Abstract:
A flexible, convergent-divergent strategy for the asymmetric total synthesis of the isolactarane sesquiterpenes has been developed, and the synthesis of both (-)-sterepolide and (-)-merulidial have been achieved. These syntheses established for the first time the absolute stereochemistry of both molecules, and this assignment suggests that the isolactaranes are derived from the same enantiotopic folding of farnesyl pyrophosphate as has been established for the illudanes, marasmanes and sterpuranes. The strategy employs the versatile palladium-catalyzed cycloisomerization technology to provide 1,2-bisalicylidenecyclopentanes further demonstrating the value of this method for the creation of valuable building blocks for polycycle construction. This method also includes the retrosynthetic application of an asymmetric functional group interconversiontransformation of an achiral center in a target molecule into a stereogenic center of an intermediate. The initial stereogenic carbinol center was synthetically introduced in an efficient and enantioselective manner using a modified MosherDarvon alcoholflithium aluminum hydride asymmetric reduction. After the palladium-catalyzed cycloisomerization of the resulting enyne to the highly functionalized 1,2-bisalkylidenecyclopenetane, the stereogenicity was multiplied in a diastereoselective Diels-Alder cycloaddition. Then having performed its required function, this temporal stereochemical control element was erased in a final step of the synthesis. Also within this exercise, a practical, one pot method for the reduction of a carboxylic acid in the presence of other sensitive functionality with sodium borohydride was introduced. This procedure is based on the activation of the carboxylate as its hydroxybenzoiriazole ester and the use of tetrahydrofuran as the reaction media. Overall this facile route produces enantiomerically pure (-)-merulidial in just 16 steps and 14% overall yield and enantiomerically pure (-)-sterepolide in just 11 steps and 30% overall yield. Also of note was the preparation of unnatural (±)-merulidial via this same route. Finally and most importantly these two syntheses demonstrate the capacity of the method to differentially functionalize every carbon atom in the polyhydrindane skeleton at will. Due to this ability, this approach should prove to be of general use for the synthesis of any polyhydrindane including other isolactaranes, illudanes, sterpuranes, marasmanes and even other as-yet-undiscovered protoilludane-derived sesquiterpenes.
