Total Synthesis of Labile Antibacterial Polyketide Thailandamide A and a More Stable but Equally Potent Morpholine...

First, a chemical route for the stereoselective total synthesis of structurally challenging and labile polyketide natural product thailandamide A has been disclosed. The key features of the synthesis include Krische antidiastereoselective carbonyl crotylation and allylation to generate half of the chiral centers of the molecule, whereas Negishi reaction, Zincke aldehyde reaction, cross-metathesis, and Takai olefination to access different olefin moieties. Furthermore, Julia-Kocienski olefination, amide coupling, and Negishi and Heck coupling have been adopted as the pivotal steps to furnish the complete skeleton of the natural product. Thailandamide A showed potent activity against different pathogenic and nonpathogenic bacteria. But the metabolite was found to be quite unstable. A stable morpholine amide variant of thailandamide A has been accessed which exhibited a similar antibacterial effect (MIC: ∼7 μg/mL) against multidrug-resistant pathogenic Gram-positive bacteria, Staphylococcus aureus, as compared to the natural product and significant activity (MIC: ∼15 μg/mL) against nonpathogenic Gram-positive bacteria Bacillus subtilis as well. The morpholine amide variant of thailandamide A, synthesized chemically, can act as its promising surrogate in the antibacterial domain.