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Synthesis of Glycaro‐1,5‐lactams and Tetrahydrotetrazolopyridine‐5‐carboxylates: Inhibitors of β ‐ D ‐Glucuronidase and α ‐ L ‐Iduronidase
Author(s) -
Pabba Jagadish,
Rempel Brian P.,
Withers Stephen G.,
Vasella Andrea
Publication year - 2006
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/hlca.200690066
Subject(s) - chemistry , lactam , stereochemistry , yield (engineering) , substrate (aquarium) , dihydroxylation , organic chemistry , enantioselective synthesis , catalysis , oceanography , materials science , metallurgy , geology
The known glucaro‐1,5‐lactam 8 , its diastereoisomers 9 – 11 , and the tetrahydrotetrazolopyridine‐5‐carboxylates 12 – 14 were synthesised as potential inhibitors of β ‐ D ‐glucuronidases and α ‐ L ‐iduronidases. The known 2,3‐di‐ O ‐benzyl‐4,6‐ O ‐benzylidene‐ D ‐galactose ( 16 ) was transformed into the D ‐galactaro‐ and L ‐altraro‐1,5‐lactams 9 and 11 via the galactono‐1,5‐lactam 21 in twelve steps and in an overall yield of 13 and 2%, respectively. A divergent strategy, starting from the known tartaric anhydride 41 , led to the D ‐glucaro‐1,5‐lactam 8 , D ‐galactaro‐1,5‐lactam 9 , L ‐idaro‐1,5‐lactam 10 , and L ‐altraro‐1,5‐lactam 11 in ten steps and in an overall yield of 4–20%. The anhydride 41 was transformed into the L ‐threuronate 46 . Olefination of 46 to the ( E )‐ or ( Z )‐alkene 47 or 48 followed by reagent‐ or substrate‐controlled dihydroxylation, lactonisation, azidation, reduction, and deprotection led to the lactams 8 – 11 . The tetrazoles 12 – 14 were prepared in an overall yield of 61–81% from the lactams 54, 28 , and 67 , respectively, by treatment with Tf 2 O and NaN 3 , followed by saponification, esterification, and hydrogenolysis. The lactams 8 – 11 and 40 and the tetrazoles 12 – 14 are medium‐to‐strong inhibitors of β ‐ D ‐glucuronidase from bovine liver. Only the L ‐ ido ‐configured lactam 10 ( K i = 94 μ M ) and the tetrazole 14 ( K i = 1.3 m M ) inhibit human α ‐ L ‐iduronidase.