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Article

Asymmetric Total Syntheses of Both Enantiomers of Plymuthipyranone B and Its Unnatural Analogues: Evaluation of anti-MRSA Activity and Its Chiral Discrimination

1
Department of Chemistry, School of Science and Technology, Kwansei Gakuin University, 2-1 Gakuen, Sanda 669-1337, Japan
2
Division of Pharmacodynamics, Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan
*
Author to whom correspondence should be addressed.
Academic Editor: Quezia Bezerra Cass
Pharmaceuticals 2021, 14(9), 938; https://doi.org/10.3390/ph14090938
Received: 1 August 2021 / Revised: 8 September 2021 / Accepted: 8 September 2021 / Published: 19 September 2021
(This article belongs to the Special Issue Chirality in Drug Discovery)
Chiral total syntheses of both enantiomers of the anti-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-2H-pyran-2-one structure. The starting synthetic step utilized a privileged asymmetric Mukaiyama aldol addition using Ti(OiPr)4/(S)-BINOL or Ti(OiPr)4/(R)-BINOL catalysis to afford the corresponding (R)- and (S)-δ-hydroxy-β-ketoesters, respectively, with highly enantiomeric excess (>98%). Conventional lactone formation and successive EDCI-mediated C-acylation produced the desired products, (R)- and (S)-plymuthipyranones B and three (R)- and (S)- synthetic analogues, with an overall yield of 42–56% with a highly enantiomeric excess (95–99%). A bioassay of the anti-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 (S)-plymuthipyranone B exhibited significantly higher activity than the unnatural (R)-antipode against both AACCs. (iii) The natural (R)-plymuthipyranone B and (R)-undecyl synthetic analogue at the C6 position exhibited the highest activity. The present work is the first investigation of the SAR between chiral R and S forms of this chemical class. View Full-Text
Keywords: anti-MRSA activity; asymmetric total syntheses; enantiomers; chiral discrimination; plymuthipyranone B anti-MRSA activity; asymmetric total syntheses; enantiomers; chiral discrimination; plymuthipyranone B
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MDPI and ACS Style

Moriyama, M.; Liu, X.; Enoki, Y.; Matsumoto, K.; Tanabe, Y. Asymmetric Total Syntheses of Both Enantiomers of Plymuthipyranone B and Its Unnatural Analogues: Evaluation of anti-MRSA Activity and Its Chiral Discrimination. Pharmaceuticals 2021, 14, 938. https://doi.org/10.3390/ph14090938

AMA Style

Moriyama M, Liu X, Enoki Y, Matsumoto K, Tanabe Y. Asymmetric Total Syntheses of Both Enantiomers of Plymuthipyranone B and Its Unnatural Analogues: Evaluation of anti-MRSA Activity and Its Chiral Discrimination. Pharmaceuticals. 2021; 14(9):938. https://doi.org/10.3390/ph14090938

Chicago/Turabian Style

Moriyama, Mizuki, Xiaoxi Liu, Yuki Enoki, Kazuaki Matsumoto, and Yoo Tanabe. 2021. "Asymmetric Total Syntheses of Both Enantiomers of Plymuthipyranone B and Its Unnatural Analogues: Evaluation of anti-MRSA Activity and Its Chiral Discrimination" Pharmaceuticals 14, no. 9: 938. https://doi.org/10.3390/ph14090938

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