Divergent Synthesis of Natural Derivatives of (+)-Saxitoxin Including 11-Saxitoxinethanoic Acid

Abstract

The bis-guanidinium toxins are a collection of natural products that display nanomolar potency against select isoforms of eukaryotic voltage-gated Na⁺ ion channels. We describe a synthetic strategy that enables access to four of these poisons, namely 11-saxitoxinethanoic acid, C13-acetoxy saxitoxin, decarbamoyl saxitoxin, and saxitoxin. Highlights of this work include an unusual Mislow-Evans rearrangement and a late-stage Stille ketene acetal coupling. The IC₅₀ value of 11-saxitoxinethanoic acid was measured against rat Na_V 1.4, and found to be 17.0 nm, similar to those of the sulfated toxins gonyautoxin II and III.

Keywords: Stille coupling; guanidinium toxins; rearrangement; sodium channels; sulfoxide.

Figure 1.

Selected bis-guanidinium natural products.

Figure 2.

Comparative potencies of C11-substituted toxins against Na_V1.4.

Scheme 1.

Retrosynthetic analysis of 11-saxitoxinethanoic acid (SEA). Tces = 2,2,2-trichloroethoxysulfonyl, Troc = 2,2,2-trichloroethoxycarbonyl, R = Si^tBuPh₂.

Scheme 2.

Sulfoxide synthesis from N,O-acetal 4. Reagents and conditions: (a) PhSH, BF₃•OEt₂, CH₂Cl₂, 84%; (b) urea•H₂O₂, HFIP, 88%. HFIP = hexafluoro-2-propanol.

Scheme 3.

Synthesis of the fully elaborated bis-guanidine toxin core. Reagents and conditions: (a) Dess-Martin periodinane, CH₂Cl₂, 95%; (b) 25 mol % [Ir(cod)(PCy₃)(py)]PF₆, B(OⁱPr)₃, 500 psi H₂, CH₂Cl₂, 75%; (c) n-Bu₄NF, AcOH, THF, −78–23 °C, 86%.

Scheme 4.

Access to three bis-guanidinium toxin natural products from a common precursor 9. Reagents and conditions: (a) 1 atm H₂, PdCl₂, CF₃CO₂H, MeOH/H₂O, 14–46%. (b) 1,1’-carbonyldiimidazole, THF; then 0.5 M NH₃ in THF, 69%; (c) CH₃C(O)CN, DMAP, CH₂Cl₂, 64%.

Scheme 5.

Selective α-iodination of enaminone 8.

Scheme 6.

Preparation of (2,2-diethoxyvinyl)tin 13 for Pd-mediated Stille cross coupling.

Scheme 7.

Completed synthesis of 11-saxitoxinethanoic acid. Reagents and conditions: (a) ⁿBu₃SnCH=C(OEt)₂, 50 mol% Pd(PPh₃)₄, CuTC, NMP; then NH₄Cl. 35%; (b) 30 mol% [Ir(cod)(PCy₃)(py)]PF₆, B(Oi-Pr)₃, 500 psi H₂, CH₂Cl₂, 80%, 2.5:1 dr; (c) n-Bu₄NF, AcOH, THF, −78–23 °C, 80%; (d) CDI, THF then 0.5 M NH₃ in THF, 35%; (e) 1 atm H₂, PdCl₂, CF₃CO₂H, MeOH/H₂O; then 1.0 M aqueous HCl, 50%. NMP = N-methyl-2-pyrrolidone.