美国哈佛大学Jacobsen, Eric N.团队报道了几何预组织对S_N2途径的催化作用。相关研究成果于2024年7月18日发表在国际顶尖学术期刊《自然》。

双分子亲核取代（S_N2）机制在有机化学领域的历史发展和教学中占据着中心地位。尽管S_N2途径在合成中很重要，但即使在生物催化中，对离子S_N2途径的催化控制也很少见，这反映了催化剂和反应离子对之间的任何静电相互作用都必然会稳定其电荷，进而降低极性反应性。亲核卤化酶通过使用几何预组织来补偿亲核性的衰减，将卤化物亲核试剂精确地解溶并定位在S_N2轨迹上，从而在这种权衡中确定正确途径。

该文中，研究人员通过概括酶所采用的几何预组织原理，证明了小分子（646 Da）氢键供体（HBD）催化剂加速了对映选择性Michaelis-Arbuzov反应的S_N2步骤。机理和计算研究表明，HBD降低了氯化物亲核试剂的反应性，但通过将鏻阳离子和氯化物阴离子重新组织成一种几何形状，加速了决定脱烷基速率的步骤，该几何形状被预处理以进入S_N2过渡态。这种新的对映选择性Arbuzov反应提供了对一系列H-次膦酸酯的高度对映选择性制备，这些H-次膦酸盐又是多功能的P-对映体构建块，可以进行无数衍生化。

该项工作首次证明了鏻脱烷基步骤的催化对映体控制，为合成P-对映体化合物建立了一个新的平台。

附：英文原文

Title: Catalysis of an SN2 pathway by geometric preorganization

Author: Lovinger, Gabriel J., Sak, Marcus H., Jacobsen, Eric N.

Issue&Volume: 2024-07-18

Abstract: Bimolecular nucleophilic substitution (SN2) mechanisms occupy a central place in the historical development and teaching of the field of organic chemistry1. Despite the importance of SN2 pathways in synthesis, catalytic control of ionic SN2 pathways is rare and notably uncommon even in biocatalysis2,3, reflecting the fact that any electrostatic interaction between a catalyst and the reacting ion pair necessarily stabilizes its charge and, by extension, reduces polar reactivity. Nucleophilic halogenase enzymes navigate this tradeoff by desolvating and positioning the halide nucleophile precisely on the SN2 trajectory, using geometric preorganization to compensate for the attenuation of nucleophilicity4. Here we show that a small-molecule (646 Da) hydrogen-bond-donor (HBD) catalyst accelerates the SN2 step of an enantioselective Michaelis–Arbuzov reaction by recapitulating the geometric preorganization principle employed by enzymes. Mechanistic and computational investigations reveal that the HBD diminishes the reactivity of the chloride nucleophile yet accelerates the rate-determining dealkylation step by reorganizing both the phosphonium cation and the chloride anion into a geometry that is primed to enter the SN2 transition state. This new enantioselective Arbuzov reaction affords highly enantioselective access to an array of H-phosphinates, which are in turn versatile P-stereogenic building blocks amenable to myriad derivatizations. This work constitutes, to our knowledge, the first demonstration of catalytic enantiocontrol of the phosphonium dealkylation step, establishing a new platform for the synthesis of P-stereogenic compounds.

DOI: 10.1038/s41586-024-07811-4

Source: https://www.nature.com/articles/s41586-024-07811-4