Title

Oxabicyclic Building Blocks as Key Intermediates in the Synthesis of Natural Products

Date of Completion

January 2011

Keywords

Chemistry, Organic|Health Sciences, Pharmacy

Degree

Ph.D.

Abstract

The [4+2] cycloaddition leads to rapid formation of molecular complexity that can be achieved in a single synthetic transformation. In addition, the inherent rigidity of the oxabicyclic scaffold allows many functionalization reactions to occur with high regio- and stereoselectivities. The ability to effect subsequent cleavage, annulation and rearrangement of the bridged-ether intermediates has allowed for the synthesis of natural and non-natural bioactive small molecules. ^ A novel approach to access a number of natural products has been developed. In this approach, a complexity-building cyclocondensation of perhalogenated cyclopropenes and substituted or annulated furans is exploited. The products of the cycloaddition have served as highly versatile seven-membered ring building blocks, which can be elaborated with exquisite stereo- and regiocontrol. The use of annulated furans containing a prochiral center has provided enantioselective access to the frondosin family of natural products. The synthesis of frondosin B features a step-wise annulation of the benzofuran domain by taking advantage of the differential reactivity of the a-and 13-bromides along with a novel and highly efficient trialkylphosphine mediated ether cleavage/deoxygenation reaction. Employing a 2,3-disubstituted furan has allowed for the synthesis of the antibiotic, platensimycin. Two sequential annulations on the oxabicyclo[3.2.1]octane core establish the hydrophobic domain found in the natural product. A highly regioselective Sml2-mediated opening of the ether bridge of a substituted oxabicyclo[3.2.1]octadiene is described and provides access to an array of biologically active tropolones. ^ The utility of a suitably functionalized oxabicyclo[2.2.1]heptene has enabled the synthesis of the spirocyclic domain of the natural product cyclopamine. A metathesis mediated bond-reorganization event has provided this sub-unit in only four-steps from a readily available 2-substituted furan. ^