One-pot reactions accelerate the synthesis of active pharmaceutical ingredients.
One-pot reactions accelerate the synthesis of active pharmaceutical ingredients.
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DOI：
10.1002/anie.201100059
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发表时间：
2011-04
影响因子：
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通讯作者：
Carine Vaxelaire;Philipp Winter;M. Christmann
中科院分区：
文献类型：
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作者：
Carine Vaxelaire;Philipp Winter;M. Christmann
“Eintopf”一词(Lit.恩格尔One pot)在德语中通常用来描述在一锅中烹饪一顿饭的所有配料的简单化技术。它也在化学语言中被称为“一锅反应”或“一锅工艺”，特别是强调一系列的化学转化是在一个烧瓶中进行的。与厨房里的厨师类似，合成化学家努力通过避免多步骤合成中各个步骤之间的净化来节省时间和资源，从而将材料在容器之间的转移降至最低。在战略规划阶段，引入了几个概念，以便验证替代合成路线。因此，容易测量的参数的比较可以作为确定最经济方法的标尺。在原子经济性中，简单反应A+B！C+D的效率商由所需产物C的相对分子质量除以反应物的结合相对分子质量(A+B)得出。对于100%的原子效率，D必须是不存在的，也就是说，A和B中的所有原子最终都会生成C。这样的“理想”反应包括Diels-Alder反应和催化氢化反应，而Gabriel合成(用作合成当量氨的邻苯二甲酰亚胺)和Hantzsch酯氢化反应(使用二氢吡啶作为二氢当量)是原子效率较低的反应的例子。合成步骤的质量和数量(步骤经济性)以及氧化态的变化(氧化还原经济性)被认为是比较分析多步合成的决定性参数。克拉克等人。最近在上面的列表中添加了pot Economy，最终目标是“在一个锅中完成整个多步骤、多反应的合成”。现在，林研究小组已经实现了这一雄心勃勃的目标，他们一锅全合成了二肽基肽酶IV(DPP4)选择性抑制剂ABT-341(方案1)。在讨论综合之前，重要的是概述授权方法的发展。众所周知，多米诺骨牌反应和多组分反应是以经济的方式快速构建复杂分子支架的银弹，具有内置的步骤和锅的经济。在这个方向上，有机催化开辟了新的前景，允许在通常温和的反应条件下合并不同的活化模式。Enders等人的三重瀑布。是一个早期的例子，充分释放了有机催化多米诺反应的潜力。Enders等人得到的环己烯衍生物。(例如，1)与()-奥司他韦(达菲)和ABT-341(方案1)的碳环核非常相似。在经典的一锅反应中，所有试剂都按顺序加入反应瓶中，然后进行工作和提纯。Hayashi和他的同事们披露了一种名为“不间断反应序列”的策略。与经典的一锅反应或叠合合成不同的操作(提取、蒸馏)的数量最少相比，通过蒸馏从反应容器中去除挥发物是明确允许的。他们追求最大限度地减少烧瓶之间的物质转移的最初应用是开发一种有机催化合成()-奥司他韦。第一次发表的合成由三个一锅反应组成，后来被缩短为两个连续的一锅工艺(方案2)。在设计不间断的反应序列时，有利的是使用低沸点的溶剂和方案1的试剂，这些溶剂在高真空下很容易去除。来自Enders三级联的环己烯衍生物1，()-奥司他韦(达菲)和ABT-341。
The word “Eintopf” (lit. Engl. one pot) is used generically in the German language to describe a simplistic technique of cooking all the ingredients of a meal in a single pot. It has also found its way into the chemical language as “one-pot reaction” or “one-pot process”, in particular to emphasize that a sequence of chemical transformations is run in a single flask. Similar to the cook in the kitchen, synthetic chemists strive to save time and resources by avoiding purifications between individual steps within a multistep synthesis, thus minimizing the transfer of material between vessels. In the strategic planning stage, several concepts are introduced so that alternative synthetic routes can be validated. Thus, the comparison of easy-to-measure parameters serves as a yardstick to identify the most economic approach. In atom economy, the efficiency quotient of the simple reaction A + B!C + D is derived from the molecular weight of the desired product C divided by the combined molecular weight of the reactants (A+B). For 100% atom efficiency, D must be non-existent, that is, all the atoms in A and B end up in the product C. Such “ideal” reactions include the Diels–Alder reaction and catalytic hydrogenations, whereas the Gabriel synthesis (phthalimide used as the synthetic equivalent of ammonia) and Hantzsch ester hydrogenations (with dihydropyridines used as dihydrogen equivalents) are examples of reactions with lower atom efficiency. The quality and quantity of the synthetic steps (step economy) as well as the changes in the oxidation state (redox economy) have been suggested as decisive parameters for a comparative analysis of the multistep syntheses. Clarke et al. recently added pot economy to the above list, with the ultimate aim “to complete an entire multi-step, multi-reaction synthesis in a single pot”. Now, this ambitious goal has been achieved by the Hayashi research group in their one-pot total synthesis of the dipeptidylpeptidase IV (DPP4) selective inhibitor ABT-341 (Scheme 1). Before discussing the synthesis, it is important to outline the development of the enabling methodology. It is well understood that domino reactions and multicomponent reactions are the silver bullets for the rapid construction of complex molecular scaffolds in an economic fashion, with built-in step and pot economy. In this direction, organocatalysis has opened up new vistas by allowing the merger of different modes of activation under the typically mild reaction conditions. The triple cascade of Enders et al. was an early example which unleashed the full potential of organocatalytic domino reactions. The cyclohexene derivatives obtained by Enders et al. (for example, 1) bear a remarkable resemblance to the carbocyclic core of ( )-oseltamivir (Tamiflu) and ABT-341 (Scheme 1). In a classical one-pot reaction, all the reagents are added sequentially to the reaction flask, followed by work-up and purification. Hayashi and co-workers have disclosed a strategy called an “uninterrupted sequence of reactions”. In contrast to the classical one-pot reaction or telescoped synthesis, where the number of different operations (extractions, distillations) is minimized, the removal of volatiles from the reaction vessel by distillation is explicitly allowed. An initial application, in their pursuit to minimize the transfer of material between flasks, was the development of an organocatalytic synthesis of ( )-oseltamivir. The first published synthesis, which consisted of three one-pot reactions, was later shortened to two consecutive one-pot processes (Scheme 2). In the design of an uninterrupted sequence of reactions it is advantageous to use low-boiling solvents, which are easily removed under high vacuum, and reagents that are Scheme 1. A cyclohexene derivative 1 from Enders’ triple cascade, ( )-oseltamivir (Tamiflu), and ABT-341.