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Type of Document Dissertation Author Risatti, Christina Ann Author's Email Address crisatti@nd.edu URN etd-04122005-142743 Title Synthesis of Cyclopropanes via Aldehyde Homologation Degree Doctor of Philosophy Department Chemistry and Biochemistry Advisory Committee
Advisor Name Title Marvin J. Miller Committee Member Marya Lieberman Committee Member Paul Helquist Committee Member Richard E. Taylor Committee Member Keywords
- cyclopropane
- cyclopropyl aldehyde
- homoaldol
Date of Defense 2005-03-31 Availability unrestricted Abstract Cyclopropanes have played a prominent role in the organic community. They are present in numerous natural products and have been used extensively as a reactive intermediate for the formation of complex structures. They have also been used as probes for determining structure activity and conformation activity relationships, in addition to providing synthetic analogs with improved biological profiles. This dissertation will describe a novel cationic approach for the formation of these interesting three-membered rings.
The methodology requires control of homoallylic cation rearrangements though strategic introduction of cation-stabilizing groups to trap the cyclopropane intermediate and ultimately allow its isolation. Initially, stabilization via a b-silicon was used for this purpose, however complications during iteration prompted exploration of alternative stabilizing groups. A heteroatom-stabilized route affords a two-step aldehyde homologation to provide cyclopropyl aldehydes and is readily
amenable to iteration for the formation of contiguous cyclopropane structures. An initial homoaldol reaction provides an O-enecarbamate and activation of the alcohol with triflic anhydride in the presence of 2,6-lutidine affords a cyclopropyl aldehyde.
Initial efforts focused on developing a racemic protocol; however the methodology was developed and applied to the formation of chiral, nonracemic 1,2,3-trisubstituted cyclopropyl aldehydes. O-Enecarbamates are formed with high diastereoselectivity and enantioselectivity by the method of Hoppe. Since (-)-sparteine was the source of chirality, and (+)-sparteine is not readily available, an alternative approach was necessary to access the other enantiomer of our desired 1,2,3-trisubstituted aldehydes. Enantiocomplementary N-enecarbamates were accessed through the method of Beak. In essence, using the same source of chirality but varying the chiral auxiliary used, both enantiomers of our desired 1,2,3-trisubstituted cyclopropyl aldehydes were formed. Application of this methodology to a complex peptide mimic, discovered by Stephen Martin, has been investigated. Furthermore, application of Helmchen’s chiral auxiliary method resulted in chiral 1,2-disubstituted cyclopropyl aldehydes.
Finally, since the methodology proceeds through reactive iminium or oxonium ion intermediates, we were incited to investigate their tendency toward trapping with nucleophiles for the formation of structurally diverse cyclopropane products. Introduction of allyltributyltin to our reaction conditions furnished interesting cyclopropane architectures.
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