A new synthesis of unsaturated nitriles : total synthesis of stephalic acid

This thesis describes the total synthesis of (±)-stephalic acid (96), the development of methodology for the conversion of ketones into α,β-unsaturated nitriles and exploratory studies aimed at developing a synthetic approach to cis-clerodane diterpenoids. In the total synthesis of (±)-stephalic acid (96), the ketone 94 (previously synthesized from 3-methyl-2-cyclohexen-1-one (105)) was converted into the enol trifluoromethanesulfonate (triflate) 108. The enol triflate 108 was coupled with lithium cyanide in the presence of a Pd(0) catalyst to provide the α,β-unsaturated nitrile 102. The latter substance was transformed into the α,β-unsaturated aldehyde 104, which was stereoselectively converted into the enol silyl ether 111. A novel triisobutylaluminum-promoted Claisen rearrangement-reduction process converted the enol allyl ether 103, obtained from the enol silyl ether 111, into the diene alcohol 118. The diene alcohol 118 was transformed via a series of reactions into (±)-stephalic acid (96). Conversion of the ketone 94 into the α,β-unsaturated nitrile 102 required the development of new methodology for the conversion of ketones into the corresponding α,β-unsaturated nitrites. Reaction of the enol triflates 158 and 162-167 with lithium cyanide in benzene (room temperature) in the presence of catalytic amounts of 12-crown-4 and tetrakistriphenylphosphinepalladium(0) provided the α,β-unsaturated nitriles 168 and 170-175, respectively. Conversion of the ketone 92 (previously synthesized from 2-methyl-2-cyclohexen-1-one (191)) into the enol silyl ether 204 was accomplished via an eight step sequence. Several features of this sequence should prove useful in the development of synthetic routes to the cw-clerodane family of diterpenoids. [diagrams omitted]Science, Faculty ofChemistry, Department ofGraduat