Total synthesis of kealiiquinone: the regio-controlled strategy for accessing its 1-methyl-4-arylbenzimidazolone core

Abstract

A practical, concise and straightforward total synthesis of kealiiquinone 1, a naphtho[2,3-d]imidazole alkaloid obtained from the Micronesian marine sponge Leucetta sp. was accomplished. The squaric acid chemistry to construct the 1,4-quinoid ring and the regioselective N-methylation through a benzo[c][1,2,5]selenadiazolium heterocycle are the key features in this report. The full details of the representative approaches involving the different attempted synthetic strategies are also presented. Finally a successful total synthesis of this complex secondary metabolite is described.

Fig. 1. Representative imidazole alkaloids isolated from the Leucetta sp. sponge.

Scheme 1. Described total synthesis of kealiiquinone to date.

Scheme 2. First strategy towards the total synthesis of kealiiquinone 1.

Scheme 3. Synthesis of benzimidazolones 4 and 5 for preparing 9.

Scheme 4. Second strategy towards the total synthesis of kealiiquinone 1.

Scheme 5. Synthesis of the regio-differentiated arylbenzimidazolone 20.

Scheme 6. Attempts to synthesize the aniline 23a and benzimidazolone 26.

Scheme 7. Successful retrosynthetic analysis of the kealiiquinone 1.

Scheme 8. Synthetic route for accessing to the 1-methyl-4-arylbenzimidazolone 21 of the kealiiquinone.

Scheme 9. Completion of the total synthesis of kealiiquinone 1.