Preparation of a 1,2-isoxazolidine synthon for the synthesis of zetekitoxin AB

Abstract

A synthesis of the 1,2-isoxazolidine fragment of the potent voltage gated sodium channel blocker, zetekitoxin AB is described. The synthesis utilizes an intramolecular nitrone –olefin 1,3-dipolar cycloaddition to establish the stereochemistry of the cis-1,2-isoxazolidine. The oxidative cleavage of an all anti-triol with the excision of the central carbon is central to using α-D-glucopyranoside as a traceless stereochemical template. This route furnishes a suitably protected synthon for the synthesis of zetekitoxin AB.

Synthetic Approaches to Zetekitoxin AB, a Potent Voltage-Gated Sodium Channel Inhibitor

“…This interesting observation might be attributed to the unusual macrolactam structure in ZTX (8), and synthetic studies of model compounds have been carried out to understand the origin of this unusual chemical shift. In the following section, we discuss the stereoselective isoxazolidine syntheses reported by Nishikawa's [93] and Lopper's groups [94].…”

“…In 2015, Lopper and co-workers reported a synthesis of isoxazolidine 59 (Scheme 6) [94]. Aldehyde 45 was synthesized from commercially available methyl α-d-glucopyranoside (43) by the iodination of 44 with iodine and PPh 3 , acetylation of the hydroxyl group, and reductive cleavage of the pyran ring with zinc in acetic acid [95].…”

“…As discussed above, the 13 C NMR chemical shift of the carbonyl group at C13 in ZTX (8) has been observed at 156.5 ppm [49], which is a higher value compared with usual amide carbonyl groups (170-175 ppm). To address the issue, Nishikawa's and Looper's groups independently examined the 13 C chemical shifts of the carbonyl group at C13 in some model compounds (Figure 9) [93,94]. Simple N-acyl isoxazolidine models 60, 42, and 59 showed chemical shifts of 171.0, 172.7, 171.0 ppm, respectively, which are quite similar to those of regular cyclic N-acyl amides.…”

A Direct C11 Alkylation Strategy on the Saxitoxin Core: A Synthesis of (+)-11-Saxitoxinethanoic Acid

“…Du Bois’ solution utilized the C11 iodo-enaminone to participate in a Stille reaction with a novel tributyltin-ketene acetal reagent . While these represent practical solutions to C–C bond formation at C11, our proposed entry to 11-SEA and ZTX necessitates the C15 carbon electrophile to be introduced as an sp 3 hybridized carbon . Herein, we report the execution of this strategy in both an inter- and intramolecular fashion to forge the C11–C15 bond and ultimately 11-SEA (Figure C).…”