• DOI:10.1002/anie.201102494
• Corpus ID: 11169764

A synthetic route to the saxitoxin skeleton: synthesis of decarbamoyl α-saxitoxinol, an analogue of saxitoxin produced by the cyanobacterium Lyngbya wollei.

@article{Sawayama2011ASR,
  title={A synthetic route to the saxitoxin skeleton: synthesis of decarbamoyl $\alpha$-saxitoxinol, an analogue of saxitoxin produced by the cyanobacterium Lyngbya wollei.},
  author={Yusuke Sawayama and Toshio Nishikawa},
  journal={Angewandte Chemie},
  year={2011},
  volume={50 31},
  pages={
          7176-8
        }
}

• Yusuke Sawayama, T. Nishikawa
• Published 25 July 2011
• Chemistry, Biology
• Angewandte Chemie

Saxitoxin (1), which was first isolated as a paralytic shellfish poison, is a potent and specific blocker of voltage-gated sodium channels, similar to tetrodotoxin, the puffer fish toxin. This unique biological activity prompted us to use saxitoxin and tetrodotoxin as biochemical tools for the study of voltage-gated sodium channels and other ion channels in the field of neurophysiology. Recently, molecular genetic analyses have revealed that ten subtypes of voltage-gated sodium channels are expressed in mammals, and that these subtypes appear to have specific functions in different organs. However, the specific functions of these channels have yet to be clarified. Our group is interested in developing a subtype-selective blocker of voltage-gated sodium channels based on natural compounds, such as tetrodotoxin and saxitoxin, and have previously established synthetic methods for tetrodotoxin and its analogues. To expand the range of available candidate subtype-selective blockers against voltage-gated sodium channels, we are attempting to develop a novel synthetic route for saxitoxin and its analogues, including neo-saxitoxin, gonyautoxin 3, and zetekitoxin AB, which was isolated from a Panamanian golden frog (Figure 1). Since its structural elucidation in 1975, saxitoxin has been an attractive target molecule for total synthesis owing to its potent biological activity, as well as its unique densely functionalized structure, which features a bicyclic guanidinium condensed with a pyrrolidine and a hydrated form of the C12 carbonyl group. The total synthesis of saxitoxin was first reported by Kishi and co-workers in 1977 and subsequently by Jacobi et al. in 1984. During the last five years, Du Bois and co-workers, and Nagasawa and co-workers have independently studied the synthesis; these studies culminated in the total syntheses of saxitoxin and its analogues, including gonyautoxin 3. Herein, we describe a novel synthetic route for the saxitoxin skeleton; this route enabled us to synthesize decarbamoyl a-saxitoxinol (2), which is a nontoxic, naturally occurring analogue of saxitoxin produced by the cyanobacterium Lyngyba wollei. To synthesize saxitoxin (1) and its analogues, we developed a novel bromocyclization strategy for the syntheses of cyclic guanidines from simple acyclic substrates; fiveand sixmembered cyclic guanidines were formed from propargyl and homopropargyl guanidine, respectively. Scheme 1 shows an example of the bromocyclization; this reaction yielded the six-membered cyclic guanidine 4 possessing a spiro-aminal structure, which is fully functionalized for the saxitoxin skeleton. However, subsequent reduction of the azide group of 4 in preparation for the installation of the second guanidine functional group proved to be difficult, probably because of the severe steric hindrance arising from the geminal dibromo substituents. In the course of these synthetic experiments, we incidentally found a novel reaction involving the transformation of the gem-dibromomethylene group of 4 into a carbonyl functionality, as shown in Scheme 1. In this reaction, dibromo spiro-aminal compound 4 was treated with acetic anhydride and triethylamine in dichloromethane at room temperature to afford enol acetate 5 as an unstable product, and alcohol 6 was isolated after a reduction with NaBH4 and a Figure 1. Structures of saxitoxin (1) and its naturally occurring analogues.