Date of Award
Ph.D. in Pharmaceutical Sciences
John M. Rimoldi
Bonnie A. Avery
Ascaulitoxin aglycone is a structurally unique bis-amino acid isolated from the fungal species Ascochyta caulina, with herbicidal activity against Chenopodium album. Ascaulitoxin aglycone's potent herbicidal activity coupled with an unknown but novel mechanism of action makes it a perfect candidate for further study in the pursuit of new natural product herbicides. This dissertation research will illustrate three synthetic strategies towards the total synthesis of ascaulitoxin aglycone from chiral pool building blocks. Strategy 1 invokes the use of the Henry reaction as a key step for the construction of the central C4-C5 cis-aminohydroxy group, which was moderately successful, but abandoned in favor of olefination protocols. Strategy 2 invoked the Wittig reaction as a key reaction for the formation of a C4-C5 olefin, but was also abandoned due to lack of reactivity of an unstabilized ylide with an advanced aldehyde coupling partner. The key C4-C5 olefin was successfully installed by using a Grubbs olefin metathesis reaction of benzyl protected D-allylglycine (homodimerization) with 2nd generation catalysts in the presence of copper iodide. Subsequent asymmetric Sharpless aminohydroxylation of the precursor olefin substrate resulted in creation of the key C4-C5 aminohydroxy unit, with requisite syn-stereochemistry and formation of inseparable diastereomers. Catalytic hydrogenation and transfer catalytic hydrogenation reactions using Pd catalysts were employed for the complete deprotection of three N-CBz and two carboxybenzyl groups towards target ascaulitoxin aglycone, but were met with limited success due to potential catalyst poisoning events.
Morgan, Jeffery Brian, "Progress Toward The Total Synthesis Of The Natural Product Herbicide Ascaulitoxin Aglycone" (2015). Electronic Theses and Dissertations. 691.
Emphasis: Medicinal Chemistry