis-
indolylmaleimides 11a–b, smoothly occurred in DMF at rt in good
yields (60–87%). As expected, when the C-3, C-4 diol of the bis-
aziridines 9 is involved in a cyclic acetal, the aminocyclization of
The NH-bis-aziridines 9 and 10 were synthesized in 6 steps
from D-mannitol as previously reported,23 followed by N-protec-
tions:23a,c,24 N-sulfonamide groups [p-toluenesulfonyl (Ts), 2-(tri-
methylsilyl)ethanesulfonyl (SES), 2,4,6-trimethylbenzenesulfonyl
(Mts)] which are comparable in terms of reactivity, as well as
N-Boc, confer a decrease in reactivity towards the nucleophilic
opening of the aziridine ring in aprotic medium. To date, very little
Scheme 2 Reagents and conditions: i, 9a or 10a (1 eq): 11a (1.1 eq), NaH (1.2 eq), DMF, 0 ◦C then rt, 2 h; 9b or 10b (1 eq): 11a (1.5 eq), NaH (1.7 eq),
DMF, 0 ◦C then rt, 2 h; 9b (1 eq): 11b (1.1 eq), NaH (1.2 eq), DMF, 0 ◦C then rt, 2 h; 9d (1 eq): 11a (1.5 eq), NaH (1.7 eq), DMF, 0 ◦C then rt, 4 h.
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the rigid analog is forced to follow exclusively the 6-endo process
(Scheme 2, path a) providing the piperidine derivatives 17a–d. On
the other hand, conformally flexible bis-aziridines 10 lead through
the more favorable 5-exo process (Scheme 2, path b) to pyrrolidine
(18a, 18b) in addition to piperidine (19a, 19b) derivatives in a
5/1 and 3/1 ratio, respectively. Furthermore, the corresponding
anhydrides were obtained under these mild conditions during
the reaction from bis-aziridines 9a,d.28 It is noteworthy, that the
nucleophilic opening of the N-SES bis-aziridines 9b and 10b
proceeded in satisfactory yields (86 and 83%) by using 1.5 eq of N-
SEM bis-indolylmaleimide 11a. Indeed, using only 1.2 eq of 11a
or 11b led to 17b,c in ~60% yields without recovering any N-SES
bis-aziridine 9b, probably because decomposition of the starting
material occurred competitively under the basic experimental
conditions. Secondly, whatever the experimental conditions used,
11a was unable to perform ring-opening of the less reactive N-Boc
aziridines 9c and 10c.
MeOH),29 it was unfortunately inefficient for both N-tosyl bis-
indolylmaleimide 20a and indolocarbazole 21a piperidines. We
typically observed decomposition products and in some cases, the
starting material. Under harsh reaction conditions (SmI2, DMPU,
THF), heating 20a gave only partial reduction of the maleimide
nucleus without any free amine being formed.
From N-SES derivatives 17b and 17c. To avoid these problems,
we envisaged to use as an alternative the reactive N-SES bis-
aziridine (Scheme 3). Both endocyclic amine and indole of the
piperidine derivatives 17b and 17c were deprotected with 3 eq
of TBAF under reflux to afford 20b and 20c in 82% and 76%
yields, respectively. The fully deprotected bis-indolylmaleimide
piperidines 7a and 7b were obtained after liberation of the primary
amines by heating with CsF in DMF followed by hydrolysis of the
acetonide in presence of trifluoroacetic acid.
After obtaining the fully deprotected compounds, we were
interested in preparing some monoaminoprotected piperidine
derivatives having either a free primary or secondary amine.
In order to check the validity of our methodology to provide
new aza-analogs of rebeccamycin, we pursued our study starting
from the bis-indolylmaleimide piperidine derivatives 17a–c.
Functionalization of the bis-indolylmaleimide piperidine derivative
17b
Deprotection of bis-indolylmaleimide piperidine derivatives 17a-c:
Access to 7a and 7b
Given the apparent importance of the nitrogen functionality in
bioactive systems, we wanted to access diverse nitrogen-containing
products (Scheme 4), and we envisioned using the widespread
acetyl group on each amino group of the piperidine. In order
to carry out stepwise functionalization of the piperidine moiety,
regioselective deprotection of one N-SES group out of two was
required while keeping the SEM protecting group of 17b. The
selective deprotection of the N-SES endocyclic group was achieved
by gentle reflux in THF for 1 h in presence of 2.5 eq of TBAF,
furnishing 23b in 62% yield, as well as a very small amount of the
starting material 17b (0–5%). Thus, with the same reagent, a slight
From N-tosyl derivative 17a. Since it is well known that the
stringency of the desulfonylation of sulfonamides leads to serious
problems and therefore limits the utility of the reaction sequence,
we attempted reductive deprotection of the tosylamide groups
from the bis-indolylmaleimide and the corresponding indolocar-
bazole derivatives in order to sustain the feasability of the key step
in presence of the functionalized piperidine moiety (Scheme 3).
After removal the N-SEM group of 17a by tetrabutylammo-
nium fluoride, the bis-indolylmaleimide 20a underwent oxidative
cyclization with Pd(OCOCF3)2 into indolocarbazole piperidine
21a in 57% yield, with an optimal result obtained after 15–
20 min. Although deprotection of the tosylamide was extensively
investigated (Na, NH3; Na2HPO4, MeOH; Na (Hg) 6%; Mg,
◦
variation of temperature (5 C) can afford selective deprotection
of the SES over the SEM group to yield 23b allowing further
transformations of the amino function.
Scheme 3 Reagents and conditions: i, 17a (1 eq), TBAF (5 eq), THF, reflux, 3 h, 87% for 20a; 17b or 17c (1 eq), TBAF (3 eq), THF, reflux, 3 h, 82% for
20b and 76% for 20c; ii, Pd(OCOCF3)2 (2.5 eq), DMF, 90 ◦C, 20 min, 57%; iii, From 20b: CsF (5 eq), DMF, 100 ◦C, 5 h, 63%; From 20c: CsF (10 eq),
DMF, 100 ◦C, 15 h, 43%; iv, TFA-H2O (9/1), 0 ◦C, 45 min, 84% for 7a and 74% for 7b.
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Scheme 4 Reagents and conditions: i, TBAF (2.5 eq), THF, gentle reflux, 1 h, 63% for 23b and 83% for 29b; ii, Ac2O (2.6 eq), NEt3 (2.1 eq), CH2Cl2, rt,
4 h, 95%; iii, TBAF (5 eq), THF, reflux, 6 h, 66%; iv, CsF (7 eq), DMF, 120 ◦C, 7 h, 73%; v, TFA-H2O (9/1), 0 ◦C, 1 h, 32%; vi, Boc2O (1.3 eq), DMAP
(1.3 eq), CH2Cl2, rt, 2 h, 90%; vii, Ac2O (2 eq), NEt3 (1.7 eq), CH2Cl2, rt, 2.5 h, 97%; viii, TBAF (10 eq), THF, reflux, 2.5 h, 60%; ix, HCl 1 M, THF, 1 h;
x, TBAF (2.5 eq), THF, reflux, 2 h, 80%; xi, HCl 1 M, THF-EtOH, 100%.
Acetylation of the endocyclic amine of 23b followed by succes-
sive deprotection of the indole group of 24b and liberation of the
primary amine of 25b by CsF gave 26b in 46% overall yield. The
diol 27b was then liberated by acidic hydrolysis of the acetonide
with TFA-H2O (unoptimized yield).30 After Boc group protection
of the secondary amine of 23b, SES group removal of 28b was
surprisingly achieved with TBAF under mild conditions allowing
the acetylation of the primary amine of 29b.31 Unfortunately, total
deprotection of 31b in acidic medium led to 27b, i.e. migration of
the acetyl to the endocyclic amine function.
Furthermore, we took advantage of the selective deprotection
of N-SES endocyclic group to yield the mono-SES piperidinyl
derivative 32b. Treatment of 23b with fluorine ions for SEM-group
deprotection followed by acid hydrolysis furnished the diol 32b in
80% overall yield.
moderate yield (41%) along with some C2-symmetric dialkylated
compound 34b (28%) resulting from in situ deprotection of the
Boc group. Further insights into the pathway leading to the
formation of 34b could be obtained by performing the reaction
with excess of bis-aziridine and base in presence of 11d, having
potential reactivity at both indolic nitrogen atoms. Compound
34b was obtained in only 4% yield and the monoalkylated
compound 35b in 48% yield (Table 1, entry 2) showing that the
relative nucleophilicity of indolic nitrogen of the intermediate
was dramatically reduced since in the former case the presence
of 35b was not observed (Table 1, entry 1). Ring opening of
the N-SES bis-aziridine 9b by bis-indolylmaleimide 11d in the
standard conditions furnished the desired N–H monosubstituted
bis-indolylmaleimide piperidine 35b in 52% yield along with 5% of
34b (Table 1, entry 3) whereas increasing the amounts of 11d and
NaH improved the formation of 35b (68% yield) (Table 1, entry
4). Thus, alkylation of 11c followed by in situ deprotection of the
N-Boc group were the most favorable conditions to obtain 34b,
because the intermediate is monocharged, whereas from 11d the
intermediate is a dianion.
Alternative strategies were envisaged to access the indolocar-
bazole derivatives because of non orthogonal deprotection of the
SEM indole group out of the SES function.
Access to indolocarbazole piperidine derivative 5
The access to the rebeccamycin-like piperidine series is illus-
trated in Scheme 5 from 35b. Compound 33b was easily converted
into 35b in the presence of methylamine. Subsequent oxidative
cyclization with Pd(OTf)2 gave 36b, and acidic hydrolysis then
led to the diol 37b in ~60% overall yield. Attempts to deprotect
the endocyclic N-SES group were particularly critical32 either
from 36b or 37b, and total liberation of the secondary amine
with TBAF was only achieved from 37b.33 Surprisingly, the
resulting amino piperidine derivative 38b was slightly less polar
than 37b, probably due to the existence of a hydrogen bond
between the N–H indolic group, either with the newly secondary
amino group, leading to a “closed conformation” as already
observed in rebeccamycin analogs,34 or with the exocyclic NHSES
as suggested by preliminary molecular modeling results.35 The
First, we investigated the ring-opening of N-SES bis-aziridine
9b by the indolocarbazoles 12 under basic conditions. Unsur-
prisingly, the indolocarbazole 12a is less nucleophilic than the
corresponding bis-indolylmaleimide 11a and even under more
vigorous conditions, aziridine ring-opening did not occur. On the
other hand, alkylation of bis-NH indolocarbazole 12b took place
in the presence of NaH at room temperature for 16 h but in very
poor yield (~25%) and the separation of the desired compound
from the excess of 12b was difficult. To develop a general access
to unsymmetrical substituted derivatives, we continued with the
nucleophilic opening of the N-activated bis-aziridine 9b by the N-
Boc bis-indolylmaleimide 11c (Table 1, entry 1). Using standard
alkylation conditions, the desired product 33b was obtained in
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Table 1 Double nucleophilic opening of bis-aziridine 9b by bis-indolylmaleimides 11c and 11d
Entrya
9b, eq
11 (eq)
NaH, eq
33b (%)
35b (%)
34b (%)
1
2
3
4
1.0
2.2
1.0
1.0
11c (1.4)
11d (1.0)
11d (1.3)
11d (1.5)
1.5
2.5
1.4
3.4
41
28
4
48
52
68
5
nib
a conditions: i, DMF, 0 ◦C then rt, 2–3 h b Not isolated.
Scheme 5 Reagents and conditions: i, MeNH2, MeOH, rt, 2 h, 99%; ii, Pd(OCOCF3)2 (2.5 eq), DMF, 90 ◦C, 20 min, 60%; iii, HCl 1M, THF, 5 h, 100%;
iv, TBAF (5 eq), THF, reflux, 5 h, 75%; v, CsF (10 eq), DMF, 100 ◦C, 10 h, 71%.
resulting secondary amine 38b was then fully deprotected using
CsF, providing the diamine 5 in 71% yield.
starting from the corresponding anhydride 17¢d to achieve selec-
tivity.
Experimental section (See also ESI†)
Conclusion
General methods
The many important pathological processes in which various
PKC isoforms and topoisomerase are involved illustrate the
need to develop selective PKC inhibitors and to introduce new
DNA sequence specificity for the DNA topoisomerase-mediated
cleavage of targeted tumor cells or viruses.
We propose a unique and elegant new methodology that relies
on the nucleophilic opening of N-sulfonamide bis-aziridines 9 and
10 by bis-indolylmaleimides 11 and allows divergent access to
many novel derivatives of natural alkaloids 1–4. Moreover, the
synthesized bis-indolylmaleimide and indolocarbazole analogs,
in which the sugar moiety is replaced by highly functionalized
azasugar, dramatically increases the aqueous solubility. The access
to N–H maleimide derivatives is currently under investigation
Commercial reagents were used without purification unless men-
tioned. Prior to use, THF and Et2O were distilled from sodium-
benzophenone and CaH2, respectively. Anhydrous DMF and
toluene were purchased from Acros or Aldrich and were stored
under argon. All anhydrous reactions were carried out under argon
atmosphere.
Analytical thin layer chromatography (TLC) was performed
on Merck 60F-254 precoated silica (0.2 mm) on glass. Flash
chromatography was performed with Merck Kieselgel 60 (250–
500 mm). Flash chromatography of N-protected bis-aziridine
was performed with a Flash Master Personal using BP-SUP
20–40 mm column (AIT) or a Biotage apparatus (InterChim).
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Melting points were determined in open capillary tubes or on
Koeffler apparatus and are uncorrected. Specific optical rotations
d: -1.4 ((CH3)3Si), 17.5 (CH2Si), 21.4, 21.5 (CH3), 24.1 (NCH3),
26.2, 26.4 (C(CH3)2), 41.7 (C-1), 44.7 (C-6), 53.1 (C-5), 55.4 (C-2),
65.8 (OCH2), 75.1, 75.2 (C-4, C-3), 76.0 (OCH2N), 106.2, 106.7,
109.1, 110.1, 111.0, 120.0, 120.9, 122.0, 122.3, 122.6, 126.0, 126.8,
127.0, 127.3, 128.1, 128.9, 129.6, 131.9, 132.2, 135.9, 136.1, 136.7,
143.5, 143.7 (C(CH3)2, CH-Ar, Cq-Ar), 172.3 (2 x CO); MS (CI):
m/z 964 ([M + H]+, 100%), 846 (M–(CH3)3SiCH2CH2O, 80%);
HRMS (CI): m/z calcd for C50H58N5O9S2Si [M + H]+ 964.3445,
found 964.3435.
[a]D were given in 10-1 deg cm2 g-1 and measured on a Perkin-
20
Elmer 241C polarimeter with sodium (589 nm) lamp. IR spectra
were recorded on a Perkin-Elmer FT-IR spectrometer (n in cm-1).
1H and 13C spectra were recorded at 250 MHz and 63 MHz on a
Brucker AM250, respectively. Chemical shifts (d) are reported in
parts per million (ppm). 13C chemical attributions were assigned
1
using H-decoupled spectra. UV/Vis spectra were recorded on
a UV mc2 Safas (lmax in nm). Mass spectra (MS and HRMS)
were performed by the Service de Spectrome´trie de Masse, Ecole
Nationale Supe´rieure, Paris.
17¢a: Rf 0.30 (toluene/EtOAc, 8/2); mp 122–125 ◦C; [a]D20 +41
(c 1.0 in CH2Cl2); IR (ATR) 3648, 3277, 2917, 2849, 1818, 1752,
1628, 1611, 1529, 1464, 1400, 1375, 1337, 1260, 1206, 1159, 1085;
1H NMR (CDCl3) d: -0.08 (s, 9 H, (CH3)3Si), 0.83 (t, J = 8.0 Hz,
2 H, CH2Si), 1.24, 1.36 (2 s, 6 H, C(CH3)2), 2.30, 2.41 (2 s, 6 H,
CH3), 3.00 (dd, J= 13.9, 10.7 Hz, 1 H, H-6ax), 3.16 (m, 1 H, H-5),
3.27 (dd, J = 9.1, 5.8 Hz, 1 H, H-3), 3.40 (t, J = 7.9 Hz, 2 H,
OCH2), 3.60 (t, J = 9.7 Hz, 1 H, H-4), 4.10–4.30 (m, 2 H, H-1,
H-6eq), 4.45 (dd, J = 14.6, 2.2 Hz, 1 H, H-1¢), 4.80 (m, 1 H, H-2),
5.40 (s, 2 H, OCH2N), 5.55 (br s, 1 H, NH), 6.60–6.75 (m, 2 H,
H-Ar), 6.84 (t, J = 7.6 Hz, 1 H, H-Ar), 7.01 (d, J = 7.9 Hz, 2 H,
H-Ar), 7.00–7.25 (m, 4 H, H-Ar), 7.25–7.35 (m, 4 H, H-Ar), 7.43
(d, J = 8.2 Hz, 1 H, H-Ar), 7.71 (s, 1 H, H-Ar), 7.73 (s, 1 H,
H-Ar), 7.78 (d, J = 8.0 Hz, 2 H, H-Ar); 13C NMR (CDCl3) d:
-1.4 ((CH3)3Si), 17.6 (CH2Si), 21.5 (CH3), 26.3, 26.5 (C(CH3)2),
42.2 (C-1), 44.8 (C-6), 53.2 (C-5), 55.3 (C-2), 66.1 (OCH2), 75.2
(C-4, C-3), 76.0 (OCH2N), 105.7, 106.0, 109.6, 110.5, 111.3, 120.7,
121.5, 122.4, 123.0, 123.1, 125.7, 126.7, 127.3, 129.8 133.0, 133.5,
136.2, 136.6, 143.8, 143.9 (C(CH3)2, CH-Ar, Cq-Ar), 166.5, 166.8
(CO); MS (CI): m/z 968 ([M + NH4]+, 100%), 950 (M, 15%).
IUPAC nomenclature was used to name the different com-
pounds but for homogeneity in NMR attribution of pyrrolidine
and piperidine moieties, carbon 1 was the methylene attached
to the bis-indolymaleimide or to the indolocarbazole, as shown
below:
General procedure for the synthesis of 17a–d, 18a–b, 19a–b, 33b,
34b and 35b. To a solution of NaH 60% suspension in mineral
oil (1.2–1.7 eq) in DMF (1 M) at 0 ◦C, were added, a solution of
bis-indolylmaleimide 11a–d (1.1–1.5 eq) in DMF (2 M) and after
15 min, a solution of bis-aziridine 9 or 10 (1.0 eq) in DMF (1 M).
After further stirring at rt for 3 h, the mixture was poured at 0 ◦C
in a solution of saturated NH4Cl then extracted with EtOAc. The
organic layers were then washed with brine, dried over MgSO4,
filtered and concentrated. The residue was then purified by column
chromatography (toluene/EtOAc: 85/15) to yield the desired bis-
indolylmaleimide and the excess of indole.
3-{1-[(2S,3R,4R,5S)-5-(2-[Trimethylsilyl]ethylsulfonyl)amino-1-
(2-[trimethylsilyl]ethylsulfonyl)-3,4-O-isopropylidene-piperidin-2-
yl-methyl]-1H-indol-3-yl}-4-{1-(2-[trimethylsilyl]ethoxymethyl)-
1H-indol-3-yl}-1-methyl-1H-pyrrole-2,5-dione (17b). NaH 60%
(40 mg, 1.0 mmol, 1.7 eq), 11a (415 mg, 0.88 mmol, 1.5 eq) and
9b (300 mg, 0.58 mmol, 1.0 eq) yielded 17b (495 mg, 86%) as
3-{1-[(2S,3R,4R,5S)-5-(para-Toluenesulfonyl)amino-1-(para-tol-
uenesulfonyl)-3,4-O-isopropylidene-piperidin-2-yl-methyl]-1H-ind-
ol-3-yl}-4-{1-(2-[trimethylsilyl]ethoxymethyl)-1H-indol-3-yl}-1-me-
thyl-1H-pyrrole-2,5-dione (17a) and 3-{1-[(2S,3R,4R,5S)-5-(para-
toluenesulfonyl)amino-1-(para-toluenesulfonyl)-3,4-O-isopropylide-
ne-piperidin-2-yl-methyl]-1H-indol-3-yl}-4-{1-(2-[trimethylsilyl]-
ethoxymethyl)-1H-indol-3-yl}-2,5-dihydrofurane-2,5-dione (17¢a).
NaH 60% (13 mg, 0.33 mmol, 1.2 eq), 11a (136.9 mg, 0.29 mmol,
1.1 eq) and 9a (130 mg, 0.26 mmol, 1.0 eq) yielded 17a (221 mg,
87%) and 17¢a (0–5%) as orange solids.
◦
an orange solid; Rf 0.30 (toluene/EtOAc, 8/2); mp 122–124 C;
[a]D -109 (c 1.0 in CH2Cl2); 1H NMR (CDCl3) d: -0.30, -0.05,
20
0.07 (3 s, 27 H, 3 x Si(CH3)3), 0.57 (td, J = 13.5, 4.3 Hz, 2 H,
CH2Si), 0.89 (t, J = 7.9 Hz, 2 H, CH2Si), 1.10 (m, 2 H, CH2Si),
1.41 (s, 6 H, C(CH3)2), 1.83, 2.39 (2 td, J = 13.5, 4.4 Hz, 2 H,
CH2SO2), 3.00–3.25 (m, 3 H, H-6ax, CH2SO2), 3.16 (s, 3 H,
NCH3), 3.48 (t, J = 8.0 Hz, 2 H, CH2O), 3.60 (m, 1 H, H-5),
3.69 (m, 2 H, H-3, H-4), 4.17 (m, 2 H, H-1, H-6eq), 4.48 (m,
1 H, H-1¢), 4.77 (m, 2 H, NH, H-2), 5.48 (s, 2 H, NCH2O), 6.55
(t, J = 7.6 Hz, 1 H, H-Ar), 6.67 (m, 2 H, H-Ar), 6.87 (d, J =
7.9 Hz, 1 H, H-Ar), 7.02 (t, J = 7.5 Hz, 1 H, H-Ar), 7.05 (t, J =
7.6 Hz, 1 H, H-Ar), 7.24 (m, 1 H, H-Ar), 7.41 (d, J = 8.2 Hz,
1 H, H-Ar), 7.72 (s, 2 H, H-Ar); 13C NMR (CDCl3) d: -2.5, -1.9,
-1.4 (Si(CH3)3), 9.5, 10.5, 17.6 (CH2Si), 24.3 (NCH3), 26.4, 26.7
(C(CH3)2), 41.5 (C-1), 45.2 (C-6), 49.6 (CH2SO2), 54.4 (C-5), 55.0
(C-2), 66.0 (CH2O), 75.6 (C-3, C-4), 75.9 (NCH2O), 106.1, 106.7
(Cq-Ar), 109.2, 110.2 (CH-Ar), 110.6 (C(CH3)2), 120.4, 120.7,
121.7, 122.2, 122.8 (x 2) (CH-Ar), 125.8, 126.2, 127.0, 127.4
(Cq-Ar), 131.4, 132.3 (CH-Ar), 135.3, 136.0 (Cq-Ar), 172.3, 172.5
(CO); MS (CI): m/z 1001 ([M + NH4]+, 100%), 984 ([M + H]+,
60%), 866 (M–(CH3)3SiCH2CH2O, 35%); HRMS (CI): m/z calcd
for C46H70N5O9S2Si3 [M + H]+ 984.3923, found 984.3914.
17a: Rf 0.20 (toluene/EtOAc, 8/2); mp 138–141 ◦C; [a]D +33
20
(c 1.0 in CH2Cl2); 1H NMR (CDCl3) d: -0.07 (s, 9 H, (CH3)3Si),
0.86 (t, J = 7.9 Hz, 2 H, CH2Si), 1.24, 1.37 (2 s, 6 H, C(CH3)2),
2.27, 2.44 (2 s, 6 H, 2 x CH3), 2.87 (dd, J = 10.4, 4.5 Hz, 1 H,
H-6ax), 3.17 (m, 4 H, NCH3, H-5), 3.35–3.55 (m, 2 H, H-3, H-
4), 3.44 (t, J = 7.8 Hz, 2 H, OCH2), 4.13 (dd, J = 14.9, 9.4 Hz,
1 H, H-1), 4.31 (dd, J = 15.1, 4.3 Hz, 1 H, H-6eq), 4.42 (dd, J =
14.9, 2.3 Hz, 1 H, H-1¢), 4.86 (m, 2 H, H-2, NH), 5.44 (s, 2 H,
OCH2N), 6.63 (t, J = 7.5 Hz, 1 H, H-Ar), 6.70–6.85 (m, 2 H,
H-Ar), 6.95 (d, J = 8.0 Hz, 2 H, H-Ar), 6.95–7.10 (m, 3 H, H-Ar),
7.15 (d, J = 8.9 Hz, 1 H, H-Ar), 7.23 (d, J = 8.0 Hz, 2 H, H-Ar),
7.42 (d, J = 8.3 Hz, 1 H, H-Ar), 7.57 (s, 1 H, H-Ar), 7.69 (s,
1 H, H-Ar), 7.78 (d, J = 8.1 Hz, 2 H, H-Ar); 13C NMR (CDCl3)
712 | Org. Biomol. Chem., 2009, 7, 706–716
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53.1 (C-5), 55.4 (C-2), 65.8 (OCH2), 75.1, 75.2 (C-4, C-3), 76.0
(OCH2N), 106.2, 106.7, 109.1, 110.1, 111.0, 120.0, 120.9, 122.0,
122.3, 122.6, 126.0, 126.8, 127.0, 127.3, 128.1, 129.0, 129.6, 131.9,
132.2, 135.9, 136.1, 136.7, 143.5, 143.6 (C(CH3)2, CH-Ar, Cq-Ar),
172.3 (2 CO); FAB–MS: m/z 1019 ([M]+, 100%); HRMS (FAB):
m/z calcd for C54H65N5O9S2Si (M)+ 1019.3993, found 1019.3967.
17¢d: Rf 0.40 (toluene/EtOAc, 8/2); mp 123–125 ◦C; [a]D20 +17
(c 0.2 in CH2Cl2); IR (ATR) 3312, 2940, 1820, 1755, 1606, 1531,
3-{5-Fluoro-1-[(2S,3R,4R,5S)-5-(2-[trimethylsilyl]ethylsulfonyl)-
amino-1-(2-[trimethylsilyl]ethylsulfonyl)-3,4-O-isopropylidene-pi-
peridin-2-yl-methyl]-1H-indol-3-yl}-4-{5-fluoro-1-(2-[trimethylsil-
yl]ethoxymethyl)-1H-indol-3-yl}-1-methyl-1H-pyrrole-2,5-dione
(17c). NaH 60% (19 mg, 0.48 mmol, 1.2 eq), 11b (220 mg,
0.43 mmol, 1.1 eq) and 9b (200 mg, 0.39 mmol, 1.0 eq) yielded
17c (240 mg, 60%) as an orange solid; Rf 0.30 (toluene/EtOAc,
8/2); mp 121–123 ◦C; [a]D -98 (c 1.0 in CH2Cl2); H NMR
(CDCl3) d: -0.26, -0.05, 0.06 (3 s, 27 H, 3 x Si(CH3)3), 0.60, 1.10
(2 m, 4 H, CH2Si), 0.90 (t, J = 8.0 Hz, 2 H, CH2Si), 1.47, 1.48
(2 s, 6 H, C(CH3)2), 1.90, 2.47 (2 td, J = 13.5, 4.5 Hz, 2 H, 2 x
CH2SO2), 2.95–3.15 (m, 3 H, H-6ax, 2 x CH2SO2), 3.15 (s, 3 H,
NCH3), 3.48 (t, J = 8.0 Hz, 2 H, CH2O), 3.64 (m, 1 H, H-5), 3.73
(m, 2 H, H-3, H-4), 4.15–4.40 (m, 2 H, H-1, H-6eq), 4.54 (dd,
J = 15.3, 2.8 Hz, 1 H, H-1¢), 4.76 (m, 1 H, H-2), 4.86 (d, J =
6.3 Hz, 1 H, NH), 5.47, 5.50 (AB, J = 11.2 Hz, 2 H, NCH2O),
6.25 (dd, J = 9.8, 2.3 Hz, 1 H, H-Ar), 6.48 (dd, J = 9.9, 2.3 Hz,
1 H, H-Ar), 6.70–7.00 (m, 2 H, H-Ar), 7.23 (m, 1 H, H-Ar), 7.36
(dd, J = 8.9, 4.3 Hz, 1 H, H-Ar), 7.77 (s, 1 H, H-Ar), 7.81 (s,
1 H, H-Ar); 13C NMR (CDCl3) d: -2.5, -2.0, -1.5 (Si(CH3)3),
9.6, 10.5, 17.4 (CH2Si), 24.2 (NCH3), 26.4, 26.7 (C(CH3)2), 42.2
(C-1), 45.4 (C-6), 49.6 (2 CH2SO2), 54.4 (C-5), 55.1 (C-2), 66.0
(CH2O), 75.6, 76.0, 76.5 (C-3, C-4, NCH2O), 105.8 (d, J = 3.9 Hz,
Cq-Ar), 106.3 (d, J = 4.0 Hz, Cq-Ar), 106.5 (d, J = 24.8 Hz,
CH-Ar), 107.0 (d, J = 24.9 Hz, CH-Ar), 110.3 (d, J = 9.9 Hz,
CH-Ar), 110.8 (C(CH3)2), 111.2 (d, J = 26.0 Hz, 2 CH-Ar), 111.7
(d, J = 9.9 Hz, CH-Ar), 126.0 (Cq-Ar), 126.4 (d, J = 10.6 Hz,
Cq-Ar), 127.0 (Cq-Ar), 127.6 (d, J = 10.4 Hz, Cq-Ar), 132.0
(Cq-Ar), 132.5 (CH-Ar), 132.6 (Cq-Ar), 133.9 (CH-Ar), 157.6 (d,
J = 237 Hz, CF), 158.0 (d, J = 237 Hz, CF), 171.9, 172.0 (CO);
MS (CI): m/z 1037 ([M + NH4]+, 100%), 1020 ([M + H]+, 40%),
902 (M–(CH3)3SiCH2CH2O, 15%); HRMS (CI): m/z calcd for
C46H68F2N5O9S2Si3 [M + H]+ 1020.3734, found 1020.3723.
20
1
1
1455, 1382, 1332, 1249, 1154, 1085; H NMR (CDCl3) d: -0.04
(s, 9 H, (CH3)3Si), 0.89 (t, J = 8.0 Hz, 2 H, CH2Si), 1.36, 1.41
(2 s, 6 H, C(CH3)2), 2.10, 2.31 (2 s, 6 H, 2 x CH3), 2.24, 2.64 (2 s,
12 H, 4 x CH3), 2.99 (dd, J = 14.3, 10.7 Hz, 1 H, H-6ax), 3.31 (m,
1 H, H-5), 3.48 (t, J = 7.9 Hz, 2 H, OCH2), 3.67 (t, J = 9.7 Hz,
1 H, H-4), 3.79 (dd, J = 9.7, 5.2 Hz, 1 H, H-3), 4.21 (dd, J =
14.8, 8.2 Hz, 1 H, H-1), 4.45 (dd, J = 14.6, 4.3 Hz, 1 H, H-6eq),
4.40–4.60 (m, 2 H, H-1¢, H-2), 5.39 (d, J = 4.4 Hz, 1 H, NH), 5.47
(s, 2 H, OCH2N), 6.45–6.65 (m, 4 H, H-Ar), 6.74 (t, J = 7.5 Hz,
1 H, H-Ar), 6.85–7.35 (m, 6 H, H-Ar), 7.45 (d, J = 8.2 Hz, 1 H,
H-Ar), 7.69 (s, 1 H, H-Ar), 7.74 (s, 1 H, H-Ar); 13C NMR (CDCl3)
d: -1.4 ((CH3)3Si), 17.6 (CH2Si), 20.9 (x 2), 22.7, 22.8 (CH3), 26.4,
26.6 (C(CH3)2), 42.8 (C-1), 44.5 (C-6), 53.8 (C-5), 54.8 (C-2), 66.2
(OCH2), 75.3, 75.5 (C-4, C-3), 76.2 (OCH2N), 105.6, 106.1, 109.5,
110.4, 111.4, 120.6, 121.2, 122.2, 122.3, 122.8, 123.1, 125.2, 125.7,
126.4, 126.7, 128.2, 128.3, 129.0, 131.4, 131.9, 132.1, 132.4, 133.2,
133.7, 135.7, 136.1, 139.4, 142.5, 142.7 (C(CH3)2, CH-Ar, Cq-Ar),
166.6 (2 CO); MS (CI): m/z 1024 ([M + NH4]+, 100%), 1006 (M,
5%); HRMS (CI): m/z calcd for C53H66N5O10S2Si (M + NH4)+
1024.4020, found 1024.4033.
3-{1-[(2S,3R,4R,5R)-5-(para-Toluenesulfonyl)aminomethyl-1-
(para-toluenesulfonyl)-3,4-dibenzyloxy-pyrrolidin-2-yl-methyl]-1H-
indol-3-yl}-4-{1-(2-[trimethylsilyl]ethoxymethyl)-1H-indol-3-yl}-
1-methyl-1H-pyrrole-2,5-dione (18a) and 3-{1-[(2S,3R,4R,5S)-5-
(para-toluenesulfonyl)amino-1-(para-toluenesulfonyl)-3,4-dibenzy-
loxy-piperidin-2-yl-methyl]-1H-indol-3-yl}-4-{1-(2-[trimethylsilyl]-
ethoxymethyl)-1H-indol-3-yl}-1-methyl-1H-pyrrole-2,5-dione (19a).
NaH 60% (14 mg, 0.35 mmol, 1.2 eq), 11a (145 mg, 0.31 mmol,
1.1 eq) and 10a (180 mg, 0.28 mmol, 1.0 eq) yielded 18a (215 mg,
69%) and 19a (43 mg, 14%) as orange solids.
3-{1-[(2S,3R,4R,5S)-5-(2,4,6-Trimethylphenylsulfonyl)amino-1-
(2-[2,4,6-trimethylphenylsulfonyl)-3,4-O-isopropylidene-piperidin-
2-yl-methyl]-1H-indol-3-yl}-4-{1-(2-[trimethylsilyl]ethoxymethyl)-
1H-indol-3-yl}-1-methyl-1H-pyrrole-2,5-dione (17d) and 3-{1-
[(2S,3R,4R,5S)-5-(2,4,6-Trimethylphenylsulfonyl)amino-1-(2-[2,4,
6-trimethylphenylsulfonyl)-3,4-O-isopropylidene-piperidin-2-yl-me-
thyl]-1H-indol-3-yl}-4-{1-(2-[trimethylsilyl]ethoxymethyl)-1H-in-
dol-3-yl}-2,5-dihydrofurane-2,5-dione (17¢d). NaH 60% (16 mg,
0.40 mmol, 1.7 eq), 11b (180 mg, 0.35 mmol, 1.5 eq) and 9d
(130 mg, 0.23 mmol, 1.0 eq) yielded 17d (36 mg, 15%) and 17¢d
(145 mg, 61%) as orange solids.28
17d: Rf 0.26 (toluene/EtOAc, 8/2); 1H NMR (CDCl3) d: -0.07
(s, 9 H, (CH3)3Si), 0.86 (t, J = 7.9 Hz, 2 H, CH2Si), 1.24, 1.37 (2 s,
6 H, C(CH3)2), 2.27, 2.44 (2 s, 6 H, 2 x CH3), 2.24, 2.64 (2 s, 12 H,
4 x CH3), 2.87 (dd, J = 10.4, 4.5 Hz, 1 H, H-6ax), 3.17 (m, 4 H,
NCH3, H-5), 3.35–3.55 (m, 2 H, H-3, H-4), 3.44 (t, J = 7.8 Hz,
2 H, OCH2), 4.13 (dd, J = 14.9, 9.4 Hz, 1 H, H-1), 4.31 (dd, J =
15.1, 4.3 Hz, 1 H, H-6eq), 4.42 (dd, J = 14.9, 2.3 Hz, 1 H, H-1¢),
4.86 (m, 2 H, H-2, NH), 5.44 (s, 2 H, OCH2N), 6.55–6.70 (m, 2 H,
H-Ar), 6.74 (t, J = 7.5 Hz, 1 H, H-Ar), 6.95 (d, J = 8.0 Hz, 1 H,
H-Ar), 6.95–7.10 (m, 3 H, H-Ar), 7.15 (d, J = 8.9 Hz, 1 H, H-Ar),
7.23 (d, J = 8.0 Hz, 2 H, H-Ar), 7.42 (d, J = 8.3 Hz, 1 H, H-Ar),
7.57 (s, 1 H, H-Ar), 7.69 (s, 1 H, H-Ar), 7.78 (d, J = 8.1 Hz, 1 H, H-
Ar); 13C NMR (CDCl3) d: -1.4 ((CH3)3Si), 17.5 (CH2Si), 21.4, 21.5
(CH3), 24.1 (NCH3), 26.2, 26.4 (C(CH3)2), 41.7 (C-1), 44.7 (C-6),
18a: Rf 0.65 (toluene/EtOAc, 8/2); mp 102–104 ◦C; [a]D20 +175
(c 1.0 in CH2Cl2); IR (ATR) 2897, 1698, 1534, 1453, 1383, 1337,
1
1248, 1160, 1088; H NMR (CDCl3) d: -0.04 (s, 9 H, (CH3)3Si),
0.86 (t, J = 8.1 Hz, 2 H, CH2Si), 2.16, 2.38 (2 s, 6 H, 2 x CH3),
3.17 (s, 3 H, NCH3), 3.20 (m, 2 H, 2 x H-6), 3.50 (m, 3 H, H-3,
OCH2), 3.79 (m, 1 H, H-5), 3.89 (m, 2 H, H-2, H-4), 3.92, 4.00
(AB, J = 12.0 Hz, 2 H, OCH2Ph), 4.26 (s, 2 H, OCH2Ph), 4.41
(dd, J = 13.8, 10.6 Hz, 1 H, H-1), 4.90 (dd, J = 13.9, 2.8 Hz,
1 H, H-1¢), 5.27 (t, J = 4.8 Hz, 1 H, NH), 5.45 (s, 2 H, OCH2N),
6.65–7.80 (m, 29 H, H-Ar); 13C NMR (CDCl3) d: -1.4 ((CH3)3Si),
17.6 (CH2Si), 20.9, 21.4 (CH3), 24.1 (NCH3), 45.3 (C-1, C-6),
62.3 (C-2), 64.6 (C-5), 66.0 (OCH2), 70.5, 72.1 (OCH2Ph), 76.5
(OCH2N), 79.0 (C-4), 81.3 (C-3), 106.5, 106.6, 109.9, 110.2, 120.6,
122.0, 122.3, 122.6, 122.7, 127.5, 127.7, 128.2, 128.6, 129.7, 131.7,
132.2, 136.3, 136.4, 136.7, 143.4, 144.3 (CH-Ar, Cq-Ar), 172.1,
172.3 (CO); MS (CI): m/z 1121 ([M + NH4]+, 45%), 1103 (M,
40%), 986 (M–(CH3)3SiCH2CH2O, 50%); HRMS (CI): m/z calcd
for C61H65N5O9S2Si (M)+ 1103.3993, found 1103.3993.
◦
20
19a: Rf 0.45 (toluene/EtOAc, 8/2); mp 98–100 C; [a]D +45
(c 1.0 in CH2Cl2); IR (ATR) 3282, 2923, 1736, 1696, 1612, 1533,
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1
1454, 1382, 1338, 1248, 1209, 1158, 1087; H NMR (CDCl3) d:
H-6eq), 4.39 (m, 1 H, H-2), 4.66, 4.76 (AB, J = 11.4 Hz, 2 H,
OCH2Ph), 4.81, 4.95 (AB, J = 11.2 Hz, 2 H, OCH2Ph), 5.18 (br s,
1 H, NH), 5.33 (s, 2 H, NCH2O), 6.50–6.70 (m, 3 H, H-Ar), 6.80–
7.00 (m, 3 H, H-Ar), 7.06 (t, J = 7.6 Hz, 1 H, H-Ar), 7.10–7.45
(m, 11 H, H-Ar), 7.55, 7.60 (2 s, 2 H, H-Ar); 13C NMR (CDCl3) d:
-2.5, -2.1, -1.4 (Si(CH3)3), 9.4, 10.2, 17.6 (CH2Si), 24.3 (NCH3),
41.7 (C-1), 44.0 (C-6), 48.9, 49.5 (CH2SO2), 54.5 (C-2), 55.4 (C-5),
66.0 (CH2O), 74.0, 75.6 (OCH2Ph), 75.9 (NCH2O), 78.9 (C-4),
81.1 (C-3), 106.0, 106.7 (Cq-Ar), 109.1, 110.2, 120.3, 120.7, 121.7,
122.4, 122.7, 125.2, 125.6, 125.9, 127.1, 127.3, 127.5, 127.9, 128.0,
128.1, 128.2, 128.4, 128.7, 128.9, 131.4, 132.6 (CH-Ar, Cq-Ar),
135.3, 136.1, 137.4, 137.9 (Cq-Ar), 172.1, 172.7 (CO); MS (CI):
m/z 1141 ([M + NH4]+, 100%), 1051 (M–C3H8Si, 40%); HRMS
-0.07 (s, 9 H, (CH3)3Si), 0.84 (t, J = 7.9 Hz, 2 H, CH2Si), 2.25,
2.41 (2 s, 6 H, 2 x CH3), 2.90 (m, 2 H, H-6ax, H-5), 3.17 (s, 3 H,
NCH3), 3.40 (m, 1 H, H-4), 3.43 (t, J = 7.9 Hz, 2 H, OCH2),
3.56 (dd, J = 8.7, 5.6 Hz, 1 H, H-3), 4.12 (m, 2 H, H-6eq, H-1),
4.40–4.80 (m, 3 H, H-1¢, H-2, NH), 4.50, 4.59 (AB, J = 12.2 Hz,
2 H, OCH2Ph), 4.63, 4.74 (AB, J = 11.5 Hz, 2 H, OCH2Ph), 5.40
(s, 2 H, OCH2N), 6.60–7.60 (m, 28 H, H-Ar); 13C NMR (CDCl3)
d: -1.4 ((CH3)3Si), 17.6 (CH2Si), 21.4, 21.6 (CH3), 24.1 (NCH3),
42.1, 43.6 (C-1, C-6), 53.6 (C-5), 54.9 (C-2), 65.9 (OCH2), 73.9,
74.8 (OCH2Ph), 76.0 (OCH2N), 78.0, 79.4 (C-4, C3), 106.4, 106.7,
109.1, 110.2, 120.0, 120.9, 122.3, 122.6, 126.0, 126.7, 126.9, 127.2,
127.4, 127.9, 128.2, 128.3, 128.6, 128.7, 129.5, 129.7, 131.9, 132.1,
136.0, 136.2, 137.2, 137.5, 143.2, 143.7 (CH-Ar, Cq-Ar), 172.2,
172.3 (CO); MS (CI): m/z 1121 ([M + NH4]+, 30%), 1104 ([M +
H]+, 30%), 986 (M–(CH3)3SiCH2CH2O, 100%); HRMS (CI): m/z
calcd C61H65N5O9S2Si (M)+ 1103.3993, found 1103.4003.
+
(CI): m/z calcd for C57H81N6O9S2Si3 (M + NH4 ) 1141.4814, found
1141.4818.
3-{1-[(2S,3R,4R,5S)-5-(2-[Trimethylsilyl]ethylsulfonyl)amino-
1-(2-[trimethylsilyl]ethylsulfonyl)-3,4-O-isopropylidene-piperidin-
2-yl-methyl]-1H-indol-3-yl}-4-{1-tert-butyloxycarbonyl-1H-indol-
3-yl}-1-methyl-1H-pyrrole-2,5-dione (33b). NaH 60% (55 mg,
1.38 mmol, 1.5 eq), 11c (550 mg, 1.25 mmol, 1.4 eq) and 9b
(465 mg, 0.91 mmol, 1.0 eq) and yielded 33b (355 mg, 41%
yield) as an orange solid; Rf 0.50 (toluene/EtOAc, 7/3); mp
3-{1-[(2S,3R,4R,5R)-5-(2-[Trimethylsilyl]ethylsulfonyl)amino-
methyl-1-(2-[trimethylsilyl]ethylsulfonyl)-3,4-dibenzyloxy-pyrroli-
din-2-yl-methyl]-1H-indol-3-yl}-4-{1-(2-[trimethylsilyl]ethoxyme-
thyl)-1H-indol-3-yl}-1-methyl-1H-pyrrole-2,5-dione (18b) and 3-
{1-[(2S,3R,4R,5S)-5-(2-[trimethylsilyl]ethylsulfonyl)amino-1-(2-
[trimethylsilyl]ethylsulfonyl)-3,4-dibenzyloxy-piperidin-2-yl-methyl]-
1H-indol-3-yl}-4-{1-(2-[trimethylsilyl]ethoxymethyl)-1H -indol-3-
yl}-1-methyl-1H-pyrrole-2,5-dione (19b). NaH 60% (31 mg,
0.78 mmol, 1.7 eq), 11a (325 mg, 0.69 mmol, 1.5 eq) and 10b
(300 mg, 0.46 mmol, 1.0 eq) yielded 18b (320 mg, 62%) and 19b
(98 mg, 19%) as orange solids.
140–143 ◦C; [a]D -80 (c 0.5 in CH2Cl2); H NMR (CDCl3) d:
-0.29, 0.07 (2 s, 18 H, 2 x Si(CH3)3), 0.58 (td, J = 13.5, 4.3 Hz,
2 H, CH2Si), 1.09 (m, 2 H, CH2Si), 1.46 (s, 6 H, C(CH3)2),
1.67 (s, 9 H, C(CH3)3), 1.84, 2.38 (2 td, J = 13.5, 4.4 Hz, 2 H,
CH2SO2), 3.02 (dd, J = 15.0, 10.0 Hz, 1 H, H-6ax), 3.11 (m, 2
H, CH2SO2), 3.19 (s, 3 H, NCH3), 3.50–3.80 (m, 3 H, H-3, H-4,
H-5), 4.05–4.30 (m, 2 H, H-1, H-6eq), 4.41 (d, J = 15.0 Hz, 1
H, H-1¢), 4.75 (m, 1 H, H-2), 4.85 (br s, 1 H, NH), 6.66 (t, J =
7.4 Hz, 2 H, H-Ar), 6.76 (d, J = 7.9 Hz, 2 H, H-Ar), 6.95–7.25
(m, 3 H, H-Ar), 7.78 (s, 1 H, H-2ind), 8.09 (d, J = 9.1 Hz, 1
H, H-Ar); 13C NMR (CDCl3) d: -2.5, -2.0 (Si(CH3)3), 9.5, 10.4
(CH2Si), 24.4 (NCH3), 26.2, 26.6 (C(CH3)2), 28.0 (C(CH3)3),
41.6 (C-1), 45.3 (C-6), 49.6 (2 CH2SO2), 54.4 (C-5), 54.8 (C-2),
75.6, 75.8 (C-3, C-4), 84.6 (C(CH3)3), 106.0, 109.3 (Cq-Ar), 110.5
(C(CH3)2), 110.7 (Cq-Ar), 114.9, 121.0, 122.5 (CH-Ar), 123.1,
123.3 (Cq-Ar), 124.5, 125.9, 128.1 (CH-Ar), 128.4, 130.7 (Cq-Ar),
133.2 (CH-Ar), 134.6, 135.3 (Cq-Ar), 149.1 (CO-Boc), 171.7,
172.1 (CO); FAB–MS: m/z 953 (M, 50%), 853 (M–C4H8–CO2,
70%), 354 (M–C4H8–CO2–piperidine, 100%); HRMS (CI): m/z
calcd for C45H63N5O10S2Si2 (M+) 953.3554, found 953.3541.
20
1
18b: Rf 0.50 (toluene/EtOAc, 85/15); mp: 78–80 ◦C; [a]D20 +74
(c 0.5 in CH2Cl2); H NMR (CDCl3) d: -0.05, -0.00, 0.08 (3 s,
1
27 H, 3 x Si(CH3)3), 0.90 (t, J = 7.9 Hz, 2 H, CH2Si), 0.90–1.25
(m, 4 H, 2 x CH2Si), 1.86, 2.18 (2 m, 2 H, 2 x CH2SO2), 2.95 (m,
2 H, 2 x CH2SO2), 3.21 (s, 3 H, NCH3), 3.42 (d, J = 6.1 Hz, 2 H,
H-6), 3.51 (t, J = 8.0 Hz, 2 H, CH2O), 3.85 (d, J = 5.1 Hz, 1 H,
H-4), 3.93 (t, J = 6.4 Hz, 1 H, H-5), 4.15–4.30 (m, 2 H, H-2, H-3),
4.34 (dd, J = 13.9, 10.2 Hz, 1 H, H-1), 4.35, 4.47 (AB, J = 11.0 Hz,
2 H, OCH2Ph), 4.54, 4.59 (AB, J = 12.2 Hz, 2 H, OCH2Ph), 4.93
(dd, J = 13.7, 3.3 Hz, 1 H, H-1¢), 5.16 (t, J = 5.9 Hz, 1 H, NH),
5.47 (s, 2 H, NCH2O), 6.77 (q, J = 8.0 Hz, 2 H, H-Ar), 6.94 (d,
J = 8.0 Hz, 1 H, H-Ar), 7.00–7.45 (m, 13 H, H-Ar), 7.47 (d, J =
8.2 Hz, 1 H, H-Ar), 7.56 (d, J = 8.0 Hz, 1 H, H-Ar), 7.65, 7.85
(2 s, 2 H, H-Ar); 13C NMR (CDCl3) d: -2.3, -2.1, -1.5 (Si(CH3)3),
9.3, 10.4, 17.5 (CH2Si), 24.0 (NCH3), 43.5, 49.6 (CH2SO2), 45.2
(C-1), 45.6 (C-6), 62.2 (C-2), 65.9 (CH2O), 66.3 (C-5), 71.7, 72.4
(OCH2Ph), 75.9 (NCH2O), 79.6 (C-3), 80.9 (C-4), 106.6 (Cq-Ar),
109.9, 110.2, 120.2, 120.5, 122.0, 122.6, 125.1, 126.3, 126.5, 127.0,
127.4, 127.7, 128.1, 128.3, 128.5, 128.9, 131.6, 131.7, 136.1, 136.2,
136.6, 136.8 (CH-Ar, Cq-Ar), 172.1 (2 CO); MS (CI): m/z 1141 ([M
+ NH4]+, 100%), 1051 (M–C3H8Si, 50%); HRMS (CI): m/z calcd
3-{1-[(2S,3R,4R,5S)-5-(2-[Trimethylsilyl]ethylsulfonyl)amino-
1-(2-[trimethylsilyl]ethylsulfonyl)-3,4-O-isopropylidene-piperidin-
2-yl-methyl]-1H-indol-3-yl}-4-{1H-indol-3-yl}-1-methyl-1H-pyr-
role-2,5-dione (35b). NaH (16 mg, 0.40 mmol, 1.4 eq), 11d
(133 mg, 0.38 mmol, 1.3 eq) and 9b (150 mg, 0.29 mmol, 1.0
eq) yielded 35b (111 mg, 52% yield) which could also be obtained
from 33b. A solution of 33b (300 mg, 0.31 mmol, 1.0 eq) and
methylamine in EtOH (100 mmol) was stirred at rt for 2 h
and poured in EtOAc. The organic layer was washed with a
solution of saturated NH4Cl, brine, dried over MgSO4, filtered
and concentrated. The residue was then purified by column
chromatography (cyclohexane/EtOAc, 6/4) to yield compound
35b (265 mg, 99%)◦as a red solid; Rf 0.55 (cyclohexane/EtOAc,
+
for C57H81N6O9S2Si3 (M + NH4 ) 1141.4814, found 1141.4810.
19b: Rf 0.30 (toluene/EtOAc, 85/15); mp 76–78 ◦C; [a]D -76
20
(c 0.5 in CH2Cl2); IR (ATR) 3309, 2923, 2853, 1753, 1697, 1612,
1534, 1454, 1383, 1333, 1249, 1209, 1139, 1095, 1026; H NMR
1
(CDCl3) d: -0.33, -0.04, -0.03 (3 s, 27 H, 3 x Si(CH3)3), 0.35–
0.65 (m, 2 H, CH2Si), 0.86 (t, J = 8.0 Hz, 2 H, CH2Si), 1.03 (m,
2 H, CH2Si), 1.65, 2.25 (2 m, 2 H, CH2SO2), 2.97 (m, 3 H, H-
6ax, CH2SO2), 3.22 (s, 3 H, NCH3), 3.30–3.60 (m, 4 H, H-4, H-5,
CH2O), 3.75–3.95 (m, 2 H, H-1, H-3), 4.05–4.25 (m, 2 H, H-1¢,
20
5/5); mp 125–127 C; [a]D -124 (c 0.25 in CH2Cl2); IR (ATR)
3356, 2918, 2850, 1756, 1694, 1613, 1532, 1443, 1383, 1333, 1262,
1
1199, 1170, 1140, 1091; H NMR (CDCl3) d: -0.32, 0.08 (2 s,
714 | Org. Biomol. Chem., 2009, 7, 706–716
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18 H, 2 x Si(CH3)3), 0.55 (td, J = 13.5, 4.3 Hz, 2 H, CH2Si), 1.14
(m, 2 H, CH2Si), 1.42 (s, 6 H, C(CH3)2), 1.67, 2.38 (2 td, J = 13.5,
4.4 Hz, 2 H, CH2SO2), 2.86 (dd, J = 14.0, 9.7 Hz, 1 H, H-6ax),
3.14 (m, 2 H, CH2SO2), 3.21 (s, 3 H, NCH3), 3.35–3.85 (m, 4 H,
H-1, H-3, H-4, H-5), 4.07 (m, 2 H, H-1¢, H-6eq), 4.61 (m, 1 H,
H-2), 5.34 (d, J = 7.4 Hz, 1 H, NH), 6.62 (m, 3 H, H-Ar), 6.89 (d,
J = 8.1 Hz, 1 H, H-Ar), 7.00 (t, J = 7.3 Hz, 2 H, H-Ar), 7.15 (d,
J = 8.2 Hz, 1 H, H-Ar), 7.30 (d, J = 8.1 Hz, 1 H, H-Ar), 7.58 (s,
1 H, H-Ar), 7.67 (s, 1 H, H-Ar), 8.90 (brs, 1 H, NH); 13C NMR
(CDCl3) d: -2.5, -2.0 (Si(CH3)3), 9.5, 10.5 (CH2Si), 24.3 (NCH3),
26.4, 26.7 (C(CH3)2), 41.2 (C-1), 44.9 (C-6), 49.7 (2 CH2SO2), 54.5
(C-5), 54.8 (C-2), 75.7, 75.9 (C-3,C-4), 106.0, 106.7 (Cq-Ar), 109.1
(Cq-Ar), 110.5 (C(CH3)2), 111.5, 120.2, 120.5, 121.4, 122.3, 122.6,
122.8 (CH-Ar), 125.8 (x 2), 126.6, 127.2 (Cq-Ar), 128.4, 132.4
(CH-Ar), 135.2, 135.7 (Cq-Ar), 172.4, 173.0 (CO); FAB–MS: m/z
853 (M, 100%), 354 (M–piperidine, 75%).
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3,4-Bis{1-[(2S,3R,4R,5S)-5-(2-[trimethylsilyl]ethylsulfonyl)ami-
no-1-(2-[trimethylsilyl]ethylsulfonyl)-3,4-O-isopropylidene-piperi-
din-2-yl-methyl]-1H-indol-3-yl}-1-methyl-1H-pyrrole-2,5-dione
(34b). This compound was obtained as a by product during the
synthesis of 33b and 35b from 9b and 11c or 11d (4% to 28%
◦
20
yield); Rf 0.25 (toluene/EtOAc, 7/3); mp 94–96 C; [a]D -127
(c 0.2 in CH2Cl2); IR (ATR) 3274, 2960, 2923, 2853, 1698, 1612,
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1
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1536, 1446, 1383, 1334, 1262, 1229, 1203, 1171, 1138, 1088; H
NMR (CDCl3) d: -0.25, 0.06 (2 s, 36 H, 4 x Si(CH3)3), 0.63 (td,
J = 13.8, 4.2 Hz, 4 H, 2 x CH2Si), 1.11 (m, 4 H, 2 x CH2Si), 1.46
(s, 12 H, 2 x C(CH3)2), 1.91, 2.43 (2 td, J = 13.6, 4.1 Hz, 4 H, 2 x
CH2SO2), 2.85 (m, 2 H, 2 x H-6ax), 3.13 (m, 4 H, 2 x CH2SO2),
3.16 (s, 3 H, NCH3), 3.58 (m, 2 H, 2 x H-5), 3.70 (m, 4 H, 2 x H-3,
2 x H-4), 4.05 (dd, J = 14.9, 3.2 Hz, 2 H, 2 x H-6eq) 4.11 (d, J =
14.5 Hz, 2 H, 2 x H-1), 4.49 (d, J = 14.8 Hz, 2 H, 2 x H-1¢), 4.77
(m, 2 H, 2 x H-2), 4.85 (d, J = 6.5 Hz, 2 H, 2 x NH), 6.73 (t, J =
7.4 Hz, 2 H, H-Ar), 6.90–7.35 (m, 6 H, H-Ar), 7.57 (s, 2 H, H-Ar);
13C NMR (CDCl3) d: -2.3, -2.0 (Si(CH3)3), 9.7, 10.5 (CH2Si),
25.5 (NCH3), 26.5, 26.7 (C(CH3)2), 42.6 (C-1), 45.4 (C-6), 49.7
(2 CH2SO2), 54.5 (C-5), 55.2 (C-2), 75.6, 76.1 (C-3, C-4), 106.3
(Cq-Ar), 109.4 (CH-Ar), 110.8 (C(CH3)2), 120.7, 122.3, 122.9
(CH-Ar), 126.3, 126.8 (Cq-Ar), 132.1 (CH-Ar), 135.6 (Cq-Ar),
172.3 (2 CO); MS (CI): m/z 1383 ([M + NH4]+, 20%), 871 (100%).
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Acknowledgements
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The authors are grateful to the “Association Nationale Contre le
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27 (a) J. Thierry and V. Servajean, Tetrahedron Lett., 2004, 45, 821; (b) X. E.
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28 To avoid the formation of the anhydride 17¢, in addition to obvious
anhydrous conditions, bis-aziridines 9 and 10 were dried under vacum
12 h prior to use. When 9d was dried only 1 h, 17d and 17¢d have been
obtained in 15% and 61% yields, respectively.
29 T. W. Greene, and P. G. M. Wuts, In Protective groups in Organic
Synthesis, 3rd ed. John Wiley & Sons Eds, Wiley-Interscience, New
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32 During the course of the reaction, difficulties were met monitoring by
TLC because of the similarity of the retention factors of the starting
material and the product.
33 Likewise, bis-indolylmaleimide 32b has been obtained from 35b follow-
ing the same reaction sequence.
34 S. Messaoudi, F. Anizon, S. Le´once, A. Pierre´, B. Pfeiffer and M.
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30 Later on, the yields of acetonide hydrolysis were improved by use of
HCl 1 M in THF or in THF-EtOH.
35 For the same reasons about polarity, these hypotheses are also suitable
for 32b.
716 | Org. Biomol. Chem., 2009, 7, 706–716
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