A Convenient Synthesis of Pyrrolnitrin and Related Halogenated Phenylpyrroles

This thesis details a straightforward synthetic route to the antifungal compound pyrrolnitrin 1.2, along with several analogous halogenated phenylpyrroles. The proposed synthetic protocol involved the Suzuki-Miyaura cross-coupling of appropriately halogenated pyrrole pinacolboronate esters and aryl compounds. In the efforts towards preparing the cross-coupling partners, we report a regiospecific and high yielding synthesis of a 3-chloro pyrrole compound 2.14, its brominated analog 2.16, an iodinated analog 2.17, and the corresponding pinacolboronate ester 2.18. We also report a generalized reaction sequence (lithiation/carboxylation/Schmidt reaction/oxidation) for the preparation of halogenated benzoic acids, anilines and nitrobenzenes. In particular, we synthesized the desired halogenated nitrobenzene coupling partner 3.27 in excellent yield. We were also able to show that the conditions employed in this sequence were mild enough to allow preparation of the 2-bromo-6-iodo compound 3.33. Once the coupling partners were prepared, we developed the optimal conditions for our Suzuki-Miyaura cross-coupling reactions. In doing so, we were able to prepare our target compound 1.2 and several halogenated analogs in good yields. We also prepared brominated and deuterated arylpyrroles 4.27 and 4.28, respectively, for future use in mechanistic studies of the pyrrolnitrin biosynthetic enzymes, PrnB, Prn C and PrnD. This required preparation of the corresponding brominated and deuterated pyrrole pinacolboronate esters 4.24 and 4.26.

Department dc:contributor.department

Chemistry

Year dc:date.issued

2009

Author dc:creator

• Morrison, Matthew

Advisor dc:contributor.supervisor

• Pratt, Derek A.

• pyrrolnitrin, halogenases, Schmidt reaction, Directed ortho Metalation, 2,6-dihaloanilines, 2,6-dihalonitrobenzenes, 3-substituted pyrroles, cross-coupling with pyrroles

Language dc:language.iso

eng

Handle dc:identifier.uri

http://hdl.handle.net/1974/5265

OAI identifier oai:identifier

oai:queensu.scholaris.ca:1974/5265