Pipecolic Acid Derivatives Research Articles

Structural Genomics Support for Infectious Disease Drug Design.

Structural Genomics Support for Infectious Disease Drug Design.

Nucleophilic Addition Reaction to the Iminium Salts Generated from Pipecolic Acid Derivatives and Application to the Synthesis of Bicyclic Compounds

AbstractNucleophilic addition of Grignard reagents to the iminium salts generated by the oxidation of cyclic amino ketene silyl acetals derived from pipecolic acid gave α‐quaternary amino ester derivatives. Bicyclic compounds were prepared from N‐allylated and homoallylated derivatives with vinylaion, allylation, or homoallylation followed by ring‐closing metathesis. Application of this method to the synthesis of (±)‐S22178, a potent 5‐HT1A agonist, was also described.

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

Enantioselective Diels–Alder Cycloadditions in the Synthesis of Two Enantiomeric Sets of Chiral Polyhydroxylated Pipecolic Acid Derivatives

(2E)-Penta-2,4-dien-1-ol was combined with electrophilic tert-butyl 2H-azirine-3-carboxylate by using a Lewis acid-catalyzed self-assembled Diels–Alder methodology with 1,1′-binaphthalene-2,2′-diol (BINOL) as a chiral inductor. By changing the chirality of the BINOL inductor, both enantiomeric forms of the resulting cycloadducts could be obtained with high enantioselectivities and yields. Simple chemical transformations of the cyclo­adducts gave two types of polyhydroxylated pipecolic acids. The synthetic strategy provides the first reported synthesis of chain-branched pipecolic acids.

ChemInform Abstract: Organocatalytic Enantioselective γ‐Aminoalkylation of Unsaturated Ester: Access to Pipecolic Acid Derivatives.

AbstractA NHC‐catalyzed cyclocondensation of α,β‐unsaturated esters with hydrazones of type (II) is developed to yield enantioenrichend δ‐lactams.

Organocatalytic Enantioselective γ-Aminoalkylation of Unsaturated Ester: Access to Pipecolic Acid Derivatives

The direct γ-carbon functionalization of α,β-unsaturated esters via N-Heterocyclic Carbene (NHC) catalysis is disclosed. This catalytically generated nucleophilic γ-carbon undergoes highly enantioselective additions to hydrazones. The resulting δ-lactam products can be readily transformed to optically enriched pipecolic acid derivatives.

ChemInform Abstract: 6‐Alkynyl‐ and 6‐Aryl‐Substituted (R)‐Pipecolic Acid Derivatives.

AbstractCompound I is derived from (R)‐α‐aminoadipic acid.

6-Alkynyl- and 6-Aryl-Substituted (R)-Pipecolic Acid Derivatives

(R)-α-Aminoadipic acid is a readily available enantiomerically pure starting material for the synthesis of (R)-pipecolic acid and its derivatives. Sonogashira or Suzuki cross-coupling reactions of an N-formyl pipecolate-derived vinyl bromide furnish 6-alkynyl or aryl derivatives. Reduction with sodium cyanoborohydride and subsequent N-deformylation provide 6-alkynyl substituted (R)-pipecolic acid derivatives, valuable building blocks for amino acid and peptide chemistry.

Highly stereoselective cycloadditions of Danishefsky's diene to (−)-8-phenylmenthyl and (+)-8-phenylneomenthyl glyoxylate N-phenylethylimines

Enantiopure 4-oxo-pipecolic acid derivatives were obtained by double asymmetric induction aza-Diels–Alder reactions between chiral glyoxylate N-phenylethylimines and Danishefsky's diene mediated by zinc iodide. The key to success was the use of iminoacetates possessing two chiral auxiliaries, N-(S)- or N-(R)-1-phenylethyl and (−)-8-phenylmenthyl or (+)-8-phenylneomenthyl. Adducts were formed in good yields (78–81%), with complete regioselectivity and high diastereoselectivity (87–96%). The absolute configuration of the adducts formed was unequivocally assigned through NMR, specific optical rotation and X-ray data of appropriated derivatives. These cycloadducts can serve as precursors for bioactive piperidinic azasugars and pipecolic acid derivatives.

Asymmetric Synthesis of Pipecolic Acid and Derivatives

The nonproteinogenic α-amino acid, <sc>l</sc>-pipecolic acid and its derivatives are components of a wide range of pharmacologically active compounds. The significant biological activity of these compounds has resulted in the development of many synthetic approaches for their preparation. This review highlights these key methods as well as the application of these compounds for the preparation of enzyme inhibitors, conformationally restricted building blocks and peptidomimetics. 1 Introduction 2 Chiral Pool Approaches 2.1 From Amino Acids 2.2 From Carbohydrates 3 Asymmetric Reactions 3.1 Auxiliary-Based Approaches 3.2 Catalytic Asymmetric Methods 4 Chemoenzymatic Methods 4.1 Enzymatic Kinetic Resolution 4.2 Miscellaneous Enzymatic Methods 5 Synthesis of Pipecolic Acid Derivatives for Biological Applications 5.1 Synthesis of Novel Medicinal Agents 5.2 Synthesis of Conformationally Restricted Building Blocks (Peptide and Nucleic Acid Mimics) 6 Conclusions

Stereoselective Access to Fluorinated and Non‐fluorinated Quaternary Piperidines: Synthesis of Pipecolic Acid and Iminosugar Derivatives

The preparation of optically pure quaternary piperidines, both fluorinated and non-fluorinated, has been achieved from a chiral imino lactone derived from (R)-phenylglycinol. In the case of the fluorinated derivatives, the addition of (trifluoromethyl)trimethylsilane (TMSCF(3)) followed by iodoamination and migration of the CF(3) group allowed access to four derivatives of α-(trifluoromethyl)pipecolic acid. A theoretical study of the CF(3)-group rearrangement has been carried out to help establish the reaction mechanism of this uncommon transformation. Moreover, a route to trifluoromethyl-substituted iminosugars was also developed through the diastereoselective dihydroxylation of suitable synthetic intermediates. Conversely, alkylation of the starting substrate and subsequent cross-metathesis and aza-Michael reactions led to α-alkyl derivatives of the target compounds.

The effect of a novel frizzled 8-related antiproliferative factor on in vitro carcinoma and melanoma cell proliferation and invasion

Antiproliferative factor (APF) is a potent frizzled protein 8-related sialoglycopeptide inhibitor of bladder epithelial cell proliferation that mediates its activity by binding to cytoskeletal associated protein 4 in the cell membrane. Synthetic asialylated APF (as-APF) (Galβ1-3GalNAcα-O-TVPAAVVVA) was previously shown to inhibit both normal bladder epithelial as well as T24 bladder carcinoma cell proliferation and heparin-binding epidermal growth factor-like growth factor (HB-EGF) production at low nanomolar concentrations, and an L: -pipecolic acid derivative (Galβ1-3GalNAcα-O-TV-pipecolic acid-AAVVVA) was also shown to inhibit normal bladder epithelial cell proliferation. To better determine their spectrum of activity, we measured the effects of these APF derivatives on the proliferation of cells derived from additional urologic carcinomas (bladder and kidney), non-urologic carcinomas (ovary, lung, colon, pancreas, and breast), and melanomas using a (3)H-thymidine incorporation assay. We also measured the effects of as-APF on cell HB-EGF and matrix metalloproteinase (MMP2) secretion plus cell invasion, using qRT-PCR, Western blot and an in vitro invasion assay. L: -pipecolic acid as-APF and/or as-APF significantly inhibited proliferation of each cell line in a dose-dependent manner with IC(50)'s in the nanomolar range, regardless of tissue origin, cell type (carcinoma vs. melanoma), or p53 or ras mutation status. as-APF also inhibited HB-EGF and MMP2 production plus in vitro invasion of tested bladder, kidney, breast, lung, and melanoma tumor cell lines, in a dose-dependent manner (IC(50) = 1-100 nM). Synthetic APF derivatives are potent inhibitors of urologic and non-urologic carcinoma plus melanoma cell proliferation, MMP2 production, and invasion, and may be useful for development as adjunctive antitumor therapy(ies).

Normalization of Proliferation and Tight Junction Formation in Bladder Epithelial Cells from Patients with Interstitial Cystitis/Painful Bladder Syndrome by d‐Proline and d‐Pipecolic Acid Derivatives of Antiproliferative Factor

Interstitial cystitis/painful bladder syndrome is a chronic bladder disorder with epithelial thinning or ulceration, pain, urinary frequency and urgency, for which there is no reliably effective therapy. We previously reported that interstitial cystitis/painful bladder syndrome bladder epithelial cells make a glycopeptide antiproliferative factor or 'APF' (Neu5Acα2-3Galβ1-3GalNAcα-O-TVPAAVVVA) that induces abnormalities in normal cells similar to those in interstitial cystitis/painful bladder syndrome cells in vitro, including decreased proliferation, decreased tight junction formation, and increased paracellular permeability. We screened inactive APF derivatives for their ability to block antiproliferative activity of asialylated-APF ('as-APF') in normal bladder cells and determined the ability of as-APF-blocking derivatives to normalize tight junction protein expression, paracellular permeability, and/or proliferation of interstitial cystitis/painful bladder syndrome cells. Only two of these derivatives [Galβ1-3GalNAcα-O-TV-(d-pipecolic acid)-AAVVVA and Galβ1-3GalNAcα-O-TV-(d-proline)-AAVVVA] blocked as-APF antiproliferative activity in normal cells (p < 0.001 for both). Both of these antagonists also 1) significantly increased mRNA expression of ZO-1, occludin, and claudins 1, 4, 8, and 12 in interstitial cystitis/painful bladder syndrome cells by qRT-PCR; 2) normalized interstitial cystitis/painful bladder syndrome epithelial cell tight junction protein expression and tight junction formation by confocal immunofluorescence microscopy; and 3) decreased paracellular permeability of (14) C-mannitol and (3) H-inulin between confluent interstitial cystitis/painful bladder syndrome epithelial cells on Transwell plates, suggesting that these potent APF antagonists may be useful for the development as interstitial cystitis/painful bladder syndrome therapies.

ChemInform Abstract: Intramolecular Hydroamination of Dithioketene Acetals: An Easy Route to Cyclic Amino Acid Derivatives.

AbstractThe reaction is efficiently achieved in the presence of catalytic BuLi to give proline and pipecolic acid derivatives in good yields.

A Simple and Highly Sensitive HPLC Method with Fluorescent Detection for Determination of Pipecolic Acid in Mouse Brain Areas

A simple and highly sensitive high-performance liquid chromatography method for the determination of pipecolic acid in mouse brain areas was developed. After homogenization of brain and pretreatment with o-phthalaldehyde, the pipecolic acid and (2S,3S)-3-methylpyrrolidine-2-carboxylic acid (internal standard) were derivatized with 4-(5,6-dimethoxy-2-phthalimidinyl)-2-methoxyphenylsulfonyl chloride at 70 °C for 15 min in basic medium (pH 9.0). The fluorescent derivatives of pipecolic acid and internal standard were separated on a reversed-phase column by stepwise elution using acetic acid (30 mM)-acetonitrile at 50 °C and detected by fluorescence measurement at 316 nm (excitation) and 403 nm (emission). The detection limit (signal-to-noise ratio=3) of pipecolic acid was 13 fmol per injection. The recovery was about 106.7%. The precision (relative standard deviation) was 3.2%.

Pipecolic Acid Derivatives As Small-Molecule Inhibitors of the Legionella MIP Protein

The macrophage infectivity potentiator (MIP) protein is a major virulence factor of Legionella pneumophila, the causative agent of Legionnaires' disease. MIP belongs to the FK506-binding proteins (FKBP) and is necessary for optimal intracellular survival and lung tissue dissemination of L. pneumophila. We aimed to identify new small-molecule inhibitors of MIP by starting from known FKBP12 ligands. Computational analysis, synthesis, and biological testing of pipecolic acid derivatives revealed a promising scaffold for new MIP inhibitors.

A derivatization procedure for the simultaneous analysis of iminosugars and other low molecular weight carbohydrates by GC–MS in mulberry (Morus sp.)

Different derivatization procedures were assayed to simultaneously analyse iminosugars such as deoxynojirimycin (DNJ) or fagomine and other carbohydrates of low molecular weight by gas chromatography coupled to mass spectrometry (GC–MS) in Morus sp. Both oximation+trimethylsilylation and oximation+acetylation allowed the separation of target compounds, whereas trimethylsilyl (TMS) and acetylated derivatives showed several coelutions. Nevertheless, oximation+acetylation were discarded for giving inaccurate results for ketoses due to their incomplete derivatization. Different conditions for the conversion into trimethylsilyl oximes (TMSO) were assayed, the best results being achieved using hexamethyldisilazane with trifluoroacetic acid as silylation agent. Contents of iminosugars (DNJ, fagomine and pipecolic acid derivatives) and other carbohydrates such as mono and disaccharides, myo-inositol and galactinol isomers in mulberry extracts (fruits, leaves and branches) were determined by GC–MS using the TMSO procedure.

Intramolecular Hydroamination of Dithioketene Acetals: An Easy Route To Cyclic Amino Acid Derivatives

Catalytic intramolecular hydroamination of dithioketene acetals was developed for the synthesis of cyclic amino acid derivatives. Triggered by the addition of a catalytical amount of n-BuLi, the reaction proceeds to give proline and pipecolic acid derivatives in excellent yields and diastereoselectivity.

Intramolecular Anodic Olefin Coupling Reactions: Use of the Reaction Rate To Control Substrate/Product Selectivity

Look out—it's a trap! The anodic coupling of olefins with amine trapping groups to form proline and pipecolic acid derivatives with a quaternary α carbon atom (see scheme) was successful despite the significantly lower oxidation potential of the product relative to that of either functional group in the substrate: owing to the very fast cyclization, the oxidation potential of the substrate is lower than that of the product. Ts=p-toluenesulfonyl.

ChemInform Abstract: Enantioselective Synthesis of Pipecolic Acid Derivatives via an Ene- Iminium Cyclization.

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