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Expanding Complex Morpholines Using Systematic Chemical Diversity

2024; American Chemical Society; Volume: 26; Issue: 17 Linguagem: Inglês

10.1021/acs.orglett.4c00528

1523-7060

Sunny Ann Tang, Afton Fults, Shelton R. Boyd, Nikhil Gattu, Kevin Tran, Jiayi Fan, Kevin R. MacKenzie, Timothy Palzkill, Damian W. Young, Srinivas Chamakuri,

Advanced Synthetic Organic Chemistry

The morpholine heterocycle is a structural unit found in many bioactive compounds and FDA-approved drugs, but the generation of more complex C-functionalized morpholine derivatives remains considerably underexplored. Using systematic chemical diversity (SCD), a concept that guides the expansion of saturated drug-like scaffolds through regiochemical and stereochemical variation, we describe the synthesis of a collection of methyl-substituted morpholine acetic acid esters starting from enantiomerically pure amino acids and amino alcohols. In total, 24 diverse substituted morpholines were produced that vary systematically in regiochemistry and stereochemistry (relative and absolute). These diverse C-substituted morpholines can be directly applied in fragment screening or incorporated as building blocks in medicinal chemistry and library synthesis.