Recent Advances in Indole Aryne Cycloaddition Chemistry. Part I: Total Synthesis of (±)-cis-Trikentrin B. Part II: Investigation into the Regioselectivity of 6,7-Indole Aryne Cycloadditions. Part III: Synthesis and Reactions of Novel Tribromoindoles

Since their discovery in the Buszek laboratories in 2007, the indole arynes and their cycloaddition chemistry has demonstrated its significance in achieving the total synthesis of biologically active indole alkaloid natural products such as the trikentrins and herbindoles in a facile manner. The application of 6,7-indole aryne cycloaddition methodology towards the total synthesis of (±)-cis-trikentrin B, one of the representative members of the trikentrin family of natural products is described. The 5,6,7-tribromoindole served as the 6,7-indole aryne precursor which was synthesized via an adapted Leimgruber-Batcho synthetic protocol. The success with achieving annulation at the 6,7-position of the indole nucleus in (±)-cis-trikentrin B relied heavily on one crucial question i.e., whether the key intermediate 5,6,7-tribromo-N-TBS-indole would undergo selective metal-halogen exchange at C-7. Gratifyingly the indole underwent selective metal-halogen exchange at C-7 and subsequent elimination to give exclusively the 6,7-indole aryne which underwent Diels-Alder cycloaddition with cyclopentadiene. To complete the synthesis, the remaining unreacted C-5 bromo position was subjected to Stille cross-coupling to install the trans-butenyl side chain at this site. The original regiochemical observations in 6,7-indole aryne cycloadditions werewere made with N-Me-4-phenyl-6,7-dibromoindole resulting predominantly in the contrasteric regiosiomer .This phenomenon was observed by the virtue of the polarized nature of the 6,7-indole aryne as revealed by computational studies involving ab initio calculations. In order to probe further into the regioselective cycloadditions of 6,7-indole arynes, a series of 6,7-dibromoindoles were synthesized to investigate the effect of 2-, 3-, 4- and 5-substitution on the regioselectivity of 6,7-indole aryne cycloadditions with 2-tert-butylfuran. The results of this investigation indicated that the degree of polarization of the 6,7-indole aryne bond depends on electronic nature and the positions of the various substituents on the pyrrole and benzene rings of the indole which in turn is responsible for imparting regioselectivity in the 6,7-indole aryne cycloadditions. The Buszek laboratories have previously demonstrated the exclusive generation of 6,7-indole arynes from 4,6,7- and 5,6,7-tribromoindoles via a remarkable selective metal-halogen exchange at C-7 for use in natural products total synthesis and library development. In connection to these previous efforts, synthesis of the 4,5,6- and 4,5,7-tribromoindoles, the remaining two members of the tribromoindole series, is described. Treatment with n-BuLi followed by quenching with various electrophiles reveals a strong preference for initial metal-halogen exchange at the C-7 position in the case of 4,5,7-tribromoindoles, and at the C-4 position in the case of the 4,5,6-tribromoindole scaffold. Exclusive generation of the 4,5-indole aryne in either system followed by cycloaddition with 2-tert-butylfuran shows only a modest regiochemical preference in the cycloadducts. Finally, the 4,5-benzannulated scaffolds were subjected to Negishi cross-coupling with dimethyl and diethylzinc to demonstrate the proof-of-concept for library development.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Doctoral

Discipline thesis:degree_discipline

Chemistry (UMKC)

Grantor

University of Missouri--Kansas City

Year dc:date.issued

2015

Author dc:creator

• Nerurkar, Alok

Advisor dc:contributor.advisor

• Buszek, Keith R.

Language dc:language.iso

en_US

Handle dc:identifier.uri

https://hdl.handle.net/10355/47996

OAI identifier oai:identifier

oai:mospace.umsystem.edu:10355/47996