New Synthetic Methodologies to Access N-Heterocycles

拟议的研究属于合成有机化学的范畴，更具体地说是开发新的反应和合成方法以应用于天然产物合成。我们还建议合成一种新的热响应和光响应支架来制造分子开关。 拟议的研究分为四个部分，第一部分涉及开发一种新的铬氨基卡宾（CAMC）的（4 1）环加成反应，旨在制造五元N-杂环。后者是天然生物碱中普遍存在的分子片段。第二部分是对获得诺贝尔奖的闭环复分解（RCM）反应的一个新的转变：我们已经发现并希望利用新发现的 CAMC 反应来制造二烯胺。这些片段对于制造更复杂的 N-杂环结构非常有用。第三部分涉及 N-活化内酰胺的光化学或热环收缩。它还旨在制造 N-杂环和最终的天然生物碱。我们建议研究、开发和扩展每种方法。将探讨反应的机理，以更好地理解它们，从而更好地控制反应性和选择性问题。我们还建议在天然生物碱的全合成中使用每种方法，以强调其有用性。 拟议研究的最后一部分是对我们实验室新研究领域的冒险。我们相信我们已经发现了一种可用于制造分子开关的新结构支架。该支架很容易制备，并且之前为完全不同的目的制备的一种这样的分子支架显示了分子开关的主要属性：它在两种稳定状态之间发生热异构化和光化学异构化。然而，在我们将其称为新的热响应和光响应核心结构之前，还需要对其进行研究和开发。该合成是模块化的，可以轻松进行结构改变。在这个阶段，我们提出了概念验证，并将为下一个发现拨款申请留下更复杂的研究和设备。

The proposed research falls in the category of synthetic organic chemistry, more specifically developing new reactions and methods of synthesis for application in natural products synthesis. We also propose to synthesize a new thermo- and photoresponsive scaffold to make molecular switches. The proposed research is divided in four parts, the first is concerned with developing a new (4+1)-cycloaddition reaction of chromium aminocarbenes (CAMCs) destined to make 5-membered N-heterocycles. The latter are molecular fragments ubiquitously found in natural alkaloids. The second part is a new twist to the Nobel-Prize winning ring-closing metathesis (RCM) reaction: we have found and would like to exploit a newly discovered reaction of CAMCs to make dienamines. Such fragments can be very useful to make more complex N-heterocyclic structures. The third part is concerned with the photochemical or thermal ring-contraction of N-activated lactams. It is also aimed at making N-heterocycles and ultimately natural alkaloids. We propose to study, develop, and expand each methodology. Mechanistic aspects of the reactions will be probed to better understand them and thus be better able to control reactivity and selectivity issues. We also propose to use each method in total synthesis of natural alkaloids as a way to underscore their usefulness. The last part of the proposed research is a venture into a new area of research in our laboratory. We believe we have discovered a new structural scaffold that could be used to make molecular switches. The scaffold is easily prepared and one such molecular scaffold, previously prepared for a totally different purpose, displayed the main attributes of a molecular switch: it isomerizes thermally and photochemically between two stable states. However, it needs to be studied and developed before we can call it a new thermo- and photoresponsive core structure. The synthesis is modular allowing for easy structural changes. We propose, at this stage, a proof of concept and will leave more complex studies and devices for a next discovery grant application.