Synthetic Studies on Shellfish Toxin Azaspiracid

azaspiracid -1 （AZA-1）是一种新型贝类中毒综合征azaspiracid poisoning （AZP）的致病毒素，自1995年11月以来在欧洲沿海地区流行。1998年，日本东北大学的Yasumoto和Satake领导的团队对AZA-1进行了分离和结构解析，2004年，Nicolaou团队对AZA-1进行了首次全合成和结构修正。我们一直致力于AZA-1的合成，以制备用于开发贝类毒素抗体的半抗原。首先，我们合成了一个C21-C40 efghi环片段如下。以已知中位- 2,4 -二甲基- 1,5 -戊二醇和d -谷氨酸分别制备了C32-C40二硫烷和C28-C35环氧化物的偶联片段的合成。利用Yb(Otf)_3的催化量操纵保护基团和随后的螺胺形成，可以立体选择性地产生与hi环片段对应的所需螺胺。在生成C28-C40醛后，用InCl_3与e -环烯丙基锡烷进行键偶联反应，得到收率较高的均烯丙醇。最后，通过hf -吡啶的作用构建fg环，完成了AZA-1的C21-C40片段的合成。以d -谷氨酸为原料，经最长的37步线性合成，总收率为0.025%。然后对合成途径进行修饰以合成半抗原；1)优化了C40氨基官能团的保护基团为2-（三甲基硅基）氨基甲酸乙酯；2)在构建C27-C28键之前，采用α-磺酰基吡喃偶联方法确定了AZA-1片段与蛋白质（如BSA）之间的正己基连接体。目前，合成研究已进入实现这一目标的最后阶段。

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.