We have developed a Lewis-acid catalyzed, diastereoselective aza-Cope rearrangement— Mannich cyclization (ACM) to form acyl pyrrolidines from conformationally mobile substrates. Earlier studies from our lab have shown that substituted acyl pyrrolidines can be synthesized with diastereoselectivity of 50:1 trans to cis, and that unsubstituted pyrrolidines can be synthesized with 13:1 enantioselectivity. This study attempted to observe the stereochemical outcomes of the ACM for disubstituted pyrrolidine systems using oxazolidine starting materials. A proof of concept dimethyl-substituted oxazolidine was subjected to ACM conditions, producing the pyrrolidine with good yields. However, when methyl-phenyl substituted oxazolidine was subjected to ACM conditions, undesired byproduct was formed. We believe that the requisite iminium cation for the ACM reaction is quite stable, causing an unusually high aza- Cope activation barrier and allowing for an undesired pathway to be favored. Destabilization of the iminium cation intermediate via an electron withdrawing group may allow for the reaction to proceed. Enantiomeric control of dimethyl substituted oxazolidine was also observed. Under ACM conditions, 8.5:1 beta to alpha selectivity was observed with good yields. This work emphasizes the ability of the ACM reaction to produce stereoselective pyrrolidine products.
","abstract_html":"<p>We have developed a Lewis-acid catalyzed, diastereoselective aza-Cope rearrangement— Mannich cyclization (ACM) to form acyl pyrrolidines from conformationally mobile substrates. Earlier studies from our lab have shown that substituted acyl pyrrolidines can be synthesized with diastereoselectivity of 50:1 <em>trans</em> to <em>cis</em>, and that unsubstituted pyrrolidines can be synthesized with 13:1 enantioselectivity. This study attempted to observe the stereochemical outcomes of the ACM for disubstituted pyrrolidine systems using oxazolidine starting materials. A proof of concept dimethyl-substituted oxazolidine was subjected to ACM conditions, producing the pyrrolidine with good yields. However, when methyl-phenyl substituted oxazolidine was subjected to ACM conditions, undesired byproduct was formed. We believe that the requisite iminium cation for the ACM reaction is quite stable, causing an unusually high aza- Cope activation barrier and allowing for an undesired pathway to be favored. Destabilization of the iminium cation intermediate via an electron withdrawing group may allow for the reaction to proceed. Enantiomeric control of dimethyl substituted oxazolidine was also observed. Under ACM conditions, 8.5:1 beta to alpha selectivity was observed with good yields. This work emphasizes the ability of the ACM reaction to produce stereoselective pyrrolidine products.</p>","abstract_has_math":false,"creators":["Hunt, Joshua"],"institution":null,"degree_name":"Master of Science (MS)","degree_level":"Open Access Thesis","degree_discipline":"Chemistry","degree_department":null,"school":null,"contributors":["Cory Emal, Ph.D.","Maria Milletti, Ph.D."],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2016,"date_issued":"2016-07-14T07:00:00Z","date_published":"2016-07-14T07:00:00Z","updated_at":"2026-07-24T02:17:06Z","subjects":["Aza-Cope","chirality transfer","Diastereoselectivity","oxazolidine","pyrrolidine","stereochemistry","Chemistry"],"languages":[],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://commons.emich.edu/theses/684","outbound_label":"Repository record","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Cory Emal, Ph.D.","Maria Milletti, Ph.D."]},{"key":"dc:creator","label":"Author","values":["Hunt, Joshua"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.available","label":"Dc Date Available","values":["2017-05-30T07:00:00Z"]},{"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":["Aza-Cope","chirality transfer","Diastereoselectivity","oxazolidine","pyrrolidine","stereochemistry","Chemistry"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["https://commons.emich.edu/theses/684"]}]},{"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 (ACM) to form acyl pyrrolidines from conformationally mobile substrates. Earlier studies from our lab have shown that substituted acyl pyrrolidines can be synthesized with diastereoselectivity of 50:1 trans to cis, and that unsubstituted pyrrolidines can be synthesized with 13:1 enantioselectivity. This study attempted to observe the stereochemical outcomes of the ACM for disubstituted pyrrolidine systems using oxazolidine starting materials. A proof of concept dimethyl-substituted oxazolidine was subjected to ACM conditions, producing the pyrrolidine with good yields. However, when methyl-phenyl substituted oxazolidine was subjected to ACM conditions, undesired byproduct was formed. We believe that the requisite iminium cation for the ACM reaction is quite stable, causing an unusually high aza- Cope activation barrier and allowing for an undesired pathway to be favored. Destabilization of the iminium cation intermediate via an electron withdrawing group may allow for the reaction to proceed. Enantiomeric control of dimethyl substituted oxazolidine was also observed. Under ACM conditions, 8.5:1 beta to alpha selectivity was observed with good yields. This work emphasizes the ability of the ACM reaction to produce stereoselective pyrrolidine products.
"]},{"key":"dc:title","label":"Title","values":["Diastereoselective aza-cope rearrangement-mannich cyclizations of conformationally mobile iminium cations"]}]}],"canonical_facts":{"dc:contributor":["Cory Emal, Ph.D.","Maria Milletti, Ph.D."],"dc:creator":["Hunt, Joshua"],"dc:date.available":["2017-05-30T07:00:00Z"],"dc:description.abstract":["We have developed a Lewis-acid catalyzed, diastereoselective aza-Cope rearrangement— Mannich cyclization (ACM) to form acyl pyrrolidines from conformationally mobile substrates. Earlier studies from our lab have shown that substituted acyl pyrrolidines can be synthesized with diastereoselectivity of 50:1 trans to cis, and that unsubstituted pyrrolidines can be synthesized with 13:1 enantioselectivity. This study attempted to observe the stereochemical outcomes of the ACM for disubstituted pyrrolidine systems using oxazolidine starting materials. A proof of concept dimethyl-substituted oxazolidine was subjected to ACM conditions, producing the pyrrolidine with good yields. However, when methyl-phenyl substituted oxazolidine was subjected to ACM conditions, undesired byproduct was formed. We believe that the requisite iminium cation for the ACM reaction is quite stable, causing an unusually high aza- Cope activation barrier and allowing for an undesired pathway to be favored. Destabilization of the iminium cation intermediate via an electron withdrawing group may allow for the reaction to proceed. Enantiomeric control of dimethyl substituted oxazolidine was also observed. Under ACM conditions, 8.5:1 beta to alpha selectivity was observed with good yields. This work emphasizes the ability of the ACM reaction to produce stereoselective pyrrolidine products.
"],"dc:identifier":["https://commons.emich.edu/theses/684"],"dc:subject":["Aza-Cope","chirality transfer","Diastereoselectivity","oxazolidine","pyrrolidine","stereochemistry","Chemistry"],"dc:title":["Diastereoselective aza-cope rearrangement-mannich cyclizations of conformationally mobile iminium cations"],"thesis:degree_discipline":["Chemistry"],"thesis:degree_level":["Open Access Thesis"],"thesis:degree_name":["Master of Science (MS)"]},"updated_at":"2026-07-24T02:17:06Z"}