A new approach to N-protected staurosporinones

Article abstract of DOI:10.1016/j.tetlet.2004.01.089

A completely regioselective synthesis of two advanced precursors to glycosidic indolopyrrolo[2,3-a]carbazole alkaloids is described.

Full text of DOI:10.1016/j.tetlet.2004.01.089

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 2347–2349
A new approach to N-protected staurosporinones
Maria M. M. Santos, Ana M. Lobo,* Sundaresan Prabhakar* and M. Manuel B. Marques
ꢀ
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ꢀ
Secßc~ao de Quımica Organica Aplicada, Departamento de Quımica, CQFB-REQUIMTE and SINTOR-UNINOVA, campus Faculdade
de Ci^encias e Tecnologia, Universidade Nova de Lisboa, Quinta da Torre, 2829 Monte de Caparica, Portugal
Received 5 December 2003; accepted 20 January 2004
Abstract—A completely regioselective synthesis of two advanced precursors to glycosidic indolopyrrolo[2,3-a]carbazole alkaloids is
described.
Ó 2004 Elsevier Ltd. All rights reserved.
One of the major difficulties associated with the syn-
thesis1 of structurally interesting and biological active2
alkaloids such as K252a (1) is the regiocontrol required
in the glycosidation step of an advanced precursor such
as 2 (Fig. 1).
exchange. The resulting iodide 8c on reaction with
12
Me6Sn2 and Pd2(dba)3 furnished the stannylated a,b-
unsaturated imide 8d (ca. 65% overall yield from 8a)
(Scheme 2).
Left undiscriminated to the last, the attachment of a
chiral sugar moiety to a specific indolic nitrogen of 2
(R1 ¼ R2 ¼ H) occurs nonselectively producing regio-
isomers.3;4
Our interest in the synthesis of alkaloids such as
staurosporine (3),5 K252a (1),6 K252d (4)7 and holyrine
A (5)8 prompted us to examine an approach leading to a
structure of type 2 (wherein the N12 and N13 are differ-
entiated), that could serve as an appropriate precursor
to the substances mentioned above (Fig. 1).
Accordingly the known urea 69 derived from 2,20-bis-
indole, was treated with an equivalent of potassium
tert-butoxide in anhydrous benzene in the presence of
18-crown-6-ether to yield the N-Boc derivative 7a
(Scheme 1).10 Selective iodination in the more nucleo-
philic indole ring was achieved from the derived indolyl
anion and I2 in DMF. Owing to its slight instability the
resulting iodo bis-indole 7b was isolated as the N-acetyl
derivative 7c in an overall yield of ca. 81% from 6.
The other partner 8d, required for a Stille reaction with
7c, was secured from the known tetramic acid 8a11 by
conversion first into the mesylate 8b, followed by Iꢀ ion
Keywords: Alkaloids; Protecting groups.
* Corresponding authors. Tel.: +351-212948387; fax: +351-212948550;
e-mail addresses: aml@fct.unl.pt; sprabhakar@fct.unl.pt
Figure 1.
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.01.089

2348
M. M. M. Santos et al. / Tetrahedron Letters 45 (2004) 2347–2349
9a
i
ii
(58%)
(89%)
COPh
N
COPh
N
O
O
Scheme 1. Reagents and conditions: (i) t-BuOK, C6H6, crown ether,
45 min, rt; (ii) NaH, I2, DMF, 20min, rt; (iii) KH, Ac 2O, 4-DMAP,
DMF, 20min, rt.
N
H
N
N
N
Boc
Ac
H
9b
9c
Scheme 4. Reagents and conditions: (i) KH, DMF, 1.5 h, 0 °C; (ii) )))/
SiO2.
COPh
Scheme 2. Reagents and conditions: (i) NEt3, 4-DMAP, CH2Cl2, t.a.;
(ii) ClSO2Me, 1 h, 0 °C; (iii) BzNEt3I, BF3(OEt)2, CH2Cl2, 22 h reflux;
(iv) (Me3Sn)2, Pd2dba3, AcOEt, 40min, rt.
N
O
9a
9b
9c
i
The coupling between 7c and 8d promoted by
Pd(PPh3)4/CuCl/LiCl in degassed DMSO13 occurred
smoothly to afford an excellent yield of a mixture of 9a
and b (94%; 1:2 ratio as determined by 1H NMR). Since
separation into pure components proved to be difficult
the mixture was reacetylated and the resulting product
purified by chromatography to provide the fully pro-
tected triacyl compound 9a (overall 78%) (Scheme 3).
N
R
N
R
1
2
i ) h
ν
10a R = Ac; R = Boc (65%)
1
2
10b R = H; R = Boc (48%)
1
2
10c R = Ac; R = H (69%)
1
2
Scheme 5.
This key intermediate can be chemoselectively manipu-
lated so as to furnish either the N12-deacetyl or the N13-
H compounds, 9b and c, respectively. Thus, whilst
exposure of 9a to KH in DMF, generated the former,
ultrasonic irradiation14 of an intimate mixture of the
same with silica gel afforded the latter 9c (Scheme 4).
two such linkages. Further progress in this area will be
reported elsewhere.
Acknowledgements
All the three compounds 9a, b15 and c,15 incorporating a
trienic system, underwent photocyclisations to furnish
the corresponding indolocarbazoles 10a,16;17 b18 and c in
65%, 48% and 69% yield, respectively (Scheme 5).
It is a pleasure to express our gratitude to Dr. S. N.
Swami (Pfizer, U.K.) and Professor E. Becalli for their
~
^
interest in the work and to Fundacao para a Ciencia e
ß
Tecnologia (FEDER, POCTI) (Lisbon, Portugal) for
the award of a doctoral fellowship to one of us
(M.M.M.S.) and partial financial support.
Thus the N6,N13-diacyl substituted (10b) or the N6,N12-
protected (10c) staurosporinones, secured in 22 and 48%
overall yields (from 9a), respectively, are both of value
in the stereocontrolled synthesis of indolocarbazole
alkaloids containing either a single N-glycosidic bond or
References and notes
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N
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i
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1
ii (83%)
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1
Scheme 3. Reagents and conditions: (i) LiCl, Pd(PPh3)4, CuCl,
DMSO, 19 h, rt; (ii) KH, Ac2O, 4-DMAP, DMF, 1 h, 0 °C.

M. M. M. Santos et al. / Tetrahedron Letters 45 (2004) 2347–2349
2349
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;
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J ¼ 7:3 Hz), 6.90(1H, s), 6.80(1H, s), 1.53 (9H, s) ppm.
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sample17 thereby confirming the presence of the aglycone
common to the alkaloids mentioned above.
^
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