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)- (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 .

Heteroatom-Directed Reverse Wacker Oxidations. Synthesis of the Reported Structure of (−)-Herbaric Acid

“…Compound ( S )- 5 was treated with 1,1′-carbonyldiimidazole and diethylamine to furnish the carbamate 4 , which upon treatment with n -BuLi led to smooth intramolecular acylation and subsequent acid-mediated lactonization to deliver the key vinylphthalide 3 . A similar intramolecular Parham-type cyclization served us and others well during the total syntheses of the spirolaxine antibiotics and was employed in this instance, especially since the aryllithium derived from 4 readily underwent protonation when quenched with external electrophiles (e.g., DMF), even under strictly anhydrous conditions.…”

Synthesis and anti-Helicobacter pylori activity of analogues of spirolaxine methyl ether

“…It was next realised that the five carbon polymethylene chain spiroacetal alcohol 33 could be coupled to the phthalide aldehyde 14 reported by Brimble et al 14a,24 using a Julia-Kocienski olefination to form the long chain (eight carbon) phthalide analogue 6. To that effect, spiroacetal alcohol 33 was transformed into the sulfide using a Mitsunobu protocol, 25 that was then oxidised to sulfone 16 using m-CPBA. Julia-Kocienski olefination was performed between sulfone 16 and phthalide aldehyde 14 in the presence of potassium bis(trimethylsilyl)amide.…”

Asymmetric Total Synthesis of (+)-Fusarisetin A via the Intramolecular Pauson–Khand Reaction

“…In the event, addition of chloromethylithium, generated from chloroiodomethane and n -BuLi, to aldehyde 13 at −78 °C gave epoxide 12 in 72% yield, together with its diastereoisomer 12a in 12% yield (Scheme ). Further reaction of epoxide 12 with lithium acetylide 14 at −78 °C in THF in the presence of BF 3 ·Et 2 O gave the requisite enyne 11 in 60% yield.…”