Total Synthesis of (+)-Hyacinthacine A1, (+)-7a-epi-Hyacinthacine A1, (6R)-6-Hydroxyhyacinthacine A1, and (6S)-6-Hydroxy-7a-epi-hyacinthacine A1

Year: 2011

Authors: D’Adamio G., Goti A., Parmeggiani C., Moreno-Clavijo E., Robina I., Cardona F.

Autors Affiliation: Dipartimento di Chimica “Ugo Schiff ”, Università di Firenze, Polo Scientifico e Tecnologico, via della Lastruccia 3–13, 50019 Sesto Fiorentino, Firenze, Italia;
Departmento de Química Orgánica, Facultad de Química, Universidad de Sevilla, 41012 Sevilla, Spain

Abstract: The total synthesis of natural (+)-hyacinthacine A1 (6), (+)-7a-epi-hyacinthacine A1 (7) and their 6-hydroxy analogues 21 and 16 was achieved by the nitrone cycloaddition strategy using a D-ribose-derived cyclic nitrone 8 as the dipole and tert-butyl acrylate as dipolarophile. After separation of the adducts, reductive cleavage of the N-O bond followed by lactam reduction and deprotection afforded the two non-natural hydroxy analogues in excellent yields. The synthesis of (+)-hyacinthacine A1 (6) and of (+)-7a-epi-hyacinthacine A1 (7), which required deoxygenation at C(6), was finally accomplished by DIBAL-H reduction of the mesylate derivatives of the pyrrolizidinols 20 and 15, respectively. Evaluation of the synthesized compounds against a panel of 12 commercially available glycosidases showed that hyacinthacine A1 (6) and its 6(R)-hydroxy analogue 21 are good inhibitors of amyloglucosidase; the non natural compound 21 is also a strong inhibitor of -glucosidase, while 6 shows only moderate inhibition. The non-natural (+)-7a-epi-hyacinthacine A1 (7) is a moderate inhibitor of amyloglucosidase and -L-fucosidase, and the presence of a 6(S)-hydroxy group in compound 16 results in a decreased activity.

Journal/Review: EUROPEAN JOURNAL OF ORGANIC CHEMISTRY

Volume: 2011 (35)      Pages from: 7155  to: 7162

KeyWords: natural products; pyrrolizidines; total synthesis; nitrone cycloaddition; glycosidase inhibition
DOI: 10.1002/ejoc.201101096

Citations: 40
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