title: High-throughput purification of combinatorial libraries II: Automated separation of single diastereomers from a 4-amido-pyrrolidone library containing intentional diastereomer pairs.
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.
authors.affiliation: ChemRx Division, Discovery Partners International, Inc., 385 Oyster Point Blvd., South San Francisco, California 94080, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Irving
authors.forename: Clinton A
authors.initials: CA
authors.lastname: Krueger
authors.forename: Janice V
authors.initials: JV
authors.lastname: Wade
authors.forename: John C
authors.initials: JC
authors.lastname: Hodges
authors.forename: Kyle
authors.initials: K
authors.lastname: Leopold
authors.forename: Nathan
authors.initials: N
authors.lastname: Collins
authors.forename: Cecilia
authors.initials: C
authors.lastname: Chan
authors.forename: Suzan
authors.initials: S
authors.lastname: Shaqair
authors.forename: Alex
authors.initials: A
authors.lastname: Shornikov
authors.forename: Bing
authors.initials: B
authors.lastname: Yan