Australine

Synthesis of multibranched australine derivatives from reducing castanospermine analogues through the Amadori rearrangement of gem-diamine intermediates: selective inhibitors of beta-glucosidase.[Pubmed:25390345]

J Org Chem. 2014 Dec 5;79(23):11722-8.

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 beta-glucosidase and are promising candidates as pharmacological chaperones for Gaucher disease.

Stereocomplementary routes to hydroxylated nitrogen heterocycles: total syntheses of casuarine, australine, and 7-epi-australine.[Pubmed:23828462]

Chemistry. 2013 Aug 5;19(32):10595-604.

Addition of lithiated 1-benzyloxyallene to a D-arabinose-derived cyclic nitrone occurred with perfect diastereoselectivity furnishing a bicyclic 1,2-oxazine derivative, which is an excellent precursor for pyrrolizidine alkaloids hydroxylated at C-7 with optional configuration at this stereogenic center. Depending on the stage of the N-O bond cleavage and ring re-closure, 7-hydroxypyrrolizidines with 7R or 7S configuration were obtained, as a result of completely selective addition reactions occurring complementarily at the bottom or top face of the endocyclic C-C double bond in six- and five-membered B rings, respectively. Applicability of these stereodivergent routes to obtain polyhydroxy pyrrolizidine alkaloids is demonstrated by the efficient syntheses of casuarine and Australine as examples of the two classes of diversely configured 7-hydroxypyrrolizidine alkaloids. An alternative synthesis of Australine and two strategies for the preparation of 7-epi-Australine are also reported, which demonstrate that the stereoselectivity of hydride reduction of an exocyclic C-O double bond is independent of the ring size, occurring preferentially from the top face either in a six- or five-membered ring.

Australine, a pyrrolizidine alkaloid that inhibits amyloglucosidase and glycoprotein processing.[Pubmed:2497772]

Biochemistry. 1989 Mar 7;28(5):2027-34.

Australine [(1R,2R,3R,7S,7aR)-3-(hydroxymethyl)-1,2,7-trihydroxypyrrolizid ine] is a polyhydroxylated pyrrolizidine alkaloid that was isolated from the seeds of the Australian tree Castanospermum australe and characterized by NMR and X-ray diffraction analysis [Molyneux et al. (1988) J. Nat. Prod. (in press)]. Since swainsonine and catanospermine are polyhydroxylated indolizidine alkaloids that inhibit specific glycosidases, we tested Australine against a variety of exoglycosidases to determine whether it would inhibit any of these enzymes. This alkaloid proved to be a good inhibitor of the alpha-glucosidase amyloglucosidase (50% inhibition at 5.8 microM), but it did not inhibit beta-glucosidase, alpha- or beta-mannosidase, or alpha- or beta-galactosidase. The inhibition of amyloglucosidase was of a competitive nature. Australine also inhibited the glycoprotein processing enzyme glucosidase I, but had only slight activity toward glucosidase II. When incubated with cultured cells, this alkaloid inhibited glycoprotein processing at the glucosidase I step and caused the accumulation of glycoproteins with Glc3Man7-9(GlcNAc)2-oligosaccharides.

Synthesis and glycosidase inhibition of australine and its fluorinated derivatives.[Pubmed:25621897]

Org Lett. 2015 Feb 6;17(3):716-9.

Australine (1), 7-epi-Australine (2), and their C-7-fluorinated derivatives 4 and 5 have been synthesized efficiently from D-arabinose-derived cyclic nitrone 11. Fluorination at the C-7 position enhanced the inhibition against A. niger alpha-glucosidase, and this constitutes the first example of fluorination substitution for a hydroxyl increasing the inhibition of any glycosidases. The enantiomers synthesized from nitrone ent-11 showed no inhibition of the corresponding enzymes.

Total synthesis of uniflorine A, casuarine, australine, 3-epi-australine, and 3,7-di-epi-australine from a common precursor.[Pubmed:20028000]

J Org Chem. 2010 Feb 5;75(3):815-24.

A flexible method for the diastereoselective total synthesis of the pyrrolizidine alkaloids uniflorine A, casuarine, Australine, and 3-epi-Australine and the unnatural epimer 3,7-di-epi-Australine from a common chiral 2,5-dihydropyrrole precursor is described.