Department of Biomedical Engineering, Boston University, Boston, Massachusetts 02215, United States.
Department of Chemistry, Boston University, Boston, Massachusetts 02215, United States.
J Org Chem. 2020 Oct 2;85(19):12044-12057. doi: 10.1021/acs.joc.0c00510. Epub 2020 Sep 18.
The alkene-isocyanate cycloaddition method affords β-lactams from glycals with high regio- and stereoselectivity, but the factors that determine substrate reactivity are poorly understood. Thus, we synthesized a library of 17 electron-rich alkenes (glycals) with varied protecting groups to systematically elucidate the factors that influence their reactivity toward the electron-poor trichloroacetyl isocyanate. The experimentally determined reaction rates exponentially correlate with the computationally determined highest occupied molecular orbital-lowest unoccupied molecular orbital (HOMO-LUMO) gap and natural bond orbital (NBO) valence energies. The electron-withdrawing ability of the protecting groups, but not bulk, impacts the electron density of the glycal allyloxocarbenium system when oriented -axially (i.e., stereoelectronics). In this conformation, ring σ* orbitals oriented antiperiplanar to the allyloxocarbenium system decrease glycal reactivity via negative hyperconjugation as protecting group electron withdrawal increases. Transition-state calculations reveal that protecting group stereoelectronics direct the reaction to proceed via an asynchronous one-step mechanism through a zwitterionic species. The combined experimental and computational findings, along with experimental validation on an unknown glycal, provide insight on the reaction mechanism and the role of distant protecting groups in glycal reactivity. Together, these studies will aid in the synthesis of new β-lactam antibiotics, β-lactamase inhibitors, and bicyclic carbohydrate-β-lactam monomers prepared by the alkene-isocyanate method.
烯属异氰酸酯环加成方法提供了β-内酰胺从高区域和立体选择性甘醛，但决定底物反应性的因素知之甚少。因此，我们合成了一个 17 个富电子烯烃（甘醛）的库，带有不同的保护基团，以系统地阐明影响其对电子缺乏的三氯乙酰异氰酸酯反应性的因素。实验测定的反应速率与计算得出的最高占据分子轨道-最低未占据分子轨道（HOMO-LUMO）隙和自然键轨道（NBO）价能呈指数相关。保护基团的吸电子能力，但不是体积，当定向 - 轴向（即立体电子学）时，影响甘醛烯丙氧甲硅烷基正碳离子体系的电子密度。在这种构象中，与烯丙氧甲硅烷基正碳离子体系反式平行取向的环 σ*轨道通过负超共轭作用降低甘醛的反应性，因为保护基团的电子抽取增加。过渡态计算表明，保护基立体电子学通过两性离子物种引导反应通过异步一步机制进行。实验和计算相结合的研究结果，以及对未知甘醛的实验验证，为反应机制以及远程保护基团在甘醛反应性中的作用提供了深入的了解。总的来说，这些研究将有助于通过烯属异氰酸酯法合成新的β-内酰胺抗生素、β-内酰胺酶抑制剂和双环碳水化合物-β-内酰胺单体。
