Polyhydroxylated Piperidines Research Articles

Cyclisations and Strategies for Stereoselective Synthesis of Piperidine Iminosugars.

This personal account focuses on synthesis of polyhydroxylated piperidines, a subset of compounds within the iminosugar family. Cyclisations to form the piperidine ring include reductive amination, substitution via amines, iminium ions and cyclic nitrones, transamidification (N-acyl transfer), addition to alkenes, ring contraction and expansion, photoinduced electron transfer, multicomponent Ugi reaction and ring closing metathesis. Enantiomerically pure piperidines are obtained from chiral pool precursors (e. g. sugars, amino acids, Garner's aldehyde) or asymmetric reactions (e. g. epoxidation, dihydroxylation, aminohydroxylation, aldol, biotransformation). Our laboratory have contributed cascades based on reductive amination from glycosyl azide precursors as well as Huisgen azide-alkene cycloaddition. The latter's combination with allylic azide rearrangement has given substituted piperidines, including those with quaternary centres adjacent to nitrogen.

Influence of multiple and cooperative hydrogen bonding on the acidity of polyhydroxylated piperidines: electron density topological analysis

Hydrogen bonds are the presiding concepts for arranging the three-dimensional forms of biological molecules like proteins, carbohydrates, and nucleic acids, and act as guides for proton transfer reactions. Gas-phase acidity and pKa calculations in dimethyl sulfoxide on a line of polyhydroxylated piperidines specify that multiple hydrogen bonds lead to enhance acidities. The gas-phase acidity (GPA) of polyhydroxylated piperidines was investigated by MP2/6-311++G(d,p)//B3LYP/6-311++G(d,p) method. For each structure, varied primary and secondary hydroxyl groups were deprotonated. The natural bond orbital (NBO) and quantum theory of atoms in molecules (QTAIM) analyses have also been used to realize the character of the hydrogen bonding interactions in these compounds. The results show by adding each hydroxyl group, ΔHacid in the gas phase becomes less endothermic and pKa value in the solution phase will decrease. Therefore, intramolecular hydrogen bonds lead to enhance the acid strength. In both the gas and solution phases, the β-nojirimycin-OH2 (β-1-OH2) was found to be the most acidic compound with calculated GPA of 349.4 kcal·mol-1 and the pKa value of 22.0 (8.0 pKa units more acidic than 1-propanol). It was also shown, by applying the polarized continuum model (PCM), there is a superior linear correlation with the GPAs of polyhydroxylated piperidines and their calculated pKa (DMSO) values.

Recent research advances of 1-deoxynojirimycin and its derivatives

The 1-DNJ named 1-deoxynojirimycinis (2R,3R,4R,5S)-2-(hydroxymethyl) piperidine-3,4,5-triol, which is the nature active components existingin mulberryresources including leaves, stems, roots and silkworm larva, silkworm chrysalis, etc.The 1-deoxynojirimycin is a polyhydroxylated piperidine alkaloid, which was first found in Streptomyces as an antibiotic. Then the Japanese researchers isolated it from the mulberry root. 1-DNJ can inhibit postprandial hyperglycemia by suppressing intestinal alpha glucosidase. Therefore, 1-DNJ is often used to treat treating diabetes and complicating disease and to prevent obesity and weight-related disorders. With the development of the researches, 1-deoxynojirimycin and its derivtiv was discovered to possess anti-hyperglycemic, anti-virus, anti-tumor functions and so on. Therefore,based on our current studythe existing knowledge on source, technique preparation process, pharmacokinetics, bioactivties,and in silico target fishing of 1-DNJ were summarized, so that the researchers may use it to explore future perspective of research on 1-DNJ.

Short synthesis of racemic 5-hydroxy-6-hydroxymethylpiperidin-2-one

Abstract A short synthetic sequence to rac-5‑hydroxy‑6-hydroxymethylpiperidin-2-one, a useful intermediate in the synthesis of polyhydroxylated piperidine alkaloids, was based on the hydroboration/oxidation reaction of a 6-furanyl-1,2,3,4-tetrahydropyridine derivative prepared from δ-valerolactam by a Suzuki–Miyaura reaction of the corresponding enol phosphate. Two subsequent RuO2-catalyzed oxidation steps concluded the synthesis. By this approach, the title lactam was readily obtained in a suitably protected form on the nitrogen and oxygen atoms for its further elaboration. All new compounds were fully characterized by NMR spectroscopy and mass spectrometry.

1-Deoxynojirimycin: Sources, Extraction, Analysis and Biological Functions

1-Deoxynojirimycin (DNJ), a natural polyhydroxylated piperidine alkaloid, is attracting growing attention due to its important biological functions. This paper introduces the discovery and origins of DNJ, its extraction, purification, and physiological functions in the treatment of diabetes. The mechanisms of DNJ in the inhibition of fat accumulation and tumor cell metastasis are also discussed. In addition, the prospects and challenges of DNJ for practical production are proposed. This work aims to provide technical advice on obtaining DNJ and a fuller understanding of its biological activities.

A common approach to the total synthesis of l-1-deoxyallonojirimycin, l-homo-1-deoxyazaallose and triacetyl derivative of 5-epi hyacinthacine A5

A common strategy for the synthesis of polyhydroxylated piperidines l-1-deoxyallonojirimycin, l-homo-1-deoxyazaallose and triacetyl derivative of 5-epi hyacinthacine A5 from the readily available d-ribose as a starting material has been described.

Concise and highly stereoselective syntheses of d-fagomine and 2-epi-fagomine

Highly stereoselective total syntheses of polyhydroxylated piperidines d-fagomine and 2-epi-fagomine have been developed starting from 3,4,6-tri-O-benzyl-d-glucal which is a derivative of d-Glucose. Key steps in the synthesis of these azasugars involved N-Boc-protected amine preparation from oxime followed by stereo specific iodination of alcohol and cascade cyclization triggered by N-Boc deprotection.

Synthesis of Polyhydroxylated Piperidine and Pyrrolidine Peptidomimetics via One-Pot Sequential Lactam Reduction/Joullié–Ugi Reaction

A direct approach to the synthesis of polyhydroxylated piperidine and pyrrolidine peptidomimetics is described. The presented strategy is based on one-pot reduction of sugar-derived lactams with Schwartz's reagent followed by a multicomponent Ugi-Joullié reaction.

Asymmetric syntheses of (-)-3-epi-Fagomine, (2R,3S,4R)-dihydroxypipecolic acid, and several polyhydroxylated homopipecolic acids.

A range of enantiopure polyhydroxylated piperidines, including (2R,3S,4R)-dihydroxypipecolic acid, (-)-3-epi-fagomine, (2S,3S,4R)-dihydroxyhomopipecolic acid, (2S,3R,4R)-dihydroxyhomopipecolic acid, and two trihydroxy-substituted homopipecolic acids, have been prepared using diastereoselective olefinic oxidations of a range of enantiopure tetrahydropyridines as the key step. The requisite substrates were readily prepared from tert-butyl sorbate using our diastereoselective hydroamination or aminohydroxylation protocols followed by ring-closing metathesis. After diastereoselective olefinic oxidation of the resultant enantiopure tetrahydropyridines and deprotection, enantiopure polyhydroxylated piperidines were isolated as single diastereoisomers (>99:1 dr) in good overall yield.

Sequential Biocatalytic Aldol Reactions in Multistep Asymmetric Synthesis: Pipecolic Acid, Piperidine and Pyrrolidine (Homo)Iminocyclitol Derivatives from Achiral Building Blocks

AbstractA multistep chemoenzymatic synthesis for stereodiverse polyhydroxypipecolic acid analogues, homoiminocyclitols and polyhydroxylated piperidine and pyrrolidine derivatives combining glycine‐dependent aldolases and both D‐fructose‐6‐phosphate aldolase (FSA) or dihydroxyacetone phosphate (DHAP)‐dependent aldolases is presented. The methodology allowed the preparation of known and innovative imine‐derived molecules with a great structural diversity from simple achiral substrates. The strategy consisted of two key aldol addition steps: a first aldol addition of glycine to dimethoxyacetaldehyde catalyzed by L‐ and D‐glycine aldolases and a second aldol addition of DHAP, dihydroxyacetone, hydroxyacetone or glycolaldehyde using FSA or DHAP‐dependent aldolases as catalysts to a conveniently transformed aldol adduct from the first aldol addition. Catalytic reductive amination on the aldol adducts rendered the polyhydroxypipecolic acid analogues, (homo)iminocyclitols and polyhydroxylated pyrrolidine iminocyclitols. The reported strategy is thus designed to create up to five new stereogenic centers in three steps, four of them being controlled in two enzymatic reactions. Moreover, it allowed the installation of diverse functionalities in the molecules. This was possible by taking the full advantage of using aldolases in a multistep approach by virtue of their stereocomplementarity, stereoselectivity and broad substrate tolerance.magnified image

Novel 2-aryl-3,4,5-trihydroxypiperidines: Synthesis and glycosidase inhibition

Three pairs of novel 2-aryl-3,4,5-trihydroxypiperidines (6–8 and their enantiomers), the piperidine analogues of the pyrrolidine alkaloids radicamine A and radicamine B, were prepared from six-membered cyclic nitrones through a concise two-step procedure, i.e., Grignard reagent addition and deprotection. These novel polyhydroxylated piperidine iminosugars were assayed against 10 types of enzymes. Only compound 8 exhibited weak inhibition (IC50 1080 μmol/L) against β-galactosidase from rat intestinal lactases.

A concise synthesis of (5R,6S)-tert-butyl 5-acetoxy-6-(hydroxymethyl)-5,6-dihydropyridine-1(2H)-carboxylate

An efficient synthesis of (5 R,6 S)-tert -butyl 5-acetoxy-6-(hydroxymethyl)-5,6-dihydropyridine- 1(2 H)-carboxylate 1, a common intermediate for various polyhydroxylated piperidines is reported in six steps with 32% overall yield starti ng from Garner's aldehyde. The key steps include the diastereoselective nucleophilic additio n and intramolecular cyclization. (5 R,6 S)-tert - butyl 5-acetoxy-6-(hydroxymethyl)-5,6-dihydropyridine-1(2 H)-carboxylate is a common precursor for the synthesis of 1-deoxy- L-mannojirimycin, 1-deoxy-L-idonojirimycin, L- fagomycin and related analogues.

Hydroxymethyl‐Branched Piperidines from Hydroxymethyl‐Branched Lactones: Synthesis and Biological Evaluation of 1,5‐Dideoxy‐2‐C‐hydroxymethyl‐1,5‐imino‐D‐mannitol, 1,5‐Dideoxy‐2‐C‐hydroxymethyl‐1,5‐imino‐L‐gulitol and 1,5‐Dideoxy‐2‐C‐hydroxymethyl‐1,5‐imino‐D‐talitol

AbstractThree homochiral polyhydroxylated piperidines containing a quaternary carbon branch at C‐2 of the heterocyclic ring, which can be considered as branched analogues of deoxymannorijimycin (DMJ), and their corresponding lactams were synthesised from readily available and versatile carbohydrate lactones containing a 2‐C‐hydroxymethyl branch. The key step in the synthesis of these iminosugars, 1,5‐dideoxy‐2‐C‐hydroxymethyl‐1,5‐imino‐D‐mannitol, 1,5‐dideoxy‐2‐C‐hydroxymethyl‐1,5‐imino‐L‐gulitol and 1,5‐dideoxy‐2‐C‐hydroxymethyl‐1,5‐imino‐D‐talitol, was an efficient modified Kiliani reaction performed on the readily available ketose starting materials L‐sorbose and D‐fructose. The introduction of the carbon branch at C‐2 resulted in loss of glycosidase inhibitory activity, which could be advantageous for therapeutic use of such compounds as chaperones.

Aza-Claisen rearrangement of 2-C-hydroxymethyl glycals as a versatile strategy towards synthesis of isofagomine and related biologically important azasugars

Synthesis of isofagomine has been achieved by implementation of aza-Claisen rearrangement of 2-C-hydroxymethyl glycals as a key step. The above rearrangement has also been utilized in the synthesis of biologically important polyhydroxylated piperidine frameworks such as isogalactofagomine, ent-isogalactofagomine and their analogues and some other azasugars as glycosidase inhibitors.

Enantioselective Synthesis of Deoxymannojirimycin Based on Sharpless Asymmetric Epoxidation of a Highly Functionalized Allylic Alcohol

AbstractAn efficient enantioselective synthesis of deoxymannojirimicin is reported. It is based on the unusual Sharpless asymmetric epoxidation of a silyl‐substituted allylic 1,4‐amino alcohol coupled with a further highly stereoselective intramolecular aldolization. Both enantiomers of deoxymannojirimicin are available. An orthogonally protected polyhydroxylated piperidine was prepared, which could formally lead to other members of this piperidine family.

Syntheses and Biological Activities of Iminosugars as α-L-Fucosidase Inhibitors

A review dealing with iminosugars as inhibitors of α-L-fucosidases is presented. The different synthetic approaches for the preparation of the most relevant ones as well as their inhibitory properties are presented. Keywords: Azafagomines, hydroxylated azepanes, piperidines, pyrrolidines, fucosidase inhibitors, iminosugars, azasugars, L-Fucosidase Inhibitors, glycosylation, glycosylation reactions, hydrolysis, glycoconjugates, carcinomas, L-fucosidases, Thermotoga maritima, Thermotoga maritima enzyme, iminocyclitols, hydrophobic, POLYHYDROXYLATED PYRROLIDINES, meso-pyrrolidine 1, human placenta, chromatography, Holzapfel, Crous method, Oxime, Bayon's method, pyrrolidinethylphosphonate, nitrone, Cope-House cyclization, tetraacetate, POLYHYDROXYLATED PIPERIDINES, POLYHYDROXYHEXAHYDROPYRIDAZINES, POLYHYDROXYAZEPANES

Asymmetric aza-Michael addition under ultra-high pressure: short bias to polyhydroxylated piperidines

Two polyhydroxylated piperidines have been prepared in short sequences from diacetone gluco- and allofuranose. The key step is a piezo-aza-Michael addition of diphenylmethanamine to enoates bearing a sugar moiety in the γ-position. The combination of ultra-high pressure associated to the presence of readily available sugars chiral pool led to the expected chiral amines in good yields and excellent stereoselectivities.

ChemInform Abstract: Piperidine Analogues of D-Galactose as Potent Inhibitors of α-Galactosidase: Synthesis by Stannane-Mediated Hydroxymethylation of 5-Azido-1,4-lactones. Structural Relationships Between D-Galactosidase and L-Rhamnosidase Inhibitors.

The syntheses of the polyhydroxylated piperidines deoxygalactonojirimycin 2, homogalactonojirimycins 7 and 9, and other 2,6-iminoheptitol derivatives, including an analogue of L-altropyranose, are reported. 5-Azidoaldono-1,4-lactones undergo chain extension to afford azido lactols by the addition of a hydroxymethyllithium species 18, generated by transmetallation of a protected stannylmethanol derivative 17. Hydrogenation results in azide reduction with subsequent intramolecular reductive amination to give piperidine ring systems. The deprotected iminogalactopyranose analogues are potent and selective α-galactosidase inhibitors. Observations on the structural features determining selectivity of inhibition of α-galactosidases over naringinase (L-rhamnosidase) are also reported.

Chemistry and Biology of Iminosugar Di- and Oligosaccharides

This review will describe the recent advances in the field of oligosaccharides containing at least one unit of a polyhydroxylated piperidine or pyrrolidine. The review will cover both chemical and biological aspects concerning their preparation and/or occurrence in Nature as well as their biological properties which include glycosylase, and glycosyl transferase inhibition, among others. These enzymatic inhibitory properties are the basis for the potential use of the title compounds in viral infections, cancer and genetic disorders.

Stereoselective Synthesis of L-Deoxyaltronojirimycin from L-Serine

(2S,3R)-3-Hydroxy-2-(hydroxymethyl)-3,6-dihydro-2H-pyridine 8, an important precursor for the synthesis of polyhydroxylated piperidine azasugars, has been prepared from L -serine. Highly stereoselective nucleophilic addition to amino aldehyde 5 gave the corresponding allylic alcohol 6 which proceeded to give dihydro-2H-piridine 7a via a Grubbs 11 catalyzed RCM. Stereoselective H-bond directed epoxidation of allylic alcohol led to the oxiranyl alcohol 9 which was easily converted to L-deoxyaltronojirimycin by regioselective ring opening.