Practical access to the proline analogs (S,S,S)- and (R,R,R)-2-methyloctahydroindole-2-carboxylic acids by HPLC enantioseparation

• Published in: Chirality (New York, N.Y.) N.Y.), 2011-08, Vol.23 (7), p.507-513
• Main Authors: Sayago, Francisco J., Pueyo, María J., Calaza, M. Isabel, Jiménez, Ana I., Cativiela, Carlos
• Format: Article
• Language: English
• Subjects: Amino acids; Analogs; Carboxylic Acids - chemical synthesis; Carboxylic Acids - chemistry; Carboxylic Acids - isolation & purification; chiral HPLC; Chirality; Chiralpak IC; Chromatography, High Pressure Liquid - methods; Ethers; HPLC resolution; Indoles - chemical synthesis; Indoles - chemistry; Indoles - isolation & purification; Integrated circuits; perhydroindole-2-carboxylic acid; polysaccharide-derived chiral stationary phase; Precursors; Proline; Proline - analogs & derivatives; Stereoisomerism; Transformations; α-tetrasubstituted amino acid
• ISSN: 0899-0042; 1520-636X; 1520-636X
• DOI: 10.1002/chir.20952

An efficient methodology for the preparation of the α‐tetrasubstituted proline analog (S,S,S)‐2‐methyloctahydroindole‐2‐carboxylic acid, (S,S,S)‐(αMe)Oic, and its enantiomer, (R,R,R)‐(αMe)Oic, has been developed. Starting from easily available substrates and through simple transformations, a racemic precursor has been synthesized in excellent yield and further subjected to HPLC resolution using a cellulose‐derived chiral stationary phase. Specifically, a semipreparative (250 mm × 20 mm ID) Chiralpak® IC column has allowed the efficient resolution of more than 4 g of racemate using a mixture of n‐hexane/tert‐butyl methyl ether/2‐propanol as the eluent. Multigram quantities of the target amino acids have been isolated in enantiomerically pure form and suitably protected for incorporation into peptides. Chirality, 2011. © 2011 Wiley‐Liss, Inc.