High-throughput purification of combinatorial libraries II: Automated separation of single diastereomers from a 4-amido-pyrrolidone library containing intentional diastereomer pairs

Journal of Combinatorial Chemistry
Mark IrvingBing Yan

Abstract

A 4-amido-pyrrolidone library that was intentionally synthesized as pairs of diastereomers was produced by solution-phase parallel syntheses and purified by an automated high-throughput purification system. A total of 2592 4-amido-pyrrolidinones were ultimately isolated as single diastereomers from a matrix of 1920 syntheses. After the four-step synthesis and HPLC purification, the average yield of a single diastereomer was 36.6%. The average chemical purity was >90%, and the average diastereomeric purity was >87%. The choice of chiral amines used to make amides with heterocyclic acid chlorides had a dramatic effect on success. Analysis of the relationship between amines used for synthesis and the diastereomeric separation showed that amides made from chiral 1,2-amino alcohols gave superior separation to amides from chiral morpholines. The presence of a hydrogen bond donor on the amide side chain seems to be required for a better diastereomeric separation.

References

Feb 13, 2001·Current Opinion in Biotechnology·J N KyranosW K Goetzinger
May 10, 2001·Drug Discovery Today·W C. RipkaJ Krakover

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Citations

Mar 17, 2012·ACS Combinatorial Science·Patrice KozaJacques Pelleter
Jan 10, 2008·Journal of Combinatorial Chemistry·John Isbell
Nov 23, 2007·Mass Spectrometry Reviews·Annette S FangJames N Kyranos
Jul 23, 2019·ACS Combinatorial Science·Jack Silver
Nov 15, 2005·Journal of Combinatorial Chemistry·Roland E Dolle
Sep 13, 2005·Journal of Combinatorial Chemistry·Marcus KoppitzMarion Wenz
Nov 9, 2004·Journal of Combinatorial Chemistry·Anne L VergnonMark R Player

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