Polyhydroxylated Indolizidines Research Articles

Intramolecular α-acylamino radical cyclizations with acylsilanes in the preparation of polyhydroxylated alkaloids: (+)-lentiginosine, (+)-1,8a-di- epi-lentiginosine, and (+)-1,2-di- epi-swainsonine

Acylsilanes with latent α-acylamino radical functionality were prepared from different chiral templates. Radical cyclizations of these acylsilanes efficiently constructed polyhydroxylated indolizidine derivatives with excellent stereoselectivity at the bridgehead position. These cyclization products were converted to (+)-lentiginosine, (+)-1,8a-di- epi-lentiginosine, and (+)-1,2-di- epi-swainsonine.

A Versatile Strategy for Divergent and Diastereoselective Synthesis of Natural Product-Like Polyhydroxylated Indolizidines

A general and versatile method for the divergent and diastereoselective synthesis of polyhydroxylated indolizidines has been established. The annulation reactions of a readily available enantiopure dihydroxylated cyclic secondary enamine with alpha,beta-unsaturated carboxylates including methyl acrylate, methyl crotonate, methyl 2-hexenoate, allenoate, and dimethyl acetylenedicarboxylate and with malonyl chloride produced hexahydro- or tetrahydro-5-indolizinone-8-carboxylates in high yields. The resulting 5-indolizinone derivatives were converted into diverse polyhydroxylated indolizidines in good yields through practical hydrogenation and reduction reactions.

Synthesis of Indolizidines Bearing Quaternary Stereocenters

The synthesis of two new polyhydroxylated indolizidines by stereoselective allyl­silane addition to tertiary N-acyliminium ions at a bicyclic ring junction is described. Starting from readily available A (N. Langlois, B. K. Le Nguyen J. Org. Chem. 2004, 69, 7558-7564), a two-step procedure leads stereoselectively to B bearing a quaternary allyl group. Chiral auxiliary removal followed by simple silicon protection and N-allylation affords intermediate C, which, upon subjection to metathesis, dihydroxylation and further manipulation, furnishes isomeric products D and E in 10 steps and 2% and 15% overall yields, respectively. The structure and absolute configuration of the products was established on the basis of the X-ray single-crystal structure analysis of intermediate F and NMR spectral correlations.

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.

Creation of quaternary stereocentres: synthesis of new polyhydroxylated indolizidines

(6R,7S,8aR)- and (6S,7R,8aR)-8a-tert-butyldimethylsilyloxymethyl-6,7-dihydroxy-indolizidin-3-ones 14 and 15 were synthesized from bicyclic silyloxypyrrole 2 by the selective formation of a quaternary stereogenic centre and a ring-closing metathesis as the main steps. They were converted into new polyhydroxyindolizidines 20 and 21 with high diastereoselectivity.

Synthetic Approaches to Polyhydroxy Indolizidines and Related Azabicyclic Scaffolds

Approaches to the synthesis of unnatural polyhydroxylated indolizidines are described. Key reactions involve addition of 2- (trimethylsilyloxy)furan to iminium salts, and ring-closure metathesis as second alternative.

A Concise Sequential Photochemical‐Metathesis Approach for the Synthesis of (+)‐Castanospermine and Possible Uniflorine‐A Stereoisomers.

AbstractFor Abstract see ChemInform Abstract in Full Text.

A concise sequential photochemical-metathesis approach for the synthesis of (+)-castanospermine and possible uniflorine-A stereoisomers

A recently developed strategy for polyhydroxylated indolizidine ring construction has been applied to the synthesis of (+)-castanospermine and possible isomers of uniflorine-A. The routes to these targets rely on the use of the earlier discovered photocyclization reaction of pyridinium perchlorate in a concise route for preparation of a key N-allylacetamidocyclopentendiol intermediate. Ring rearrangement metathesis of this substance gives an allyl-tetrahydropyridine, which is then transformed to the targets by execution of regio- and stereo-controlled hydroxylation processes followed by indolizidine ring construction.

Diastereoselective synthesis of new polyhydroxylated indolizidines from ( l)-glutamic acid

A diastereoselective synthesis of two new swainsonine's analogues 1a and 1b with the piperidine ring fused to a phenyl nucleus at C6-C7, namely (1 R, 2 S, 10 R, 10a R)-(+)-1,2,10-trihydroxy-1,2,3,5,10,10a-hexahydrobenzo[ f] indolizine ( 1a ) and (1 S, 2 R, 10 R, 10a R)-(+)-1,2,10-trihydroxy-1, 2, 3, 5, 10, 10a-hexahydrobenzo[ f] indolizine ( 1b ), is described. Throughout this work, the effectiveness of the tricyclic indolizidine dione 5 , readily available in three steps from the cheap l-glutamic acid, as an attractive platform for chemo- and stereodivergent transformations is illustrated. The key steps involved totally diastereoselective ketone reduction of compound 5 and catalytic cis-dihydroxylation of the unsaturated amide 10 . The synthetic strategy also allowed for the diastereoselective synthesis of benzoanalogues of the 1,8a-di- epi-lentiginosine 3a ((1 R, 2 S, 10a R)-(+)-1,2-dihydroxy-1, 2, 3, 5, 10, 10a-hexahydrobenzo[ f]indolizine) and 2,8a-di- epi-lentiginosine 3b ((1 S, 2 R, 10a R)-(+)-1,2-dihydroxy-1,2,3,5,10,10a-hexahydrobenzo[ f]indolizine).

Stereoselective Synthesis of Polyhydroxylated Indolizidines Based on Pyridinium Salt Photochemistry and Ring Rearrangement Metathesis.

AbstractFor Abstract see ChemInform Abstract in Full Text.

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.

Stereoselective synthesis of polyhydroxylated indolizidines based on pyridinium salt photochemistry and ring rearrangement metathesis.

Ruthenium-catalyzed ring rearrangement metathesis (RRM) reactions of stereochemically diverse, differentially protected 4-N-allylacetamidocyclopenten-3,5-diols, prepared by using pyridinium salt photochemistry, have been explored as part of a program to develop novel routes for the synthesis of polyhydroxylated indolizidines. The RRM reactions, which produce selectively protected 1-acetyl-2-allyl-3-hydroxy-1,2,3,6-tetrahydropyridines, were found to take in high yields and with high levels of regioselectivity. The significance of RRM reactions of 4-N-allylacetamidocyclopenten-3,5-diols in the context of polyhydroxylated indolizidine synthesis is demonstrated by an application to the concise preparation of the potent glycosidase inhibitor, (-)-swainsonine.

A short route toward chiral, polyhydroxylated indolizidines and quinolizidines.

In this paper, a rapid route toward functionalized bicyclic alkaloids is presented. In only three steps, an easily accessible carbohydrate derivative was converted into iodomethyl indolizidine 13, which can equilibrate to the corresponding iodoquinolizidine 15. We provide strong evidence that this equilibration proceeds via an aziridinium ion intermediate. Furthermore, nucleophilic substitution of the iodomethyl indolizidine as well as the aziridinium intermediate gives access to highly functionalized indolizidine and quinolizidine alkaloids.

Stereoisomeric sugar-derived indolizines as versatile building blocks: synthesis of enantiopure di- and tetrahydroxyindolizidines.

The synthesis of the sugar-derived (1S,2R,8aR)-1,2-di-O-isopropylidene-1,2,3,5,6,8a-hexahydro-5-oxoindolizine (8) and by analogy of the corresponding stereoisomers ent-8 and ent-7, an epimer at C2 of ent-8, has been accomplished in a straightforward manner. The carbon-carbon double bond and the carbonyl functionalities on the six-membered ring make these nitrogen-containing heterocycles useful building blocks for the efficient preparation of a variety of enantiopure polyhydroxylated indolizidines of interest for their glycosidase inhibitory activity. We report here the synthesis of 2,8a-diepilentiginosine 12 from 8 and the preparation of stereoisomeric 1,2,7,8-tetrahydroxyindolizidines 9-11 performed by OsO4-catalyzed double bond syn dihydroxylation of 7 and 8, followed by deoxygenation of the amide group.

Heterologous Over-expression ofα-1,6-Fucosyltransferase fromRhizobium sp.: Application to the Synthesis of the Trisaccharideβ-D-GlcNAc(1→4)- [α-L-Fuc-(1→6)]-D-GlcNAc, Study of the Acceptor Specificity and Evaluation of Polyhydroxylated Indolizidines as Inhibitors

An efficient heterologous expression system for overproduction of the enzyme alpha-1,6-Fucosyltransferase (alpha-1,6-FucT) from Rhizobium sp. has been developed. The gene codifying for the alpha-1,6-FucT was amplified by PCR using specific primers. After purification, the gene was cloned in the plasmid pKK223-3. The resulting plasmid, pKK1,6FucT, was transformed into the E. coli strain XL1-Blue MRF'. The protein was expressed both as inclusion bodies and in soluble form. Changing the induction time a five-fold increase of enzyme expressed in soluble form was obtained. In this way five units of enzyme alpha-1,6-FucT can be obtained per liter of culture. A crude preparation of the recombinant enzyme was used for the synthesis of the branched trisaccharide alpha-D-GlcNAc-(1-->4)-[alpha-L-Fuc-(1-->6)]-D-GlcNAc (3), from chitobiose (2) and GDP-Fucose (1). After purification, the trisaccharide 3 was obtained in a 84% overall yield. In order to elucidate the structural requirements for the acceptors, the specificity of the enzyme was studied towards mono-, di- and trisaccharides, which are structurally related to chitobiose. The enzyme uses, among others, the disaccharide N-acetyl lactosamine as a good substrate; the monosaccharide GlcNAc is a weak acceptor. Finally, several racemic polyhydroxylated indolizidines have been tested as potential inhibitors of the enzyme. Indolizidine 21 was the best inhibitor with an IC50 of 4.5 x 10(-5) M. Interestingly, this compound turned out to be the best mimic for the structural features of the fucose moiety in the presumed transition state.

ChemInform Abstract: Sugar-Mimic Glycosidase Inhibitors: Natural Occurrence, Biological Activity, and Prospects for Therapeutic Application

Abstract Alkaloids mimicking the structures of monosaccharides are now believed to be widespread in plants and microorganisms, and these sugar mimics inhibit glycosidases because of a structural resemblance to the sugar moiety of the natural substrate. Naturally occurring sugar mimics with a nitrogen in the ring are classified into five structural classes: polyhydroxylated piperidines, pyrrolidines, indolizidines, pyrrolizidines and nortropanes. Glycosidases are involved in a wide range of important biological processes, such as intestinal digestion, post-translational processing of glycoproteins and the lysosomal catabolism of glycoconjugates. The realization that alkaloidal sugar mimics might have enormous therapeutic potential in many diseases such as viral infection, cancer and diabetes has led to increasing interest and demand for these compounds. Most of these effects can be shown to result from the direct or indirect inhibition of glycosidases. The glycosphingolipid (GSL) storage diseases are relatively rare hereditary disorders that are severe in nature and frequently fatal. Possible strategies for the treatment of these lysosomal storage diseases include enzyme replacement therapy, gene therapy and substrate deprivation. Recently, quite a new therapy for lysosomal storage diseases has been reported, namely a ‘chemical chaperone therapy’ for Fabry disease. In this report, the structural basis for the specificity of inhibition of alkaloidal sugar mimics and their current and potential application to biomedical problems will be reviewed.

ChemInform Abstract: Stereoselective Synthesis of Polyhydroxylated Indolizidines from γ‐Hydroxy α,β‐Unsaturated Sulfones.

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Decarbonylation of α-tertiary amino acids application to the synthesis of polyhydroxylated indolizidines from D,L-pipecolic acid

The decarbonylation of the bicyclic α-tertiary carboxamido acid 11 led to the enamide 12, easily transformed into the indolizidine alkaloid 8,8a- trans-8-hydroxy-indolizidine 14. Likewise, the same process applied to the α-substituted pipecolic acid derivative 5 led to the unsaturated ester 6 which was easily transformed either into δ-coniceine 9 or to 14. The thermal fragmentation of the acyl derivative 22 led to the enamide 24 which has been transformed into (±)-swainsonine 26.

Stereoselective Synthesis of Polyhydroxylated Indolizidines from γ-Hydroxy α,β-Unsaturated Sulfones

The polyhydroxylated indolizidines castanospermine and swainsonine as well as some of their stereoisomers are powerful glycosidase inhibitors. An efficient and stereochemically flexible synthesis of racemic 1,7,8-trihydroxylated and 1,6,7,8-tetrahydroxylated indolizidines (castanospermine stereoisomers) from readily available N-substituted γ-oxygenated α,β-unsaturated sulfones 3 and 4 has been developed. The construction of the bicyclic skeleton of 1-hydroxyindolizidine has been accomplished by intramolecular conjugate addition of the nitrogen moiety of 3 and 4 to the α,β-unsaturated sulfone unit to give the pyrrolidine intermediates 5 and 6, followed by formation of the C(7)−C(8) bond by intramolecular acylation (or alkylation) of the α-sulfonyl carbanion. The stereoselectivity of the pyrrolidine synthesis was highly dependent on the bulkiness of the γ-oxygenated function; thus, the free alcohols gave predominantly cis-pyrrolidines while the OTIPS derivatives led to the trans isomers. After straightforward functional group transformations, the removal of the sulfonyl group at C(8) either by Julia reaction or by basic elimination (depending on the substrate used) afforded the key C(7)C(8) unsaturated indolizidines 10, 22, 30, and 31, whose stereoselective dihydroxylations with OsO4 gave a variety of cis C(1)C(8a) and trans C(1)C(8a) trihydroxylated and tetrahydroxylated indolizidines, among which (±)-1,7-di-epi-castanospermine and (±)-1,8-di-epi-castanospermine have been reported for the first time.

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.