Date of Award
Doctor of Philosophy
Jason S. Chen
Levi M. Stanley
The breitfussins are highly modified halogenated marine alkaloids, containing an unprecedented indole-oxazole-pyrrole structure and breitfussin A is only known iodo-oxazole containing the natural product. Due to lack of enough information from conventional tools like NMR, mass spectroscopy, and IR, their structures were determined by an unusual application of atomic-force microscopy (AFM) along with other computational tools.
In the absence of selective halogenation on oxazole-pyrrole containing a molecular frame, the site-selective halogenation was studied on the model compound of breitfussins. It has been found that the oxazole and pyrrole rings proved to be comparably reactive towards electrophilic halogenation by N-chlorosuccinimide (NCS), N-bromosuccinimide (NBS), N-iodosuccinimide and iodine-monochloride (ICl). Solvent and protecting group selection were found to be an effective means of tuning the halogenation site selectivity. The iodination site selectivity was controlled with the help of protecting group while acetone favoring oxazole bromination and pyridine favoring the pyrrole bromination. This tunable site-selective halogenation was used in the synthesis of breitfussin A by using only one protecting group in 14 steps with 6.5% overall yield and a protecting group-free synthesis of breitfussin B that proceeded in 9.2% yield over 12 reactions steps. A bromo-oxazole analog of breitfussin A was also prepared by late-stage bromination but isomerized on silica gel to form breitfussin B. This isomerization appeared to proceed through a unimolecular pathway.
Akbar Husain Khan
Khan, Akbar Husain, "Total synthesis and characterization of breitfussins A and B" (2017). Graduate Theses and Dissertations. 16284.