Preparation of tricyclic enones as templates for stereocontrolled natural product synthesis
AuthorBaron, James Andrew, 1971-
AdvisorMash, Eugene A.
MetadataShow full item record
PublisherThe University of Arizona.
RightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
AbstractSmall cycloalkanones with adjacent fused cyclopropane rings are excellent substrates for highly diastereoselective (α'-alkylations of enolates derived from these systems. Diastereoselectivity can be attributed to steric interactions between the cyclopropane endo methylene hydrogen and the incoming electrophile, since this atom shields the face of the enolate cis to the cyclopropane. Monoalkylation of enolates derived from bicyclo[3.1.0]hexan-2-one, bicyclo[4.1.0]heptan-2-one and bicyclo[5.1.0]octan-2-one with general electrophiles resulted in the corresponding 3-alkylated cyclopropyl ketone derivatives in synthetically useful yields. Diastereoselectivities for these systems ranged from 4:1 for six-membered cyclopropyl ketones to >20:1 for five- and seven-membered cyclopropyl ketones. Enolates derived from these 3-alkylated cyclopropyl ketones exhibited similar diastereoselectivities and yields to give the corresponding 3,3-dialkylated derivatives when alkylated with similar electrophiles. The relative stereochemistry of alkylation was determined to be trans to the cyclopropane through analysis of anisotropic shielding interactions between alkyl side chains containing phenyl rings and the endo protons on the cyclopropane carbon. This relative stereochemistry can be controlled by the sequence of alkylation, since reversal in the alkylative steps results in an inversion at the newly formed quaternary center. Synthesis of tricyclic enones was carried out through application of this (α'-alkylation methodology using electrophiles that could later be modified to give the corresponding 1,3- and 1,4-cyclopropyl diketones. Cyclization of these diketone intermediates through intramolecular aldol condensations resulted in a series of tricyclic enones whose ring junction relative stereochemistry is controlled through correct ordering of electrophiles in the alkylation steps. The result is a broadly applicable toolbox of annulated materials that can be applied towards the synthesis of natural products containing fused five- and six-membered rings with a defined stereochemistry at the ring junction.
Degree ProgramGraduate College