| N-Methylwelwitindolinone C isothiocyanate is a potent multiple drug resistance reversing agent that is composed of a strained and densely functionalized bicyclo[4.3.1]decanone, consisting of an indolinone and cyclohexenone linked via a seven-membered ring, four stereocenters, a gem-dimethyl substituent, and the sensitive vinyl chloride and isothiocyanate functionalities. Despite numerous synthetic efforts over the last fifteen years, no total synthesis has been reported.;Two new methodologies were developed and used toward the total synthesis of N-methylwelwitindolinone C isothiocyanate. In the first methodology, we expanded the application of the non-aldol aldol rearrangement to the synthesis of alpha-alkyl beta-silyloxy cycloalkanones from cyclic alpha-alkyl epoxy silyl ethers. In the second methodology, we developed a novel route for the preparation of highly substituted dibenzopyranones through the Diels-Alder reaction of 4-cyanocoumarins and 1-oxygenated dienes followed by elimination/aromatization with base. The cycloaddition was highly regio- and stereoselective and served as an efficient method to synthesize the functionalized AD ring system of N-methylwelwitindolinone C isothiocyanate.;Reductive opening of the lactone of the cycloadduct followed by selective alcohol protection gave a fully elaborated aryl triflate and set the stage for the closure of the seven-membered ring C through an intermolecular Stille reaction or an intramolecular Heck reaction. Unfortunately, both coupling reactions were unsuccessful most likely due to the steric hindrance about the aryl triflate. As a result, the reactions had to be conducted at higher than expected temperatures and led to the decomposition of starting materials and/or products.;Two attempts were also made to circumvent the steric hindrance problem by removing the TBS protecting group from the reaction center. First, we utilized our non-aldol aldol methodology, but failed to convert a cyclic alpha-allyl epoxy silyl ether into the corresponding alpha-allyl beta-silyloxy cycloalkanone. We presume the reaction was unsuccessful because the Lewis acid was unable to coordinate to the epoxide at a temperature low enough to induce the 1,2-hydride shift but to not decompose the product. Second, we implemented a nucleophilic conjugate addition onto a functionalized enone and obtained the desired product. However, the resulting ketone was thermally unstable and decomposed upon heating. |
