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UBC Theses and Dissertations

Metal-alkyne complex initiated cyclization reactions : enesulfonamides and enecarbamates as nucleophiles Harrison, James Tyler


The use of enesulfonamides and enecarbamates as π-nucleophiles has been investigated in the context of metal catalyzed cycloisomerization reactions with a tethered alkyne and the results of these investigations are presented. This dissertation is divided into 5 chapters. Chapter 1 provides an overview of the evolution and development in the field of transition metal catalyzed cycloisomerization reactions with primary focus on the use of platinum, silver and gold catalysts. Chapter 2 discloses investigations into the platinum(II) and silver(I) salt catalyzed cycloisomerization of 1,2,3,4-tetrahydropyridine derivatives with an alkyne moiety tethered at the 4-position of the ring. Reaction of these substrates in the presence of catalytic quantities of metal salts resulted in the formation of five-membered rings in 20-88% yield. The resultant dienes were efficiently reacted in situ in Diels-Alder cycloadditions, triethylsilane reductions and hydrogenation reactions. A series of enesulfonamides were reduced to the resulting piperidine derivatives with catalytic quantities of silver(I) trifluoromethanesulfonate and an equivalent of triethylsilane in 82-98% yield, whereas the alkyne moieties of these enyne substrates were hydrosilylated in the presence of platinum(II) chloride and triethylsilane. Chapter 3 discloses the silver(I) and gold(I) catalyzed formation of pyrrole rings from a variety of 4-pentyn-1-ones. The conversion of 4-pentyn-1-ones and a suitable primary amine into the corresponding pyrrole rings was investigated with 19 examples. Catalysis by silver(I) trifluoromethanesulfonate provided pyrroles with yields ranging 1-92%. Catalysis by either PPh₃AuCl-AgOTf or PPh₃-AuCl-AgOTf gold(I) catalyst systems afforded pyrrole products in 27-88% yield. Chapter 4 discloses a high yielding and operationally straightforward synthesis of the bread aroma compound 6-acetyl-1,2,3,4-tetrahydropyridine. The desired target is obtained via a 3-pot, 4-step sequence in 59% overall yield. Chapter 5 discloses the platinum(II) catalyzed carbocyclization of 1,2,3,4-tetrahydropyridine derivatives with an alkyne tethered at the 3-position of the ring to form quaternary carbon centers within spiro-fused five-membered rings. The effects of N -functionalization, heterocycle size and alkyne-functionalization were investigated with 20 different substrates. Successful reactions provided spiro-fused five-membered rings in 50-83% yield. The position of the resultant double bond was strictly controlled by the use of either PtCl₂ or PtCl₂-AgOTf catalyst systems. Controlled formation of the double bond migration product by use of the PtCl₂-AgOTf catalyst system enabled a 4-step conversion to a 2:1 mixture of the natural products isonitramine and nitramine. Substrates containing an aryl-substituted alkyne proceeded via a one-step cycloisomerization/Friedel-Crafts tandem process to afford tetracyclic scaffolds in 65-78% yield, where initial attack of the π-nucleophile onto the metal complexed alkyne favors a 6-endo mode of cyclization. This chemistry proved promising for application to natural product total synthesis in model studies towards the tricyclic core of fawcettidine.

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