Polyhydroxylated Pyrrolidines Research Articles

New Polyhydroxylated Pyrrolidines Derived from Enantiopure 3,6-Dihydro-2H-1,2-oxazines

[reaction: see text] Diastereoselective hydroborations of enantiopure 3,6-dihydro-2H-1,2-oxazines led to dihydroxy-substituted 1,2-oxazines. Samarium diiodide-induced N-O bond cleavage generated 1,4-amino alcohols which were recyclized to polyhydroxylated pyrrolidines which are potential glycosidase inhibitors.

Entropy-Controlled Selectivity in the Vinylation of a Cyclic Chiral Nitrone. An Efficient Route to Enantiopure Polyhydroxylated Pyrrolidines

A short synthesis of 1,4-dideoxy-1,4-imino-L-arabinitol (LAB1) (4) and of 1,4-dideoxy-1,4-imino-D-galactitol (5), two azasugars active as enzymatic inhibitors, is reported. The key reaction is the addition of vinylmagnesium chloride to (3S,4S)-3,4-bis(benzyloxy)-3,4-dihydro-2H-pyrrole 1-oxide (3), a nitrone easily available from L-tartaric acid. Unexpectedly, the reaction affords the corresponding (2S,3S,4S)-1-hydroxy-2-ethenyl-3,4-bis(benzyloxy)pyrrolidine (9) in very good yield and in 93/7 diastereomeric ratio (dr) independently of the reaction temperature, thus representing a unique case of entropy-controlled reaction in a 100 K interval (from +20 degrees C to -80 degrees C). The trans intermediate 9 is converted in two steps (reduction, N-protection) into the common intermediate (2S,3S,4S)-1-(benzyloxycarbonyl)-3,4-bis(benzyloxy)-2-ethenylpyrrolidine (11). Double bond oxidation followed by reductive debenzylation opens a route to the target pyrrolidine azasugars 4 and 5.

ChemInform Abstract: Asymmetric Syntheses of (-)-8-epi-Swainsonine Triacetate and (+)-1,2-Di-epi-swainsonine. Carbonyl Addition Thwarted by an Unprecedented Aza-Pinacol Rearrangement.

Indolizidines (-)-8-epi-swainsonine triacetate and (+)-1, 2-di-epi-swainsonine were synthesized from the O'Donnell Schiff base ester 1 derived from D-serine. Reductive-alkenylation of 1 with (i)()Bu(5)Al(2)H/H(2)C=CHMgBr followed by substrate-directed dihydroxylation of the pendant allylic group with OsO(4), reduction of imine, and cyclization with Ph(3)P/CCl(4) gave the polyhydroxylated pyrrolidines 8a and 8b as advanced intermediates. Efficient protecting group manipulations converted pyrrolidines 8a and 8b to their corresponding partially protected analogues 10a and 10b, which upon Swern oxidation and diastereoselective Keck-type allylation with BF(3).Et(2)O afforded the required three-carbon homologues (10a, >20:1 de; 10b, 3.5:1 de). Use of the chelating Lewis acid MgBr(2) instead of BF(3).Et(2)O with 10a led to a novel aza-pinacol rearrangement and allylation at the alpha-carbon to yield amino alcohol 17, which is similar to a hydride migration in the biosynthetic pathway of indolizidine alkaloids. Subsequent hydroboration, cyclization, and deprotection furnished (-)-8-epi-swainsonine triacetate 15a and (+)-1,2-di-epi-swainsonine 16b in good overall yields (6.3% for 1 --> 15a, 13 steps, and 4.0% for 1 --> 16b, 14 steps).

An efficient, enantioselective synthesis of branched polyhydroxylated pyrrolidines

The enantioselective synthesis of branched polyhydroxylated pyrrolidines from a novel α-methylene bicyclic lactam ( 4b) is described.

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.

Asymmetric syntheses of (-)-8-epi-swainsonine triacetate and (+)-1, 2-Di-epi-swainsonine. Carbonyl addition thwarted by an unprecedented aza-pinacol rearrangement.

Indolizidines (-)-8-epi-swainsonine triacetate and (+)-1, 2-di-epi-swainsonine were synthesized from the O'Donnell Schiff base ester 1 derived from D-serine. Reductive-alkenylation of 1 with (i)()Bu(5)Al(2)H/H(2)C=CHMgBr followed by substrate-directed dihydroxylation of the pendant allylic group with OsO(4), reduction of imine, and cyclization with Ph(3)P/CCl(4) gave the polyhydroxylated pyrrolidines 8a and 8b as advanced intermediates. Efficient protecting group manipulations converted pyrrolidines 8a and 8b to their corresponding partially protected analogues 10a and 10b, which upon Swern oxidation and diastereoselective Keck-type allylation with BF(3).Et(2)O afforded the required three-carbon homologues (10a, >20:1 de; 10b, 3.5:1 de). Use of the chelating Lewis acid MgBr(2) instead of BF(3).Et(2)O with 10a led to a novel aza-pinacol rearrangement and allylation at the alpha-carbon to yield amino alcohol 17, which is similar to a hydride migration in the biosynthetic pathway of indolizidine alkaloids. Subsequent hydroboration, cyclization, and deprotection furnished (-)-8-epi-swainsonine triacetate 15a and (+)-1,2-di-epi-swainsonine 16b in good overall yields (6.3% for 1 --> 15a, 13 steps, and 4.0% for 1 --> 16b, 14 steps).

Flexible Synthesis of Polyhydroxylated 2,2-Disubstituted Pyrrolidines

Many polyhydroxylated pyrrolidines and piperidines have attracted considerable attention because they have been shown to selectively inhibit the oligosaccharide processing enzymes by mimicking the transition state.2 Especially their potential to exhibit antibacterial, antiviral3 and cancerostatic activities4 has led to a tremendous interest and demand for flexible synthetic strategies.

Synthesis of amphiphilic polyhydroxylated pyrrolidines as potential glycosidase inhibitors

Several polyhydroxylated pyrrolidines with an aliphatic long chain on the ring nitrogen were prepared starting from d-mannitol. An amphiphilic bis-azasugar scaffold has been also prepared. These products behave as cationic surfactants and show a promising anti HIV-1 activity.

Syntheses of iminolyxitols via tandem reduction-alkenylation of O'Donnell's Schiff bases

The concise enantioselective synthesis of iminolyxitol glycosidase inhibitors starting from benzophenone imines of D-serine and L-alanine esters is very efficient. The reductive-alkenylation of the Schiff bases followed by substrate-directed dihydroxylation and amino dehydration gave the polyhydroxylated pyrrolidines in excellent overall yields (19.6% for 3 → 8, 9.9% for 9 → 13.)

ChemInform Abstract: 2,5‐Dihydropyrrole Derivatives as Enantiomerically Enriched Building Blocks: Synthesis of the Geissman‐Waiss Lactone and Polyhydroxylated Pyrrolidines.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

2,5-Dihydropyrrole derivatives as enantiomerically enriched building blocks: Synthesis of the Geissman-Waiss lactone and polyhydroxylated pyrrolidines

Starting from enantiomerically pure 2,5-dihydropyrroles substituted at 2-position, efficient stereoselective syntheses of the (+)-Geissman-Waiss lactone and of (+)-1,4,5-trideoxy-1,4-imino-D-ribo-hexitol hydrochloride have been achieved. This work illustrates the high potential of 2,5-dihydropyrroles for the obtention of polyhydroxylated nitrogen heterocycles.

ChemInform Abstract: Synthesis from Lactose of New Enantiomerically Pure Polyhydroxylated Pyrrolidines with Branched Structures.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Enantiospecific and Stereoselective Synthesis of Polyhydroxylated Pyrrolidines and Indolizidines from trans-4-Hydroxy-L-proline.

We have developed a short, efficient, and stereoselective synthesis of polyhydroxylated pyrrolidine and indolizidine glycosidase inhibitors starting from 4-hydroxy-L-proline. The regio- and stereoselective hydroxylation of an N-Pf-4-oxoproline enolate and the stereoselective reduction of the resulting keto alcohol allowed us to introduce the cis diol present in the target compounds. The different side chains needed to complete the syntheses of the target compounds were introduced by reduction of the ester group of a substituted proline or by reaction of organolithium or organomagnesium reagents with the same group followed by stereoselective reduction of the resulting ketones. Hydrogenolysis of the alcohols thus obtained gave the hydrochlorides of the desired pyrrolidine glycosidase inhibitors, which were obtained in nine steps in overall yields greater than 50%. The indolizidine glycosidase inhibitor 8-epi-swainsonine was also prepared using this approach.

Synthesis from lactose of new enantiomerically pure polyhydroxylated pyrrolidines with branched structures

Synthesis from lactose of new enantiomerically pure polyhydroxylated pyrrolidines with branched structures

Enantiospecific synthesis of 3-pyrrolines: A route to novel polyhydroxylated pyrrolidines

Enantiopure acetamido ketones are converted by an intramolecular Wittig reaction into enantiopure 3-pyrrolines; the product from (S)-serine provides access to novel polyhydroxylated pyrrolidines.

The structural basis of the inhibition of human α-mannosidases by azafuranose analogues of mannose

Eight pyrrolidine, five pyrrolizidine and one indolizidine analogue(s) of the known alpha-mannosidase inhibitor, the azafuranose, 1,4-dideoxy-1,4-imino-D-mannitol (DIM), have been tested for inhibition of the multiple forms of alpha-mannosidase in human liver in vitro. Substitution of the ring nitrogen markedly decreased or abolished inhibition, but loss of the C-6 hydroxy group, as in 6-deoxy-DIM and 6-deoxy-6-fluoro-DIM, enhanced inhibition, particularly of the lysosomal alpha-mannosidase. Addition of the anomeric substituent-CH2OH decreased inhibition. To be a potent inhibitor of the lysosomal, Golgi II and neutral alpha-mannosidases, a polyhydroxylated pyrrolidine must have the same substituents and chirality as mannofuranose at C-2, C-3, C-4 and C-5. These four chiral centres can also be part of a polyhydroxylated indolizidine, e.g. swainsonine, but not of a pyrrolizidine, e.g. cyclized DIM, ring-contracted swainsonine or 1,7-diepi-australine. DIM did not inhibit lysosomal alpha-mannosidase intracellularly, but both 6-deoxy-DIM and 6-deoxy-6-fluoro-DIM caused accumulation of partially catabolized glycans in normal human fibroblasts. Analysis of these induced storage products by h.p.l.c. showed that both compounds also inhibited Golgi alpha-mannosidase II and that 6-deoxy-6-fluoro-DIM was also a good inhibitor of the endoplasmic reticulum alpha-mannosidase and specific lysosomal alpha (1-6)-mannosidase. None of the mannofuranose analogues appeared to inhibit Golgi alpha-mannosidase I.

Ketene S,S-acetals as 1,3-dipolarophiles: application to the synthesis of polyhydroxylated pyrrolidines

Two approaches to the synthesis of the hydroxylated pyrrolidines 3 and 4, based on exploiting the reactivity of a ketene S,S-acetal as a 1,3-dipolarophile, are described. Both routes utilize a carbohydrate starting material and the strategy based on D-erythrose was successfully concluded. The use of D-ribose, although not successful in terms of the synthetic objectives, does serve to probe the scope and limitations of ketene S,S-acetals as highly functionalised dipolarophiles.

Polyhydroxylated pyrrolidines from sugar lactomes: Synthesis of 1,4-dideoxy-1,4-imino-d-glucitol from d-galactonolactone and syntheses of 1,4-dideoxy-1,4-imino-d-allitol, 1,4-dideoxy-1,4-imino-d-ribitol, and (2s,3r,4s)-3,4-dihydroxyproline from d-gulonolactone

The use of readily available sugar lactones in the synthesis of polyhydroxylated pyrrolidines is illustrated by the preparation of the glucosidase inhibitor 1,4-dideoxy-1, 4-imino-D-glucitol from D-galactonolactone and by the conversion of D-gulonolactone into 1,4-dideoxy-l,4-imino-D-allitol, 1,4-dideoxy-l,4-imino-D-ribitol, and (2S,3R,4S)-3,4-dihydroxyproline.

Synthesis of some polyhydroxylated pyrrolidine derivatives.

Polyhydroxylated pyrrolidine derivatives, 7, 11, 15, and 18, were synthesized from 4, a. key intermediate for our total synthesis of swainsonine (1). The immunostimulating activities of these new derivatives were found to be moderate and less than that of swainsonine.