We have previously developed a one-step three-component reaction, wherein an amine, an aldehyde-type carbonyl compound, and an organoboronic acid are combined to form multi-functionalized amines and amino acids. This metal-free process is typically performed in an organic solvent, it is atom economical, and its only by-product is boric acid, a small, non-toxic compound. Herein, we disclose a novel application of this multicomponent process, that involves the use of water as the only solvent. By using components that are at least partially soluble in water, the reaction proceeds with high diastereoselectivity, typically with &gt;99%de. This process is applicable for the stereocontrolled total synthesis of amino acids and peptidomimetic derivatives. The conformational dynamics exhibited by the synthesized compounds, were studied and elucidated. Both time-dependent 1H NMR studies and DFT at the B3LYP/6-31++G** level were used to study conformational geometries. Finally, DFT calculations allowed us to investigate the source of high diastereoselectivity observed for this process. Geometry optimizations on the iminium intermediates provided clues on the source of stereoselectivity, and these findings may provide a benchmark for the design and synthesis of useful chiral amines and amino acid derivatives.

Stereocontrolled multicomponent synthesis of amino acids and peptidomimetics in water

2019 Fall National Meeting

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