Polyhydroxylated Indolizidine Alkaloids Research Articles

Asymmetric Syntheses of 1-Deoxy-6,8a-di-epi-castanospermine and 1-Deoxy-6-epi-castanospermine

Asymmetric syntheses of both 1-deoxy-6,8a-di-epi-castanospermine and 1-deoxy-6-epi-castanospermine, polyhydroxylated indolizidine alkaloids that act as selective glycosidase inhibitors, have been accomplished in seven steps. The key feature of our unique syntheses includes the stereoselective introduction of the C-3 and C-4 hydroxyl groups utilizing the aza-Claisen rearrangement-induced ring expansion of 1-acyl-2-alkoxyvinyl pyrrolidine and a substrate-controlled stereoselective transannulation of the resulting azoninone intermediate.

Concise synthesis of two advanced intermediates for the asymmetric synthesis of polyhydroxylated indolizidine alkaloids

National Natural Science Foundation of China [20832005]; National Basic Research Program (973 Program) of China [2010CB833200]

Polyhydroxylated indolizidine alkaloids—synthesis of dideoxycastanospermine

The key transformation developed in this work is the anti-Kishi selective dihydroxylation, which proceeds by way of intramolecular participation of the nitrogen protecting group to furnish the desired stereochemistry required for castanospermine like structures. In this paper, we completed a first synthesis of a novel dideoxycastanospermine 6.

Synthesis of 1-Deoxy-1-hydroxymethyl- and 1-Deoxy-1-epi-hydroxymethyl Castanospermine as New Potential Immunomodulating Agents

Two new C-1 epimeric hydroxymethyl castanospermine congeners 2a and 2b, synthesized by stereocontrolled intramolecular double reductive amination of D-glucose derived beta-keto ester as a key step, showed impressive immuno-potentiating property. The bioactivity was mediated through up-regulation of T(H1)/T(H2) cytokine ratio. The finding suggested that immunmodulatory activity of polyhydroxylated indolizidine alkaloids can be tuned by minor structural/stereochemical alterations.

Intramolecular 5-endo-Trig Aminomercuration of β-Hydroxy-γ-alkenylamines: Efficient Route to a Pyrrolidine Ring and Its Application for the Synthesis of (+)-Castanospermine and Analogues

The intramolecular aminomercuration reaction of sugar-derived beta-hydroxy-gamma-alkenylamines 8a-c undergoes 5-endo-trig cyclization in high yield. The sugar-substituted pyrrolidines thus obtained were elaborated to the synthesis of polyhydroxylated indolizidine alkaloids, namely, castanospermine 1a, 1-epi-castanospermine 1b, and 8a-epi-castanospermine 1c, having promising glycosidase inhibitory activities.

1,3-Dipolar Cycloaddition Reaction of d-Glucose-Derived Nitrone with Allyl Alcohol: Synthesis of 2-Hydroxy-1-deoxycastanospermine Analogues

[reaction: see text] The synthesis and evaluation of glycosidase inhibitory activity of polyhydroxylated indolizidine alkaloids namely 2-hydroxy-1-deoxycastanospermine 3a,b and 2-hydroxy-1-deoxy-8a-epi-castanospermine 3c,d is reported. The key step involves the intermolecular 1,3-dipolar cycloaddition of allyl alcohol to d-glucose-derived nitrone 4, followed by tosylation, that afforded four diastereomeric sugar-substituted isoxazolidines 5a-d with the desired regioselectivity. The one-pot conversion of 5a-d to pyrrolidines 8a-d by hydrogenolysis, removal of 1,2-acetonoide functionality, and hydrogenation afforded corresponding target molecules 3a-d.

Polyhydroxylated indolizidine alkaloids—an efficient synthesis of 1-deoxy-8,8a-di- epi-castanospermine

A new and efficient enantioselective total synthesis of the title deoxycastanospermine derivative has been developed, based on amino acid and β-ketophosphonate chemistry, as well as employment of internal asymmetric induction for the creation of the new chiral centers proved successful. With proper choice of reaction conditions, the approach can also be applied in selective preparation of several isomers of deoxycastanospermine. The length (9 steps) and overall yield of the title compound trihydroxyindolidine 1 , 7.3%, compares well with the literature syntheses of similar compounds.

Efficient Synthesis of Indolizidine Alkaloids from γ-Hydroxy-α,β-unsaturated Sulfones

An efficient and stereoselective synthesis of polyhydroxylated indolizidine alkaloids from readily available N-substituted γ-hydroxyvinyl sulfones is described.

Efficient Synthesis of Indolizidine Alkaloids from γ-Hydroxy-α,β-unsaturated Sulfones

An efficient and stereoselective synthesis of polyhydroxylated indolizidine alkaloids from readily available N-substituted γ-hydroxyvinyl sulfones is described.

Australine, a pyrrolizidine alkaloid that inhibits amyloglucosidase and glycoprotein processing

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.