Palladium-catalyzed cross-coupling reactions of organosilanolates: Methods development and application in the total synthesis of (+)-papulacandin D

New methods for the palladium-catalyzed cross-coupling of organosilanols have been developed. First, the preparation of 5-substituted-2-arylindoles by palladium-catalyzed cross-coupling of sodium 5-substituted-dimethyl(2-indolyl)silanols with aryl iodides is described. The cross-coupling process was developed through extensive optimization of the following key variables: (1) identification of stable metal silanolates in solution, (2) identification of conditions for in situ formation of the silanolate salts using a metal hydride or organic bases, and (3) selection of the protecting group on the nitrogen of indole. It was found that the alkali metal silanolates, formed in situ, offered a significant rate enhancement and broader substrate scope over the use of silanols activated by Bronsted bases such as sodium tert-butoxide. In addition, the optimized conditions for the cross-coupling of 2-indolylsilanolates were readily applied to the cross-coupling of a variety of 5-substituted-dimethyl(2-indolyl)silanol and aryl iodides.;Second, an application of silanolate-based cross-coupling is presented in the total synthesis of (+)-papulacandin D. The synthesis was achieved in 31 steps, in a 9.2% overall yield from commercially available materials. The synthetic strategy divided the molecule into two nearly equal sized subunits, the spirocyclic C-arylglycopyranoside and the polyunsaturated fatty acid side chain. The C-arylglycopyroanoside was prepared in 11 steps in a 30% overall yield from triacetoxyglucal. The fatty acid side chain was also prepared in 11 steps in a 30% overall yield from geraniol. The key strategic transformations in the synthesis are: (1) a palladium-catalyzed, organosilanolate-based cross-coupling reaction of a dimethylglucal-silanol with an electron rich and sterically hindered aromatic iodide and (2) a Lewis base-catalyzed, enantioselective allylation reaction of a dienal and allyltrichlorosilane. A critical element in the successful execution of the synthesis was the development of a suitable protecting group strategy that satisfied a number of stringent criteria.;Finally, an E,Z-1,4-bissilylbutadiene reagent was prepared for the synthesis of unsymmetrical, highly conjugated systems. Two distinct silyl substituents were differentiated in the cross-coupling reaction through the initial use of base-promoted reaction conditions where only one silyl group was reactive with a range of aryl halides. The second silyl substituent then reacted under fluoride-promoted reaction conditions to provide the desired unsymmetrical products.