UC Santa Barbara

Asymmetric synthesis is key in the construction of complex natural products, many of which possess chiral centers. Xestospongin compounds are chiral, medicinally intriguing compounds, of which (+)-desmethylxestospongin B has demonstrated potential as a targeted anti-tumor therapeutic. The work conducted and reported here shall discuss the syntheses of (+)-desmethylxestospongin B and (+)-9,9’-difluoroxestospongin C, the latter of which utilizing knowledge gained from our investigation into the synthesis and Ireland-Claisen rearrangement of -fluoroallylic esters. The production of these materials aimed to support ongoing research regarding the medicinal properties of (+)-desmethylxestospongin B. Our lab’s preexisting synthesis of (+)-desmethylxestospongin B served as a foundation to produce this valuable chemical; the target is distinguished from other compounds in the xestospongin family by its C9 oxidation and lack of C2 symmetry. Herein the execution of synthetic strategies solving scalability issues found within the original route is reported, the updated synthesis yielding this product at a total yield increasing that of the original by 50%. To achieve this, critical analysis was undertaken to elucidate unresolved issues in the published synthesis. A notable restructuring of the route’s front-end showed instant results in increased yield and material efficiency. While the previous synthesis depended on kinetic resolution to make four of the six stereocenters in (+)-desmethylxestospongin B’s original synthesis, the improved route features an asymmetric epoxidation step, using novel work performed on terminal alkenes. This method delivered the desired epoxide in high yield and dr while simultaneously increasing material efficiency. Furthermore, different protecting group strategies to avoid problems with their subsequent removal were considered and enacted; to this end, two superfluous protecting/deprotecting steps were discarded. Furthermore, using different protecting groups in the modified synthesis saw retention of material into the route, where the previous strategies lost material in affecting undesired global deprotection. While the late-stage lactam semi-reduction under Birch conditions still requires optimization, the updated synthesis of (+)-desmethylxestospongin B reported increased scalability, affording 0.37 g of this natural product for continued biological studies. A total synthesis can be adapted to generate analogues, as was the case for (+)-9,9’-difluoroxestospongin C. The results and valuable information obtained from studying the stereoselective Ireland-Claisen rearrangement to afford -fluorocarboxylic acids supported the proposed synthesis of fluorinated xestospongin analogues. Previously, (–)-9,9’-difluoroaraguspongine B had been afforded within our lab, however this compound’s bioactivity could not be studied due to poor solubility. The executed modular synthesis set to investigate if inversion at (–)-9,9’-difluoroaraguspongin B’s C9’ would decrease crystal packing due to broken symmetry, and thus improve the difluorinated xestospongin’s solubility. With (+)-9,9’-difluoroxestospongin C as the proposed target, the modified synthesis of (+)-desmethylxestospongin B was executed to yield 13 mg of this target, which was noted to have improved solubility than its predecessor.