CJ-12,954 and Its Congeners, New Anti-Helicobacter pylori Compounds Produced by Phanerochaete velutina:Fermentation, Isolation, Structural Elucidation and Biological Activities.

Abstract

Seven new phthalide compoundswith anti-i7elicobacter pylori activities were isolated from the basidiomycete Phanerochaete velutina CL6387, The two most potent phthalide compounds, CJ-12,954 and CJ-13,014, have MICs of 5 ng/ml. The structure-activity relationship shows that the presence of a spiroketal part in addition to the phthalide part, greatly enhances the activity. The phthalide compoundsappear to be specific for H. pylori, since they did not show antibacterial activities when tested against a panel of other microorganisms.Gastric and duodenal ulcers affect a significant portion of the humanpopulation worldwide. Many recent studies have shown a relation between the presence of the

Synthesis of a spiroacetal intermediate for the synthesis of the anti-Helicobacter pylori agent CJ-12, 954

“…The acetylenes 13 and 14 were prepared using via [2,3]-sigmatropic rearrangement of allyl propargyl ether 16 (Scheme 2). Propargyl alcohol was converted to its C-trimethylsilyl derivative 15 8 via formation of the dianion using two equivalents of butyllithium followed by quenching with trimethylsilyl chloride.…”

“…Treatment of allyl propargyl ether 16 with butyllithium at -78 o C for 10 min. effected smooth [2,3]-sigmatropic rearrangement to alcohol 17.…”

“…It was envisaged that acetylene 14 would be available in enantioenriched form by extending the key [2,3]-sigmatropic rearrangement of allyl propargyl ether 16 in an asymmetric sense.…”

“…Towards this end, allyl propargyl ether was subjected to [2,3]-sigmatropic rearrangement using butyllithium in the presence of the chiral bases (-)-sparteine, 20 (1R,2S)-(-)-norephedrine and [R-(R*,R*)]-(+)-bis(α-methylbenzylamine). Disappointingly alcohol 17 was only obtained as a racemic mixture in all cases.…”

“…It now remains to append the phthalide fragment 8 to this spiroacetal fragment. The inability to effect the key [2,3]-sigmatropic rearrangement of allyl propargyl ether 16 to alcohol 17 in an asymmetric fashion has necessitated that future work also be directed towards a synthesis of this 5,5-spiroacetal 9 using methodology that enables control of the stereochemistry at C-2 and C-7 of the spiroacetal ring system.…”