An efficient synthetic route to homocarbonyltopsentine

Article abstract of DOI:10.1055/s-2003-40843

Efficient synthesis of homocarbonyltopsentine Ia, starting from readily available triiodoimidazole 9 and 3-formylindoles 2 and 18 is described. The key steps of the synthesis are selective halogen-metal exchanges at the imidazole nucleus and subsequent ad

Full text of DOI:10.1055/s-2003-40843

LETTER
1533
An Efficient Synthetic Route to Homocarbonyltopsentine
Efficient
S
ynthet
y
r
omocarb
i
onylto
l
psentine Montagne, Guy Fournet, Benoît Joseph*
Laboratoire de Chimie Organique 1, UMR-CNRS 5622, Université Claude Bernard – Lyon 1, CPE Bâtiment 308, 43,
Boulevard du 11 Novembre 1918, 69622 Villeurbanne cedex, France
Fax +33(4)72431214; E-mail: benoit.joseph@univ-lyon1.fr
Received 19 May 2003
Imidazole 1 was deprotonated at –78 °C using 1 equiva-
lent of BuLi and reacted with the aldehyde 2 to give the
expected alcohol 3 in 79% yield.7 The latter was then
quantitatively oxidised using manganese oxide (MnO2) in
dichloromethane at room temperature to lead to the ketone
4.8 Unfortunately, it has not been possible to perform effi-
ciently the second deprotonation/addition process using
BuLi or LDA as base.
Abstract: Efficient synthesis of homocarbonyltopsentine Ia, start-
ing from readily available triiodoimidazole 9 and 3-formylindoles 2
and 18 is described. The key steps of the synthesis are selective
halogen-metal exchanges at the imidazole nucleus and subsequent
addition to formylated indoles.
Key words: indoles, metalation, regioselectivity, addition reac-
tions, alkaloids
Homocarbonyltopsentines I are known to exhibit anti-in-
flammatory activity in vivo (Figure 1).1 The structure of
these compounds is closely related to well known families
of naturally occurring bis-indole alkaloids extracted from
marine organisms, such as hamacanthins, topsentins, and
rhopaladins.2 The latter display a wide spectrum of phar-
macological properties such as antiviral, cytotoxic, anti-
inflammatory and anti-fungal activities3 and represent
new targets for synthetic and medicinal chemists. Several
groups have already reported total syntheses of these com-
pounds using different strategies.4
Herein, we wish to report our synthetic efforts to access
the homocarbonyltopsentine skeleton in order to prepare
new derivatives and then evaluate more deeply their bio-
logical activities.
Scheme 1 i) BuLi (1 equiv), THF, –78 °C, 30 min then 2 (1.1 equiv),
–78 °C, 45 min, 79%; ii) MnO2, CH2Cl2, r.t., 15 h, quantitative.
According to the methodology described by Achab9 for
the synthesis of topsentin, selective iodine/lithium ex-
change at position-5 of 4,5-diiodoimidazole 5 was carried
out in the presence of BuLi. The 5-lithio-4-iodoimidazole
was equilibrated within 45 min at –78 °C into the 2-lithio-
4-iodoimidazole 6 and added to aldehyde 2 (1.1 equiv) to
give 7 in 42% yield (not optimised). The corresponding
ketone 8 was readily prepared by oxidation in 92% yield.
In our hands, a second exchange at position-410 of the im-
idazole ring with BuLi or EtMgBr was much more prob-
lematic and the expected alcohol was not obtained
(Scheme 2). Similarly, deprotonation at position-5 using
LDA as base failed.
Figure 1
Our first strategy was to start from properly N-protected
imidazole and perform selective metalations followed by
additions to formylated indoles and subsequent oxidation
of the alcohols formed (Scheme 1).5 Ethoxymethyl
(EOM) was preferred as protective group for the imida-
zole NH because of its stability under basic/nucleophilic
conditions and its ability to stabilise imidazolium deriva-
tives.6
Finally, the protected triiodoimidazole 9 was used as start-
ing material, as the second exchange reaction should be
easier in position-5 than in position-4, due to the stabilisa-
tion of the lithium by the oxygen of the ethoxymethyl
group; the last iodine being removed before final depro-
tections.
Selective exchange at position-2 of triiodoimidazole de-
rivative 9 using 1 equivalent of BuLi occurred at –78 °C
in 5 minutes. Subsequent trapping of the anion formed by
Synlett 2003, No. 10, Print: 05 08 2003.
Art Id.1437-2096,E;2003,0,10,1533,1535,ftx,en;G11103ST.pdf.
© Georg Thieme Verlag Stuttgart · New York

1534
C. Montagne et al.
LETTER
bonate afforded the reduced bis-indole 14 in 85% yield.
The protective groups were then sequentially removed
first under basic conditions and then under acidic condi-
tions to give the final compound 1611 in good yield
(Scheme 4).
Scheme 2 i) BuLi (1 equiv), THF, –78 °C, 45 min then 2 (1.1
equiv), –78 °C, 45 min, 42%; ii) MnO2, CH2Cl2, r.t., 15 h, 92%.
the appropriate aldehyde 2 produced the expected alcohol
10 in fair yield. The latter was then oxidised using MnO2
to give the ketone 11 in good yield. The second exchange
reaction, at position-5, was performed under the condi-
tions used for the first one, and we were pleased to ob-
serve that it occurred cleanly, giving after reaction with 2,
the alcohol 12. Subsequent oxidation produced the ex-
pected diketone 13 in good yield (Scheme 3).
Scheme 4 i) H2 (15 bar), Pd/C 10%, K2CO3, EtOH/CH2Cl2, 15 h,
85%; ii) NaOH aq, 1,4-dioxane, 70 °C, 30 min, 89%; iii) HCl aq, 1,4-
dioxane, 70 °C, 30 min, 90%.
After having set up the conditions for the preparation of
the simplest member of the family, we carried out the 8
steps synthesis of homocarbonyltopsentine Ia (Scheme 5)
from starting materials 9 and tert-butyl 6-benzyloxy-3-
formyl-1H-indole-1-carboxylate 1812 in 20% overall
yield.
In summary, we have developed an efficient synthesis of
homocarbonyltopsentine Ia using selective metal-halogen
exchange reactions with the protected triiodoimidazole 9.
Scheme 3 i) BuLi (1 equiv), THF, –78 °C, 5 min then 2 (1.1 equiv),
45 min, 73%; ii) MnO2, CH2Cl2, r.t., 4 h, 90%; iii) BuLi (1 equiv),
THF, –78 °C, 5 min then 2 (1.1 equiv), 45 min, 71%; iv) MnO2,
CH2Cl2, r.t., 5 h, 84%.
Removal of the iodine atom of the imidazole was then in-
vestigated. Exchange with BuLi and subsequent hydroly-
sis gave unsatisfactory results confirming the difficulty to
realise exchange at position-4, of our substrates. Cleavage
under homolytic conditions using n-Bu3SnH proved to be
inefficient even with an excess of reagent and heating, the
expected compound being obtained only in 57% yield (not
shown). Finally, hydrogenolysis of 13 using palladium on
charcoal 10% as catalyst in the presence of potassium car-
Scheme 5 i) BuLi (1 equiv), THF, –78 °C, 5 min then 18 (1 equiv),
45 min, 75%; ii) MnO2, CH2Cl2, r.t., 4 h, 91%; iii) BuLi (1 equiv),
THF, –78 °C, 5 min then 2 (1.1 equiv), 45 min, 61%; iv) MnO2,
CH2Cl2, r.t., 5 h, 84%; v) H2 (15 bar), Pd/C 10%, K2CO3, EtOH/
CH2Cl2, 15 h, 89%; vi) NaOH aq, 1,4-dioxane, 70 °C, 30 min, 85%;
vii) HCl aq, 1,4-dioxane, 70 °C, 30 min, 83%; viii) HCOONH4, Pd/C
10%, EtOH, reflux, 2 h, 91%.
Synlett 2003, No. 10, 1533–1535 © Thieme Stuttgart · New York

LETTER
An Efficient Synthetic Route to Homocarbonyltopsentine
1535
(8) LaMattina, J. L.; Mularski, C. J. J. Org. Chem. 1986, 51,
413.
(9) Achab, S. Tetrahedron Lett. 1996, 37, 5503; and references
cited therein.
Preparation of derivatives taking advantage of the pres-
ence of iodine on the imidazole ring is currently under
way in our laboratory.
(10) Turner, R. M.; Ley, S. V.; Lindell, S. D. Synlett 1993, 748.
(11) All new compounds gave satisfactory spectroscopic and
analytical data. Selected spectroscopic data: 16: white solid,
mp >210 °C; IR (KBr): 3198, 1609, 1590, 1512, 1415, 1110,
859 cm–1; 1H NMR (300 MHz, DMSO-d6): d 7.22–7.30 (m,
4 H, HAr), 7.53–7.59 (m, 2 H, HAr), 8.02 (s, 1 H, HAr), 8.37–
8.40 (m, 2 H, HAr), 8.97 (s, 1 H, HAr), 9.14 (s, 1 H, HAr),
12.00 (s, 1 H, NH), 12.21 (s, 1 H, NH), 13.70 (s, 1 H, NH);
13C NMR (75 MHz, DMSO-d6): d 112.2 (CH), 112.5 (CH),
113.4 (C), 114.9 (C), 121.6 (CH), 121.7 (2 CH), 122.3 (CH),
122.9 (CH), 123.2 (CH), 124.3 (CH), 126.5 (C), 126.7 (C),
135.7 (CH), 136.2 (C), 136.3 (C), 137.1 (CH), 143.3 (C),
145.5 (C), 176.5 (CO), 181.6 (CO); MS (ESI):
Acknowledgment
This research work was supported by a grant from the Ministère de
la Jeunesse, de l’Education Nationale et de la Recherche to C.M.
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Synlett 2003, No. 10, 1533–1535 © Thieme Stuttgart · New York