Atropo-Enantioselective Total Synthesis of Knipholone and Related Antiplasmodial Phenylanthraquinones

Abstract

The "lactone concept" has been efficiently employed for the first atropo-enantioselective synthesis of knipholone and related natural phenylanthraquinones. Besides the regio- and stereoselective construction of the biaryl axis, another important step was the "synthetically late" introduction of the C-acetyl group, either by a Friedel-Crafts type acetylation or by an ortho-selective Fries rearrangement first tested on simplified model systems and subsequently applied to the highly atroposelective preparation of the natural products and of simplified analogs thereof for biotesting. The synthetic availability of these natural biaryls, their precursors, and their unnatural analogs permitted a broader investigation of the antiplasmodial activities of these interesting biaryls.

Bulbine-Knipholone, a New, Axially Chiral Phenylanthraquinone fromBulbine abyssinica (Asphodelaceae): Isolation, Structural Elucidation, Synthesis, and Antiplasmodial Activity

“…[13,14] Besides bulbine-knipholone (6), the known phenylanthraquinones knipholone (4), [8] knipholone anthrone, [15] 6Ј-O-methylknipholone, [10] and 4Ј-O-demethylknipholone [16] were also detected in the crude extract of the roots of Bulbine abyssinica, by means of HPLC comparison with the previously synthesized authentic compounds as reference materials. [17] Because of hindered rotation around the central biaryl bond, bulbine-knipholone is configurationally stable and optically active Ϫ a property also observed for all the other known natural 4-phenylanthraquinones. [8,9,15,18] The absoScheme 1.…”

Natural Products Active Against African Trypanosomes: A Step Towards New Drugs

“…In this review, several compounds isolated from a natural source had an IC 50 in the submicromolar range. Only 12 of them (1,6,34,35,56,57,67,83,84,95,104,120) were revealed to be relatively selective (SI ≥ 20) whereas no information on selectivity was given for two others (49 combined with glycerol and 71). Additionally, synthetic chemical modifications of natural substances, such as 37,42, 44,80, led to compounds which also exhibit activity, while the parent molecule does not, illustrating once again how natural products can serve as a basis to develop derivatives with increased activity and/or lower toxicity.…”

“…Other closely related compounds, differing only in the O-methylation pattern of the acetylphloroglucinol unit and/or in the oxidation state of the tricyclic portion (anthraquinone vs. anthrone) have been tested as well: knipholone anthrone 89 was more cytotoxic to L6 cells than to trypanosomes, 4Ј-O-demethylknipholone 90 was slightly more active on trypanosomes (IC 50 =13.6 µM). 67 The 4Ј-O-β--glucoside of 90, 91, isolated from the roots of Bulbine frutescens (Asphodelaceae) was 13 times more active than 90 on T. b. brucei bloodstream trypomastigotes (IC 50 = 1.2 µM) with some selectivity (IC 100 on L6 cells = 154 µM). Gaboroquinones A 92 and B 93, two isomers isolated from the same plant, were less active on trypanosomes: 92 was active in the same concentration range as 90 (IC 50 = 11.3 µM), while 93 was inactive (IC 50 = 101 µM).…”

Atropselektive Synthese axial‐chiraler Biaryle

“…[6,7] Dieses Molekül enthält drei Arten von Stereoelementen -mehrere Stereozentren, zwei Chiralitäts-ebenen und eine stereogene Biarylachse; alle zusammen bedingen die starre 3D-Struktur, die für eine effiziente Bindung an die Zellwandpeptide von Bakterien notwendig ist. [6] Knipholon [8] (2) ist lediglich axial-chiral und kommt in der Natur mit unterschiedlicher Enantiomerenreinheit vor; [9] Verbindungen dieser Familie von 1-Phenylanthrachinonen, speziell die M-konfigurierten, haben kürzlich gute Antimalaria- [10] und Antitumoraktivitäten [11] gezeigt. Von Mastigophoren A (3), einem C 2 -symmetrischen Bisphenol mit zusätzli-chen Stereozentren, ist bekannt, dass es das Nervenwachstum stimuliert.…”