Directed Palladium Catalyzed Acetoxylation of Indolines and Enantioselective Total Synthesis of (–)-Voacinol and (–)-Voacandimine C

I. Directed Palladium Catalyzed Acetoxylation of Indolines. Total Synthesis of N-Benzoylcylindrocarine We describe a palladium catalyzed C7-acetoxylation of indolines with a range of amide directing groups. While a variety of substituents are tolerated on the indoline-core and the N1-acyl group, the acetoxylation is most sensitive to the C2- and C6-indoline substituents. The practicality of this indoline C7-acetoxylation is demonstrated using a cinnamamide substrate on mmol-scale. Several N1-acyl groups, including those present in natural alkaloids, guide C7-acetoxylation of indoline substrates over a competitive C5-oxidation. The application of this chemistry allowed for the first synthesis of N-benzoylcylindrocarine by late-stage C17-acetoxylation of N-benzoylfendleridine. II. Total Synthesis of (–)-Voacinol and (–)-Voacandimine C We describe the first total synthesis of complex aspidosperma alkaloids (–)-voacinol and (–)-voacandmine C via a biogenetically inspired late-stage C7-methylenation strategy. We envisioned rapid access to these natural alkaloids from a common symmetrical precursor assembled by methylenation of a D-ring oxidized variant of the related natural product (–)-deoxoapodine. Chemoselective N9-oxidation of a pentacyclic deoxoapodine precursor enabled the synthesis of the corresponding hexacyclic C8-aminonitrile. Stereocontrolled methylenation of a C8-enamine derivative of deoxoapodine, accessed by ionization of the C8-aminonitrile, afforded a symmetrical dodecacyclic bis-aminonitrile. Final-stage biogenetically inspired controlled reductive opening of the oxolanes of this dodecacyclic intermediate provided a unified approach to (–)-voacinol and (–)-voacandmine C, while direct reduction of the same intermediate afforded structurally related (–)-methylenebisdeoxoapodine.

Name thesis:degree_name

Doctoral

Department dc:contributor.department

Massachusetts Institute of Technology. Department of Chemistry

Grantor dc:publisher

Massachusetts Institute of Technology

Year dc:date.issued

2022

Author dc:creator

• Flynn, Kristen M.

Advisor dc:contributor.advisor

• Movassaghi, Mohammad

Statement dc:rights

• In Copyright - Educational Use Permitted
• Copyright MIT

Licence dc:rights.uri

• http://rightsstatements.org/page/InC-EDU/1.0/

Handle dc:identifier.uri

https://hdl.handle.net/1721.1/143259

OAI identifier oai:identifier

oai:dspace.mit.edu:1721.1/143259