der Poorten Olivier Van, Jida Mouhamad, Tourwe Dirk, Ballet Steven
Research Group of Organic Chemistry, Departments of Chemistry and Bioengineering Sciences, Vrije Universiteit Brussel, Pleinlaan 2, B-1050, Brussels, Belgium.
Med Chem. 2018;14(4):400-408. doi: 10.2174/1573406413666171002122233.
Benzazepines received great attention in the field of medicinal chemistry since this scaffold has been recognized to belong to the important family of privileged templates. More specifically, the 4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one (Aba) is used as a core structure in a variety of constrained therapeutic peptide (turn) mimetics.Most of the synthetic approaches towards this template have focused on cyclizations which form the central 7-membered azepine ring.
Previous investigations in our group allowed an expansion of the substitution patterns in the 4-amino-benzazepin-3-one scaffold by introduction of methyl substituents at positions 4 and 5 of the azepinone ring system, but also to 1-aryl substituted compounds. These were the only trisubstituted analogues obtained to date. To introduce an additional point of diversification and conformational constraint useful for peptide mimicry, one can use bifunctional substrates in the Ugi reaction as reported in the present manuscript.
The 1-carboxamido-substituted Aba scaffold has been synthesized via the Ugi-3CR reaction starting from N-Phth-protected 2-formyl-L-Phe-OH with a set of amine and isocyanide derivatives. The most suited reaction conditions were applied, involving preformation of the imine in MeOH (0.1 M) in the presence of anhydrous Na2SO4 during 2 hours at room temperature, followed by the addition of an equimolar quantity of isocyanide prior to heating the reaction mixture at 80 °C for 20 hours, using sealed vial reaction conditions.
The substituted Aba scaffolds were isolated in moderate yields (and diastereomeric ratio). This is due to the requirement for a double N-phthaloyl protection of the bifunctional building block, which prevents the use of an excess of amine reagent to drive the reaction conversion to completion, and some starting substrate always remains. Despite the moderate yields, the methodology is efficient since it only requires a limited number of synthetic steps in a final one-pot reaction. In most cases, the diastereomers could be separated by preparative RP-HPLC or via silica gel column chromatography. This is interesting from a medicinal chemistry point of view, since access is provided to the individual diastereomers.
We have developed an efficient and useful one-pot strategy to access 1-substituted 4- aminobenzazepinone (Aba) derivatives via the Ugi-3CR reaction. To the best of our knowledge, these scaffolds are only accessible through the presented methodology. The obtained structural complexity, as well as the substitution versatility of these trisubstituted scaffolds, will allow their use in various biological applications.
苯并氮杂卓在药物化学领域备受关注，因为这种骨架已被认为属于重要的特权模板家族。更具体地说，4-氨基-1,2,4,5-四氢-2-苯并氮杂卓-3-酮（Aba）被用作多种受限治疗性肽（转角）模拟物的核心结构。大多数针对该模板的合成方法都集中在形成中心七元氮杂卓环的环化反应上。
我们小组之前的研究通过在氮杂卓酮环系统的4位和5位引入甲基取代基，以及引入1-芳基取代的化合物，扩大了4-氨基-苯并氮杂卓-3-酮骨架中的取代模式。这些是迄今为止获得的仅有的三取代类似物。为了引入对肽模拟有用的额外多样化点和构象限制，可以如本手稿中所报道的那样，在Ugi反应中使用双功能底物。
通过Ugi-3CR反应，从N-邻苯二甲酰亚胺保护的2-甲酰基-L-苯丙氨酸-OH与一组胺和异腈衍生物开始，合成了1-羧酰胺基取代的Aba骨架。应用了最适合的反应条件，包括在室温下于甲醇（0.1 M）中在无水硫酸钠存在下预形成亚胺2小时，然后在将反应混合物加热至80℃20小时之前加入等摩尔量的异腈，使用密封小瓶反应条件。
取代的Aba骨架以中等产率（和非对映体比例）分离得到。这是由于双功能构建块需要双重N-邻苯二甲酰保护，这阻止了使用过量的胺试剂来驱动反应完全转化，并且总会有一些起始底物残留。尽管产率中等，但该方法是有效的，因为它在最终的一锅反应中只需要有限数量的合成步骤。在大多数情况下，非对映体可以通过制备型反相高效液相色谱或硅胶柱色谱分离。从药物化学的角度来看，这很有趣，因为可以获得各个非对映体。
我们已经开发了一种高效且有用的一锅法策略，通过Ugi-3CR反应获得1-取代的4-氨基苯并氮杂卓酮（Aba）衍生物。据我们所知，这些骨架只能通过所提出的方法获得。所获得的结构复杂性以及这些三取代骨架的取代多样性，将使其可用于各种生物学应用。
