Separation of Etiracetam Enantiomers Using Enantiospecific Cocrystallization with 2-Chloromandelic Acid.

Chirality plays an important role in the pharmaceutical industry since the two enantiomers of a drug molecule usually display significantly different bioactivities, and hence, most products are produced as pure enantiomers. However, many drug precursors are synthesized as racemates, and hence, enantioseparation has become a significant process in the industry. Cocrystallization is one of the attractive crystallization approaches to obtain the desired enantiomer from racemic compounds. In this work, we propose a chiral resolution route for an antiepileptic drug, S-etiracetam (S-ETI), via enantiospecific cocrystallization with S-2-chloro-S-mandelic acid (CLMA) as a coformer. The experiments indicate that the system is highly enantiospecific; S-2CLMA cocrystallizes only with S-ETI but not with R-ETI or RS-ETI. Therefore, the chiral purification of S-ETI can be achieved efficiently with a 69.1% yield and close to 100% enantiopurity from the racemic solution. Additionally, structural simulations of the S-ETI:S-2CLMA cocrystal reveal that the cocrystal structure has higher thermodynamic stability than that of R-ETI:S-2CLMA by about 5.5 kcal/mol (per cocrystal formula unit), which helps to confirm the favorability of the enantiospecification in this system.

Biotransformation of 1α,11α-dihydroxyisopimara-8(14),15-diene by Cunninghamella echinulata NRRL 1386 and their neuroprotective activity.

The isopimarane diterpene, 1α,11α-dihydroxyisopimara-8(14),15-diene (1), is the major constituents from the rhizomes of Kaempferia marginata (Zingiberaceae), a Thai medicinal plant. The microbial transformation of parent compound 1 by the fungus Cunninghamella echinulata NRRL 1386 gave five new metabolites, 7α,11α-dihydroxy-1-oxoisopimara-8(14),15-diene (2), 3ß,7α,11α-trihydroxy-1-oxoisopimara-8(14),15-diene (3), 7ß,11α-dihydroxy-1-oxoisopimara-8(14),15-diene (4), 7α-hydroxy-1,11-dioxoisopimara-8(14),15-diene (5) and 1α,7ß,11α-trihydroxyisopimara-8(14),15-diene (6), together with three known metabolites, 7-9. The structures of the new metabolites were elucidated by spectroscopic techniques. The known compounds were identified by comparison of the spectroscopic and physical data with those of reported values. The parent compound 1 and the metabolites have been neuroprotective activities evaluated against Aß25-35-induced damage in human neuroblastoma cells (SK-N-SH). Among them, compounds 1-3, 5 and 7-9 had significant neuroprotective activities at a concentration of 2.5 µM. The results demonstrated that these compounds might be worth for further development into therapeutic agents for the treatment of neurodegenerative diseases.

Isopimarane Diterpenoids from the Rhizomes of Kaempferia marginata and Their Potential Anti-inflammatory Activities.

Six new isopimarane diterpenes, marginaols A-F (1-6), along with eight known compounds (7-14), were isolated from the rhizomes of Kaempferia marginata. The structures and absolute configurations of 1-6 were established on the basis of spectroscopic methods and the experimental and calculated ECD data as well as comparison with the literature values. Most of the isolated compounds were tested for their nitric oxide (NO) inhibitory effects in lipopolysaccharide-activated RAW264.7 cells. Among them, marginaol B (2) was found to reduce NO levels in murine macrophage cells with an IC50 value of 28.1 ± 1.7 µM.

Polymerization of ε-Caprolactone Using Bis(phenoxy)-amine Aluminum Complex: Deactivation by Lactide.

Polymerizations of biodegradable lactide and lactones have been the subjects of intense research during the past decade. They can be polymerized/copolymerized effectively by several catalyst systems. With bis(phenolate)-amine aluminum complex, we have shown for the first time that lactide monomer can deactivate the aluminum complex during the ongoing polymerization of ε-caprolactone to a complete stop. After hours of dormant state, the aluminum complex can be reactivated again by heating at 100 °C without the addition of any external chemicals still giving polymer with narrow dispersity. Studies using NMR, in situ FTIR, and single-crystal X-ray crystallography indicated that the coordination of the carbonyl group in lactyl unit was responsible for the unusual behavior of lactide. In addition, the unusual methyl-migration from methyl lactate ligand to the amine side chain of the aluminum complex was observed through intermolecular nucleophilic-attack mechanism.