We have developed a Lewis-acid catalyzed, diastereoselective aza-Cope rearrangement— Mannich cyclization to form acyl pyrrolidines from conformationally mobile substrates. In earlier studies from our lab, Brønsted acid-catalyzed reactions to form the same acyl pyrrolidines resulted in diastereoselectivities of 8:1 trans to cis at elevated temperatures (60 °C) over the course of 150 minutes. We have demonstrated an improvement in our method yielding exclusively the trans isomers at ambient temperature with substoichiometric amounts of BF3•OEt2 within 3 minutes. Catalyst loadings as low as 0.05 equivalents of BF3•OEt2 initiate this transformation. Our synthetic method employs the oxazolidine starting material as a mixture of diastereomers to produce one pyrrolidine diastereomer. Both ethyland substituted phenyl-oxazolidines were successfully rearranged. This work is the first example of a truly catalytic aza-Cope—Mannich reaction and provides the first examples of diastereoselective syntheses of 2-phenyl-4-acylpyrrolidines via this reaction.
","abstract_html":"<p>We have developed a Lewis-acid catalyzed, diastereoselective aza-Cope rearrangement— Mannich cyclization to form acyl pyrrolidines from conformationally mobile substrates. In earlier studies from our lab, Brønsted acid-catalyzed reactions to form the same acyl pyrrolidines resulted in diastereoselectivities of 8:1 <em>trans</em> to <em>cis</em> at elevated temperatures (60 °C) over the course of 150 minutes. We have demonstrated an improvement in our method yielding exclusively the <em>trans</em> isomers at ambient temperature with substoichiometric amounts of BF<sub>3</sub>•OEt<sub>2</sub> within 3 minutes. Catalyst loadings as low as 0.05 equivalents of BF<sub>3</sub>•OEt<sub>2</sub> initiate this transformation. Our synthetic method employs the oxazolidine starting material as a mixture of diastereomers to produce one pyrrolidine diastereomer. Both ethyland substituted phenyl-oxazolidines were successfully rearranged. This work is the first example of a truly catalytic aza-Cope—Mannich reaction and provides the first examples of diastereoselective syntheses of 2-phenyl-4-acylpyrrolidines via this reaction.</p>","abstract_has_math":false,"creators":["St. Germaine, Danielle"],"institution":null,"degree_name":"Master of Science (MS)","degree_level":"Open Access Thesis","degree_discipline":"Chemistry","degree_department":null,"school":null,"contributors":["Harriet Lindsay, PhD, Chair","Cory Emal, PhD","Timothy Friebe, PhD"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2014,"date_issued":"2014-01-01T08:00:00Z","date_published":"2014-01-01T08:00:00Z","updated_at":"2026-07-24T02:17:27Z","subjects":["Ge","Chemistry"],"languages":[],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://commons.emich.edu/theses/911","outbound_label":"Repository record","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Harriet Lindsay, PhD, Chair","Cory Emal, PhD","Timothy Friebe, PhD"]},{"key":"dc:creator","label":"Author","values":["St. Germaine, Danielle"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.available","label":"Dc Date Available","values":["2018-08-23T07:00:00Z"]},{"key":"thesis:degree_discipline","label":"Discipline","values":["Chemistry"]},{"key":"thesis:degree_level","label":"Degree Level","values":["Open Access Thesis"]},{"key":"thesis:degree_name","label":"Degree Name","values":["Master of Science (MS)"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Ge","Chemistry"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["https://commons.emich.edu/theses/911"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["We have developed a Lewis-acid catalyzed, diastereoselective aza-Cope rearrangement— Mannich cyclization to form acyl pyrrolidines from conformationally mobile substrates. In earlier studies from our lab, Brønsted acid-catalyzed reactions to form the same acyl pyrrolidines resulted in diastereoselectivities of 8:1 trans to cis at elevated temperatures (60 °C) over the course of 150 minutes. We have demonstrated an improvement in our method yielding exclusively the trans isomers at ambient temperature with substoichiometric amounts of BF3•OEt2 within 3 minutes. Catalyst loadings as low as 0.05 equivalents of BF3•OEt2 initiate this transformation. Our synthetic method employs the oxazolidine starting material as a mixture of diastereomers to produce one pyrrolidine diastereomer. Both ethyland substituted phenyl-oxazolidines were successfully rearranged. This work is the first example of a truly catalytic aza-Cope—Mannich reaction and provides the first examples of diastereoselective syntheses of 2-phenyl-4-acylpyrrolidines via this reaction.
"]},{"key":"dc:title","label":"Title","values":["Advancements in the diastereoselective synthesis of acyl pyrrolidines via the tandem aza-Cope—Mannich cyclization pathway"]}]}],"canonical_facts":{"dc:contributor":["Harriet Lindsay, PhD, Chair","Cory Emal, PhD","Timothy Friebe, PhD"],"dc:creator":["St. Germaine, Danielle"],"dc:date.available":["2018-08-23T07:00:00Z"],"dc:description.abstract":["We have developed a Lewis-acid catalyzed, diastereoselective aza-Cope rearrangement— Mannich cyclization to form acyl pyrrolidines from conformationally mobile substrates. In earlier studies from our lab, Brønsted acid-catalyzed reactions to form the same acyl pyrrolidines resulted in diastereoselectivities of 8:1 trans to cis at elevated temperatures (60 °C) over the course of 150 minutes. We have demonstrated an improvement in our method yielding exclusively the trans isomers at ambient temperature with substoichiometric amounts of BF3•OEt2 within 3 minutes. Catalyst loadings as low as 0.05 equivalents of BF3•OEt2 initiate this transformation. Our synthetic method employs the oxazolidine starting material as a mixture of diastereomers to produce one pyrrolidine diastereomer. Both ethyland substituted phenyl-oxazolidines were successfully rearranged. This work is the first example of a truly catalytic aza-Cope—Mannich reaction and provides the first examples of diastereoselective syntheses of 2-phenyl-4-acylpyrrolidines via this reaction.
"],"dc:identifier":["https://commons.emich.edu/theses/911"],"dc:subject":["Ge","Chemistry"],"dc:title":["Advancements in the diastereoselective synthesis of acyl pyrrolidines via the tandem aza-Cope—Mannich cyclization pathway"],"thesis:degree_discipline":["Chemistry"],"thesis:degree_level":["Open Access Thesis"],"thesis:degree_name":["Master of Science (MS)"]},"updated_at":"2026-07-24T02:17:27Z"}