A Convenient Preparation of Diastereomerically Pure, Diversely Substituted Piperazine-2,5-diones from N-Protected α-Amino Acids

Abstract

The products of the Ugi reaction of various N-tert-but­oxy­carbonyl-protected α-amino acids, aldehydes, amines and tert-butyl isocyanide, after tert-butoxycarbonyl deprotection, undergo efficient microwave-assisted cyclization in acetic acid to give dia­stereomerically pure, racemic piperazine-2,5-diones. The formation of a single diastereomer is rationalized via an enolization equilibration process in acetic acid at high temperature which enriches the product mixture in the more stable diastereomer. The relative ste­reo­chemistry of the products are confirmed by NOESY experiments and are consistent with molecular mechanics calculations.

Key words

piperazine-2,5-diones - Ugi multicomponent reaction - post-Ugi modification - microwave-assisted - enolization

References

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Nikulnikov, M.; Krasavin, M. Poster Abstract 18, 4th International Conference on Multi-Component Reactions and Related Chemistry, Ekaterinburg, 24-28 May, 2009.

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The ^¹H NMR spectra (300 MHz, DMSO-d ₆) of the crude products 2 displayed strongly broadened signals when run at ambient temperature, most likely, due to restricted amide bond rotation. On running some of the spectra at increased temperature (314 K), it was possible to confirm that products 2 were obtained as equal mixtures of diastereomers, as would be expected from the non-diastereoselective course of the Ugi reaction.

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Sigma-Aldrich chemistry products catalogue: www.sigmaaldrich.com.

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Molecular mechanics (MM2) calculations were performed using ChemBio3D Ultra 11.0, CambridgeSoft.