185142-24-9Relevant articles and documents
COMPOUNDS HAVING PROLYL OLIGOPEPTIDASE INHIBITORY ACTIVITY
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Page 30-31, (2010/02/07)
The invention provides a compound of formula (I), wherein in the formula X, R1, R2 and R3 are as defined in claim 1, or a pharmaceutically acceptable salt or ester thereof, useful as a prolyl oligopeptidase inhibitor. The compounds of formula (I) can be used for the treatment of diseases or conditions where prolyl oligopeptidase inhibitors are indicated to be effective, for example for the treatment of neurodegenerative diseases, such as Alzheimer's disease and senile dementia
5-tert-butylproline
Beausoleil,L'Archeveque,Belec,Atfani,Lubell
, p. 9447 - 9454 (2007/10/03)
Steric effects on the isomer equilibrium of amides N-terminal to proline can be explored with 5-alkylprolines having bulky 5-position substituents. Enantiopure 5-tert-butylprolines were thus synthesized from glutamic acid via an acylation/diastereoselective reductive amination sequence. Double deprotonation of γ-methyl N-(PhF)glutamate (2) with LiN(SiMe3)2 and C-acylation with pivaloyl chloride provided β-keto ester 3, which upon γ-ester hydrolysis and decarboxylation gave δ-oxo-α-[N-(PhF)amino]heptanoic acid (4). Syntheses of (2S,5R)- and (2R,5S)-N-(BOC)-5-tert-butylprolines ((2S,5R)-1 and (2R,5S)-1) were accomplished by catalytic hydrogenation of their respective (2S)- and (2R)-methyl δ-oxo-α-[N-(PhF)amino]heptanoates ((2S)-5a and (2R)-5a) in methanol with di-tert-butyl dicarbonate followed by chromatography and ester hydrolysis with potassium trimethylsilanolate. The 5-tert-butylproline cis-diastereomers were proven to be of >99% enantiomeric purity after their conversion to diastereomeric α-methylbenzylamides 10. Good diastereoselectivity in favor of the trans-diastereomer was observed when (2S,5S)-5-tert-butylproline was synthesized from (2S)-δ-oxo-α-[N-(PhF)amino]heptanoate ((2S)-4) by solvolysis of the PhF group in trifluoroacetic acid and subsequent reduction of 5-tert-butyl-Δ5-dehydroproline (11) with tetramethylammonium triacetoxyborohydride; however, imino acid 11 was shown to be configurationally labile and racemized under acidic conditions. 5-tert-Butyl-Δ5-dehydroproline N'-methylamide 15 was configurationally stable in acid, yet preliminary attempts to reduce 15 favored cis-diastereomer 16. Alternatively, enantiopure trans-diastereomer, (2R,5R)-methyl N-(BOC)-5-tert-butylprolinate (9) was prepared by epimerization of (2S,5R)-9. In summary, this synthetic methodology now provides access to all four enantiopure 5-tert-butylproline isomers from inexpensive L- and D-glutamate as chiral educts.
