Strategies for innovation in multicomponent reaction design.
Strategies for innovation in multicomponent reaction design.
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DOI：
10.1021/ar800214s
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发表时间：
2009-03-17
影响因子：
18.3
通讯作者：
Ganem, Bruce
中科院分区：
文献类型：
--
作者：
Ganem, Bruce
多组分反应（MCR）通过在一个步骤中从三种或更多种反应物产生结构复杂性，使得以更高的效率和原子经济性合成目标化合物成为可能。这类反应的历史可以追溯到世纪中期，当时Strecker首先通过醛与氨和氰化氢的缩合反应制备了α-氨基腈。最近，学术化学家们重新对MCR产生了兴趣。在某种程度上，制药行业推动了这种复苏，因为越来越需要组装结构复杂的物质库，以评估药物发现和开发计划中的先导化合物。MCR在这一日益重要的目标中的应用仍然受到数量相对较少的此类反应的限制，这些反应可以广泛应用于制备生物学相关或天然产物样分子框架。我们有兴趣应用基于逻辑的方法，如我们的单一反应物替代（SRR）方法，作为一种改善已知MCR和设计新的多组分生物活性结构路线的方法。本帐户提供了几个例子，说明如何将SRR与已知的MCR一起用作这一领域综合创新的起点。作为我们工作假设的一部分，我们最初探索了对已知MCR进行工程改进的策略，或者是通过增加维度（即将n组分改变为（n+1）组分反应），或者是扩大有用输入结构的范围，或者两者兼而有之。通过将逆合成分析详尽地应用于同源MCR以识别和利用进入整体反应歧管的替代入口点，我们设计了几种这样的重新设计的MCR。偶然的发现也增加了我们的逻辑启发方法的有用发展的产量。在某些情况下，我们已经确定了不同化合物家族之间令人惊讶的联系，为化学库合成提供了有用的新切入点。在其他情况下，同样的重新设计逻辑使得将某些非基本的双组分反应转化为更高阶的MCR成为可能（有时以意想不到的方式）。虽然逻辑也可能激发寻找新的MCR，但设计过程需要额外的化学创造力，这不能简化为一个简单的公式。我们的研究的长期目标是扩大有用的剧目，这些反应，这是重要的复杂性生成工具，在组合和多样性导向的合成。
By generating structural complexity in a single step from three or more reactants, multicomponent reactions (MCRs) make it possible to synthesize target compounds with greater efficiency and atom economy. The history of such reactions can be traced to the mid-nineteenth century when Strecker first produced α-aminonitriles from the condensation of aldehydes with ammonia and hydrogen cyanide. Recently, academic chemists have renewed their interest in MCRs. In part, the pharmaceutical industry has fueled this resurgence because of the growing need to assemble libraries of structurally complex substances for evaluation as lead compounds in drug discovery and development programs. The application of MCRs to that increasingly important objective remains limited by the relatively small number of such reactions that can be broadly applied to prepare biologically relevant or natural-product-like molecular frameworks. We were interested in applying logic-based approaches, such as our single reactant replacement (SRR) approach, as a way both to improve known MCRs and design new multiple-component routes to bioactive structures. This Account provides several examples that illustrate the use of SRR with known MCRs as starting points for synthetic innovation in this area. As part of our working hypothesis, we initially explored strategies for engineering improvements into known MCRs, either by increasing the dimensionality—i.e. changing an n-component to an (n+1)-component reaction—or broadening the scope of useful input structures, or both. By exhaustively applying retrosynthetic analysis to the cognate MCR to identify and exploit alternative entry points into the overall reaction manifold, we have devised several such re-engineered MCRs. Serendipitous findings have also augmented the yield of useful developments from our logic-inspired approach. In some cases, we have identified surprising links between different compound families that provide useful new entry points for chemical library synthesis. In other cases, the same re-engineering logic made it possible (sometimes in unexpected ways) to transform certain non-elementary two-component reactions into higher order MCRs. While logic may also inspire the search for new MCRs, the design process requires added chemical creativity, which cannot be reduced to a simple formula. The long-term goal of our research is to expand the useful repertoire of such reactions, which are important as complexity-generating tools in both combinatorial and diversity-oriented synthesis.
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影响因子：
5.2
作者：
Fan, Lijun;Lobkovsky, Emil;Ganem, Bruce
通讯作者：
Ganem, Bruce
影响因子：
56.9
作者：
Moody, DB;Young, DC;Brenner, MB
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Brenner, MB
影响因子：
1.6
作者：
FONTAIN, E;BAUER, J;UGI, I
通讯作者：
UGI, I
影响因子：
15
作者：
Gilman, H;Van Ess, PR
通讯作者：
Van Ess, PR
影响因子：
2.1
作者：
Huang, WS;Zhang, YX;Yuan, CY
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Yuan, CY