摘要：

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.

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