A Dual Catalytic Strategy for Enantioselective Pyridinium Photochemistry

项目摘要/摘要 光化学过程对映体选择性的控制仍然是一个悬而未决的问题。 尽管光驱动方法的内在承诺是提供广泛的 与医学相关的支架。事实上，光子的能量吸收能够使大量的 分子复杂性的增加(与现代药物相称) 产生任何额外的废物。关键的挑战是，控制大量的能量投入 并将其用于选择性地形成单一对映体，已经遇到了有限的 人工合成社区的成功。在这个竞技场上的胜利将代表着重要的一步 期待我们合成具有生物重要性的化合物的集体能力，使 将开发下一代救生药物和诊断探头，同时 为现有制造流程削减成本和减少浪费。这份提案概述了一个 绕过这一领域的中心挑战的新战略，通过结合使用 氢键供体和伯胺有机催化剂选择性地激活底物 光化学转化。这种双重催化反应流形已经令人难以置信地 在过去成功地生成、稳定和对映面部控制无数 阳离子中间体，并延伸到光化学反应空间将进一步 该战略的综合潜力极大。研究计划勾勒出了一条具体的攻击线 用于确定合适的催化剂体系以实现对映体选择性吡啶 光化学，获得密集官能化的氨基环戊酮基序，这些基序依次 准备对各种各样的生物活性分子进行合成精加工。关键的战略 支撑是在吸收光谱中诱导红移的能力 底物通过共价和非共价与催化剂对络合 互动。近年来LED技术的进步使这一特定的科学进步 在实际掌握中，这里概述的催化战略的实施已蓄势待发 来兑现对映体选择性光化学的承诺。此外，对映体诱导将在 转而允许收集机械信息。通过提取精确的结构活性 关系，可以得到一个背后的速率限制光激发步骤一瞥。总的来说， 拟议的研究将使人们能够方便地获得与药物相关的复杂化合物 在方法上新颖和高效，同时大幅增加科学知识。

Project Summary/Abstract Control over the enantioselectivity of photochemical processes has remained an open problem despite the inherent promise of light-driven methodologies to deliver a broad range of medicinally-relevant scaffolds. Indeed, absorption of a photon energetically enables substantial increases in molecular complexity (commensurate with modern pharmaceuticals) without the generation of any additional waste. The key challenge, to reign in the substantial energetic input and direct it towards selective formation of a single enantiomer, has been met with limited success by the synthetic community. Triumph in this arena would represent a major step forward for our collective ability to synthesize biologically important compounds, enabling the next generation of life-saving pharmaceuticals and diagnostic probes to be developed, while cutting costs and reducing waste for existing manufacturing processes. This proposal outlines a novel strategy to circumvent the central challenges in this sphere by employing a combination of hydrogen-bond donor and primary amine organocatalysts to selectively activate substrates for photochemical transformation. This dual catalytic reactivity manifold has been fabulously successful in the past for the generation, stabilization, and enantiofacial control of myriad cationic intermediates, and extension into photochemical reaction space will further the synthetic potential of the strategy immensely. The research plan outlines a specific line of attack for identifying an appropriate catalyst system to enable enantioselective pyridinium photochemistry, accessing densely functionalized aminocyclopentenone motifs which are in turn poised for synthetic elaboration to a wide variety of bioactive molecules. The key strategic underpinning is the ability to induce a bathochromic shift in the absorption spectrum of the substrate upon complexation with the catalyst pair via both covalent and non-covalent interactions. Advances in LED technology in recent years put this specific scientific advance within tangible grasp, and the implementation of the catalytic strategy outlined herein is poised to deliver on the promise of enantioselective photochemistry. Moreover, enantioinduction will in turn allow for mechanistic information to be gleaned. By extracting precise structure-activity relationships, a glimpse behind the rate-limiting photoexcitation step can be obtained. Overall, the proposed research will enable facile access to complex medicinally relevant compounds in a methodologically novel and efficient fashion while substantially increasing scientific knowledge.