| Lamellarins, a family of marine natural products isolated from the prosobrach mollusc lamellaria sp and ascidians, show interesting biological activities including inhibition of cell division, cytotoxicity, immunomodulation, reversal of multidrug resistance (MDR) and HIV-1 integrase inhibition. In the total synthesis of Lamellarin G trimethyl ether we have successfully constructed the Lamellarin core using sequential, regiocontrolled halogenation/Suzuki cross-coupling reactions starting from a simple pyrrole ester. One of the key attributions of this synthetic route is that a wide array of analogs with modified aryl rings, missing tethers, and even missing rings can be prepared. During the synthesis, the problem of dehalogenation was solved. At the same time, some issues regarding the stability of highly oxygenated boronic acids were overcome as improvements on the original synthesis.; In an effort to develop an even more concise route to tri- and tetrasubstituted pyrroles, the regioselective coupling of dihalopyrroles has been investigated. In particular, the electronic and steric influences upon the regioselectivity of the Suzuki coupling of 4,5-, 3,4-, and 3,5-dibromopyrrole systems have been examined. Variations in the conditions used for the Suzuki coupling reaction have led to further improvements in the inherent selectivity observed in these reactions. What is of great interest is that the regioselectivity can be reversed in the case of ethyl 3,5-dibromopyrrole-2-carboxylate by simply changing the reaction solvent. During these studies, an effective method of protecting the pyrrole nitrogen with carbamate groups was developed by employment of tetrabutylammonium iodide. Finally, initial efforts have shown that not only can regioselectivity be achieved, but that two couplings can actually be carried out in a sequential, one-pot method. |
