Diels-Alder reactivity and some synthetic applications of (E)-1-(3-indolyl)-3-tert-butyldimethylsiloxy-1,3-butadienes

Article abstract of DOI:10.1016/S0040-4039(01)01487-3

The preparation of (E)-1-(3-indolyl)-3-tert-butyldimethylsiloxy-1,3-butadienes and their Diels-Alder reaction with selected dienophiles at room temperature is described. The utility of these heteroaryldienes for the construction of different (3-indolyl)-planar systems is shown by the synthesis of a grooved analogue of arcyriaflavin A.

Full text of DOI:10.1016/S0040-4039(01)01487-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 7233–7236
Diels–Alder reactivity and some synthetic applications of
(E)-1-(3-indolyl)-3-tert-butyldimethylsiloxy-1,3-butadienes
Esther Caballero, Nicolas Longieras, Elodie Zausa, Benedicto del Rey, Manuel Medarde and
Fernando Tome´*
Laboratorio de Qu´ımica Orga´nica y Farmace´utica, Facultad de Farmacia, 37007 Salamanca, Spain
Received 17 July 2001; revised 8 August 2001; accepted 13 August 2001
Abstract—The preparation of (E)-1-(3-indolyl)-3-tert-butyldimethylsiloxy-1,3-butadienes and their Diels–Alder reaction with
selected dienophiles at room temperature is described. The utility of these heteroaryldienes for the construction of different
(3-indolyl)-planar systems is shown by the synthesis of a grooved analogue of arcyriaflavin A. © 2001 Elsevier Science Ltd. All
rights reserved.
Recently, we started a research project directed at the
synthesis of alkaloid analogues having a (3-indolyl)-pla-
nar system as a common structural feature and taking,
among others, the natural cytotoxic alkaloids wakayin,1
murrapanine2 and eudistomin U3 as models.
The methodology selected is based on the Diels–Alder
reaction of (E)-1-(3-indolyl)-3-tert-butyldimethylsiloxy-
1,3-butadienes, which represents an extension (aryl to
heteroaryl) of our research on the use of phenyl- and
phenoxy-trialkylsiloxy-dienes for the synthesis of natu-
O
O
H
N
H
N
Planar system
N
MeO
N
H
O
N
N
H
N
R
N
H
N
H
Wakayin
Murrapanine
Eudistomin U
Analogues
ral product analogues.7 This approach has successfully
been applied in our new synthesis of the indolocarba-
zole alkaloid arcyriaflavin A.8
Some of these natural models have been reported to act
by inhibiting topoisomerase4 (top) and our proposed
family of analogues have the structural requirements
(i.e. planar system, minor DNA groove binding unit,
variable substituents on the top of the structure)
described as pharmacophore for such an activity.5 In
consequence, in agreement with the postulated possible
existence of a dual pharmacophore for top-1/top-2
inhibitors,6 we expect these novel alkaloid analogues to
be topoisomerase inhibitors.
There are few references about the Diels–Alder reactiv-
ity of 1-heteroaryl-1,3-dienes and even less about 1-het-
eroaryl-equivalents to Danishefsky’s diene. Examples of
the first group are some reported syntheses of murrapa-
nine, yuehchukene (a dimeric alkaloid) and ana-
logues starting from (E)-1-(3-indolyl)-1,3-butadienes2,9
and a recently reported synthesis of dimeric coumarins
via 7-methoxy-8-(3-methyl-1,3-butadienyl)coumarins,10
whereas an example of the second group has been
communicated by a russian group who prepared some
furyl-planar systems from (E)-1-(2-furyl)-3-trimethyl-
siloxy-1,3-butadienes.11
Keywords: dienes; Diels–Alder reactions; indoles; alkaloids.
* Corresponding author. Tel.: 34 923 294528; fax: 34 923 294515;
e-mail: frena@usal.es
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01487-3

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E. Caballero et al. / Tetrahedron Letters 42 (2001) 7233–7236
In this communication we describe the preparation of
(E)-1-(N-methyl-3-indolyl)-3-tert-butyldimethylsiloxy-
1,3 - butadiene (1) and (E) - 1 - (3 - indolyl) - 3 - tert-
butyldimethylsiloxy-1,3-butadiene (2), an exploratory
study on their behavior in the Diels–Alder reaction
and the synthesis of a grooved analogue of arcyria-
flavin A, as a proof of their synthetic applications.
compounds with 3-indolyl and/or N-(tert-butyl-
dimethylsilyl)-3-indolyl as the (IND) unit.
All these products were obtained as single dia-
stereomers, originated from the expected endo cycload-
dition, all the spectroscopic data (two-dimensional
NMR, NOE experiments) and molecular modeling of
transition states being in agreement with our former
studies7c,7f on this kind of cycloadducts and their cor-
responding ketones generated by acidic hydrolysis of
the silyl enol ether moiety.
Dienes 1 and 2 were obtained from the corresponding
indole-3-carbaldehydes (Scheme 1). The first was eas-
ily prepared by Claisen–Schmidt condensation of N-
methylindole-3-carbaldehyde and acetone (20 equiv.)
to give the corresponding enone, followed by enol-
sylilation with TBDMSOTf/Et3N. As the condensa-
tion with acetone did not work well with
indole-3-carbaldehyde, we used a Wittig reaction to
build the appropriate enone which underwent enol-
sylilation to diene 2; in this case, depending on the
proportion of TBDMSOTf used, dienes 2a or 2b (N-
silylated) were obtained.
Most of the cycloadducts or ketones in this way
obtained are appropriate building blocks for the
preparation of the proposed natural product ana-
logues. As both an exploratory synthetic study and a
proof of the synthetic utility of these indolyl-dienes,
we have obtained14 (Scheme 2) a grooved (between
indole and pyrrolocarbazole units) analogue, 26, of
the indolocarbazole alkaloid arcyriaflavin A, following
a similar approach to that used in our synthesis of
this alkaloid8 and its open analogues.7b,7f It is worth
noting that only traces of the corresponding regioiso-
mer of 25 from the Fischer indolization reaction were
obtained.
We next studied the Diels–Alder reactivity of these
new dienes, against the following representative
dienophiles: N-phenylmaleimide, N-methylmaleimide,
4 - phenyl - 1,2,4 - triazoline - 3,5 - dione, dimethyl acetyl-
enedicarboxylate,
1,4-benzoquinone,
1,4-naphto-
quinone and 4a,9a-epoxy-4a,9a-dihydroanthracene-
1,4,9,10-tetraone.12 The outcome of the Diels–Alder
reactions13 is summarized in Table 1; the yields were
calculated by the 1H signals integration from 1H
NMR spectra and, when possible, the reaction prod-
ucts were isolated either as slightly impure cycload-
ducts by insolubilization (diethyl ether or hexane) or
as the parent ketones by hydrolysis (HCl–CH2Cl2 or
AcOH–THF–H2O) and crystallization. The low yields
(not optimized) observed in some hydrolysis could be
attributed to that this kind of compounds are prone
to aromatization. It should be pointed out that the
structure depicted for cycloadducts coming from reac-
tions with dienes 2a, 2b or 2a/2b mixtures refers to
Compound 26 has the planar system (pyrrolo[3,4-
c]carbazole) bearing the 3-indolyl unit, thus, fulfilling
the general structure and being the first compound
obtained within the proposed alkaloid analogues.
We are currently exploring the Diels–Alder reactivity
of similar N-(R-sulphonyl)protected dienes with the
aim of synthesizing with reasonable yields similar and
more elaborated 3-indolyl-planar compounds with free
indolic -NH-, in order to enable interactions through
hydrogen bonds with the expected biological targets.
The results of the cytotoxic activity of this family of
natural product analogues will be communicated in
due course.
O
OTBDMS
O
OHC
(20 equiv)
TBDMSOTf (2.5 equiv)
Et3N / CH2Cl2 90 min
NaOH / MeOH-H2O
N
(0.26 M)
48 h
N
N
(95%)
O
1 (100%)
OTBDMS
O
OHC
Ph3P
(2.2 equiv)
TBDMSOTf (2-4.5 equiv)
Et3N / CH2Cl2 90 min
Toluene, reflux
12 h
N
H
N
H
N
R
(73%)
2a (R = H)
(100%)
2b (R = TBDMS)
Scheme 1. Synthesis of dienes 1 and 2.

E. Caballero et al. / Tetrahedron Letters 42 (2001) 7233–7236
7235
Table 1. Outcome of the Diels–Alder reactions (rt, 2 days) of 1 and 2 with selected dienophiles
DIENOPHILES
O
DIENES
CYCLOADDUCTS
KETONES
O
O
O
H
H
H
OTBDMS
1 or 2
H+
RN
RN
RN
Acetone or
CH2Cl2
H
O
O
O
IND
IND
3 (90%) R = Ph, IND = N-methylindol-3-yl
4 (65%) R = Ph, IND = indol-3-yl
5 (90%) R = Me, IND = N-methylindol-3-yl
6 (75%) R = Me, IND = indol-3-yl
7
8
9
(60%)
(30%)
(55%)
R = Ph or Me
10 (40%)
O
O
O
2
OTBDMS
O
N
N
N
H+
N
PhN
PhN
PhN
N
O
N
CH2Cl2
O
O
IND
11 (50%)
IND
12 (<20%)
IND = indol-3-yl
COOMe
COOMe
MeOOC
MeOOC
OTBDMS
H+
MeOOC
MeOOC
O
1 or 2
Acetone or
CH2Cl2
IND
IND
15 (50%)
16 (<30%)
13 (85%) IND = N-methylindol-3-yl
14 (60%) IND = indol-3-yl
O
O
O
H
H
H+
1 or 2
O
OTBDMS
Acetone or
CH2Cl2
H
H
O
O
IND
O
IND
17 (60%) IND = N-methylindol-3-yl
18 (40%) IND = indol-3-yl
19 (10%)
O
O
O
H
H
1 or 2
OTBDMS
O
H+
Acetone or
CH2Cl2
H
O
H
O
IND
O
IND
20 (85%) IND = N-methylindol-3-yl
21 (50%) IND = indol-3-yl
22 (45%)
O
O
O
O
O
O
O
O
O
O
O
O
O
H
H
H
OTBDMS
H+
O
1
Acetone
H
O
IND
IND = N-methylindol-3-yl
O
IND
23 (75%)
24 (30%)
Acknowledgements
(SA24/99, the Consejer´ıa de Educacio´n y Cultura and
the European Social Fund). N.L. and E.Z.
(ENSSPICAM, Marseille, France) thank the
European Socrates Programme for their Erasmus
grants.
Financial support came from the Spanish MCYT
(PPQ2000-1179) and the Junta de Castilla y Leo´n

7236
E. Caballero et al. / Tetrahedron Letters 42 (2001) 7233–7236
H
N
N
a) Acetone
r.t. 48h
O
O
O
N
O
O
O
H
H
b) c. HCl
CH2Cl2
N
H
N
N
O
N
TBDMSO
H
9 (51%)
1
Arcyriaflavin A
p-MeO-PhNHNH2
AcOH - EtOH
reflux, 2h
N
O
O
N
O
O
H
H
DDQ
MeO
MeO
Toluene, 3h
N
N
H
N
N
H
Grooved analogue 26 (65%)
25 (58%)
Scheme 2. Synthesis of a grooved analogue of arcyriaflavin A.
8. Adeva, M.; Buono, F.; Caballero, E.; Medarde, M.; Tome´,
F. Synlett 2000, 832–834.
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25, orange oil (58%). 1H NMR (200 MHz, CDCl3): l 2.63
(s, 3H), 3.07 (m, 2H), 3.6–3.9 (m, 2H), 3.70 (s, 3H), 3.93
(s, 3H), 4.35 (d, J=7.4 Hz, 1H), 6.86 (dd, J=8.4, 2.6, 1H),
6.99 (s, 1H), 7.20 (m, 3H), 7.22 (d, J=8.4 Hz, 1H), 7.43
(s, 1H), 7.60 (d, J=8.2 Hz, 1H), 7.95 (s, 1H). 13C NMR
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1
Compound 26, red powder (65%). H NMR (400 MHz,
Pyr-d5): l 3.21 (s, 3H), 3.65 (s, 3H), 4.00 (s, 3H), 7.27 (dd,
J=8.0, 8.0, 1H), 7.37 (dd, J=8.0, 8.0, 1H), 7.41 (d, J=8.0,
1H), 7.43 (dd, J=8.6, 2.6, 1H), 7.70 (d, J=8.8, 1H), 7.95
(s, 1H), 8.01 (d, J=8.0, 1H), 8.15 (s, 1H), 9.17 (d, J=2.4,
1H), HRMS: calcd for C25H19N3O3 [M+]: 409.1426; found:
409.1655. Anal. calcd for C25H19N3O3: C, 73.34; H, 4.68;
N, 10.26; O, 11.72%; found: C, 73.30; H, 4.72; N, 10.22%.