22 Total Synthesis of Decarbamoyl-α-saxitoxinol(Oral Presentation)

• Sawayama Yusuke

  Graduate School of Bioagricultural Sciences, Nagoya University

• Nishikawa Toshio

  Graduate School of Bioagricultural Sciences, Nagoya University

Bibliographic Information

Other Title

• 22 Decarbamoyl-α-saxitoxinolの全合成(口頭発表の部)

Abstract

Saxitoxin [STX], which was first isolated as a paralytic shellfish poison, is a potent and specific blocker of voltage-gated Na+ channels [VGSC]. This unique biological activity prompted us to use STX as biochemical tools for the study of VGSC and other ion channels in the field of neurophysiology. In order to make the specific inhibitors of VGSC, an efficient synthetic route for STX skeleton has been studied in our laboratory. Here, we describe a total synthesis of decarbamoyl-a-saxitoxinol [dcSTXol (1)], a non-toxic, naturally occurring analog of STX produced by the cyanobacterium Lyngyba wollei. Our synthetic strategy for 1 is shown in Scheme 5. We envisioned that tricycle G, which contains AC ring unit of 1 could be synthesized from simple homopropargyl guanidine D by double bromocyclization and intramolecular N-alkylation (D→E→F→G). After introducing hydroxy group and second guanidine (G→H→I), opening of the hemiaminal ether and cyclic guanidine formation under an acidic condition would furnish 1. A precursor 21 for the bromocyclization reaction was synthesized from aziridine 11 in five steps, as shown in Scheme 6. Compound 11 underwent ring opening with NaN3, and the TBS ether of the product was transformed to the corresponding mesylate 19 in 2 steps. Sequential deprotection of the Ac and Boc groups yielded 21, which served as the precursor for bromocyclization. As anticipated, upon treatment of 21 with PyHBr3 in biphasic medium of CH_2Cl_2 and aqueous K_2CO_3, the key bromocyclization reaction and subsequent intramolecular N-alkylation took place to afford 24 as a single product in 36% overall yield in 6 steps from 11. After obtaining key intermediate 24, we next examined transformation of the gem-dibromomethylene group of 24 to carbonyl functionality as shown in Scheme 7. Compound 24 was successfully transformed into alcohol 26 in two steps: (i) Ac_2O, Et_3N in CH_2Cl_2 and (ii) reduction of the resulting enol acetate with NaBH_4. The azide group of 26 was then reduced under Staudinger conditions followed by conventional guanidinylation to give 27. Deprotection of the Cbz groups under hydrogenolytic conditions yielded 28. Upon treatment with B(OCOCF_3)_3 in TFA, 28 underwent ring opening of the hemiaminal ether and subsequent cyclization of the second guanidine to furnish 1 in 73% yield. In summary, we have achieved the concise total syntheis of dcSTXol (1), featuring key bromocyclization for tricyclic intermediate 24 from simple homopropargyl guanidine 21. In addition, novel transformation of the gem-dibromomethylene group to enol acetate has been developed. Further studies toward the synthesis of other STX analogs employing these methodologies are currently under investigation in our laboratory.

Journal

• Symposium on the Chemistry of Natural Products, symposium papers

  Symposium on the Chemistry of Natural Products, symposium papers 53 (0), 127-132, 2011

  Symposium on the Chemistry of Natural Products Steering Committee

Details

• CRID: 1390001206080076800
• NII Article ID: 110009986523
• DOI: 10.24496/tennenyuki.53.0_127
• ISSN: 24331856
• Text Lang: ja
• Data Source:
  • JaLC
  • CiNii Articles
• Abstract License Flag: Disallowed