The synthesis of prostacyclin analogs via a triply-convergent approach and related synthetic studies
Abstract
The stereospecific total syntheses of two new optically active substituted 2,3,3a,4,5,9b-hexahydro-1H-benz (e) indene and six new optically active substituted 1,2,3,3a,8,8a-hexahydrocyclopent (a) indene prostacyclin analogs are reported. All the syntheses were carried out with complete control of the five different stereocenters of each analog. Variations of the upper and/or lower sidechains provide the different compounds in each class. The synthetic strategy for all eight analogs involved a triply-convergent approach wherein two of the three pieces, a five ring homochiral ammonium salt and a homochiral propargyl alcohol, needed for the synthesis remained constant while the third piece, the aromatic piece, varied. Conjugate-addition of a cuprate derived from the aromatic piece to the homochiral ammonium salt provided a vinyl sulfone containing intermediate. This intermediate then underwent another conjugate-addition reaction with the anion of the homochiral acetylene followed by in situ annulation of the incipient $\alpha$-sulfonyl anion to provide the carbocyclic skeleton of the prostacyclin analogs. The highly functionalized five ring ammonium salt can be prepared in optically active form in seven steps from cyclopentadiene while the homochiral acetylene could be prepared in optically active form in four steps from cyclohexylcarboxaldehyde. The chemistry employed in these syntheses parallels the carbacyclin synthesis recently published by the Fuchs group. In one case it was necessary to develop an o-chloromethyl aryl cuprate for the conjugate-addition reaction of the aryl piece to the five ring ammonium salt. This is the first report of an alkyl halide-containing aryl cuprate. Conjugate-addition of this cuprate with various enones followed by annulation reactions to provide fluoren-1-ones is also reported.
Degree
Ph.D.
Advisors
Fuchs, Purdue University.
Subject Area
Organic chemistry
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