Syntheses of potential antimetastatic agents via vinyl sulfones and related studies

Steven Alan Hardinger, Purdue University

Abstract

The total syntheses of three new arene-fused, acetylenic tricyclic PGI$\sb2$ analogs indynaprost, isotetralynaprost and epiisotetralynaprost are reported. The synthetic strategy centered around the "smorgasbord" approach, with a variety of aryl and sidechain pieces available for assembly by the same chemistry: addition of the lower sidechain synthon (an acetylenic anion) to a gamma-(silyloxy)-alpha$\sp\prime$-alkylated vinyl sulfone, with in situ, intramolecular alkylation of the incipient alpha-sulfonyl anion via a benzyl chloride. These vinyl sulfones were derived from a highly functionalized (cyclo-pentenylphenylsulfonyl) ammonium salt, available in chiral form in 7 steps from cyclopentadiene. The substrates for vinyl sulfone conjugate addition were prepared by reaction of an oxazoline-chelated benzyl cuprate (isotetralynaprost series) or a MOM-chelated aryl-lithium species (indynaprost series) to the ammonium salt. Both of these processes were novel: the first oxazoline-derived cuprate is reported, as well as the first successful addition of a hard organolithium species to the ammonium salt. Desulfonylation via sodium amalgam late in the synthesis lead to a diastereomeric mixture at the carbon formerly attached to the sulfone; both diastereomers were converted to the corresponding PGI$\sb2$ analogs isotetralynaprost and epiisotetralynaprost. The chemistry employed parallels the carbacyclin synthesis recently published by the Fuchs group. Various other studies of vinyl sulfone chemistry are also reported, including a survey of the reactions of organometallic reagents with a variety of cyclooctenyl phenyl sulfones.

Degree

Ph.D.

Advisors

Fuchs, Purdue University.

Subject Area

Organic chemistry

COinS