Abstract
Dictyodendrins (1-5) were isolated in 2003 by Fusetani and Matsunaga from the marine sponge Dictyodendrilla verongiformis. These compounds have found to be the first marine alkaloids which possess inhibitory activity against telomerase (100% inhibition at a concentration of 50 μg/mL). They have attracted considerable attention as synthetic targets not only due to their important biological activity, but also to the unique structure consisting of the highly substituted pyrrolo[2,3-c]carbazole core. Herein, we describe an efficient total synthesis of all the member of dictyodendrins 1-5 featuring a newly developed benzyne-mediated indoline formation-functionalization sequence using magnesium bisamide. From our unsuccessful initial approaches, we learned that regioselective introduction of the substituent at the 7-position after the construction of the indoline skeleton was a difficult task due to its sterically congested environment. At this juncture, we decided to develop a straightforward and regiochemically secured methodology based on benzyne chemistry. Among a variety of bases tested, Mg(TMP)_2-2LiBr was found to be superior for smooth indoline formation and subsequent coupling reaction to give the desired product 19 in excellent yield. The double functionalization methodology was also applied to synthesis of 7-substituted indolines. Having successfully constructed the desired indoline bearing p-anisyl group at 7-position by the efficient benzyne-mediated cyclization cross coupling sequence, we then converted it to pivotal indole 20 by removal of the Boc group, DDQ oxidation to indole, and attachment of p-anisylethyl group on the nitrogen. The installation of subunits on the indole 2-position for the synthesis of dictyodendrin A (1), B (2), and E (5) was successfully carried out. Construction of the tetracyclic core skeleton followed by protecting group manipulation yielded dictyodendrin A (1), B (2), and E (5). By application of the synthetic route, we also completed total synthesis of dictyodendrin C (3) and D (4). In conclusion, we have developed the unprecedented one-pot benzyne-mediated indoline formation-cross coupling sequence via transmetallation to a copper species. This methodology provides direct access to the highly substituted indoline, which would be applicable to various nitrogen-containing heterocyclic compounds. By utilization of our methodology, we have established a highly flexible synthetic route by the introduction of the peripheral segments on the pivotal indole intermediate in a modular fashion, which enabled us to synthesize dictyodendrins A-E(1-5) systematically.
