Antimalarial 5,6-Dihydro-α-pyrones from Cryptocarya rigidifolia: Related Bicyclic Tetrahydro-α-Pyrones Are Artifacts1

Abstract

Antimalarial bioassay-guided fractionation of an EtOH extract of the root wood of Cryptocarya rigidifolia (Lauraceae) led to the isolation of the five new 5,6-dihydro-α-pyrones cryptorigidifoliols A–E (1–5) and the six bicyclic tetrahydro-α-pyrone derivatives cryptorigidifoliols F–K (6–11). The structure elucidations of all compounds were made on the basis of the interpretation of spectroscopic data and chemical derivatization, and the relative and absolute configurations were determined by NOESY, electronic circular dichroism (ECD), and 1H NMR analysis of α-methoxyphenylacetyl (MPA) derivatives. The bicyclic tetrahydro-α-pyrone derivatives were identified as products of acid-catalyzed intramolecular Michael addition of the 5,6-dihydro-α-pyrones in the presence of silica gel. A structure–activity relationship study suggested that the presence of an α,β-unsaturated carbonyl moiety is not essential for potent antimalarial activity.

Total Synthesis of Cryptorigidifoliol K: Confirmation of Structure and Absolute Configuration

“…Therefore, we devised a plan with an aim of confirming the third proposed structure and elucidating the undetermined stereochemistry at C‐2′ through total synthesis of both the isomers utilizing an intermolecular Nozaki‐Hiyama‐Kishi coupling, reaction at the end of the synthesis. This study also suggests that the revised structure for cryptorigidifoliol E should be 3 a / 3 b , as it is the precursor for the formation of cryptorigidifoliol K …”

“…The plant genus Cryptocarya (Lauraceae) includes over 200 species which are commonly distributed all over the tropical and subtropical regions of the world . Phytochemical studies on this species have led to the discovery of a variety of secondary metabolites, which include lignans, benzylisoquinolines,– proaporphine alkaloids,– flavonoids, cryptochinones, pavines,– and a variety of α ‐pyrone derivatives –. Many of these compounds display numerous biological activities, such as antioxidant, cytotoxic,, antimycobacterial, and antiparacytic activities.…”

“…In 2015, 5,6‐dihydro‐ α ‐pyrone and bicyclic tetrahydropyrone ring bearing natural products, cryptorigidifoliols A–E and cryptorigidifoliols F–K were isolated by Kingston et al. from the root wood of Cryptocarya rigidifolia . The absolute and relative stereochemistries of the cryptorigidifoliols were elucidated from 1D and 2D NMR data .…”

“…from the root wood of Cryptocarya rigidifolia . The absolute and relative stereochemistries of the cryptorigidifoliols were elucidated from 1D and 2D NMR data . In these series, cryptorigidifoliol K only exhibits antiproliferative activity (IC 50 >10 μ M) against A2780 human ovarian cancer cells and antimalarial activity (IC 50 >10 μ M) against Dd2 of Plasmodium falciparum .…”

“…The absolute and relative stereochemistries of the cryptorigidifoliols were elucidated from 1D and 2D NMR data . In these series, cryptorigidifoliol K only exhibits antiproliferative activity (IC 50 >10 μ M) against A2780 human ovarian cancer cells and antimalarial activity (IC 50 >10 μ M) against Dd2 of Plasmodium falciparum . The structure of cryptorigidifoliol K which features a bicyclic tetrahydropyrone moiety, possesses three stereogenic centers and an olefinic side chain carrying a hydroxy group .…”