Mechanistic investigation of the interrupted Bischler-Napieralski reaction and its application to the total synthesis of the aspidosperma alkaloids

I. Direct Observation of Intermediates Involved in the Interruption of the Bischler- Napieralski Reaction. The first mechanistic investigation of electrophilic amide activation of [alpha], [alpha]-disubstituted tertiary lactams and the direct observation of key intermediates by in situ FTIR, 1H, 13C, and 19F NMR in our interrupted Bischler-Napieralski based synthetic strategy to the aspidosperma alkaloids is described. Importantly, when considering base additives during electrophilic amide activation, more hindered c-quaternary tertiary lactams require the use of non-nucleophilic pyridine additives in order to avoid deactivation via a competing desulfonylation reaction. The isolation and full characterization of a tetracyclic iminium trifluoromethanesulfonate provided additional correlation between in situ characterization of sensitive intermediates and isolable compounds involved in this synthetic transformation. II. Total Synthesis of (+)-Fendleridine, (+)-Acetylaspidoalbidine, and (+)-Limaspermidine. An Tf2O-mediated electrophilic amide activation of a readily available C21-oxygenated lactam, followed by transannular cyclization and in situ trapping of a transiently formed C19-iminium ion, expediently provides access to the hexacyclic C19-hemiaminal ether alkaloids (+)- fendleridine, (+)-acetylaspidoalbidine, and (+)-limaspermidine. A highly effective enzymatic resolution of a non-[beta]-branched primary alcohol (E=22) allowed rapid preparation of both enantiomeric forms of a C21-oxygenated precursor for synthesis of these aspidosperma alkaloids. III. Development of an Ortho-Acetoxylation of Indoline Amides and its Application to the Total Synthesis of (+)-Haplocidine and (+)-Haplocine. The first total syntheses of (+)-haplocidine and its NI-amide congener (+)-haplocine is described. The concise synthesis of these alkaloids required the development of a late-stage and highly selective C-H oxidation of complex aspidosperma alkaloid derivatives. A versatile, amide directed ortho-acetoxylation of indoline amides enabled the implementation of a unified strategy for late-stage diversification of hexacyclic C19-hemiaminal ether structures via oxidation of the corresponding pentacyclic C19-iminium ions.

Department dc:contributor.department

Massachusetts Institute of Technology. Department of Chemistry.

Grantor dc:publisher

Massachusetts Institute of Technology

Year dc:date.issued

2017

Author dc:creator

• White, Kolby Lyn

Advisor dc:contributor.advisor

• Mohammad Movassaghi.

• Chemistry.

Statement dc:rights

• MIT theses are protected by copyright. They may be viewed, downloaded, or printed from this source but further reproduction or distribution in any format is prohibited without written permission.

Licence dc:rights.uri

• http://dspace.mit.edu/handle/1721.1/7582

Language dc:language.iso

eng

Handle dc:identifier.uri

http://hdl.handle.net/1721.1/109682

OAI identifier oai:identifier

oai:dspace.mit.edu:1721.1/109682