| Summary: | Chiral total syntheses of both enantiomers of the <i>anti</i>-MRSA active plymuthipyranone B and all of the both enantiomers of three unnatural and synthetic analogues were performed. These two pairs of four chiral compounds are composed of the same 3-acyl-5,6-dihydro-2<i>H</i>-pyran-2-one structure. The starting synthetic step utilized a privileged asymmetric Mukaiyama aldol addition using Ti(O<i>i</i>Pr)<sub>4</sub>/(<i>S</i>)-BINOL or Ti(O<i>i</i>Pr)<sub>4</sub>/(<i>R</i>)-BINOL catalysis to afford the corresponding (<i>R</i>)- and (<i>S</i>)-δ-hydroxy-β-ketoesters, respectively, with highly enantiomeric excess (>98%). Conventional lactone formation and successive EDCI-mediated <i>C</i>-acylation produced the desired products, (<i>R</i>)- and (<i>S</i>)-plymuthipyranones B and three (<i>R</i>)- and (<i>S</i>)- synthetic analogues, with an overall yield of 42–56% with a highly enantiomeric excess (95–99%). A bioassay of the <i>anti</i>-MRSA activity against ATCC 43300 and 33591 revealed that (i) the MICs of the synthetic analogues against ATCC 43300 and ATCC 33591 were between 2 and 16 and 4 and 16 μg/mL, respectively, and those of vancomycin (reference) were 1 μg/mL. (ii) The natural (<i>S</i>)-plymuthipyranone B exhibited significantly higher activity than the unnatural (<i>R</i>)-antipode against both AACCs. (iii) The natural (<i>R</i>)-plymuthipyranone B and (<i>R</i>)-undecyl synthetic analogue at the C6 position exhibited the highest activity. The present work is the first investigation of the SAR between chiral <i>R</i> and <i>S</i> forms of this chemical class.
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