CJ-13014

The first synthesis of the spiroacetal-containing anti-Helicobacter pylori agents ent-CJ-12,954 and ent-CJ-13,014 is reported based on the union of a heterocycle-activated spiroacetal-containing sulfone fragment with a phthalide-containing aldehyde fragment; 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 naturally occurring phthalide-containing antibiotics spirolaxine methyl ether, CJ-12,954, CJ-13,013, CJ-13,015, CJ-13,102, CJ-13,103, CJ-13,104 and CJ-13,108, have been reported to exhibit anti-H. pylori activity. However, the exact stereochemistry of spirolaxine methyl ether, CJ-12,954 or CJ-13,013, contributing to this observed activity has not been confirmed. The anti-H. pylori activity of several analogues of spirolaxine methyl ether, CJ-12,954 and CJ-13,013 of defined stereochemistry together with the anti-H. pylori activity of several indole analogues of the simpler phthalide-containing antibiotics CJ-13,102, CJ-13,104, CJ-13,108 and CJ-13,015 is reported herein. A 1:1 mixture of spiroacetals 5b and 6b in which the phthalide substituent exhibited (3R)-stereochemistry was sixty times more active than the corresponding 1:1 mixture of spiroacetals with (3S)-stereochemistry. Notably, the unnatural (2''S)-diastereomer of spirolaxine methyl ether exhibited more potent anti-H. pylori activity than the natural product spirolaxine methyl ether. The 4,6-dimethoxyindoles 9, 10, 11 and 13 were all found to be less active than their parent compounds 1, 2, 3 and 4, respectively. Chain-shortened 4,6-dimethoxyindole analogue 12 of CJ-13,108 3 and 4,6-dimethoxyindole-spiroacetal 13 exhibited weak anti-H. pylori activity thus providing future opportunity for drug discovery programs.

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