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Conformationally Biased Mimics of Mannopyranosylamines: Inhibitors of β ‐Mannosidases?
Author(s) -
Remen Lubos,
Vasella Andrea
Publication year - 2002
Publication title -
helvetica chimica acta
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.74
H-Index - 82
eISSN - 1522-2675
pISSN - 0018-019X
DOI - 10.1002/1522-2675(200204)85:4<1118::aid-hlca1118>3.0.co;2-s
Subject(s) - chemistry , cyclopropanation , conformational isomerism , stereochemistry , enol , glycoside , cleavage (geology) , alkylation , ether , silylation , medicinal chemistry , organic chemistry , catalysis , molecule , geotechnical engineering , fracture (geology) , engineering
The enol ether 7 was prepared by cleavage of the N−O bond of the known isoxazolidine 3 , followed by N ‐alkylation to 4 , silylation and oxidation to the N ‐oxide 6 , and Cope elimination. Cu‐Catalysed cyclopropanation of 7 led to the diastereoisomeric cyclopropanes 8 and 9 , which were subjected to a Curtius degradation. The resulting carbamates 12 and 16 were deprotected to the ammonium salts 14 and 18 , respectively. Both salts adopt a B 1,4 conformation, similarly as the ester 8 , while the isomeric ester 9 exists in a ca. 6 : 4 equilibrium of the 4 C 1 and B 1,4 conformers. The β ‐mannoside mimic 14 does not inhibit snail β ‐mannosidase at 10 m M , but the α ‐mannoside mimic 18 inhibits Jack bean α ‐mannosidase ( IC 50 =80 μ M ). These results are in keeping with the postulate that glycoside cleavage of β ‐ D ‐glycopyranosides requires a conformational change in agreement with the principle of stereoelectronic control.