Zirconium-promoted bicyclization reactions and studies directed toward the total synthesis of carbacyclin

Fredrik Emil Malcolm Cederbaum, Purdue University

Abstract

Enynes and diynes reacting with "ZrCp$\sb2$" generated by treating Cl$\sb2$ZrCp$\sb2$ with 2 equiv of n-BuLi can produce in excellent yields zirconabicycles. Their protonolysis can provide the corresponding exocyclic alkenes and conjugated dienes, respectively. Iodinolysis can give the corresponding diiodides, while carbonylation produces bicyclic enones. A mechanism involving oxidative coupling of Cp$\sb2$Zr(CH$\sb2$=CHEt) to the alkyne moiety, forming a zirconacyclopropene intermediate, which then undergoes an intramolecular carbometalation with the alkene moiety, is proposed for the Zr-promoted bicyclization of enynes. The intramolecular addition of an alkenyl-lithium to an alkyne provides another stereoselective route to exocyclic conjugated dienes. A versatile and highly regio- and stereo-selective method for preparing exocyclic alkenes involving the use of 2-allyl-substituted allylic alcohols as key intermediates was developed. A Cu-catalyzed allylmagnesiation of propargyl alcohols is followed by a Cu-catalyzed cross-coupling of the allylic mesylates with Mg-acetylides to give dienynes, which are subjected to the Zr-promoted bicyclization-carbonylation sequence. This methodology is applied in the study of the selective synthesis of carbacyclin. Several methods for the cross-coupling of bicyclic enones with the prostanoid $\omega$ side-chain were investigated.

Degree

Ph.D.

Advisors

Negishi, Purdue University.

Subject Area

Organic chemistry

COinS