S 6. Furochromones. Part I. The synthesis of Khellin

The chromones: history, chemistry and clinical development. A tribute to the work of Dr R. E. C. Altounyan

“…He also established the structure analytically. Khellin was ®rst synthesized by Dr (later Professor) G. R. Ramage in conjunction with R. A. Baxter and N. R. Timson at the British Schering Research Institute at Alderley Edge in Cheshire, UK in 1947 [4].…”

The Synthesis of Khellin Derivatives

“…51°). This compound yields khellin by routes established by Baxter, Ramage, and Timson (6) and Spáth and Gruber (3).…”

The Chemistry and the Physiological Action of Khellin and Related Products.

“…In the same year Baxter, Ramage, and Timson (16,25) also achieved a total synthesis of khellin by first preparing 2,6-dibenzyloxy-l,4-dimethoxybenzene (II) from pyrogallol (I), essentially by the method of Baker, Nodzu, and Robinson (13). 2,4-Dihydroxy-3,6-dimethoxybenzaldehyde (III) was obtained by subjecting II to a modified Gatterman reaction, using zinc cyanide.…”

“…Condensation with ethyl acetate and sodium gave 5-acetoacetyl-6-hydroxy-4,7-dimethoxycoumarone (XIII), which cyclized readily with ethanolic sulfuric acid or ethanolic hydrogen chloride to give khellin (XIV). Cyclization of the diketone obtained from the condensation of 5-acetyl-6hydroxy-4,7-dimethoxycoumaran with ethyl acetate gave dihydrokhellin (16). OCHs H2C-i CO /V XCH HiCxo/Xzxo/ CCHs OCHs Dihydrokhellin Murti and Seshadri (70a) also published a total synthesis of khellin in 1949 Whereas in the two syntheses described above the pyrone ring was built up on the appropriate coumarone, this synthesis involved building up the furan ring on the chromone system.…”