Studies toward the total synthesis of (+-)-agelasimine A and its analogs, and development of the tandem oxy-copeeneClaisen reaction

Abstract

The discovery and development of a novel tandem oxy-Cope/ene/Claisen reaction is described. The strategy allows for highly diastereoselective formation of trans-decalins having a quaternary carbon center at C9. Depending on the substitution pattern of the terminal olefin of the starting 1,2-divinylcyclohexanol an additional tertiary or quaternary carbon center can be introduced at C11.* The oxy-Cope/ene/Claisen reaction of 1,2-divinylcyclohexanol propargyl ethers provides decalines possessing an allene moiety.* An approach toward the total synthesis of (+/-)-agelasimine A, a clerodane-related diterpene isolated from orange sponge Agelas mauritiana , via the oxy-Cope/ene and the oxy-Cope/ene/Claisen reaction has been investigated.* The factors affecting the selectivity at C8 during the oxy-Cope/ene reaction have been studied in detail. Control over the selectivity at C8 can be achieved by either increasing the energy difference between transition states of the ene-reaction or changing the electronic properties of the substituent a to the carbonyl.* The new approach toward formation of the quaternary carbon centers via an anionic oxy-Cope/alkylation reaction is also described. The anionic oxy-Cope reaction affords the macrocyclic enolate, which geometry is predetermined by the stereochemistry of the starting material and a chair-like transition state of the oxy-Cope reaction. The conformation of the macrocycle provides excellent means for controlling facial approach of the electrophile in the following alkylation step. Cleavage of the resulting macrocyclic ketone would afford a chiral ester bearing a quaternary carbon center alpha to a carbonyl.* *Please refer to dissertation for diagrams.