Total synthesis of the potent anti-inflammatory natural product solomonamide A along with structural revision and biological activity evaluation

Abstract

Herein, we report total synthesis of solomonamide along with its structural revision for the first time. The natural product possesses very potent anti-inflammatory activity and it contains a macrocylic peptide having four consecutive stereocenters on unnatural amino acid component. Key features in present synthesis include the application of an Evans aldol reaction, ligand free Heck macrocylization and chemo-selective oxidations. The challenging task of fixing the stereochemistry of OH at C5-position was accomplished with the help of DFT calculations, applying a quantum-mechanical (QM)/NMR combined approach. Biological evaluation in mouse paw edema model revealed that low dose (0.3 mg/kg) of synthesized solomonamide A showed 74% reduction at 6 h which was comparable to high dose (10 mg/kg) standard drug dexamethasone effect (75% at 6h). Thus, we further confirmed the revised structure of solomonamide A