Synthetic Studies on Shellfish Toxin Azaspiracid

阿扎匹酸-1（Azaspiracid-1，AZA-1）是引起一种新型贝类中毒综合征的毒素，称为阿扎匹酸中毒（azaspiracid poisoning，AZP），自1995年11月以来在欧洲沿海地区流行。在1998年由东北大学的Yasumoto和Satake领导的小组进行分离和结构解析之后，2004年由Nicolaou小组进行了AZA-1的首次全合成和结构修正。为了制备用于开发贝类毒素抗体的半抗原，我们一直致力于AZA-1的合成。该片段的合成以C32-C40二噻烷和C28-C35环氧化物之间的偶联为基础，分别由已知的meso-2，4-二甲基-1，5-戊二醇和D-谷氨酸制备。操作保护基和随后的螺缩醛形成使用催化量的Yb（OTf）_3立体选择性地递送对应于HI环片段的所需螺缩醛。在生成C28-C40醛后，用InCl_3与E环烯丙基锡烷进行关键的偶联反应，以高产率得到高烯丙醇。最后，通过HF-吡啶的作用构建FG-环，以完成适当保护的AZA-1的C21-C40片段的合成。以D-谷氨酸为起始原料，经最长的线性反应路线，总收率为0.025（37个步骤）。然后修改合成途径以合成半抗原; 1）将C40氨基官能团的保护基优化为2-氨基甲酸（三甲基甲硅烷基）乙酯，和2）在构建C27-C28键之前，使用α-磺酰基吡喃偶联方法确定在AZA-1片段和蛋白质（如BSA）之间引入正己基接头。综合研究已进入最后阶段。

Azaspiracid-1 (AZA-1) is a causative toxin for a new type of shellfish poisoning syndrome named azaspiracid poisoning (AZP), prevailed since November 1995 at a coastal region in Europe. After isolation and structural elucidation by a group led by Yasumoto and Satake at Tohoku University in 1998, the first total synthesis and the structural revision of AZA-1 were made by the Nicolaou group in 2004. We have been working toward a synthesis of AZA-1 to prepare haptens used for development of antibodies for the shellfish toxin.Initially, we have synthesized a C21-C40 EFGHI-ring fragment as follows. The synthesis of the fragment strated with a coupling between a C32-C40 dithiane and a C28-C35 epoxide, prepared from known meso-2, 4-dimethyl-1, 5-pentanediol and D-glutamic acid, respectively. Manipulations of the protecting groups and subsequent spiroaminal formation using a catalytic amount of Yb(Otf)_3 delivered the desired spiroaminal corresponding to the HI-ring fragment stereoselectively. After leading to a C28-C40 aldehyde, the key coupling reaction with an E-ring allylic stannane was carried out by using InCl_3 to afford homoallylic alcohol in good yield. Finally, FG-ring was constructed by the action of HF-pyridine to accomplish the synthesis of a suitably protected C21-C40 fragment of AZA-1. The total yield was 0.025% for the longest linear pathway from D-glutamic acid (37 steps).The synthetic pathway was then modified for the synthesis of haptens; 1) the protecting group for the C40 amino functionality was optimized to a 2-(trimethylsilyl) ethyl carbamate, and 2) a n-hexyl linker between the AZA-1 fragment and proteins (such as BSA) was determined to be introduced using an α-sulfonylpyran coupling methodology before construction of the C27-C28 bond. The synthetic study is now in the final stage toward the goal.