THE TRIPLY-CONVERGENT TOTAL SYNTHESIS OF (+)-CARBACYCLIN AND RELATED SYNTHETIC STUDIES

DOUGLAS KENT HUTCHINSON, Purdue University

Abstract

A Highly efficient and versatile total synthesis of (+)-carbacyclin is described. The synthesis involves a new triply convergent, stereospecific "trimethylenemethane" strategy for the formation of cyclopentane derivatives possessing stereochemically defined exocyclic double bonds. Treatment of an optically active allylic vinyl sulfone ammonium salt with a stereochemically defined allylic halocuprate affords a high yield of a vinyl sulfone possessing the required cis -9,11-ring stereochemistry with complete regiocontrol and complete preservation of the original stereochemistry of the 5E-double bond. Thus the allylic halocuprate reagent added to the allylic ammonium salt with complete control of three elements of stereochemistry and one element of regiochemistry. After suitable functional group interconversions, the functionalized vinyl sulfone was treated with (S)-3-t-butyldimethylsilyloxy-1-octenyllithium reagent which induced ring closure by intramolecular alkylation of the intermediate $\alpha$-sulfonyl anion to give the desired bicyclo(3.3.0) octane derivative. After a series of functional group interconversions, the synthesis was completed by selective oxidation of the Cl position by means of dioxygen in the presence of a platimum (0) catalyst. In the course of this work, a completely general synthesis of cis - and trans -disubstituted cyclopentenyl sulfones was developed. Treatment of a $\beta\sp\prime$-dimethylamino vinyl sulfones with alkyllithium reagents followed by quarternization and elimination afforded trans -cyclopentenylsulfones in excellent overall yield. Alternatively, treatment of the corresponding allylic vinyl sulfone ammonium salt with less basic organometallic reagents afforded directly the cis -cyclopentenyl sulfones in excellent yield. It was also found that organocopper reagents add to a $\beta\sp\prime$-dimethylamino vinyl sulfones to give the cis -cyclopentenyl sulfones after quarternization and elimination. The stereochemical course of this reaction apparently results from the amino group-directed synfacial addition to the vinyl sulfone. Finally, the chemistry of $\alpha$-alkoxycopper reagents is explored in Appendix B. This chemistry was applied to a number of cyclohexenone derivatives of increasing steric demand and the effect of the quality of the copper (I) precursor of these results was examined in detail. This technology was then used to develop a completely stereospecific synthesis of C-glycosides by conjugate addition of $\alpha$- or $\beta$-copper (I) glucopyranosides to enones.

Degree

Ph.D.

Subject Area

Organic chemistry

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