Penostatins A and C are cytotoxic natural products that show promising selective inhibitory activity against PTP1B.Here the first asymmetric total syntheses of (+)-penostatins A and C are reported. Our strategy features (i) a new method for the synthesis of 6-alkyl-3-hydroxy-2-pyrones, (ii) a cascade involving the intramolecular Diels−Alder reaction of 2-pyrone and a retrohetero-Diels−Alder (decarboxylation) reaction, (iii) Ando−Horner−Wadsworth−Emmons olefination/lactonization, and (iv) selenoxide elimination. Our study confirmed the absolute configurations of penostatins A and C and laid the groundwork for further bioactivity studies.
Siladenoserinols A and H were found to show moderate inhibitory activity toward p53-Hdm2 interactions. Our total synthesis allowed us to further examine their bioactivities, which revealed that (i) siladenoserinols A and H were not cytotoxic against cancer cell lines and (ii) siladenoserinol A and its desulfamate analogue exhibited significant antibacterial activity against Gram-positive bacteria including MRSA. Our studies demonstrate that siladenoserinols are a promising new class of bactericidal Gram-positive antibiotics without hemolytic activity.
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