Synthesis of the anti-Helicobacter pylori agent (+)-spirolaxine methyl ether and the unnatural (2″S)-diastereomer

Abstract

The first enantioselective synthesis of the anti-Heliocbacter pylori agent (+)-spirolaxine methyl ether 2b has been carried out in a convergent fashion establishing that the absolute stereochemistry of the natural product is in fact (3R, 2″R, 5″R, 7″R) after initial synthesis of the unnatural (2″S)-diastereomer 2a. The key step in the synthesis of (+)-spirolaxine methyl ether 2b involved a heterocycle-activated Julia–Kocienski olefination between benzothiazole-based spiroacetal sulfone 4b and phthalide aldehyde 3a. (2″R, 5″S, 7″S)-Spiroacetal sulfone 4b was prepared via cyclisation of protected dihydroxyketone 6b, which in turn was derived from the coupling of the acetylide derived from (R)-acetylene 24b with aldehyde 3a. Phthalide aldehyde 3a was prepared via intramolecular acylation of bromocarbamate 15, which was available via titanium tetrafluoride-(+)-BINOL-mediated allylation of 3,5-dimethoxybenzaldehyde 13. Union of the sulfone 4b and aldehyde 3a fragments successfully completed the enantioselective synthesis of (+)-spirolaxine methyl ether 2b. The synthesis of the unnatural (3R, 2″S, 5″R, 7″R)-diastereomer of spirolaxine methyl ether 2a was also undertaken in a similar manner by union of phthalide aldehyde 3a with (2″S, 5″S, 7″S)-spiroacetal sulfone 4a derived from (S)-acetylene 24a.