The synthesis of a heterocyclic prostacyclin analog and related synthetic studies

Douglas Craig Smith, Purdue University

Abstract

The stereospecific total synthesis of a optically active 1-azatricyclo (6.3.0.0$\sp{2,6}$) undeca-5-enyl prostacyclin analog is reported. Additional efforts detailing approaches to structurally related azatricycloundecanyl analogs are also provided. Variations of the upper and/or lower sidechains provide the different compounds in each class. Construction of the tricyclic skeletons was accomplished through a triply convergent approach employing two common structural units: a homochiral cyclopentenyl methanesulfonate and a homochiral propargylly ether, in addition to various optically active pyrrolidinone derivatives. Coupling of the homochiral cyclopentenyl methanesulfonate and the pyrrolidinone derivatives was accomplished via a conjugate-addition reaction to provide bicyclic vinyl sufones. These intermediates then underwent a second conjugate-addition reaction with the lithium salt of the homochiral acetylene, followed by an in situ annulation of the intermediate $\alpha$-sulfonyl anion to provide the tricyclic framework of these analogs. Both the homochiral cyclopentenyl methanesulfonate and the optically active acetylene were prepared by methods reported within the Fuchs group while the heterocyclic units were prepared in optically active form for either D- or L-glutamic acid by reported literature methods. The chemistry of these heterocyclic intermediates were found to be considerably different from those reported in the literature by the Fuchs group. During the course of these investigations, it became necessary to develop new methodology for the conversion of amides and lactams to their corresponding thioamides and thiolactams employing phosphorous oxychloride and hexamethyldisilathiane to effect Group VI substitution. Additional methodology was developed for the construction of bicyclic thiolactams through a tandem conjugate-addition- (3.3) sigmatropic rearrangement of monocyclic thiolactams with allylic substituted cyclopentenyl vinyl sufones.

Degree

Ph.D.

Advisors

Fuchs, Purdue University.

Subject Area

Organic chemistry

COinS