Progress towards stereoselective synthesis of azaspirobicyclic ring systems and iridium(I)-catalyzed enantioselective etherification and (sulfonyl) methylation reactions

Date
2010
Authors
Reddy, Srinivasa Edara
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Abstract

Halichlorine, pinnaic acid, perhydrohistricotoxin, and lepadiformine are naturally occurring and man-made complex organic compounds with a broad range of important biological and chemical activities, as well as distinctive structural features. These compounds are structurally related and contain the unusual azaspirocyclic core skeletons, which have proved to be difficult to asymmetrically construct. So the first part of this thesis describes general and easily applicable route for the asymmetric synthesis of such an interesting and challenging structural motif.

The azaspirocyclic core has been efficiently constructed in seven steps from commercially available cyclopentene oxide. The directed aziridination reaction followed by the aziridine ring opening reaction was utilized to install the tertiary carbon-nitrogen bond in an extremely stereoselective fashion. And the intramolecular amidomercuration reaction was employed for the stereoselective construction of the azaspirobicyclic ring systems. This protocol allows for synthesis of essentially all types of azaspirobicyclic alkaloids depending on choice of precursor epoxides and chain lengthening fragments, and is amenable to modification.

The second part of this thesis focuses on development of Ir(I)-catalyzed enantioselective etherification and (sulfonyl) methylation reactions. Our recently developed catalytic system has been utilized and applied to develop the decarboxylative allylic etherification reactions. In addition, the scope and functional group tolerance of this reaction was probed with structurally diverse and/or synthetically more useful allylic substrates. Further, this methodology in combination with ring closing metathesis provided 2-phenylchromene.

The last chapter describes the synthesis of ibuprofen using the decarboxylative allylic (sulfonyl) methylation reaction.

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Chemistry