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

在化学系化学合成项目的支持下，科罗拉多州立大学的Andrew McNally和默克公司工艺研究与开发组的Matthew Maddess正在进行一项学术-工业合作，研究一种从吡啶家族的简单芳香（不饱和）含氮化合物中制备饱和氮杂环的工艺。这一努力是重要的，并且具有社会效益，因为哌啶是用作药物制剂的最广泛的化合物之一，并且大量的吡啶可以作为潜在的起始材料。整个过程包括选定的平面吡啶首先被分解成一个无环分子（所谓的“Zincke亚胺”），然后再循环成一个带正电的活性中间体（吡啶盐），随后转化为所需的三维哌啶。这项学术-工业合作涉及默克独特的技术能力加速的基础反应开发，包括高通量实验（HTE）和人工智能（AI）工具，预计将导致一系列化学反应，能够产生以前无法获得的哌啶，这可能会影响新疗法的开发。该资助项目的广泛影响还包括为研究生提供独特的培训机会，这些研究生将在项目期间接受学术和工业环境的指导，并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化合物；因此，能够以高效和选择性的方式获得哌啶衍生物的合成方法是药物开发的潜在有用工具。该项目的目标是开发和探索替代哌啶的新途径，利用最近发现的zincke型吡啶开环化学，比以前已知的变体提供更大的范围。具体来说，在吡啶作为它们的n -三氟酰基盐活化后，随后与合适的胺（例如，二苄胺）结合导致有效转化为无环锌基亚胺。这些物种将与（杂芳基）苯胺或脂肪胺环封闭，并通过氢化过程或与亲核试剂和亲电试剂的分阶段反应，将产生的n -取代吡啶盐转化为各种难以获得的取代哌啶。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氢化反应的人工智能工具，以及探索感兴趣过程的机械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罗异构哌啶衍生物的转化，也是人们关注的焦点，如果成功，将为这种轴向手性体系提供一条全新的途径。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值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.