期刊
JOURNAL OF ORGANIC CHEMISTRY
卷 88, 期 15, 页码 10381-10402出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.joc.2c01903
关键词
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This study presents the synthesis of a collection of enantiomerically pure, systematically substituted hydantoins as structural privileged universal mimetic scaffolds. The synthesis relies on a selective condensation/cyclization process between isocyanates and aspartic acid diesters, followed by hydrolysis/coupling reactions with amines. Conformational studies showed that the hydantoin-based peptidomimetics are capable of projecting their substituents in positions superimposable to common protein secondary structures.
The synthesis of a collection of enantiomerically pure, systematically substituted hydantoins as structural privileged universal mimetic scaffolds is presented. It relies on a chemoselective condensation/cyclization domino process between isocyanates of quaternary or unsubstituted alpha-amino esters and N-alkyl aspartic acid diesters followed by standard hydrolysis/coupling reactions with amines, using liquid-liquid acid/base extraction protocols for the purification of the intermediates. Besides the nature of the alpha carbon on the isocyanate moiety, either a quaternary carbon or a more flexible methylene group, conformational studies in silico (molecular modeling), in solution (NMR, circular dichroism (CD), Fourier transform infrared (FTIR)), and in solid state (X-ray) showed that the presented hydantoin-based peptidomimetics are able to project their substituents in positions superimposable to the side chains of common protein secondary structures such as alpha-helix and beta-turn, being the open alpha-helix conformation slightly favorable according to molecular modeling, while the closed beta-turn conformation preferred in solution and in solid state.
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