Drug creation involving hybrid type of low molecular weight biomolecules as lead compounds

迄今为止，探索新药的新先导化合物的研究主要集中在生物化合物的一种组分上，而不是杂合组分。本课题旨在开发由氨基酸、糖和核酸碱基组成的生物杂合化合物的最有效、最实用的合成方法，通过自由基加成-肟醚与烯烃的环化反应路线，开发了氨基酸和相关肽的新合成方法。产物顺利转化为β-氨基酸，我们还研究了未保护的天然糖通过自由基反应构建糖部分。与羰基相连的肟醚经锡自由基加成环化反应顺利地得到环状氨基醇，再转化为氨基环醇。自由基反应通过最稳定的过渡态进行，过渡态中1，3-烯丙基的含量最少，通过1，2-Wittig重排和不对称羟基化两个关键反应完成了Dysiherbine的形式合成。

Research for exploring new lead compounds for new drugs has focused to one component of biological compounds and not to hybrid components so far. We started our project to develop the most efficient and practical synthetic method for biological hybrid compounds which consist of amino acids, sugars, and nucleic bases.New synthetic method for amino acids and the related peptides has been developed via the route involving radical addition-cyclization of oxime ethers connected with olefins. The products were converted smoothly into β-amino acids.We also investigated construction of sugar parts by the radical reactions of the unprotected natural sugars. Stannyl radical addition-cyclization of oxime ethers connected with the carbonyl group proceeded smoothly to afford cyclic amino alcohols which were converted into aminocyclitols. The radical reaction was found to proceed via the most stable transition state involving minimum 1, 3-allylic strain.Formal synthesis of Dysiherbine was completed via two key reactions which are 1, 2-Wittig rearrangement and asymmetric hydroxylation respectively.