Abstract
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.
Highlights
The chiral discrimination of bioactivity between enantiomers has occupied a central position in modern research and the development of pharmaceuticals and agrochemicals.3-Acyl-5,6-dihydro-2H-pyran-2-ones are unique heterocyclic molecules with a tricarbonyl moiety at the C(3)-position and an asymmetric center at the C(6)-position [1]
Consistent with our continuing interest in chiral discrimination studies between enantiomers and diastereomers [18,19,20,21,22,23], a major topic in pharmaceutical and agrochemical research, we envisaged the chiral total syntheses of three sets of plymuthipyranones to evaluate the anti-MRSA activity of natural plymuthipyranone B, synthetic analogues 4c, 4d and novel synthetic analogue 4e
Our synthesis commenced with the privileged asymmetric Mukaiyama aldol addi2
Summary
The chiral discrimination of bioactivity between enantiomers has occupied a central position in modern research and the development of pharmaceuticals and agrochemicals. The total or formal chiral syntheses of 1 have been achieved by the following several groups: (i) the first total synthesis started from (S)-methylbutanol and methyl (R)-hydroxybutanoate (Ichihara’s group) [3,4], (ii) formal synthesis utilizing Rucatalyzed alder ene type reactions (Trost’s group) [5], (iii) formal synthesis utilizing a silyl glyoxylate three-component-coupling method (Johnson and Slade) [6] and (iv) total synthesis utilizing asymmetric Ti-Claisen condensation by our group [7,8]. Glyoxylate three-component-coupling (Johnson Sand [6] and (iv) total of synRecently, the chiral total syntheses ofmethod (R)-podoblastin (2d)Slade) and (R)-lachnelluloic acid thesis utilizing asymmetric. [9] and synthesized as racemic forms utilizing a Fries-type acyl group rearrangement [10] and 1,3-dipolar cycloaddition [11]. The chiral total syntheses of (R)-podoblastin S (2d) and (R)-lachnelluloic acid were performed utilizing catalytic asymmetric Mukaiyama aldol reactions [15]
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