A TRIPLY CONVERGENT TOTAL SYNTHESIS OF L(-)-PROSTAGLANDIN E(2)

RICHARD EUGENE DONALDSON, Purdue University

Abstract

This dissertation describes an efficient and versatile total synthesis of l-(-)-prostaglandin E(,2) (PGE(,2)). PGE(,2) was chosen as the target molecule since synthetic procedures have already been developed for transformation of PGE(,2) into most of the other prostaglandins as well as the very important prostacyclin (PGI(,2)). The synthesis features a general triply-convergent step in which the basic prostaglandin skeleton is formed via 1,4-addition of a chiral vinyllithium reagent to a chiral aminovinyl sulfone followed by subsequent in situ alkylation of the resulting sulfone-stabilized anion. Desulfonylation followed by oxidation produces epoxy-prostaglandins which result from a novel epoxidation reaction of an intermediate (alpha),(beta)-unsaturated iminium ion. The synthesis of PGE(,2) from the key intermediate makes use of an efficient peracetic acid oxidation of a secondary amine to a (beta)-siloxy oxime which is in turn desulfonylated by a unique 1,4-elimination of phenylsulfinic acid to generate an intermediate vinyl nitroso species which undergoes stereospecific 1,4-reduction by sodium borohydride to yield the oxime of PGE(,2). This oxime is hydrolyzed using paraformaldehyde and boron trifluoride catalyst to give PGE(,2) in high yield. The synthesis also features an efficient enantioconvergent process for the synthesis of the requisite chiral aminovinyl sulfone acceptor. This process utilizes stereospecific S(,N)2' reactions and a stereospecific sulfide-directed epoxidation sequence. Appendix A describes a high yield generation of 1,4-dihydroaryl silyl ethers through lithium in ammonia reduction of the corresponding tert-butyldimethyl and isopropyldimethylsilyl aryl ethers. The silyl enol ethers produced may be regiospecifically functionalized to nonconjugated (beta),(gamma)-unsaturated ketones.

Degree

Ph.D.

Subject Area

Organic chemistry

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