An enantioselective total synthesis of tremulenediol A and tremulenolide A and development of the [Rh(CO)₂Cl]₂-catalyzed direct, stereoselective allylic alkylation of unsymmetrical substrates

A method for the enantioselective construction of the [5.3.0] bicyclic carbon skeleton present in the tremulane sesquiterpenes is described. The route incorporates an enantioselective rhodium(II)-catalyzed intramolecular cyclopropanation that sets the stage for a diastereoselective rhodium(I)-catalyzed [5+2] cycloaddition as an efficient approach to the tremulane natural products tremulenediol A and tremulenolide A. The use of rhodium(I)-catalyzed carbocyclization and allylic alkylation transformations was likewise explored. To that end, a novel regio- and stereoselective [Rh(CO)2Cl]2- catalyzed allylic alkylation of unsymmetrical allylic carbonates was discovered. The regioselectivity favors product ratios in which the major product arises from substitution at the carbon that previously bore the allylic leaving group by the malonate nucleophile. When an enantiomerically enriched carbonate (≥ 99% ee) was examined, the Rh(I)- catalyzed allylic alkylation proceeded stereoselectively to provide the alkylation product with retention of absolute stereochemistry (98% ee). To establish the scope of the [Rh(CO)2Cl]2-catalyzed allylic alkylation, a variety of carbon and heteroatom nucleophiles were examined and the results described. A series of unsymmetrical allylic carbonates were treated with the sodium salts of various substituted malonates, b-ketoesters and sulfones in the presence of [Rh(CO)2Cl]2 to provide the corresponding direct substitution products in good yield and with excellent regioselectivity. Preliminary studies were conducted to include allylic etherifications utilizing sterically hindered phenols and aminations of unsymmetrical carbonates with N-alkylated sulfonamides. As an application of the rhodium(I)-catalyzed allylic alkylation, a series of novel domino reactions have been invented that involve the regioselective and stereoselective [Rh(CO)2Cl]2-catalyzed alkylation of allylic trifluoroacetates with the a-substituted sodiomalonates followed by either an intramolecular Pauson-Khand annulation, a cycloisomerization, or a [5+2] cycloaddition. A unique aspect of the method described is the use of a single catalyst to effect sequential transformations in which the catalytic activity is moderated simply by controlling the reaction temperature. This strategy thus provides a rapid and efficient entry into a variety of bicyclic carbon skeletons.