Department of Molecular Quantum Chemistry, Nesvard Institute of Molecular Sciences, Accra, Ghana.
J Mol Model. 2022 Feb 27;28(3):70. doi: 10.1007/s00894-022-05063-5.
The potential of azasteroids as novel drug candidates has prompted numerous studies towards the syntheses of heterosteroidal skeletons. The preparation of novel azasteroidal compounds and the modification of substituents on their steroidal skeletons might provide excellent congeners with useful biological properties. We present herein computational investigations on the Diels-Alder/(3 + 2) tandem sequential cycloaddition reaction of 21 distinctive derivatives of furylcinnamate with phenyl azides. First, we performed the computational study on the originally reported reaction of ester-substituted furylcinnamate derivatives 1a2 and 1b2 with phenyl azide (3) under the experimental conditions. We extended the scope of these tandem cycloaddition reactions by studying several variants of 1a1, 1b1, and 1c1 and their reactivity towards 3. In all instances of tandem reactions considered in this study, the Diels-Alder cycloaddition step is the rate-determining step (rds). Electron-withdrawing substituted 1a1, 1b1, and 1c1 decrease the barrier of the rds while electron-donating substituents substantially increase the barrier of the rds. The parent reaction (1a1) selectively proceeds via transition states T5Exa to give tandem adduct 5Exa, the experimentally observed tandem product. In the case of 1b1 and 1c1, the reaction is competitively favored via T4Ex and T5Ex to give corresponding 4Ex and 5Ex (the experimentally observed tandem adducts). The various substituents studied demonstrate that the tandem adduct obtained is highly dependent on the substituents on the Diels-Alder intermediate. Whereas electron-withdrawing groups substantially decrease the barrier of the rds, the direct opposite is true for electron-donating groups. A plot of electrophilicity indices against activation energies obtains a favorable correlation. We also investigated the unreported reactivity of a furylcinnamate (2-1a2) with several nitrile imines. Such a reaction is found to proceed through a similar mechanism as those seen for the phenyl azide. It is observed that di-substituted nitrile imines react with furylcinnamate (2-1a2) at favorable energetics than phenyl azide. Calculated GEDT values unveil that the non-polar solvent (toluene) will stabilize the non-polar reaction through van der waals interactions.
氮杂环戊二烯作为新型药物候选物的潜力促使人们进行了大量研究，以合成杂甾族骨架。新型氮杂环戊二烯化合物的制备和甾族骨架上取代基的修饰可能会提供具有有用生物特性的优秀同系物。本文提出了对 21 种不同取代的呋喃肉桂酸酯与苯基叠氮化物的 Diels-Alder/(3+2)串联顺序环加成反应的计算研究。首先，我们在实验条件下对酯取代的呋喃肉桂酸酯衍生物 1a2 和 1b2 与苯基叠氮化物（3）的原始报道反应进行了计算研究。我们通过研究几种变体 1a1、1b1 和 1c1 及其与 3 的反应性，扩展了这些串联环加成反应的范围。在所考虑的所有串联反应实例中，Diels-Alder 环加成步骤是速率决定步骤（rds）。吸电子取代的 1a1、1b1 和 1c1 降低了 rds 的势垒，而给电子取代基则大大增加了 rds 的势垒。母体反应（1a1）选择性地通过过渡态 T5Exa 进行，生成实验观察到的串联产物 5Exa。对于 1b1 和 1c1，反应通过 T4Ex 和 T5Ex 进行竞争，得到相应的 4Ex 和 5Ex（实验观察到的串联加合物）。所研究的各种取代基表明，所获得的串联加合物高度依赖于 Diels-Alder 中间体上的取代基。吸电子基团大大降低了 rds 的势垒，而给电子基团则正好相反。电导率指数与活化能的关系图得到了有利的相关性。我们还研究了未报道的呋喃肉桂酸酯（2-1a2）与几种腈亚胺的反应性。发现这种反应通过与苯叠氮化物相似的机制进行。观察到二取代腈亚胺与呋喃肉桂酸酯（2-1a2）的反应在能量上比苯叠氮化物更有利。计算的 GEDT 值揭示，非极性溶剂（甲苯）将通过范德华相互作用稳定非极性反应。
