Total Synthesis Of Prostaglandins Via Sequential Cyanocuprate Additions (lactonization, Sulfoxides).

Abstract

A systematic investigation of the reaction between cyclopentenyl allylic epoxides and cyanocuprates is described. This study provided the basis for an efficient synthesis of prostaglandins. The key steps of the synthesis involve the 1,4-trans opening of cyclopentadiene monoepoxide with a cyanocuprate reagent bearing all the requisite functionality of the prostaglandin (beta)-chain and the regioselective 1,4-addition of a second cyanocuprate reagent bearing the (alpha)-chain of prostanoids onto a silyl enol ether intermediate. Fluoride induced hydrolysis of the resulting hydroxy silyl enol ether yields the key intermediate 3(beta)- 1E)-3-tert-butyldimethylsilyloxyoct-1-enyl -2(alpha)-(7-hydroxyheptyl)-4(alpha)-hydroxycyclopentanone (69), which was converted into the bronchodilator ((+OR-))-2-decarboxy-2-hydroxymethyl-PGE(,1), PGF(,1(alpha)) and PGE(,1). A synthetic approach to the neolignan porosin and the synthesis of two oak lactones ((beta)-methyl-(gamma)-octalactones) via sulfoxide directed lactonization of vinyl sulfoxides are described. The reaction of several acyclic vinyl sulfoxides i.e., 1-(3,4-dimethoxyphenyl)-1-(p-toluenesulfinyl)-1(E)-propene (157), (Z) and (E)-1-butadienyl phenyl sulfoxide (168) and (151), and (E)-1-n-butyl-1-(p-toluenesulfinyl)-1-propene (191) with dichloroketene was found to proceed with a high degree of stereoselectivity. The desulfurization of the resulting (gamma)-arylthio-(gamma)-lactones with Raney nickel was found to proceed predominantly with retention, although in variable ratios and low yields; alternatively, tri-n-butyltin hydride afforded good yields but displayed a significant lack of stereoselectivity.Ph.D.Organic chemistryPure SciencesUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/127802/2/8600442.pd