MOLECULAR BUILDING USING N-METHYLBENZANILIDES AS A MOLECULAR SPRINT

酰胺部分具有构象和电子特征，通常决定分子的物理化学或生物学性质，它在各种分子识别事件中发挥作用。大多数具有二次酰胺键的化合物，在氮原子上有一个质子，存在反式(Z)形式。在对各种生物活性物质的研究过程中，我们发现芳香族仲酰胺或脲的N-甲基化导致了酰胺或尿素结构的构象变化，从而导致生物活性的急剧丧失。反式/顺式立体化学的重要性是显而易见的，例如在免疫抑制剂的生物化学中。研究了苯甲胺、N-甲基苯甲胺和具有邻位甲基(S)的苯甲胺在溶液和晶体中的构象。N-甲基苯甲酰胺在晶体中以顺-酰胺(E)形式存在。在氯化镉溶液中，顺胺形式也占优势(99%)，在反式-AM…中存在苯甲酰亚胺在晶体和溶液中形成更多的ide(Z)。在晶体中，所有的甲基取代的苯甲酰胺都以反式-酰胺构象存在，而邻甲基团(S)的引入使得芳环和酰胺基团(Ar-酰胺)的面角增大。N-甲基苯甲酰胺在晶体中以顺式形式存在，除了化合物(26)，它有四个甲基邻位于酰胺键。对于N-甲基苯甲酰胺，引入一个或两个邻甲基团对芳基酰胺的二面角的影响小于对仲基苯甲酰胺的影响。在溶液中，除化合物(12)在CDDl_3中有少量顺式构象(3%)外，其余均以反式构象形式存在，而N-甲基苯甲酰胺则平衡地存在于主要顺式和次要反式构象之间。观察到四甲基衍生物在晶体中以反式构象存在于溶液中。对于N-甲基苯甲酰胺，在酰胺键上引入一个甲基(S)邻位基团似乎破坏了溶液中顺胺构象的稳定性，导致反式酰胺构象的比例增加。较少

The amide moiety has conformational and electronic characteristics which often determine the physicochemical or biological properties of a molecule, and it plays role in a variety of molecular recognition events. Most compounds having a secondary amide bond, which has a proton on the nitrogen atom, exist trans (Z) form. We found in the course of investigations on various biologically active substances that N-methylation of aromatic secondary amides or ureas causes a dramatic loss of the biological activity due to conformational change of the amide or urea structre. The importance of trans/cis stereochemistry is clear, for example in the biochemistry of immunosuppressants.Conformation of benzanilide, N-methylbenzanilide and those with a methyl group (s) ortho to the amide bond in solution and in the crystal have been studied. N-Methylbenzanilide exists in cis-amide (E) form in the crystal. In CDCl_3 solution, cis-amide form is also predominant (99%), whele benzanilide exists in trans-am … More ide (Z) form in the crystal and in solution. In the crystal, all the methyl-substituted benzanilides exists in trans-amide conformation and the introduction of an ortho-methyl group (s) makes the interplanar angle of the aromatic rings and the amide group (Ar-amide) larger. N-Methylbenzanilides exist in cis form in the crystal except the compound (26) which has four methyl groups ortho to the amide bond. For the N-methylbenzanilides, the effects of introduction of one or two ortho-methyl group on the dihedral angles of Ar-amide are smaller than that of the secondary benzanilides. In solution, benzanilides exist exclusively in trans conformation except for the compound (12) which has a minor cis conformer (3%) in CDDl_3, whereas N-methylbenzanilides exist in equilibrium between the major cis-form and the minortrans-from. The tetramethyl derivative exists in trans conformation in solution as observed in the crystal. For, N-metylbenzanilides, an introduction of a methyl group (s) ortho to the amide bond seems to destabilize the cis-amide conformation in solution, resulting in an increased ratio of the trans-amide conformation. Less