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