College
College of Arts & Sciences
Mentor Information
James Leahy
Description
Darwinolide and membranolide, natural products isolated from Dendrilla membranosa, an Antarctic sponge of the family Darwinellidae, have demonstrated activity against Methicillin-resistant Staphylococcus aureus (MRSA) biofilm. The oxeatamides, natural products from the New Zealand sponge Darwinella oxeata, are structurally related to membranolide and represent promising candidates for similar biological activity, yet remain synthetically underexplored due to their limited natural abundance and complex structures. Building on prior studies in the Leahy laboratory, which established the asymmetric total synthesis of membranolide and enabled the preparation of key nitrogenous intermediates toward the oxeatamides, efforts are now directed toward the first asymmetric total synthesis of the oxeatamides. To this end, synthesis of the trimethylcyclohexyl alkyne (TMC alkyne) intermediate from isophorone is underway. This sequence includes a Luche reduction (>95% yield), an enzymatic kinetic resolution using Candida rugosa lipase (15–28% yield, >98% ee), a DCC coupling (84% yield), an Ireland–Claisen rearrangement (81% yield), a Pd/C hydrogenation and debenzylation (90% yield), a NaIO₄ oxidative cleavage (71% yield), and a Seyferth–Gilbert homologation (92% yield). Each intermediate has been purified by column chromatography, with fractions monitored by TLC, and characterized by LC-MS, ¹H NMR, and ¹³C NMR spectroscopy. These efforts aim to advance this route toward additional oxeatamide family members. Availability of these compounds will enable expanded biological evaluation, including their potential as MRSA biofilm-eradication agents, and will support future mechanistic studies and probe development to better understand their modes of action.
Towards the Asymmetric Total Synthesis of the Oxeatamides
Darwinolide and membranolide, natural products isolated from Dendrilla membranosa, an Antarctic sponge of the family Darwinellidae, have demonstrated activity against Methicillin-resistant Staphylococcus aureus (MRSA) biofilm. The oxeatamides, natural products from the New Zealand sponge Darwinella oxeata, are structurally related to membranolide and represent promising candidates for similar biological activity, yet remain synthetically underexplored due to their limited natural abundance and complex structures. Building on prior studies in the Leahy laboratory, which established the asymmetric total synthesis of membranolide and enabled the preparation of key nitrogenous intermediates toward the oxeatamides, efforts are now directed toward the first asymmetric total synthesis of the oxeatamides. To this end, synthesis of the trimethylcyclohexyl alkyne (TMC alkyne) intermediate from isophorone is underway. This sequence includes a Luche reduction (>95% yield), an enzymatic kinetic resolution using Candida rugosa lipase (15–28% yield, >98% ee), a DCC coupling (84% yield), an Ireland–Claisen rearrangement (81% yield), a Pd/C hydrogenation and debenzylation (90% yield), a NaIO₄ oxidative cleavage (71% yield), and a Seyferth–Gilbert homologation (92% yield). Each intermediate has been purified by column chromatography, with fractions monitored by TLC, and characterized by LC-MS, ¹H NMR, and ¹³C NMR spectroscopy. These efforts aim to advance this route toward additional oxeatamide family members. Availability of these compounds will enable expanded biological evaluation, including their potential as MRSA biofilm-eradication agents, and will support future mechanistic studies and probe development to better understand their modes of action.
