De Novo Assembly of Highly Substituted Morpholines and Piperazines

The
morpholine and piperazine with their remarkable physical and
biochemical properties are popular heterocycles in organic and medicinal
chemistry used in rational property design. However, in the majority
of cases these rings are added to an existing molecule in a building
block approach thus limiting their substitution pattern and diversity.
Here we introduce a versatile de novo synthesis of the morpholine
and piperazine rings using multicomponent reaction chemistry. The
large scale amenable building blocks can be further substituted at
up to four positions, making this a very versatile scaffold synthesis
strategy. Our methods thus fulfill the increasing demand for novel
building block design and nontraditional scaffolds which previously
were not accessible

吗啉（morpholine）与哌嗪（piperazine）凭借其卓越的物理及生化特性，是有机化学与药物化学领域中用于理性性质设计的热门杂环骨架。然而在绝大多数应用场景中，这类环系均通过砌块策略接入已有的分子结构中，这极大限制了其取代模式与结构多样性。本研究提出一种依托多组分反应（multicomponent reaction）化学的吗啉与哌嗪环系通用从头合成（de novo synthesis）策略。该方法所采用的可规模化砌块最多可在四个位点进行后续修饰取代，使其成为通用性极强的骨架合成方案。因此，本研究的合成策略可满足当前对新型砌块设计及此前难以获取的非传统骨架的日益增长的需求。