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V. Be´ne´teau, T. Besson / Tetrahedron Letters 42 (2001) 2673–2676
The retrosynthetic pathway described in Scheme 1 was
inspired by recent works on generation and trapping of
analogues of o-quinodimethane with dienophiles.6 Path
1 was rapidly judged unfeasible7 to the profit of path 2
in which the intermediate quinone may be expected by
Diels–Alder reaction between 4-methylene-(5-bromo-
methylene)-4,5-dihydrothiazole (generated from 4-
(b) Preparation of the pentacyclic compound 1 (Scheme
3). Fusion of the benzothiazole and the quinone skele-
tons suggested the use of 4-methylene-(5-bromo-
methylene)-4,5-dihydrothiazole 9, which have been
proved to undergo highly regioselective Diels–Alder
reactions.6 Treatment of the tribrominated precursor,
with sodium iodide in DMF,6 allowed the o-
quinodimethane 9 which was trapped in situ with the
dienophile 8 with a weak regioselectivity, leading to 10,
a mixture of two isomers 10a and 10b (ratio 10a/10b:
2:1), which were not separated whatever conditions
were used. At this part of our work, we decided to
continue the synthesis from the mixture 10 with the
hope of separating the two isomers a and b in a further
step. Because recent works have demonstrated that the
final cyclization of similar N-protected indoles can
occur when there is a strong electron-withdrawing
group linked to the indolic nitrogen,7 selective deprotec-
tion of 10 was performed. Tosylation of the intermedi-
ate quinone 11 gave 12 in a yield of 50%; the ratio of
isomers a and b remained unchanged. The primary
amine was quantitatively deprotected by treatment of
12 with trifluoroacetic acid and the cyclic imine 13 was
formed, in a very good yield (85%), by heating in ethyl
acetate in the presence of molecular sieves. Then, the
two isomers 13a (major) and 13b (minor) were easily
separated by column chromatography with dichloro-
methane/ethyl acetate (7:3, v/v) as solvent. After vari-
ous experiments, difficult deprotection of the indolic
nitrogen of the iminoquinones 13a and 13b was finally
realized at room temperature in the presence of tetra-
butylammonium fluoride in tetrahydrofuran to give 1a
and 1b,11–13 respectively (yields: 20% for 1a and 5% for
1b).
(bromomethyl)-5-dibromomethylthiazole)6
and
a
protected dioxotryptamine, itself obtained from the
commercially available 2,5-dimethoxybenzaldehyde.
(a) Synthesis of the 4,7-dioxotryptamine 8 (Scheme 2).
Nitration of 2,5-dimethoxybenzaldehyde with nitric
acid in dichloromethane at 0°C led to the 2-nitro
derivative 2,8 which was transformed in good yield
(70%) into the intermediate o,b-dinitrostyrene 3 by a
classical Henry reaction with nitromethane. Reductive
cyclization of 3 in the presence of ammonium formate
in ethanol8,9 provided the attempted indole 4 (yield:
84%), which was quantitatively formylated according to
Vilsmeier–Haack conditions to give the 4,7-dimethoxy-
3-formylindole 5 in very good yield (96%). At this step
of the synthesis, our first intention was to protect (by
tosyl group) or to alkylate (methyl or benzyl groups)
the nitrogen atom of the indole ring. Unfortunately,
preliminary experiments performed by our group7 have
shown that whatever solutions were chosen the follow-
ing steps were unsuccessful. The best alternative was to
condense nitromethane on 5 as described in step (34)
to give 6 in 76% yield. The side chain of the 3-(2-nitro-
vinyl)indole 6 was then completely reduced at room
temperature, using lithium aluminum hydride, and the
intermediate amine was subsequently treated with di-t-
butoxycarbonyl oxide (BOC2O), in the presence of 4-
dimethylaminopyridine, to give 7 in 50% yield. The
protected tryptamine 7 was oxidized into the expected
quinone 8 by treatment with ceric ammonium nitrate
(CAN)10 in the presence of 2,6-dicarboxypyridinium
oxide in aqueous acetonitrile.
In conclusion, we have described the synthesis of new
pentacyclic systems, which are structurally very close to
natural marine alkaloids such as Kuanoniamines and
pyrroloiminoquinones. Unfortunately, the low solubil-
Scheme 2. Reagents and conditions: (a) HNO3 69%, CH2Cl2, 0°C, 1 h, 79%; (b) NH4OAc, CH3NO2, reflux, 1 h, 70%; (c) Pd/C,
EtOH, HCO2NH4, reflux, 1 h, 84%; (d) POCl3, DMF, 0°C, 1.5 h, 96%; (e) NH4OAc, CH3NO2, reflux, 1 h, 76%; (f) i. LAH,
CH2Cl2/Et2O (4/1), rt, 1 h; ii. BOC2O, CH2Cl2, TEA, DMAP, 0°C, 4.5 h, 50%; (g) CAN/pyridine-2,6-dicarboxylic acid N-oxide,
CH3CN/H2O, 0°C, 30 min, 65%.