1-Phthalimido-4-(3-indolyl)-2-siloxy-1,3-butadienes: Synthesis and Diels-Alder reactivity

Article abstract of DOI:10.1016/j.tetlet.2003.12.118

New 1-phthalimido-4-(3-indolyl)-2-trialkylsiloxy-1,3-butadienes were easily prepared from 1,3-dichloropropanone and their configurations were established from NMR data. Their Diels-Alder reactivity with different maleimides and quinones was studied, high yields of the exo cycloadducts being obtained, as confirmed by X-ray diffraction studies.

Full text of DOI:10.1016/j.tetlet.2003.12.118

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 1631–1634
1-Phthalimido-4-(3-indolyl)-2-siloxy-1,3-butadienes: synthesis
and Diels–Alder reactivity
a
a
a
a
Esther Caballero,a, Dulce Alonso, Rafael Pelaez, Concepcion Alvarez, Pilar Puebla,
*
ꢀ
Francisca Sanz, Manuel Medarde and Fernando Tome
ꢀ
b
a
ꢀa
a
ꢀ
ꢀ
ꢀ
Laboratorio de Quımica Organica y Farmaceutica, Facultad de Farmacia, Campus Miguel de Unamuno, 37007 Salamanca, Spain
bServicio Difracciꢀon de Rayos X, Salamanca, Spain
Received 18 November 2003; revised 19 December 2003; accepted 23 December 2003
Abstract—New 1-phthalimido-4-(3-indolyl)-2-trialkylsiloxy-1,3-butadienes were easily prepared from 1,3-dichloropropanone and
their configurations were established from NMR data. Their Diels–Alder reactivity with different maleimides and quinones was
studied, high yields of the exo cycloadducts being obtained, as confirmed by X-ray diffraction studies.
Ó 2004 Elsevier Ltd. All rights reserved.
Several years ago, we started a research line directed at
the synthesis of new siloxydienes and the study of their
reactivity in the Diels–Alder reaction as a method to
access different bioactive compounds. We reported the
application of new 1-(methoxyphenyl)-3-siloxy-1,3-but-
adienes to the synthesis of some analogues of rebecca-
mycin.1 We also applied this methodology to the total
synthesis of the alkaloid arcyriaflavin-A from 1-(2-ni-
trophenyl)-3-tert-butyldimethylsiloxy-1,3-butadiene.2
Recently, we reported the Diels–Alder reactivity of (E)-
1-(3-indolyl)-3-tert-butyldimethylsiloxy-1,3-butadienes,
which show good reactivity towards different dieno-
philes, such as maleimides, 4-phenyl-1,2,4-triazolidine-
3,5-dione, acetylenedicarboxylate, and quinones.3 The
endo cycloadducts were always obtained in the afore-
mentioned cases.
In this communication we describe the preparation and
Diels–Alder reactivity of 1-phthalimido-4-[(N-phenyl-
sulfonyl)-3-indolyl)]-2-triisopropylsiloxy-1,3-butadiene,
designed for the synthesis of granulatimide, other nat-
ural products, and their analogues. Granulatimide (1) is
a marine alkaloid isolated from extracts of the Brazilian
ascidian Didemnum granulatum5 and shows activity as a
G2 checkpoint inhibitor.6 Our approach to the synthesis
of 1 and its analogue 2 is based on a retrosynthetic
analysis that has 4-amino-7-(aryl or heteroaryl) per-
hydroisoindole-1,3,5-triones as key synthetic intermedi-
ates, as depicted in Scheme 1.
The preparation of these new dienes follows a straight-
forward route (Schemes 2 and 3). 1,3-Dichloropropa-
none was easily transformed into the phosphorane 4,7
and a Wittig reaction between 4 (1 equiv) and N-phe-
nylsulfonylindole-3-carbaldehyde (1 equiv) yielded 5
(58%) in addition to undesired 6 (30%), which resulted
from an intramolecular Wittig reaction. When an excess
of the aldehyde (2 equiv) was added, only 5 (80%) was
obtained. Wittig reactions of cyclic imides, including
phthalimides, are known, although intramolecular
examples are relatively rare.8 Related reactions have
also been described for the synthesis of 3-hydroxypyr-
roles9 or 1H-pyrrolizine-3,6-(2H,5H)-dione.10
We have now designed new trisubstituted 1-amino-4-
(aryl or heteroaryl)-2-trialkylsiloxy-1,3-butadienes in
which the latent amino group can be introduced in dif-
ferent forms, such as phthalimido (Pht), formamido or
azido groups, to be readily unmasked later under mild
conditions. Several 1-amino-3-siloxy-1,3-butadienes and
their applications in Diels–Alder reactions have been
reported by RawalÕs group4 but, as far as we are aware,
1-amino-2-siloxy-1,3-butadienes have not yet been
reported.
The title diene was prepared by enol silylation of the
enone 5 with triisopropylsilyl triflate. The best condi-
tions were found when 4 mol of triflate and 5.4 mol of
Et3N per mol of 5 were used in CH2Cl2 for 2 h at 50 °C.
Under these conditions, only the 1Z,3E diene 7 (89%)
Keywords: Amino siloxy butadienes; Synthesis; Diels–Alder reactivity.
* Corresponding author. Tel.: +34-923-294528; fax: +34-923-294515;
e-mail: escab@usal.es
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.12.118

1632
E. Caballero et al. / Tetrahedron Letters 45 (2004) 1631–1634
H
N
H
N
O
O
O
O
NG
NG
N
OSiR3
NO2
N
N
O
NO2
H
NG = protected
Granulatimide (1)
amino group
H
H
N
O
O
N
O
O
NG
NH
NG
HN
HN
HN
N
OSiR3
O
2
Scheme 1. Retrosynthetic analysis of granulatimide (1) and its analogue 2.
O
O
O
i , ii
iii
PPh3
Cl
Cl
PPh3
Pht
Cl
3
4
Pht =
O
O
O
N
O
iv
Pht
+
N
5
6
N
O
SO2Ph
Scheme 2. Synthesis of enone 5. Reagents and conditions: (i) PPh3/THF/reflux, 4 h, 73%; (ii) Na2CO3/MeOH–H2O, rt, 30 min, 90%; (iii) Potassium
phthalimide (3 equiv), DMF, 100 °C, 6 h, 62%; (iv) N-phenylsulfonylindole-3-carbaldehyde (1 equiv), toluene, reflux, 2 days, 5 (58%) and 6 (30%).
Pht
1
OTIPS
OTIPS
Pht
O
TIPSOTf / 4 eq
Pht
3
+
Ind
Et3N /CH2Cl2
50 ºC
N
N
PhO2S
PhO2S
8: 1E, 3E
7: 1Z, 3E
Scheme 3. Synthesis of dienes 7 and 8.
was produced (Scheme 3). Longer reaction times (3 h or
more) led to a mixture of 7 with its 1E,3E stereoisomer 8
in a 3:2 ratio.11 The 1Z,3E stereochemistry for diene 7
was established by ROESY correlations (Fig. 1), which
also revealed an extended transoid conformation of the
C2–C3 single bond.
Once the preparation of 7 and 8 had been successfully
achieved, the Diels–Alder reaction was examined. We
used maleimides and quinones as dienophiles, in order
to determine the scope of this methodology. Maleimide,
N-methyl, N-phenyl, and N-benzyl-maleimides were
chosen because they are building blocks required for the
synthesis of granulatimide families and in view of their
good reactivity with related dienes.
The reaction between N-methylmaleimide and purified 7
in toluene at reflux for 35 h gave exclusively the exo
adduct 9a (70%).12 In order to improve the reaction, we
used the diene obtained without removing the excess of
the triisopropylsilyl triflate, which produced a reduction
of the reaction time down to 6 h, and the increase of the
yield up to 95% of 9a. In both cases, the 1H NMR
spectra of the crude reaction product only showed sig-
nals corresponding to one cycloadduct, irrespective of
the solvent (DMSO, CD3OD) used (Scheme 4).13
7.08
7.68
OTIPS H
H
Pht
SO2Ph
N
H
H
H
7.88
5.81
6.77
Figure 1. Selected ROESY correlations for 7.

E. Caballero et al. / Tetrahedron Letters 45 (2004) 1631–1634
1633
Pht
O
Pht
Pht
O
N
O
O
1
H
Cl
H
OTIPS
7 (1 eq)
OTIPS
O
Cl
OTIPS
4
7
8
5
3a
R
Toluene, ∆
3
Cl
1
+
7 h
R N
Toluene
O
Cl
(2 eq)
H
∆, 6 h
O
O
N
10
N
N
PhO2S
PhO2S
PhO2S
7
9a R = Me ; 9b R = H
9c R = Bn ; 9d R = Ph
Pht
O
O
O
H
H
OTIPS
7 (1 eq)
Scheme 4. Diels–Alder reaction between 7 and different maleimides.
All the products were characterized by NMR and mass spectrometry.
Toluene, ∆
13 h
(2 eq)
O
1H NMR experiments (HMQC, HMBC, COSY)
allowed us to assign unequivocally the spectroscopic
data and the ROESY correlations between H-3a/H-7a/
H-2Ind indicated that these groups are on the same face
of the molecule. These correlations and that observed
between H-6 and H-7 agree with the exo stereochemistry
for 9a, unlike the endo results obtained for the cyclo-
addition reactions of related 4-(3-indolyl)-2-siloxy-1,3-
butadienes lacking the phthalimido residue at C-1.1 The
structure of 9a was confirmed by X-ray diffraction
studies.14 As can be observed in the ORTEP drawing
(Fig. 2), the phthalimido and indolyl moieties adopt
pseudoequatorial dispositions, whereas their geminal
hydrogen atoms H-4 and H-7 are in axial disposition
and in anti arrangement with respect to H-3a and H-7a.
This conformation in the solid state of the exo adduct is
also the preferred one in solution.
N
11
PhO2S
Scheme 5. Diels–Alder reaction of 7 with quinones.
adducts, which were carried out by mean of a systematic
Monte Carlo conformational search, followed by energy
minimization using the MM2 force field with the
parameters set for the Diels–Alder reaction derived by
Houk and co-workers15 For the reaction between 7 and
N-methylmaleimide, the stabilities of exo and endo cyclo-
adducts were similar but the exo transition state was
more stable than the endo one (6.8–9.0 kJ/mol). When the
phthalimido moiety is not present in this type of dienes,1a
the endo stereoselectivity was observed, also in agree-
ment with the calculated more stable transition state and
with the absence of severe crowding for the endo
approach. Although not for the synthesis of granulat-
imide and other planar analogues, the stereochemistry of
the reaction is of great interest for the synthesis of folded
analogues and other types of derivatives.
The above stereochemical preference can be explained by
a crowded transition state in which substituents at
positions 1, 2, and 4 of the diene prevent the stabilization
of the endo approach by secondary interactions with the
dienophile. Moreover, the phthalimido and N-benzene-
sulfonylindol-3-yl moieties can interact favorably with
N-methylmaleimide during the exo approach. This ste-
reochemical outcome is also in agreement with modeling
the transition states leading to the exo and endo cyclo-
Compounds 9b, 9c, and 9d were obtained under the
conditions described for 9a, in 95–80% yield and with
the same stereochemical outcome described above.
In order to gauge the scope of the Diels–Alder reaction
we carried out several experiments with diene 7 (under
the same conditions described previously for male-
imides) and differently substituted quinones (Scheme 5).
The exo cycloadducts 1016 and 11 were obtained in high
yield (85% and 90%, respectively). The proposed regio-
chemistry was deduced from the connectivities observed
in HMBC experiments and corresponded to that pro-
duced with substituted chloroquinones and related
siloxydienes.17
In conclusion, a straightforward method for the prepa-
ration of 1-phthalimido-4-(3-indolyl)-2-trialkylsiloxy-
1,3-butadienes is described. The Diels–Alder reaction
yields the exo adducts, opposite to the results obtained
with related disubstituted dienes lacking the phthalim-
ido substituents at C-1.
Acknowledgements
Financial support was provided by the Spanish MCyT
and the European FEDER Funds (PPQ2000-1179), and
Figure 2. X-ray crystallographic analysis of 9a.

1634
E. Caballero et al. / Tetrahedron Letters 45 (2004) 1631–1634
10. Flitsch, W.; Hampel, K. Liebigs Ann. Chem. 1988, 387–
390.
ꢀ
from Junta de Castilla y Leon (SA048/03). C. Alvarez
thanks the Spanish MCyT for a predoctoral grant.
11. Data for 7: mp 198 °C (ether/MeOH). 1H NMR
(400 MHz, CDCl3) 8.01 (1H, d, J ¼ 7:2 Hz, H-7Ind),
7.73 (1H, d, J ¼ 7:2 Hz, H-4Ind), 7.9–7.5 (9H, Pht,
PhSO2), 7.68 (1H, s, H-2Ind), 7.37 (1H, dt, J1 ¼ 7:2,
J2 ¼ 1:0 Hz, H-6Ind), 7.32 (1H, dt, J1 ¼ 7:2, J2 ¼ 0:8 Hz,
H-5Ind), 7.08 (1H, d, J ¼ 16:0 Hz, H-4), 6.77 (1H, d,
J ¼ 16:0 Hz, H-3), 5.81 (1H, s, H-1), 1.0–0.9 (TIPS). EA
calculated for C35H38N2O5SSi: C 67.06, H 6.11, N 4.47, S
5.12. Found C 66.97, H 6.35, N 4.57, S 4.96.
References and notes
ꢀ
1. (a) Adeva, M.; Sahagun, H.; Caballero, E.; Pelaez-
Lamamie de Clairac, R.; Medarde, M.; Tome, F. J. Org.
ꢀ
12. Data for 9a: mp 268 °C (CHCl3/MeOH). 1H NMR
(400 MHz, CDCl3) 7.99–7.26 (14H, m, Ar), 5.02 (1H, d,
J ¼ 2:4 Hz, H-6), 4.98 (1H, m, H-4), 4.06 (1H, dt, J1 ¼ 6:8,
J2 ¼ 2:4 Hz, H-7), 3.84 (1H, t, J ¼ 8:9 Hz, H-3a), 3.30 (1H,
dd, J1 ¼ 8:9, J2 ¼ 6:8 Hz, H-7a), 3.01 (3H, s, N–Me), 1.0–
0.9 (TIPS). EA calculated for C40H43N3O7SSi: C 64.71, H
5.71, N 5.80, S 4.43. Found C 64.37, H 6.01, N 5.58, S 4.23.
HRMS m=z calcd for C40H44N3O7SSi 737.2591, found
737.2598.
Chem. 2000, 65, 3387–3394; (b) Caballero, E.; Adeva, M.;
ꢀ
ꢀ
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Calderon, S.; Sahagun, H.; Tome, F.; Medarde, M.;
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Fernandez, J. L.; Lopez-Lazaro, M.; Ayuso, M. J. Bioorg.
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3. Caballero, E.; Longieras, N.; Zausa, E.; Del Rey, B.;
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4. Kozmin, S. A.; Iwama, T.; Huang, Y.; Rawal, V. H. J.
Am. Chem. Soc. 2002, 124, 4628–4641, and references cited
therein.
5. (a) Berlinck, R. G. S.; Britton, R.; Piers, E.; Lim, L.;
Roberge, M.; Moreira da Rocha, R.; Andersen, R. J. J.
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13. During our work with related siloxydienes we have always
observed only one stereoisomer. When the reactions were
carried out at higher temperatures, the isomerization of
the double bond was produced instead of the equilibration
to the thermodynamic mixture of the endo/exo diastereo-
isomers. For more details see Ref. 1a.
14. Crystallographic data have been deposited with the
Cambridge Crystallographic Data Centre as supplemen-
tary publication no. CCDC 200219. Copies of the data can
be obtained, free of charge, on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK (fax: +44(0)-1223-
336033 or e-mail: deposit@ccdc.cam.ac.uk).
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15. Raimondi, L.; Brown, F. K.; Gonzalez, J.; Houk, K. N.
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7. Caballero, E.; Guilhot, F.; Lopez, J. L.; Medarde, M.;
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J. Am. Chem. Soc. 1992, 114, 4796–4804.
16. Data for 10: mp 242 °C (Hexane/AcOEt). 1H NMR
(400 MHz, CDCl3) 8.56 (1H, s, Ar), 8.2–7.2 (13H, m,
Ar), 7.17 (1H, s, Ar), 5.12 (1H, dd, J1 ¼ 6:0, J2 ¼ 1:2 Hz,
H-6), 5.04 (1H, dt, J1 ¼ 10:8, J2 ¼ 1:2 Hz, H-8), 4.77 (1H,
dd, J1 ¼ 6:0, J2 ¼ 1:2 Hz, H-5), 4.27 (1H, d, J ¼ 10:8 Hz,
H-8a), 1.0–0.9 (TIPS). HRMS (FAB) m=z calcd for
C41H41N2O7SSiCl2 802.1703, found 802.1780.
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Sahagun, H.; Tome, F. Tetrahedron Lett. 1996, 37, 6951–
6954.
8. (a) Bestmann, H. J.; Moenius, T.; Soliman, F. Chem. Lett.
1986, 1527–1528; (b) Aitken, R. A.; Cooper, H. R.;
Mehrotra, A. P. J. Chem. Soc., Perkin Trans. 1 1996, 9,
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Lett. 1987, 28, 4395–4396; (b) Flitsch, W.; Hohenhorst, M.
Liebigs Ann. Chem. 1990, 397–399.
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and references cited therein.