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首页> 外文期刊>Chemistry: A European journal >Diversity-Oriented Synthesis of Morpholine-Containing Molecular Scaffolds
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Diversity-Oriented Synthesis of Morpholine-Containing Molecular Scaffolds

机译：面向多样性的吗啉分子支架的合成

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Since the early reports by Schreiber et al.,~[1] diversity-oriented synthesis (DOS) has become a new paradigm for developing large collections of structurally diverse small molecules as probes to investigate biological pathways and also to provide a larger array of the chemical space in drug discovery issues.~[2] The principles of DOS have evolved from the concept of generating structurally diverse compounds from a divergent approach consisting in a complexity-generating reaction followed by cyclization steps and appendage diversity, to the development of different cyclic structures through the build/couple/pair approach.~[3] The building stage of the overall DOS process involves the generation of suitable building blocks for subsequent coupling reactions, and it is generally achieved by using compounds from the chiral pool or achiral moieties as substrates for stereoselective reactions. The generation of heterocycles using amino acid and sugar derivatives as building blocks is a powerful approach to access chemical and geometrical diversity thanks to the high number of stereocenters and the polyfunctionality of such compounds, and numerous examples in the literature report the use of such substrates to access combinatorial libraries of heterocyclic compounds.~[4] During the past few years we have reported the generation of bicyclic compounds from the combination of sugar or tartaric acid and amino acid derivatives through two key steps consisting of the coupling of two components from the chiral pool followed by an intramolecular cyclization step to achieve the bicyclic structure.~[5] Recently, we turned our attention to the synthesis of morpholine rings,~[6] as among the various structures employed by medicinal chemists, this heterocycle represents a common motif.~[7] For example, the morpholine moiety can be found in several bioactive molecules, such as TACE (TNF-a converting enzyme),~[8] MMP (matrix metalloproteinase), and TNF (tumor necrosis factor) inhibitors,~[9] and it has been included in the core structure of tricyclic benzodiazepines,~[10] 6-methylidene penems as β-lactamase inhibitors,~[11] and of 8,6-fused bicyclic peptidomimetic compounds as interleukin-1β-converting enzyme inhibitors.~[12] Thus, we envisioned the possibility of using selected building blocks from the chiral pool to develop a DOS strategy to access stereochemically rich and rigid morpholine-based heterocycles according to the build/couple/pair approach.
机译：自Schreiber等人的早期报道以来，[1]面向多样性的合成（DOS）已成为开发大量结构多样的小分子的新范式，以作为探针来研究生物学途径并提供更大范围的药物发现问题中的化学空间。〜[2] DOS的原理已从产生结构多样的化合物的概念演变而来，从产生复杂性的反应，随后的环化步骤和附属物多样性的发散方法发展到了不同的环〜[3]整个DOS过程的构建阶段包括为后续的偶联反应生成合适的构件，通常通过使用来自手性池或非手性部分的化合物作为立体选择反应的底物。由于存在大量的立体中心和此类化合物的多功能性，使用氨基酸和糖衍生物作为结构单元生成杂环化合物是获得化学和几何多样性的有效方法，并且文献中的许多实例均报道了将此类底物用于访问杂环化合物的组合库。〜[4]在过去的几年中，我们已经报道了糖或酒石酸与氨基酸衍生物的结合通过两个关键步骤生成的双环化合物，这两个关键步骤包括手性化合物中两个组分的偶联[5]最近，我们将注意力转向吗啉环的合成，[6]在药物化学家采用的各种结构中，该杂环代表一个共同的基序〜[7]例如，吗啉部分可以存在于几种生物活性分子中，例如TACE（TNF-a转化酶），〜[8] MMP（基质金属蛋白酶）和TNF（肿瘤坏死因子）抑制剂，〜[9]，并已包含在三环苯并二氮杂s的核心结构中，〜[10] 6-亚甲基青霉烯为β -内酰胺酶抑制剂〜[11]和8,6-稠合的双环拟肽化合物作为白介素1β转化酶抑制剂。〜[12]因此，我们设想了使用从手性库中选择的构建基来开发DOS的可能性。根据构建/耦合/配对方法访问立体化学丰富且刚性的吗啉杂环的方法。

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