Efficient asymmetric synthesis of novel 4-substituted and configurationally stable analogues of thalidomide.
The preparation of new thalidomide derivatives 4-methyl-(3S,4R)-3a and 4-phenyl-(3S,4S)-3b starting from pyroglutamic acids (2R,3R)-7a and (2R,3S)-7b, possessing an inappropriate stereochemistry, was successfully realized due to stereochemically complete epimerization at the alpha-stereogenic center upon formation of the corresponding N-phthaloyl anhydrides 9a,b. The demonstrated conformational stability of these new thalidomide derivatives provides solid experimental evidence for practical feasibility of the approach described here to overcome the inherent problem of configurational instability of thalidomide by introducing an alkyl or aryl group in the C4 position. [reaction: see text].
Yamada
Takeshi
T
Graduate School of Science, Osaka City University, Japan.
Okada
Takuya
T
Sakaguchi
Kazuhiko
K
Ohfune
Yasufumi
Y
Ueki
Hisanori
H
Soloshonok
Vadim A
VA
D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D010796:Phthalic Anhydrides; D011761:Pyrrolidonecarboxylic Acid / Q000737:chemistry; D013237:Stereoisomerism; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000138:chemical synthesis*
D007202:Indicators and Reagents; D010796:Phthalic Anhydrides; D013792:Thalidomide; D011761:Pyrrolidonecarboxylic Acid