Synthesis and assignment of the absolute configuration of the anti-Helicobacter pylori agents CJ-12,954 and CJ-13,014

Abstract

The synthesis of the spiroacetal-containing anti-Helicobacter pylori agents (3S,2″S,5″S,7″S)-1a (ent-CJ-12,954) and (3S,2″S,5″R,7″S)-2a (ent-CJ-13,014) has been carried out based on the convergent union of a 1 : 1 mixture of heterocycle-activated spiroacetal sulfones6 and 7 with (3S)-phthalide aldehyde5a. The synthesis of the (3R)-diastereomers (3R,2″S,5″S,7″S)-1b and (3R,2″S,5″R,7″S)-2b was also undertaken in a similar manner by union of (3R)-phthalide aldehyde5b with a 1 : 1 mixture of spiroacetal sulfones6 and 7. Comparison of the ¹H and ¹³C NMR data, optical rotations and HPLC retention times of the synthetic compounds (3S,2″S,5″S,7″S)-1a and (3S,2″S,5″R,7″S)-2a and the (3R)-diastereomers (3R,2″S,5″S,7″S)-1b and (3R,2″S,5″R,7″S)-2b, with the naturally occurring compounds, established that the synthetic isomers 1a and 2a were in fact enantiomeric to the natural products CJ-12,954 and CJ-13,014. The (2S,8S)-stereochemistry in protected dihydroxyketone 21, the precursor to the mixture of spiroacetal sulfones6 and 7 was established via union of readily available (S)-acetylene 18 with aldehyde17 in which the (4S)-stereochemistry was established via asymmetric allylation. Deprotection and cyclization of protected dihydroxyketone 21 afforded an inseparable 1 : 1 mixture of spiroacetal alcohols24 and 25 that were converted into a 1 : 1 inseparable mixture of spiroacetal sulfones6 and 7. Phthalide-aldehyde 3a was prepared via intramolecular acylation of bromocarbamate 11 in which the (3S)-stereochemistry was established via asymmetric CBS reduction of ketone8.