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

在化学部化学合成计划的支持下，科罗拉多州立大学的Andrew McNally和Merck（Rahway，NJ）的工艺研究和开发组的Matthew Maddess进行学术-工业合作，以研究从吡啶族的较简单芳族（不饱和）含氮化合物制备哌啶族的饱和氮杂环的方法。这种奋进是重要的，并且具有社会效益，因为哌啶是用作药剂的最广泛的一类化合物，并且大量吡啶可用作潜在的起始材料。整个过程涉及首先将所选择的平面吡啶解旋成无环分子（所谓的“锌基亚胺”），然后将其解旋成反应性带正电荷的中间体（吡啶鎓盐），随后将其转化成所需的感兴趣的三维哌啶。这种学术-工业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，预计将导致一系列化学反应，能够产生以前无法获得的哌啶，可能会影响新疗法的开发。资助项目的更广泛影响扩展到为研究生提供独特的培训机会，他们将获得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。因此，能够以有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。这个GOALI（与工业界学术联络的赠款机会）项目的目的是开发和探索一种新的取代哌啶路线，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。具体地，在吡啶作为其N-三氟甲磺酰基盐活化后，随后与合适的胺（例如，二苄胺）导致有效转化为无环锌基亚胺。这些物质将用（杂芳基）苯胺或脂族胺闭环，并且所得的N-取代的吡啶鎓盐通过氢化方法或经由与亲核试剂和亲电试剂的逐步反应转化成各种各样的否则难以获得的取代的哌啶。在整个调查过程中，默克公司的显着技术能力，包括高通量反应筛选，人工智能工具，以协助优化对映选择性氢化反应，以及计算专业知识，以探测感兴趣的过程的机械细节，将被部署，以促进实现项目目标。新的转化吡啶盐，包括那些允许进入三维支架和阻转异构哌啶衍生物，也是一个关注的焦点，如果成功，将提供一个全新的路线到这样的轴向手性systems.This奖项反映了NSF的法定使命，并已被认为是值得通过使用基金会的智力价值和更广泛的影响审查标准进行评估的支持。

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.