Synthetic Studies Towards Mescengricin

This thesis describes the synthetic efforts towards mescengricin (80), an ɑ-carboline alkaloid isolated from a culture of Streptomyces griseoflavus. Mescengricin (80) may be a prominent neuroprotectant for ischemic injury as it protected chick primary mesencephalic neurons from L-glutamate toxicity with an EC50 of 6.0 nM. A model study was conducted to obtain the oxazoloindole to attempt the intermolecular aza- Diels-Alder reaction. Treatment of 250 to the Robinson-Gabriel cyclodehydration gratifyingly afforded 259. Though in low yield, the desired ɑ-carboline scaffold 287 was afforded after heating 259 with methyl acrylate. Deprotection of the indole nitrogen to 288 was thought to favour this aza-Diels-Alder reaction, however, 289 was produced. Establishing a route to construct the ɑ-carboline scaffold led us to pursue the same route with 298. Treatment of 298 to the Robinson-Gabriel cyclodehydration gave 291 in meagre yield. Nevertheless, the aza- Diels-Alder reaction between 291 and methyl acrylate was attempted, however, this led to complex mixtures. Deacetylation of 291 afforded 300, however, this also led to complex mixtures upon attempted aza-Diels-Alder reaction with methyl acrylate. Due to the unsuccessful synthesis of the desired methoxy ɑ-carboline, an alternative strategy was sought. We envisaged that treating 324 to formic acid for the second generation route would give 325, which would afford 323 upon cyclisation. Unfortunately, subjecting 329 to the coupling-intramolecular cyclisation pathway with 2-cyanoacetic acid (330) formed a complex mixture. We then attempted to repeat this reaction using ethyl 2-cyanoacetate (333) to form 334. With 334 in hand, it was subjected to formic acid, hoping that 336 would form and then cyclise in situ to generate 323. Unfortunately, the reaction stalled at 336 and gradually degraded upon increasing the reaction time. Next, 336 was subjected to acidic and basic conditions, however, this led to the reformation of 334 and heating the reaction led to gradual degradation. The second attempt focused on the cyclodehydration of 346 to 344. Treating 349 to oxalyl chloride and then ethanol afforded 351, which upon treatment under KOH-mediated hydrolysis, afforded a product presumed to be 352. Unfortunately, due to time constraints, further investigations could not be conducted to confirm the structure of this product.

Name thesis:degree_name

PhD

Level thesis:degree_level

Doctoral

Discipline thesis:degree_discipline

Chemistry

Grantor dc:publisher

ResearchSpace@Auckland

Year dc:date.issued

2023

Author dc:creator

• Ichikawa, Karen

Advisor dc:contributor.advisor

• Sperry, Jonathan

Statement dc:rights

• Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated.

Licence dc:rights.uri

• https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm

Handle dc:identifier.uri

https://hdl.handle.net/2292/68432

OAI identifier oai:identifier

oai:researchspace.auckland.ac.nz:2292/68432