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Synthesis of glycaro-1,5-lactams and tetrahydrotetrazolopyridine-5-carboxylates: Inhibitors of beta-D-glucuronidase and alpha-L-iduronidase

TitleSynthesis of glycaro-1,5-lactams and tetrahydrotetrazolopyridine-5-carboxylates: Inhibitors of beta-D-glucuronidase and alpha-L-iduronidase
Publication TypeJournal Article
Year of Publication2006
AuthorsPabba, J, Rempel, BP, Withers, SG, VASELLA, A
JournalHELVETICA CHIMICA ACTA
Volume89
Pagination635-666
ISSN0018-019X
Abstract

The known glucaro-1,5-lactam 8, its diastereoisomers 9-11, and the tetrahydrotetrazolopyridine-5-carboxylates 12-14 were synthesised as potential inhibitors of beta-(D)-glucuronidases and alpha-(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 beta-(D)-glucuronidase from bovine liver. Only the (L)-ido-configured lactam 10 (K(i)=94 mu(M)) and the tetrazole 14 (K(i)= 1.3 m(M)) inhibit human alpha-(L)-iduronidase.

DOI10.1002/hlca.200690066