116(P-48) 海産藍藻由来神経毒カルキトキシンの全合成研究(ポスター発表の部)

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概要

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• Kalkitoxin (1) is a potent ichthyotoxic metabolite of the marine cyanobacterium, Lyngbya majuscula collected in Curacao. It has also exhibited a neurotoxicity in rat cerebellar granule neurons. Kalkitoxin is a small molecule, which consists of 5 asymmetric carbons, N-methyl amide moiety and a thiazoline ring. Its NMR spectra are complicated due to a high degree of methylation and the presence of tertiary amide isomers. Furthermore, the amount of natural kalkitoxin is very minute, and firm assignment of structure by method other than synthesis might be difficult. According to our strategy, we initially started to synthesize (3R,7R,8S,10R,2'S)-kalkitoxin. Synthesis of the chiral alcohol 8 having 1,3-dimethyl moiety was prepared from 6 in 9 steps. The primary alcohol of 6 was converted to the corresponding azide 9 by our one-pot p-NO_2-DPPA-DBU method. Selective reduction of azide, coupling with (S)-2 using DEPC, and N-methylation afforded 10. Oxidation followed by a Horner-Emmons reaction simultaneously homologated and introduced the (R)-phenylglycine derived auxiliary. Introduction of C7 methyl group by Hruby's method proceeded smoothly to give methyl adduct 13 as a single isomer. Finally, removal of chiral auxiliary, coupling with (R)-2-amino-3-butenol and thiazoline formation by Wipf's oxazoline-thazoline interconversion provided (3R,7R,8S,10R,2'S)-kalkitoxin (16). We also prepared enimide 17 having (S)-phenylglycine derived oxazolidinone in the same manner, followed by 1,4-addition to give 7S adduct 18 selectively. As the above result, we found that the introduction of C7 methyl group using 1,4-addition could be completely controlled by the chiral auxiliary. During this investigation, the relative stereochemistry 7R^*,8S^*,10S^* was deduced and the absolute stereochemistry 3R was determined by our co-workers. Thus, we synthesized (3R,7R,8S,10S,2'S)-, (3S,7R,8S,10S,2'S)-, (3R,7S,8R,10R,2'S),- (3S,7S,8R,10R,2'S)-, and (3R,7R,8S,10S,2'R)-configurations. (3R,7R,8S,10S,2'R)-kalkitoxin was found to be identical in all respects to natural kalkitoxin (1).

• 天然有機化合物討論会の論文
• 2000-10-01

著者

• 塩入 孝之

  名市大・薬

• 塩入 孝之

  名城大院・総合学術

• 塩入 孝之

  名古屋市大・薬

• 横川 文明

  ノバルティスファーマ・筑波研

• 横川 文明

  名市大薬

• 塩入 孝之

  名市大薬

• 浅野 年展

  名市大薬

• 沖野 龍文

  オレゴン州立大

• Gerwick William

  オレゴン州立大

• 沖野 龍文

  宇大農:オレゴン州大

• Gerwick William

  オレゴン州大

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