Rapid Catalyst Identification for the Synthesis of the Pyrimidinone Core of HIV Integrase Inhibitors
Rapid Catalyst Identification for the Synthesis of the Pyrimidinone Core of HIV Integrase Inhibitors
复制标题
DOI：
10.1002/anie.201201720
复制
发表时间：
2012-01-01
影响因子：
16.6
通讯作者：
Dreher, Spencer D.
中科院分区：
文献类型：
--
作者：
Bellomo, Ana;Celebi-Olcum, Nihan;Dreher, Spencer D.
微型多重平行化学平台技术使现代合成化学家能够快速应用已知的潜在解决方案，将给定的合成转化应用于新的、高复杂性的合成问题。这种范式通常最成功地解决已经存在丰富的相关文献先例历史和对目标反应的彻底机械理解的问题。例如，可以筛选采用一系列已知有效膦配体、反应溶剂和无机碱的铃木反应平台，以发现最佳的底物特异性反应条件，并且成功的可能性很高。然而，出现了许多综合问题，而合理设计的平台是不可用的，并且由于缺乏先例或理解而无法设计。尽管如此，微型高通量实验（HTE）工具可用于最大限度地提高偶然提高反应性能的机会，最近的几份备受瞩目的报告强调了该领域的一些初步进展。[1-8]在此，我们描述了一个基础广泛的微型添加剂筛选平台，旨在最大限度地减少发现提高各种反应性能的新方法的复杂性和成本/时间瓶颈。通过使用这种方法，一名化学家能够在一天内设置并分析 475 种不同的反应条件，以确定用于制备高价值嘧啶酮杂环化合物的新催化剂，这些化合物是 HIV 整合酶抑制剂的核心。 [9, 10] 对已确定的条件结合量子力学计算进行后续研究
Microscale multiparallel chemistry platform technologies enable modern synthetic chemists to rapidly apply known potential solutions for a given synthetic transformation to new, high-complexity synthetic problems. This paradigm is typically most successful for solving problems where a rich history of relevant literature precedents and a thorough mechanistic understanding of the target reaction already exist. For example, a Suzuki reaction platform employing an array of known effective phosphine ligands, reaction solvents, and inorganic bases can be screened to uncover optimal substrate-specific reaction conditions with a high probability of success. However, many synthetic problems arise for which rationally designed platforms are not available, and cannot be designed owing to a lack of precedent or understanding. Nevertheless, microscale high-throughput experimentation (HTE) tools can be used to maximize the opportunity to serendipitously improve reaction performance, and several recent, high-profile reports have highlighted some initial progress in this area.[1–8]Herein, we describe a broad-based, microscale additivescreening platform that was designed to minimize complexity and cost/time bottlenecks in the discovery of new ways to improve the performance for a wide variety of reactions. By using this approach, a single chemist was able to set up and analyze 475 different reaction conditions in a single day to identify new catalysts for the preparation of high-value pyrimidinone heterocycles, which are at the core of HIV Integrase inhibitors.[9, 10] Follow-up investigations of identified conditions combined with quantum mechanical calculations