A flexible stereospecific synthesis of polyhydroxylated pyrrolizidines from commercially available pyranosides.
Nitrogen-containing sugar analogues, known as azasugars or iminosugars, such as polyhydroxylated piperdines, pyrrolidines, pyrrolizidines, and indolizidines, have the potential to become important therapeutic agents due to their ability to inhibit glycosidases. Synthetic pathways that are able to systematically produce a variety of these azasugars are eagerly sought after, since even minute structural or stereochemical changes often significantly alter the degree of inhibition. The synthesis of tetrahydroxylated pyrrolizidines 40 and 41 starting from methyl alpha-d-glucopyranoside is described and will be used as a template to develop syntheses of all the stereoisomers of polyhydroxylated pyrrolizidine 9 as well as other analogous bicyclic polyhydroxylated iminosugars. The key steps in this synthesis involve a one-pot conversion of a halopyranoside to a divinylamine by employing a simultaneous Zn reduction and reductive amination of the resulting aldehyde. After protection of the amine, a ring-closing metathesis results in a multifunctional eight-membered ring that then undergoes an internal S(N)2 cyclization to form an alkene-containing pyrrolizidine 33. Dihydroxylation of the alkene followed by hydrogenolysis of the benzyl protecting groups results in tetrahydroxylated pyrrolizidines 40 and 41.
Department of Chemistry, Stonehill College, 320 Washington Street, Easton, Massachusetts 02357, USA.
Ellen M
EM
Sletten
Louis J
LJ
Liotta
D001372:Aza Compounds / Q000138:chemical synthesis; D002241:Carbohydrates / Q000737:chemistry*; D003500:Cyclization; D004791:Enzyme Inhibitors / Q000138:chemical synthesis*; D006026:Glycoside Hydrolases / Q000037:antagonists & inhibitors; D006900:Hydroxylation; D050112:Imino Pyranoses / Q000138:chemical synthesis; D011758:Pyrroles / Q000138:chemical synthesis*; D011763:Pyrrolizidine Alkaloids / Q000138:chemical synthesis* / Q000737:chemistry; D013237:Stereoisomerism
D001372:Aza Compounds; D002241:Carbohydrates; D004791:Enzyme Inhibitors; D050112:Imino Pyranoses; D011758:Pyrroles; D011763:Pyrrolizidine Alkaloids; D006026:Glycoside Hydrolases