GOALI: A General Strategy for Piperidine Synthesis Using Zincke Imine Intermediates

在化学系化学合成计划的支持下，科罗拉多州立大学的Andrew McNally和默克(新泽西州拉赫韦)工艺研究和开发小组的Matthew Maddess正在进行学术和工业合作，研究从吡啶类更简单的芳香(不饱和)含氮化合物中制备哌啶类饱和氮杂环的工艺。这一努力很重要，而且具有社会效益，因为哌啶类化合物是用作药剂的最广泛的一类化合物，而且大量的吡啶类化合物可以作为潜在的起始原料。整个过程包括首先将选择的平面吡啶分解成无环分子(所谓的Zincke imine)，然后再环化成带正电荷的反应性中间体(吡啶盐)，然后将其转化为所需的三维哌啶。这种学术和产业的合作涉及由默克独特的技术能力加速的基本反应开发，包括高通量实验(HTE)和人工智能(AI)工具，预计它将导致一系列化学反应，这些化学反应能够产生以前无法获得的哌啶类化合物，可能会影响新疗法的开发。该资助项目的更广泛影响延伸到为研究生提供独特的培训机会，他们将在项目期间接受学术和工业环境的指导，并在项目期间获得默克技术的直接经验。哌啶是FDA批准的药物中最常见的含氮杂环；因此，能够高效和选择性地获得哌啶衍生物的合成方法可能是药物开发的有用工具。这个项目的目的是开发和探索一条新的路线，利用最近发现的Zincke型吡啶开环化学，提供比以前已知的变体更大的范围来取代哌啶类化合物。具体地说，当吡啶作为它们的N-三氟盐被激活时，随后与合适的胺(例如二苯甲胺)的结合导致有效地转化为无环锌亚胺。这些物种将与(杂芳基)苯胺或脂肪胺环合，生成的N-取代吡啶盐通过氢化过程或通过与亲核试剂和亲电剂的分段反应转化为各种原本难以获得的取代哌啶类化合物。在整个调查过程中，默克公司显著的技术能力，包括高通量反应筛选、协助优化对映选择性加氢反应的人工智能工具，以及探索感兴趣过程的机理细节的计算专业知识，将被用于促进项目目标的实现。吡啶盐的新转化，包括那些允许获得三维支架和阿托品异构体哌啶衍生物的转化，也是人们关注的焦点，如果成功，将提供一条进入这种轴向手性体系的全新途径。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

With the support of the Chemical Synthesis Program in the Division of Chemistry, Andrew McNally of Colorado State University and Matthew Maddess of the Process Research and Development Group at Merck (Rahway, NJ) are engaged in an academic-industrial collaboration to study a process to prepare saturated nitrogen heterocyclic of the piperidine family from simpler aromatic (unsaturated) nitrogen-containing compounds of the pyridine family. This endeavor is important, and has societal benefits, because piperidines are among the most widespread class of compounds used as pharmaceutical agents and large collections of pyridines are available as potential starting materials. The overall process involves the chosen planar pyridine being first unraveled into an acyclic molecule (a so-called 'Zincke imine') which is then recyclized into a reactive positively charged intermediate (a pyridinium salt) that is subsequently converted into the desired three-dimensional piperidine of interest. This academic-industrial collaboration involves fundamental reaction development accelerated by Merck's unique technological capabilities, including high-throughput experimentation (HTE) and artificial intelligence (AI) tools, and it is anticipated to lead to a suite of chemical reactions capable of generating previously inaccessible piperidines that may impact the development of new therapeutics. The broader impacts of the funded project extend to providing unique training opportunities for graduate students who will receive mentorship from both academic and industrial settings and gain direct experience of Merck's technologies during the project period.Piperidine is the most common nitrogenous heterocycle found in FDA approved pharmaceuticals; accordingly, synthetic methods that can access piperidine derivatives in an efficient and selective manner are potentially useful tools for drug development. The aim of this GOALI (Grant Opportunities for Academic Liaison with Industry) project is to develop and explore a new route to substituted piperidines that exploits a recently discovered Zincke-type pyridine ring-opening chemistry that offers significantly greater scope than previously known variants. Specifically, upon activation of pyridines as their N-triflyl salts, subsequent engagement with a suitable amine (e.g., dibenzylamine) results in efficient conversion to acyclic Zincke imines. These species will be ring-closed with (heteroaryl)anilines or aliphatic amines and the resulting N-substituted pyridinium salts converted into a diverse range of otherwise difficult to access substituted piperidines by hydrogenation processes or via stagewise reactions with nucleophiles and electrophiles. Throughout the investigation, Merck's notable technological capabilities, including high-throughput reaction screening, AI tools to assist with the optimization of enantioselective hydrogenation reactions, and computational expertise to probe the mechanistic details of the processes of interest, will be deployed to facilitate achievement of the project goals. New transformations of pyridinium salts, including those allowing access to three-dimensional scaffolds and atropisomeric piperidine derivatives, are also a focus of attention and, if successful, would provide an entirely new route into such axially chiral systems.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.