A Stereoselective Synthesis of (+)-Gonyautoxin 3

Abstract

The waters of the "red tide" are awash with noxious agents, the most infamous of which are the paralytic shellfish poisons (PSPs). 1 Small molecule, bis-guanidinium structuressaxitoxin, neosaxitoxin, and the gonyautoxins -unique in both their form and function, represent the principle constituents of PSPs. 2 These highly polar, heteroatom-rich compounds are exquisitely designed corks that act to stopper ion flux through voltage-gated Na + channels (Na V ), thus inhibiting electrical conduction in cells. 3 The intricate molecular shape common to these toxins coupled with their importance as pharmacological tools for ion channel study have inspired efforts aimed at their de novo assembly. Three prior works have described preparations of saxitoxin (STX) and one a decarbamoyloxy form. 4,5 The first synthetic path to any member of the more than 20 known sulfated poisons, gonyautoxin 3 (GTX 3), is outlined in this report (Figure 1). 6,7The five-membered cyclic guanidine in GTX 3 became the focal point of our synthetic analysis following our recent disclosure of an oxidative method for 2-aminoimidazoline formation. 8 This transformation is thought to proceed through the intermediacy of a Rh-bound guanidine nitrene, a reactive species capable of modifying both C-H and π-bonds. For the purpose of crafting GTX 3, amination of a pyrrole nucleus by the guanidine nitrenoid presented a novel application of this technology (Figure 1). Such a reaction could occur through either a strained aziridine 3 or dipolar species 4, attack of which by a nucleophile at either C10 or C12 would generate the desired tricyclic core. 9 This regiochemical issue notwithstanding, such a strategy simplifies the GTX problem to a rather unassuming bicyclic intermediate 1. Pursuant to this approach, a route to bis-guanidine 1 was formulated that would exploit an intramolecular addition of a pyrrole to an activated imine. Although limited in precedent, this type of PictetSpengler reaction could be quickly evaluated, as the necessary precursor 2 is easily accessed from serine.The synthesis of GTX 3 commences with a three-step sequence that transforms L-serine methyl ester to aldehyde 5 (Scheme 1). 10 Condensation of this aldehyde with allylamine is followed by treatment with BF 3 · OEt 2 , which effects the desired ring closure to furnish the transsubstituted urea 6 with >20:1 diastereoselectivity. 11 Assuming the C5/C6 stereochemistry (GTX numbering) in this product is established under kinetic control, a conformation that minimizes allylic strain between the substituents on C6 and N7 could account for the observed sense of induction. Forwarding 6 to the requisite amination precursor 7 was efficiently achieved through a sequence of four transformations; of note is the development of a single step process for sequential allyl deprotection and isothiourea formation (cf., step e, 6→7, Tces = SO 3 CH 2 CCl 3 ). Successful application of the Rh-catalyzed amination reaction with guanidine 7 assembles the tricyclic frame of GTX 3 in a singular, defining event...

Marked difference in saxitoxin and tetrodotoxin affinity for the human nociceptive voltage-gated sodium channel (Na v 1.7)

“…STX and GTX-III were synthesized according to routes previously published by our laboratory (44,45). TTX was purchased from Ascent Scientific and used without additional purification.…”

Cooccupancy of the Outer Vestibule of Voltage-Gated Sodium Channels by μ-Conotoxin KIIIA and Saxitoxin or Tetrodotoxin

“…Experiments with: 1) these congeners as well as possible synthetic derivatives of both STX and TTX (good progress in guanidinium alkaloid syntheses is promising in this regard; Andresen and Du Bois 2009; Mulcahy and Du Bois 2008;Nishikawa et al 2004;Sato et al 2008); 2) close relatives of KIIIA, such as the -conotoxins SIIIA and SmIIIA (Bulaj et al 2005;West et al 2002); and 3) mutants of the channel, such as Na V 1.2[F385C] ), should advance our understanding of the mechanism of action of guanidinium alkaloids and -conopeptides that target site 1 of VGSCs. Furthermore, if active, covalently linked alkaloid-peptide adducts can be synthesized, these should provide insights into the arrangement of the units when bound to site 1, as well as also serve as second-generation ligands for sodium channels.…”

Mutant cycle analysis with modified saxitoxins reveals specific interactions critical to attaining high-affinity inhibition of hNa V 1.7

“…Previous bis-guandinium toxinNa V mutant cycle analyses have been limited to naturally occurring derivatives (9,10). Accordingly, five monomethylated analogs (2-5 and 8, Table 1), along with two dimethylated variants (6 and 9) and decarbamoyl-STX (dcSTX, 7) were prepared from L-serine methyl ester using routes adapted from our previously disclosed studies (34). Although naturally occurring STX derivatives with substitution at N7 or C13 appear in nature, to our knowledge no N9-or C10-natural product congeners have been identified (35)(36)(37).…”

“…Toxins were prepared from L-serine methyl ester according to a previously reported route (34). All reagents used were obtained commercially unless otherwise noted.…”