Approach to the total synthesis of massileunicellins

The massileunicellins are a family of highly oxidized eunicellin diterpenes that possess a densely functionalized isobenzofuran core in which all eight of the ring carbons are stereocenters. In addition, they possess a tertiary alcohol stereocenter at C3 adjacent to the isobenzofuran.;An oxidative rearrangement-epoxidation reaction of the isobenzofuran intermediate under the conditions of PCC/NaOAc or Collins' reagent produced epoxy ketone 17.3 with the desired C11 oxygen stereochemistry. Opening the epoxide and forming the enol silyl ether 23.2 followed by Rubottom oxidation gave a dihydroxyl ketone 23.3 with the desired alpha-C13 hydroxyl group. A directed reduction of C12 carbonyl group of diol 23.3 afforded C12 hydroxyl group of triol 23.4 with desired stereochemistry. Acylation of triol 23.4 followed by oxidative cleavage gave ketone 24.2. Directed reduction with Crabtree's catalyst of ketone 24.2 afforded desired C10 beta-hydrogen. Chelation controlled carbonyl addition of ketone 27.1 assisted with Ti(OiPr)4 successfully gave alcohol 27.2 as a single diastereomer at C3.;In this thesis, a stereoselective approach to the fully functionalized isobenzofuran core structure is described. (S)-(+)-Carvone was chosen as the starting material for the total synthesis of massileunicellins. Reduction of the less hindered alkene of (S)-(+)-carvone using Willkinson's catalyst yielded dihydrocarvone. Aldol reaction of dihydrocarvone and methacrolein followed by etherification under optimized condition afforded glycolate intermediate 8.2. Cycloaldol reaction of glycolate upon treatment with KHMDS at -78°C gave isobenzofuran intermediate 15.2 as a single diastereomer.