Synthesis of Kawain

Kostermans, D. G. F. R.

doi:10.1038/166788c0

Cited by 19 publications

(3 citation statements)

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“…Thus, the various derivatives of kava extract collectively display an array of inhibitory and activating effects on the NF‐ κ B signaling pathway that provide one potential starting point for elucidating the molecular mechanism(s) underlying the TNF‐ α suppression effects of specific family members. Although there are numerous synthetic approaches to kavalactones (37–42), despite the compelling biological activities reported for this class of compounds no systematic medicinal chemistry optimization program has been described.…”

Section: Resultsmentioning

confidence: 99%

Identification and Characterization of Kava‐derived Compounds Mediating TNF‐α Suppression

et al. 2009

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There is a substantial unmet need for new classes of drugs that block TNF-α-mediated inflammation, and particularly for small molecule agents that can be taken orally. We have screened a library of natural products against an assay measuring TNF-α secretion in lipopolysaccharide (LPS)-stimulated THP-1 cells, seeking compounds capable of interfering with the TNF-α inducing transcription factor Lipopolysaccharide Induced TNF Alpha Factor (LITAF). Among the active compounds were several produced by the kava plant (Piper mysticum), extracts of which have previously been linked to a range of therapeutic effects. When tested in vivo, a representative of these compounds, kavain, was found to render mice immune to lethal doses of LPS. Kavain displays promising pharmaceutical properties, including good solubility and high cell permeability, but pharmacokinetic experiments in mice showed relatively rapid clearance. A small set of kavain analogs was synthesized, resulting in compounds of similar or greater potency in vitro compared to kavain. Interestingly, a ring-opened analog of kavain inhibited TNF-α secretion in the cell based assay and suppressed LITAF expression in the same cells, whereas the other compounds inhibited TNF-α secretion without affecting LITAF levels, indicating a potential divergence in mechanism of action.

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Section: Resultsmentioning

confidence: 99%

Identification and Characterization of Kava‐derived Compounds Mediating TNF‐α Suppression

et al. 2009

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“…Kavain and dihydrokavain are lactones isolated from the kava plant Piper methysticum (Piperaceae) . Much attention has been attracted to synthesize the kava lactones. − For enantioselective syntheses of kavain and dihydrokavain, most approaches gave less than 32% overall yield in more than five steps. 18a-f Smith completed the chiral-auxiliay-based synthesis of (+)-kavain (64% overall yield) and (+)-dihydrokavain (40% overall yield) in three steps 18g…”

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confidence: 99%

Efficient Enantioselective Hetero-Diels−Alder Reaction of Brassard's Diene with Aliphatic Aldehydes: A One-Step Synthesis of (R)-(+)-Kavain and (S)-(+)-Dihydrokavain

Lin

Chen

et al. 2008

Org. Lett.

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An efficient catalytic asymmetric hetero-Diels-Alder reaction of Brassard's diene with aliphatic aldehydes was reported. The catalyst, which was generated from (R)-BINOL, Ti(i-PrO)4, and 4-picolyl chloride hydrochloride, promoted the reaction smoothly to afford the corresponding alpha,beta-unsaturated delta-lactone derivatives in moderate-to-good yields (46-79%) with high enantioselectivities (up to 88% ee). Natural products (R)-(+)-kavain (70% ee, >99% ee after single recrystallization) and (S)-(+)-dihydrokavain (84% ee) were also prepared in one step by using this methodology.

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“…However, when the aldehyde group was activated toward nucleophilic attack (by conversion of the p-N,N-dimethylamino group to a quaternary nitrogen with chloromethyl methyl ether), the activated aldehyde underwent modified Reformatsky reaction to give 6 in 26.5% yield. Kavain (1) was also obtained (25% yield) by the condensation of the (V-butylamine Schiff base of cinnamaldehyde reduction products were mainly tetrahydrokavaic acid (23) and analogues (obtained by opening of lactone ring and subsequent hydrogenation); however, the model compound 4methoxy-6-methyl-2-pyrone ( 27) was reduced to the intact lactone 3-methoxy-5-hydroxy-2-hexenoic acid lactone (28) in 85% yield.…”

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confidence: 99%