Guo Renyu, Brown M Kevin
Department of Chemistry, Indiana University, 800 E. Kirkwood Ave, Bloomington, Indiana 47405, United States.
Acc Chem Res. 2023 Aug 15;56(16):2253-2264. doi: 10.1021/acs.accounts.3c00334. Epub 2023 Aug 4.
ConspectusCycloaddition reactions are an effective method to quickly build molecular complexity. As predicted by the Woodward-Hoffmann rules, concerted cycloadditions with alkenes allow for the constructions of all possible stereoisomers of product by use of either the or geometry. While this feature of cycloadditions is widely used in, for example, [4 + 2] cycloadditions, translation to [2 + 2] cycloadditions is challenging because of the often stepwise and therefore stereoconvergent nature of these processes. Over the past decade, our lab has explored Lewis acid-promoted [2 + 2] cycloadditions of electron-deficient allenes or ketenes with alkenes. The concerted, asynchronous cycloadditions allow for the synthesis of various cyclobutanes with control of stereochemistry.Our lab developed the first examples of Lewis acid-promoted ketene-alkene [2 + 2] cycloadditions. Compared with traditional thermal conditions, Lewis acid-promoted conditions have several advantages, such as increased reactivity, increased yield, improved diastereoselectivity, and, for certain cases, inverse diastereoselectivity. Detailed mechanistic studies revealed that the diastereoselectivity was controlled by the size of the substituent and the barrier of a deconjugation event. However, these reactions required the use of stoichiometric amounts of EtAlCl because of the product inhibition, which led us to investigate catalytic enantioselective [2 + 2] cycloadditions of allenoates with alkenes. Through the use of chiral oxazaborolidines, a broad range of cyclobutanes can be prepared with the control of enantioselectivity. Mechanistic experiments, including D-labled alkenes and Hammett analysis, illuminate likely transition state models for the cycloadditions. Additional studies led to the development of Lewis acid-catalyzed intramolecular stereoselective [2 + 2] cycloadditions of chiral allenic ketones/esters with alkenes.The methods we developed have been instrumental in the synthesis of several families of natural products. Specifically, one key lactone motif in (±)-gracilioether F was constructed by a ketene-alkene [2 + 2] cycloaddition and subsequent regioselective Baeyer-Villiger oxidation sequence. Enantioselective allenoate-alkene [2 + 2] cycloadditions allowed for the synthesis of (-)-hebelophyllene E. Another attempt of applying this method in the synthesis of (+)-[5]-ladderanoic acid failed to deliver the desired cyclobutane because of an unexpected rearrangement. The key cyclobutane was later assembled by a stepwise carboboration/Zweifel olefination process. Finally, the stereoselective [2 + 2] cycloadditions of allenic ketones and alkenes was applied in the syntheses of (-)-[3]-ladderanol, (+)-hippolide J, and (-)-cajanusine.
综述环加成反应是一种快速构建分子复杂性的有效方法。正如伍德沃德 - 霍夫曼规则所预测的那样，与烯烃的协同环加成反应能够通过使用顺式或反式几何构型来构建产物的所有可能立体异构体。虽然环加成反应的这一特性在例如[4 + 2]环加成反应中被广泛应用，但由于[2 + 2]环加成反应通常是分步进行的，因此具有立体收敛性，将其应用于[2 + 2]环加成反应具有挑战性。在过去十年中，我们实验室探索了缺电子丙二烯或烯酮与烯烃的路易斯酸促进的[2 + 2]环加成反应。这种协同的、异步的环加成反应能够在控制立体化学的条件下合成各种环丁烷。我们实验室开发了路易斯酸促进的烯酮 - 烯烃[2 + 2]环加成反应的首个实例。与传统热反应条件相比，路易斯酸促进的反应条件具有多个优点，例如反应活性提高、产率增加、非对映选择性提高，并且在某些情况下具有相反的非对映选择性。详细的机理研究表明，非对映选择性受取代基大小和解共轭事件的势垒控制。然而，由于产物抑制作用，这些反应需要使用化学计量的EtAlCl，这促使我们研究丙二酸酯与烯烃的催化对映选择性[2 + 2]环加成反应。通过使用手性恶唑硼烷，可以在控制对映选择性的条件下制备多种环丁烷。包括D标记烯烃和哈米特分析在内的机理实验阐明了环加成反应可能的过渡态模型。进一步的研究导致了路易斯酸催化的手性丙二烯酮/酯与烯烃的分子内立体选择性[2 + 2]环加成反应的发展。我们开发的方法在几个天然产物家族的合成中发挥了重要作用。具体而言，(±)-gracilioether F中的一个关键内酯基序是通过烯酮 - 烯烃[2 + 2]环加成反应以及随后的区域选择性拜耳 - 维利格氧化序列构建的。对映选择性丙二酸酯 - 烯烃[2 + 2]环加成反应使得(-)-hebelophyllene E得以合成。将该方法应用于(+)-[5]-ladderanoic acid的合成时，由于意外的重排反应，未能得到所需的环丁烷。关键的环丁烷后来通过逐步碳硼化/茨韦费尔烯化过程组装而成。最后，丙二烯酮和烯烃的立体选择性[2 + 2]环加成反应被应用于(-)-[3]-ladderanol、(+)-hippolide J和(-)-cajanusine的合成。
