Thr起始的巯基化天然氨基酸合成

NCL (natural chemical ligation) reaction is one of the most important strategies for protein synthesis, and the ligation-desulfurization strategy can expand the reaction sites to more thiol-containing amino acids. Therefore, many research groups focus on the synthesis of thiol-containing amino acids. Nonetheless, effective synthetic methods remain lacks for the synthesis of 11 amino acids, mainly due to the expensive starting materials and complicated procedures. This project will use cheap and readily available threonine as raw material, and utilize the C-H functionalization reactions to synthesis 10 amino acids: the synthesis of Leu* by double-methylation reaction; the synthesis of Lys* through oxidative Heck-hydrogenation reaction; the synthesis of Arg* through cyanide-hydrogenation reaction; synthesis of Glu*, Gln* through cyanation or carbonyl cyanide-based-hydrolysis reaction; synthesis of Pro* through the carbonyl-deoxygenation reaction; synthesis of Thr* by hydroxylation, and Met** and Asp*/Asn* can be obtained via the sulfurization and oxidation, respectively. Finally, all the product of this project will be used for the actual protein synthesis. The project meant to use chemical strategies to meet biological necessities, with high necessity and feasibility.

N端半胱氨酸的NCL（自然化学连接）反应是目前蛋白质合成的重要方法，而连接-脱硫策略可以将NCL的反应位点扩大到氨基酸的β或γ巯基衍生物。因此，国际化学生物学领域非常重视巯基化氨基酸的合成，但仍有11种巯基化氨基酸缺乏有效的合成手段，主要原因在于原料昂贵和步骤繁琐。本项目针对化学生物学的分子需求，以申请人的过渡金属催化研究为背景，提出采用廉价易得的苏氨酸为原料，通过碳氢键功能化反应合成上述11种巯基化氨基酸中的10种：通过双甲基化反应合成Leu*；通过氧化Heck-氢化反应合成Lys*；通过氰基化-氢化反应合成Arg*；通过氰基化或羰基化-水解反应合成Glu*、Gln*；通过羰基化-脱氧反应合成Pro*；通过羟基化反应合成Thr*，进而通过硫代获得Met**以及通过氧化获得Asp*和Asn*。最后，本项目的产物将用于实际蛋白质合成。该项目是化学手段和生物需求的巧妙结合，必要性强，可行性高。

非天然巯基化氨基酸是用于自然化学连接的重要分子。本项目拟通过C-H键功能化反应，结合多种化学转化方法，实现这些重要片段的合成。我们成功发展了多种新颖C-H键功能化反应，实现了多种非天然氨基酸的合成，所发展的新方法可以有效的兼容巯基等敏感官能团，完成了相关的研究目标，并且在含有亲核片段的手性氨基酸片段合成及其后续无添加偶联方面做出了富有新意的成果，为今后的研究奠定了基础。相关工作在J. Am. Chem. Soc.、Nat. Commun.、Angew. Chem. Int. Ed.等期刊上发表论文多篇，均标注、致谢了本项目资助。