An Efficient and Scalable "Second Generation" Total Synthesis of the Marine Polyketide Limaol Endowed with Antiparasitic Activity

Chemistry. 2024 May 8:e202401429. doi: 10.1002/chem.202401429. Online ahead of print.ABSTRACTThe cluster of four skipped exo-methylene substituents on the "northern" wing of limaol renders this marine natural product unique in structural terms. This arguably non-thermodynamic array gains kinetic stability by populating conformations which impede isomerization to a partly or fully conjugated polyene. This analysis suggested that the difficulties encountered in our first total synthesis had not been caused by an overly fragile character of this unusual substructure; rather, an unfavorable steric microenvironment about the spirotricyclic core was accountable. To remedy the issue, the bulky silyl ethers were replaced by acetates; this simple change allowed all problems to be addressed, the overall yield to be multiplied, and the material throughput to be increased more than eighty-fold per run. Key-to-success was a gold-catalyzed spirocyclization reaction; the reasons why a Brønsted acid cocatalyst is needed and the origin of the excellent levels of selectivity were delineated. The modified protecting group pattern also allowed for a much-improved fragment coupling process by a reagent controlled asymmetric allylation. Finally, a new route to the "northern" sector was established by leveraging the power of asymmetric hydrogenation of a 2-pyrone derivative. Limaol was found to combine appreciable antiparasitic activity with very modest cytotoxicity.PMID:38716817 | DOI:10.1002/che...

Source: Chemistry - May 8, 2024 Category: Chemistry Authors: Stephan N Hess Alois F ürstner Source Type: research