研发新颖实用的氘代反应

The potential for the use of deuterium across multiple applications is bolstered by its safety profile, its proven capacity to improve drugs, and the predictability of its effects on small molecule properties. However, the frustrating complexity of deuteration chemistry, a very limited number of deuterated building blocks available and high cost of making them hamper access to highly sought deuterated bioactive molecules. Practical and cost-effective synthesis of versatile deuterated building blocks and ‘privileged’ molecular architectures will facilitate the construction of deuterated molecules of interest. This demands new synthetic strategies capable of creating powerful transformations for such molecule construction. Toward this end, we will develop a series of new organic reactions by harnessing new reactivities and developing new catalytic systems for cost-effective synthesis of structurally diverse and versatile deuterated building blocks including aldehyde, styrenes, and 2-position of tryptophans and deuterated methyl group, epoxides and cyclopropanes. The newly produced deuterated structures will enable synthetic, medicinal and biomedical researchers to explore new chemical and biological functions. Therefore, it is expected that the innovative strategies and approaches described in this program will have broad impact in organic synthesis, drug discovery, and biomedical research.

氘代化合物在有机合成和物理有机化学中占有独特的地位，同时氘代分子能大大改进药物的成药性，这带来了最近氘代药物的兴起。但是氘代试剂以及氘代中间体数量有限、价格昂贵，而合成氘代化合物的反应方法也非常有限，这些严重阻碍了上述重要领域的发展。本项目致力于利用价廉易得的氘源，通过研究反应机理，开发新的化学活性和催化体系，来研发新颖实用的氘代反应。这些氘代反应不仅操作简单，选择性高，氘代率高，更重要的是能提供实用价廉的手段来合成已在有机合成和药物化学中得到广泛应用的关键中间体的氘代物，例如醛基氘代、苯乙烯端位氘代、色氨酸2-位氘代和氘代甲基化、环氧化、环丙烷化等。此项目的成功实现，不仅为发现有用的氘代反应提供新思路，而且为有机化学和药物研发提供有力的研究工具，将大大丰富有机化学和药物化学的内容，因而具有重要的理论价值和应用价值。

本项目按照申请书的研究内容和研究计划实施，立足于使用便宜的氘源，结合对反应机理的深入分析，利用平衡反应的原理，在催化剂的作用下把底物的非活泼氢转化为活泼氢，从而实现和便宜氘源的氢-氘交换，得到高氘代率的氘代产物。我们以氮杂环卡宾为催化剂，重水为氘源，成功实现了芳香醛、烯醛、脂肪醛甚至半缩醛的氘代，复杂的含有醛基的天然产物比如甲酰基利福霉素和螺旋霉素也可以实现高氘代率，证明了方法极高的官能团兼容性。据我们所知，这应该是目前成本最低的制备氘代醛的方法，具有极大的工业应用价值。另外，我们还以实验室常用的氘代DMSO为氘源，和常用试剂三甲基碘化亚砜（TMSOI）进行复分解平衡反应，得到氘代三甲基碘化亚砜，是一种可以代替昂贵且有毒性的氘代碘甲烷的理想方法。