Synthesis of multibranched australine derivatives from reducing castanospermine analogues through the Amadori rearrangement of gem-diamine intermediates: selective inhibitors of β-glucosidase.
A practical one-pot synthesis of bi- and triantennated australine analogues from a pivotal sp(2)-iminosugar-type reducing castanospermine precursor is reported. The transformation involves a gem-diamine intermediate that undergoes the indolizidine → pyrrolizidine Amadori-type rearrangement and proceeds under strict control of the generalized anomeric effect to afford a single diastereomer. The final compounds behave as selective competitive inhibitors of β-glucosidase and are promising candidates as pharmacological chaperones for Gaucher disease.
Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla , c/Profesor García González 1, E-41012 Sevilla, Spain.
Elena M
EM
Sánchez-Fernández
Eleuterio
E
Álvarez
Carmen
C
Ortiz Mellet
José M
JM
García Fernández
D001669:Biochemical Phenomena; D003959:Diamines / Q000737:chemistry*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005776:Gaucher Disease / Q000188:drug therapy*; D006801:Humans; D054836:Indolizidines / Q000737:chemistry / Q000494:pharmacology*; D007212:Indolizines / Q000737:chemistry*; D018832:Molecular Chaperones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D015394:Molecular Structure; D011763:Pyrrolizidine Alkaloids / Q000138:chemical synthesis* / Q000737:chemistry; D001617:beta-Glucosidase / Q000037:antagonists & inhibitors* / Q000737:chemistry*
D003959:Diamines; D004791:Enzyme Inhibitors; D054836:Indolizidines; D007212:Indolizines; D018832:Molecular Chaperones; D011763:Pyrrolizidine Alkaloids; C059794:australine; D001617:beta-Glucosidase; C037806:castanospermine