活性氮杂环骨架的高效构建及药物合成研究

Chiral nitrogen-containing heterocyclic skeleton is widely present in natural products and pharmaceutical molecules, thus it is of theoretical significance and application value to efficiently and rapidly synthesize novel chiral nitrogen-containing heterocycles for the development of new drugs. However, there is currently no general method and process available to stereoselectively construct complex nitrogen-containing heterocycles. As an attractive protocol for the rapid synthesis of multi-substituted heterocyclic rings, cascade hydrogen transfer/cyclization has the features of high bonding efficiency and high atomic economy. However, due to the limited types of hydrogen acceptors and substrate skeletons, it is severely restricted for its further application in synthetic chemistry. In view of the above important scientific issues and on the basis of our recent breakthrough of carbocation-initiated cascade hydride transfer/cyclization, we design a series of asymmetric multi-step cascade reactions to construct complex nitrogen-containing heterocycles stereoselectively, which will be further applied to the stereoselective synthesis of drug molecules such as antidepressant drugs mianserin and mirtazapine. This project provides an innovative and general synthetic strategy for the stereoselective construction of complex nitrogen-containing heterocycles, providing new molecular families and compound libraries for medicinal chemistry. The innovative strategy is highly significant for further development of novel chiral nitrogen-containing heterocyclic drugs and functional materials, as well as promotion of the development of chiral heterocyclic chemistry and pharmaceutical industry.

多元手性氮杂环骨架广泛存在于天然产物和药物分子中，高效快速地合成新型手性氮杂环化合物对新药开发具有重要理论意义和应用价值。然而目前没有一个通用的方法和工艺能够立体选择性地合成多元复杂氮杂环。串联氢迁移/环化反应作为一类快速构建多取代杂环体系的方法，具有成键效率高、原子经济性高的特点。然而由于该反应氢受体和骨架类型非常有限，限制了其进一步应用。针对上述重要科学问题，本课题组在实现了碳正离子引发串联氢迁移/环化反应的突破性进展基础上，设计了一系列不对称多步串联反应立体选择性地构建复杂多元氮杂环体系，并将该方法应用于抗抑郁药米安色林和米氮平等药物分子的合成。本项目为立体选择性地构建复杂多元氮杂环体系提供了新的通用策略和合成工具，为药物化学提供了新的分子家族和化合物库，对进一步开发新型手性氮杂环类新药和功能分子具有重要意义，同时也将推动手性杂化化学以及药物工业的发展。

多元氮杂环骨架广泛存在于天然产物和药物分子中，高效快速地合成新型氮杂环化合物对新药开发具有重要理论意义和应用价值。串联氢迁移/环化反应作为一类快速构建多取代杂环体系的方法，具有反应高效、原子经济性高等特点。然而由于该反应氢受体和骨架类型非常有限，限制了其进一步应用。针对上述重要科学问题，本课题组在以前取的串联氢迁移/环化反应的研究基础上，设计了一系列多步串联反应来立体选择性地构建复杂多元氮杂环化合物，如四氢喹啉，1，2-二氢喹啉，四氢喹唑啉，噻二嗪，2，3-二氢喹啉-4-酮，3，4-二氢喹啉-2-酮，或者通过串联氢迁移/环化反应使苯酚去芳香化等。本项目为立体选择性地构建复杂多元氮杂环体系提供了新的通用策略和合成工具，为药物化学提供了新的分子家族和化合物库，对进一步开发新型氮杂环类新药和功能分子具有重要意义，同时也将推动手性杂化化学以及药物工业的发展。