Synthesis of N -protected Nortopsentins B and D

Indole-3-carboxamidines 13 and 14, prepared from the corresponding amides 7 and 8 via the thioamides 9 and 10, were reacted with 3-bromoacetylindole 15 to give the 2,4-diindolylimidazoles 20 and 21, N -protected nortopsentins δ and B.


Introduction
Nortopsentins A-C 1-3, bis(indolyl)imidazoles isolated from the deep sea sponge Spongosorites ruetzler, are reported to have cytotoxic and antifungal properties. 1 The debrominated derivative nortopsentin δ 4 was formed by catalytic hydrogenolysis of the brominated compounds.The natural products have been synthesized by palladium(0) catalysed coupling of 3-indolylboronic acids with appropriate halogenated imidazoles, 2,3 and recently the corresponding bis(indolyl)thiazole analogues have been prepared. 4In view of our own interest in 3-indolyl substituted heterocycles (thiazoles and oxazoles), [5][6][7][8] we undertook a different approach to the nortopsentins based on the reaction of a-haloketones with amidines.
Two strategies were employed to prepare the required 3-bromoacetylindoles.The 6unsubstituted compound 15 was prepared as previously described 7 by acylation of indole with chloroacetyl chloride, 10 followed by halide exchange (Scheme 2).The N-Boc-6-bromo derivative 19 was prepared differently.Thus Vilsmeier acetylation of 6-bromoindole followed by Nprotection gave the 3-acetyl-6-bromoindole 18 in modest yield over the two steps.Bromination of the ketone using copper (II) bromide 11 gave the required 3-bromoacetylindole 19 (Scheme 2).

Scheme 2
With both the indole-3-carboxamidines and the bromoketones in hand the stage was set for the key imidazole forming reactions.Thus reaction of the indole-3-carboxamidine 13 with 3bromoacetylindole 15 in acetonitrile in the presence of potassium carbonate gave the bis(indolyl)imidazole 20 in 41% yield.Similarly, reaction of the 6-bromoindole-3carboxamidine 14 with bromoketone 15 gave the bis(indolyl)imidazole 21 (34%) (Scheme 3).However, attempts to carry out similar reactions on the 6-bromo-3-bromoacetylindole 19 were unsatisfactory and attempts to isolate and identify the desired bis(indolyl)imidazoles 22 and 23, N-protected nortopsentins C and A respectively, proved fruitless.

Scheme 3
With the N-Boc derivatives of nortopsentinsδand B in hand, efforts were made to deprotect the compounds to give the natural products.However, attempts to removed the Boc groups under the usual acidic conditions (TFA) or using sodium methoxide both failed to give the bis(indolyl)imidazoles 2 and 4.Under both sets of conditions, bright blue solutions were formed, concentration of which failed to give any recognisable products.Hence it would appear that the nortopsentins are unstable to acidic and basic conditions (or are readily oxidized); previous syntheses employed silyl protecting groups on nitrogen which were removed under neutral conditions. 2,3 t is interesting that in the original paper describing the isolation of the nortopsentins it was noted that the compounds became coloured on exposure to light hence requiring isolation and purification in dimly lit rooms.
In conclusion we have shown that simple two-component coupling of indole-3carboxamidines with 3-bromoacetylindoles can provide a route to bis(indolyl)imidazoles, although the reaction apparently fails when both indole nitrogens are protected with tertbutoxycarbonyl groups.

Experimental Section
General Procedures.For general experimental details, see refs. 5 and 7. Compounds characterised by high resolution mass spectrometry were chromatographically homogeneous, and judged pure by analysis of their high field 13 C NMR spectra.