Formation of standards for biosynthetic studies of bacillaene and difficidin and synthesis of novel enantioenriched heterocycle via desymmetrization

UNCG Author/Contributor (non-UNCG co-authors, if there are any, appear on document)
Tyler Joseph Greenstein (Creator)
The University of North Carolina at Greensboro (UNCG )
Web Site:
Kimberly Petersen

Abstract: Polyketide synthases are multidomain enzymes that act as chemical assembly lines. Polyketides produced by polyketide synthases play a vital role within bacteria, such as providing it the necessary protection to defend against other bacteria. Two polyketides of interest have been bacillaene and difficidin, which reside from Bacillus species. Structurally, they contain ß-branching that is atypical for polyketides. Since the enzymes and gene clusters of these polyketides are known, sequencing and production of the enzymes responsible for these ß-branching patterns is possible. Previous work of the Reddick group accomplished this by reacting an acetoacetyl group with pksI and dfnM separately, which are the enzymes responsible for producing the ß-branching for bacillaene and difficidin, respectively, and analyzed the products via mass spectrometry. With this data, there was confirmation that the mass corresponding to the desired ß-branching was present; however, it was difficult to verify that the enzymes produced only their respective ß-branching, as the ß-branching of these polyketides are isomers. In the first sections of this work, the formation of standards for these ß-branching mimics is accomplished by performing a coupling reaction between a carboxylic acid and a thiol. The mimics and the standards, which are chemically similar, will then be given to a member of the Reddick group to be subjected to gas chromatography mass spectrometry to obtain their fragmentation patterns, which will discern the ß-branching pattern for these mimics. This will provide insight into the mode of action for these enzymes and, subsequently, the polyketide synthases. Isomerism, much like polyketides, plays a vital role within biological systems. The difference between enantiomers can mean life or death, especially in terms of drug design and natural products. Some interesting and potentially harmful natural products come from those that contain the indole moiety. Being able to synthetically produce these natural products, especially enantioselectively, could prove to be both beneficial and difficult. Enantioselective catalysis can be a valuable tool for the creation of single enantiomers. Desymmetrization is a single step reaction where a prochiral molecule loses one or more symmetric features and is a technique for synthesizing enantiomers. Previous work of the Petersen group utilized desymmetrization reactions of malonic ester derivatives in the presence of a chiral Brønsted acid catalyst to achieve enantioenriched heterocycles. In the subsequent sections of this work, the malonic ester derivative containing an indole moiety is synthesized via a Knoevenagel Condensation reaction followed by a hydrogenation reaction. A desymmetrization is attempted utilizing this malonic ester derivative in the presence of a Brønsted acid catalyst to achieve a chiral heterocycle via a novel carbon-carbon bond formation. Once this is achieved, the desymmetrization reaction of the indole-containing starting material will be catalyzed by a chiral Brønsted acid catalyst to achieve an enantioenriched product.

Additional Information

Language: English
Date: 2021
Bacillaene, Desymmetrization, Difficidin, Heterocycle, Indole
Polyketides $x Synthesis

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