1. A novel 1 beta-methylcarbapenem antibiotic, S-4661. Synthesis and structure-activity relationships of 2-(5-substituted pyrrolidin-3-ylthio)-1 beta-methylcarbapenems
Y Iso, T Irie, Y Nishino, K Motokawa, Y Nishitani J Antibiot (Tokyo). 1996 Feb;49(2):199-209. doi: 10.7164/antibiotics.49.199.
The synthesis and biological activity of (1R,5S,6S)-2-[(3S,5S)-5-substituted pyrrolidin-3-ylthio]-6-[(1R)-1-hydroxyethyl]-1- methylcarbapen-2-em-3-carboxylic acids are described. These compounds exhibit potent antibacterial activity against a wide range of both Gram-positive and Gram-negative bacteria including Pseudomonas aeruginosa. Of these new carbapenems, (1R,5S,6S)-2-[(3S,5S)-5-sulfamoylaminomethyl pyrrolidin-3-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methylcarb apen- 2-em-3-carboxyli c acid (S-4661) showed the most potent and well balanced activity and was selected as a candidate for further evaluation.
2. Facile synthesis of (R)-4-mercaptopyrrolidine-2-thione from L-aspartic acid
M Seki, T Shimizu Biosci Biotechnol Biochem. 2001 Apr;65(4):973-6. doi: 10.1271/bbb.65.973.
An SN2-type of substitution of (S)-bromide 4, which had been prepared from L-aspartic acid, with potassium thiobenzoate provided (R)-benzoylthio derivative 5 with complete inversion of the configuration. Compound 5 was converted, via iodide 6c, to (R)-4-amino-3-benzoylthiobutyric acid 8b. (R)-4-Mercapto pyrrolidine-2-thione 1 was readily obtained from 8b through cyclization with acetic anhydride, thionation with Lawesson's reagent and facile removal of the S-benzoyl group with sodium methoxide.
3. Practical synthesis of a 1beta-methylcarbapenem, J-111,225, using 4-mercapto-2-[4-(N-methylaminomethyl)phenyl]pyrrolidine as a precursor
H Imamura, A Shimizu, H Sato, Y Sugimoto, S Sakuraba, K Yamada, H Morishima Chem Pharm Bull (Tokyo). 2001 Apr;49(4):476-9. doi: 10.1248/cpb.49.476.
An effective and practical procedure for the synthesis of J-111,225 (1), a new 1beta-methylcarbapenem, was developed using 4-mercapto-2-14-(N-methylaminomethyl)phenyl]pyrrolidine (2a) as a precursor. The coupling reaction of 2a with p-nitrobenzyl (PNB)-protected 1beta-methylcarbapenem enolphosphate 3a and successive removal of PNB group afforded J-111,225 (1) in significantly increased yield compared to the ordinary procedure using a C-2 side-chain thiol with amino-protective groups.
