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Search for "pipecolic acid" in Full Text gives 11 result(s) in Beilstein Journal of Organic Chemistry.
A versatile route towards 6-arylpipecolic acids
- Erich Gebel,
- Cornelia Göcke,
- Carolin Gruner and
- Norbert Sewald
Beilstein J. Org. Chem. 2025, 21, 1104–1115, doi:10.3762/bjoc.21.88
- Erich Gebel Cornelia Gocke Carolin Gruner Norbert Sewald Department of Chemistry, Organic and Bioorganic Chemistry, Bielefeld University, Universitätsstraße 25, D-33615 Bielefeld, Germany 10.3762/bjoc.21.88 Abstract Pipecolic acid is known as a non-proteinogenic amino acid with a secondary amine
- . It contains a six-membered ring and is, like its five-membered correlate, known for its secondary structure inducing properties, which are particularly useful in the design of peptide conformations. We present a new and improved way to generate enantiomerically pure pipecolic acid derivatives with
- accordance with coupling constants and resulting dihedral angles. Keywords: conformational restraints; dihedral angle NMR; half-chair conformation; modified amino acids; pipecolic acid; stereoselective hydrogenation; Suzuki–Miyaura cross-coupling; Introduction Non-proteinogenic amino acids play an
Graphical Abstract
Scheme 1: ᴅ-2-Aminoadipic acid (1) can be used to generate C6 aryl and alkynyl-modified pipecolic acid deriva...
Scheme 2: Methyl ester formation, followed by cyclization, N-formylation, as well as bromination under Vilsme...
Scheme 3: Suzuki–Miyaura cross-coupling reaction between bromide 2 and a variety of boronic acids 8.
Scheme 4: Reaction of 3a to (2R,6S)-9a and (2R,6R)-9a. The chromatograms prove the simple diastereoselection.
Figure 1: The minor diastereomer of the catalytic hydrogenation was assigned as (2R,6R)-9, based on the analy...
Figure 2: 1H NMR spectra with both signal sets for the chair and half-chair configuration as well as Newman p...
Figure 3: 1H NMR spectra with signal set for the chair configuration as well as Newman projection for both pr...
Scheme 5: a) Sonogashira–Hagihara cross-coupling reaction followed by b) NaBH3CN reduction of the N-acylimini...
Figure 4: 1H NMR with Newman projection for both protons H2 and H6 with corresponding dihedral angles ϕ for a...
Scheme 6: Overview of reduction and deprotection to the final pipecolic acid derivatives (2R,6S)-5.
Origami with small molecules: exploiting the C–F bond as a conformational tool
- Patrick Ryan,
- Ramsha Iftikhar and
- Luke Hunter
Beilstein J. Org. Chem. 2025, 21, 680–716, doi:10.3762/bjoc.21.54
- protonated amine. These conformational changes alter the DNA-binding mode, such that the pyrrolidine NH groups of 95 now interact with the DNA phosphates rather than the bases or the sugars [164]. Progressing now to a six-membered ring system, consider the scaffold, pipecolic acid (96, Figure 11) [165][166
Graphical Abstract
Figure 1: Fundamental characteristics of the C–F bond.
Figure 2: Incorporation of fluorine at the end of an alkyl chain.
Figure 3: Incorporation of fluorine into the middle of a linear alkyl chain.
Figure 4: Incorporation of fluorine across much, or all, of a linear alkyl chain.
Figure 5: Incorporation of fluorine into cycloalkanes.
Figure 6: Conformational effects of introducing fluorine into an ether (geminal to oxygen).
Figure 7: Conformational effects of introducing fluorine into an ether (vicinal to oxygen).
Figure 8: Effects of introducing fluorine into alcohols (and their derivatives).
Figure 9: Controlling the ring pucker of sugars through fluorination.
Figure 10: Controlling bond rotations outside the sugar ring through fluorination.
Figure 11: Effects of incorporating fluorine into amines.
Figure 12: Effects of incorporating fluorine into amine derivatives, such as amides and sulfonamides.
Figure 13: Effects of incorporating fluorine into organocatalysts.
Figure 14: Effects of incorporating fluorine into carbonyl compounds, focusing on the “carbon side.”
Figure 15: Fluoroproline-containing peptides and proteins.
Figure 16: Further examples of fluorinated linear peptides (besides fluoroprolines). For clarity, sidechains a...
Figure 17: Fluorinated cyclic peptides.
Figure 18: Fluorine-derived conformational control in sulfur-containing compounds.
Inline purification in continuous flow synthesis – opportunities and challenges
- Jorge García-Lacuna and
- Marcus Baumann
Beilstein J. Org. Chem. 2022, 18, 1720–1740, doi:10.3762/bjoc.18.182
- excellent route for the efficient and cost-effective preparation of different building blocks including nucleoside derivatives and ʟ-pipecolic acid. High efficiency was achieved with simple trapping columns downstream of the biocatalytic process, to separate the pure products from the mixture and
Graphical Abstract
Scheme 1: Automated in-line chromatography with the Advion puriFlash® system. The rightmost part of the schem...
Scheme 2: Purification via pH tuning and several Zaiput membranes. Redrawn from [51].
Scheme 3: Two-phase recirculating system for purifications of an immobilized enzyme-based reaction. Redrawn f...
Scheme 4: Countercurrent L–L purification using large Zaiput membranes in the presence of a phase transfer ca...
Scheme 5: General scheme of a telescoped flow process using L–L separators.
Scheme 6: Example of phase separation using a computer-vision approach. Redrawn from [68].
Scheme 7: Example of an inline purification using heterogeneous scavenging. Redrawn from [76].
Scheme 8: General scheme of a telescoped process using heterogenous cartridges.
Scheme 9: Comparison of two strategies for flow-based imatinib syntheses. Redrawn from [91] and [92].
Scheme 10: General purification scheme using the catch and release strategy.
Scheme 11: Exemplar catch and release purification of a stereoselective oxidation. Redrawn from [105].
Scheme 12: Catch and release-type purification using conventional SiO2. Redrawn from [107].
Scheme 13: Schematic representation of an industrial continuous crystallization. Redrawn from [109].
Scheme 14: General scheme of an academic inline crystallization approach.
Scheme 15: Simplified overview of purification options and selected criteria.
Synthesis of (−)-halichonic acid and (−)-halichonic acid B
- Keith P. Reber and
- Emma L. Niner
Beilstein J. Org. Chem. 2022, 18, 1629–1635, doi:10.3762/bjoc.18.174
- Axinyssa sp. along with the structurally related compound halichonic acid B ((+)-2) [5]. Structurally, (+)-2 is a pipecolic acid derivative containing a cyclohexenyl ring as a substituent group. This compound also features four stereogenic centers (three of which are located within the piperidine ring) and
Graphical Abstract
Figure 1: Structures of halichonic acid ((+)-1) and halichonic acid B ((+)-2).
Scheme 1: Synthesis of (−)-7-amino-7,8-dihydrobisabolene (4) and its conversion to cyclization precursor 7.
Scheme 2: Synthesis of the halichonic acids via a key intramolecular aza-Prins cyclization.
Scheme 3: Proposed intermediates for the intramolecular aza-Prins reaction leading to the formation of ethyl ...
Biochemistry of fluoroprolines: the prospect of making fluorine a bioelement
- Vladimir Kubyshkin,
- Rebecca Davis and
- Nediljko Budisa
Beilstein J. Org. Chem. 2021, 17, 439–460, doi:10.3762/bjoc.17.40
- , such as pipecolic acid [66]. In E. coli, the catabolism of proline occurs via the action of the bifunctional enzyme putA (Figure 9B) [67]. It sequentially degrades proline to glutamate, which can be later deaminated to an essential metabolite, α-ketoglutarate, with many metabolic options, such as an
Graphical Abstract
Figure 1: The structures of the fluoroprolines discussed herein.
Figure 2: The distinction between “the alanine and the proline worlds”. While the polyalanine backbone leads ...
Figure 3: Molecular volume for 20 coded amino acids and fluoroprolines. The COSMO volume was calculated for a...
Figure 4: Comparative analysis of the electrostatic potential for proline and fluoroprolines (electrostatic p...
Figure 5: Experimental logP data for methyl esters of N-acetylamino acids.
Figure 6: The conformational dependence of the proline ring on the fluorination at position 4.
Figure 7: Rotation around the peptidyl-prolyl fragments in polypeptide structures is important for correct ov...
Figure 8: The complex fate of a protein-encoded amino acid in the cell (EF-Tu – elongation factor thermo unst...
Figure 9: Metabolic routes for proline in E. coli. A) Synthesis of proline and B) degradation of proline.
Figure 10: A complete flowchart for the proline incorporation into proteins during ribosomal biosynthesis. A) ...
Figure 11: Amide bond formation capacities of fluoroprolines compared to some coded amino acids measured on ri...
Figure 12: Ribbon representation of the X-ray crystal structures of proteins containing fluoroprolines. A) Enh...
Figure 13: Problems and phenomena associated with the production of a protein-containing proline-to-fluoroprol...
Figure 14: Effects of fluoroprolines on recombinant protein expression using the auxotrophic expression host E...
Figure 15: A) Experimental setup for the incorporation of fluoroprolines into proteins. B) Adaptive laboratory...
Recent advances on the transition-metal-catalyzed synthesis of imidazopyridines: an updated coverage
- Gagandeep Kour Reen,
- Ashok Kumar and
- Pratibha Sharma
Beilstein J. Org. Chem. 2019, 15, 1612–1704, doi:10.3762/bjoc.15.165
Graphical Abstract
Figure 1: Various drugs having IP nucleus.
Figure 2: Participation percentage of various TMs for the syntheses of IPs.
Scheme 1: CuI–NaHSO4·SiO2-catalyzed synthesis of imidazo[1,2-a]pyridines.
Scheme 2: Experimental examination of reaction conditions.
Scheme 3: One-pot tandem reaction for the synthesis of 2-haloimidazopyridines.
Scheme 4: Mechanistic scheme for the synthesis of 2-haloimidazopyridine.
Scheme 5: Copper-MOF-catalyzed three-component reaction (3-CR) for imidazo[1,2-a]pyridines.
Scheme 6: Mechanism for copper-MOF-driven synthesis.
Scheme 7: Heterogeneous synthesis via titania-supported CuCl2.
Scheme 8: Mechanism involving oxidative C–H functionalization.
Scheme 9: Heterogeneous synthesis of IPs.
Scheme 10: One-pot regiospecific synthesis of imidazo[1,2-a]pyridines.
Scheme 11: Vinyl azide as an unprecedented substrate for imidazo[1,2-a]pyridines.
Scheme 12: Radical pathway.
Scheme 13: Cu(I)-catalyzed transannulation approach for imidazo[1,5-a]pyridines.
Scheme 14: Plausible radical pathway for the synthesis of imidazo[1,5-a]pyridines.
Scheme 15: A solvent-free domino reaction for imidazo[1,2-a]pyridines.
Scheme 16: Cu-NPs-mediated synthesis of imidazo[1,2-a]pyridines.
Scheme 17: CuI-catalyzed synthesis of isoxazolylimidazo[1,2-a]pyridines.
Scheme 18: Functionalization of 4-bromo derivative via Sonogashira coupling reaction.
Scheme 19: A plausible reaction pathway.
Scheme 20: Cu(I)-catalyzed intramolecular oxidative C–H amidation reaction.
Scheme 21: One-pot synthetic reaction for imidazo[1,2-a]pyridine.
Scheme 22: Plausible reaction mechanism.
Scheme 23: Cu(OAc)2-promoted synthesis of imidazo[1,2-a]pyridines.
Scheme 24: Mechanism for aminomethylation/cycloisomerization of propiolates with imines.
Scheme 25: Three-component synthesis of imidazo[1,2-a]pyridines.
Figure 3: Scope of pyridin-2(1H)-ones and acetophenones.
Scheme 26: CuO NPS-promoted A3 coupling reaction.
Scheme 27: Cu(II)-catalyzed C–N bond formation reaction.
Scheme 28: Mechanism involving Chan–Lam/Ullmann coupling.
Scheme 29: Synthesis of formyl-substituted imidazo[1,2-a]pyridines.
Scheme 30: A tandem sp3 C–H amination reaction.
Scheme 31: Probable mechanistic approach.
Scheme 32: Dual catalytic system for imidazo[1,2-a]pyridines.
Scheme 33: Tentative mechanism.
Scheme 34: CuO/CuAl2O4/ᴅ-glucose-promoted 3-CCR.
Scheme 35: A tandem CuOx/OMS-2-based synthetic strategy.
Figure 4: Biomimetic catalytic oxidation in the presence of electron-transfer mediators (ETMs).
Scheme 36: Control experiment.
Scheme 37: Copper-catalyzed C(sp3)–H aminatin reaction.
Scheme 38: Reaction of secondary amines.
Scheme 39: Probable mechanistic pathway.
Scheme 40: Coupling reaction of α-azidoketones.
Scheme 41: Probable pathway.
Scheme 42: Probable mechanism with free energy calculations.
Scheme 43: MCR for cyanated IP synthesis.
Scheme 44: Substrate scope for the reaction.
Scheme 45: Reaction mechanism.
Scheme 46: Probable mechanistic pathway for Cu/ZnAl2O4-catalyzed reaction.
Scheme 47: Copper-catalyzed double oxidative C–H amination reaction.
Scheme 48: Application towards different coupling reactions.
Scheme 49: Reaction mechanism.
Scheme 50: Condensation–cyclization approach for the synthesis of 1,3-diarylated imidazo[1,5-a]pyridines.
Scheme 51: Optimized reaction conditions.
Scheme 52: One-pot 2-CR.
Scheme 53: One-pot 3-CR without the isolation of chalcone.
Scheme 54: Copper–Pybox-catalyzed cyclization reaction.
Scheme 55: Mechanistic pathway catalyzed by Cu–Pybox complex.
Scheme 56: Cu(II)-promoted C(sp3)-H amination reaction.
Scheme 57: Wider substrate applicability for the reaction.
Scheme 58: Plausible reaction mechanism.
Scheme 59: CuI assisted C–N cross-coupling reaction.
Scheme 60: Probable reaction mechanism involving sp3 C–H amination.
Scheme 61: One-pot MCR-catalyzed by CoFe2O4/CNT-Cu.
Scheme 62: Mechanistic pathway.
Scheme 63: Synthetic scheme for 3-nitroimidazo[1,2-a]pyridines.
Scheme 64: Plausible mechanism for CuBr-catalyzed reaction.
Scheme 65: Regioselective synthesis of halo-substituted imidazo[1,2-a]pyridines.
Scheme 66: Synthesis of 2-phenylimidazo[1,2-a]pyridines.
Scheme 67: Synthesis of diarylated compounds.
Scheme 68: CuBr2-mediated one-pot two-component oxidative coupling reaction.
Scheme 69: Decarboxylative cyclization route to synthesize 1,3-diarylimidazo[1,5-a]pyridines.
Scheme 70: Mechanistic pathway.
Scheme 71: C–H functionalization reaction of enamines to produce diversified heterocycles.
Scheme 72: A plausible mechanism.
Scheme 73: CuI-promoted aerobic oxidative cyclization reaction of ketoxime acetates and pyridines.
Scheme 74: CuI-catalyzed pathway for the formation of imidazo[1,2-a]pyridine.
Scheme 75: Mechanistic pathway.
Scheme 76: Mechanistic rationale for the synthesis of products.
Scheme 77: Copper-catalyzed synthesis of vinyloxy-IP.
Scheme 78: Regioselective product formation with propiolates.
Scheme 79: Proposed mechanism for vinyloxy-IP formation.
Scheme 80: Regioselective synthesis of 3-hetero-substituted imidazo[1,2-a]pyridines with different reaction su...
Scheme 81: Mechanistic pathway.
Scheme 82: CuI-mediated synthesis of 3-formylimidazo[1,2-a]pyridines.
Scheme 83: Radical pathway for 3-formylated IP synthesis.
Scheme 84: Pd-catalyzed urea-cyclization reaction for IPs.
Scheme 85: Pd-catalyzed one-pot-tandem amination and intramolecular amidation reaction.
Figure 5: Scope of aniline nucleophiles.
Scheme 86: Pd–Cu-catalyzed Sonogashira coupling reaction.
Scheme 87: One-pot amide coupling reaction for the synthesis of imidazo[4,5-b]pyridines.
Scheme 88: Urea cyclization reaction for the synthesis of two series of pyridines.
Scheme 89: Amidation reaction for the synthesis of imidazo[4,5-b]pyridines.
Figure 6: Amide scope.
Scheme 90: Pd NPs-catalyzed 3-component reaction for the synthesis of 2,3-diarylated IPs.
Scheme 91: Plausible mechanistic pathway for Pd NPs-catalyzed MCR.
Scheme 92: Synthesis of chromenoannulated imidazo[1,2-a]pyridines.
Scheme 93: Mechanism for the synthesis of chromeno-annulated IPs.
Scheme 94: Zinc oxide NRs-catalyzed synthesis of imidazo[1,2-a]azines/diazines.
Scheme 95: Zinc oxide-catalyzed isocyanide based GBB reaction.
Scheme 96: Reaction pathway for ZnO-catalyzed GBB reaction.
Scheme 97: Mechanistic pathway.
Scheme 98: ZnO NRs-catalyzed MCR for the synthesis of imidazo[1,2-a]azines.
Scheme 99: Ugi type GBB three-component reaction.
Scheme 100: Magnetic NPs-catalyzed synthesis of imidazo[1,2-a]pyridines.
Scheme 101: Regioselective synthesis of 2-alkoxyimidazo[1,2-a]pyridines catalyzed by Fe-SBA-15.
Scheme 102: Plausible mechanistic pathway for the synthesis of 2-alkoxyimidazopyridine.
Scheme 103: Iron-catalyzed synthetic approach.
Scheme 104: Iron-catalyzed aminooxygenation reaction.
Scheme 105: Mechanistic pathway.
Scheme 106: Rh(III)-catalyzed double C–H activation of 2-substituted imidazoles and alkynes.
Scheme 107: Plausible reaction mechanism.
Scheme 108: Rh(III)-catalyzed non-aromatic C(sp2)–H bond activation–functionalization for the synthesis of imid...
Scheme 109: Reactivity and selectivity of different substrates.
Scheme 110: Rh-catalyzed direct C–H alkynylation by Li et al.
Scheme 111: Suggested radical mechanism.
Scheme 112: Scandium(III)triflate-catalyzed one-pot reaction and its mechanism for the synthesis of benzimidazo...
Scheme 113: RuCl3-assisted Ugi-type Groebke–Blackburn condensation reaction.
Scheme 114: C-3 aroylation via Ru-catalyzed two-component reaction.
Scheme 115: Regioselective synthetic mechanism.
Scheme 116: La(III)-catalyzed one-pot GBB reaction.
Scheme 117: Mechanistic approach for the synthesis of imidazo[1,2-a]pyridines.
Scheme 118: Synthesis of imidazo[1,2-a]pyridine using LaMnO3 NPs under neat conditions.
Scheme 119: Mechanistic approach.
Scheme 120: One-pot 3-CR for regioselective synthesis of 2-alkoxy-3-arylimidazo[1,2-a]pyridines.
Scheme 121: Formation of two possible products under optimization of the catalysts.
Scheme 122: Mechanistic strategy for NiFe2O4-catalyzed reaction.
Scheme 123: Two-component reaction for synthesizing imidazodipyridiniums.
Scheme 124: Mechanistic scheme for the synthesis of imidazodipyridiniums.
Scheme 125: CuI-catalyzed arylation of imidazo[1,2-a]pyridines.
Scheme 126: Mechanism for arylation reaction.
Scheme 127: Cupric acetate-catalyzed double carbonylation approach.
Scheme 128: Radical mechanism for double carbonylation of IP.
Scheme 129: C–S bond formation reaction catalyzed by cupric acetate.
Scheme 130: Cupric acetate-catalyzed C-3 formylation approach.
Scheme 131: Control experiments for signifying the role of DMSO and oxygen.
Scheme 132: Mechanism pathway.
Scheme 133: Copper bromide-catalyzed CDC reaction.
Scheme 134: Extension of the substrate scope.
Scheme 135: Plausible radical pathway.
Scheme 136: Transannulation reaction for the synthesis of imidazo[1,5-a]pyridines.
Scheme 137: Plausible reaction pathway for denitrogenative transannulation.
Scheme 138: Cupric acetate-catalyzed C-3 carbonylation reaction.
Scheme 139: Plausible mechanism for regioselective C-3 carbonylation.
Scheme 140: Alkynylation reaction at C-2 of 3H-imidazo[4,5-b]pyridines.
Scheme 141: Two-way mechanism for C-2 alkynylation of 3H-imidazo[4,5-b]pyridines.
Scheme 142: Palladium-catalyzed SCCR approach.
Scheme 143: Palladium-catalyzed Suzuki coupling reaction.
Scheme 144: Reaction mechanism.
Scheme 145: A phosphine free palladium-catalyzed synthesis of C-3 arylated imidazopyridines.
Scheme 146: Palladium-mediated Buchwald–Hartwig cross-coupling reaction.
Figure 7: Structure of the ligands optimized.
Scheme 147: Palladium acetate-catalyzed direct arylation of imidazo[1,2-a]pyridines.
Scheme 148: Palladium acetate-catalyzed mechanistic pathway.
Scheme 149: Palladium acetate-catalyzed regioselective arylation reported by Liu and Zhan.
Scheme 150: Mechanism for selective C-3 arylation of IP.
Scheme 151: Pd(II)-catalyzed alkenylation reaction with styrenes.
Scheme 152: Pd(II)-catalyzed alkenylation reaction with acrylates.
Scheme 153: A two way mechanism.
Scheme 154: Double C–H activation reaction catalyzed by Pd(OAc)2.
Scheme 155: Probable mechanism.
Scheme 156: Palladium-catalyzed decarboxylative coupling.
Scheme 157: Mechanistic cycle for decarboxylative arylation reaction.
Scheme 158: Ligand-free approach for arylation of imidazo[1,2-a]pyridine-3-carboxylic acids.
Scheme 159: Mechanism for ligandless arylation reaction.
Scheme 160: NHC-Pd(II) complex assisted arylation reaction.
Scheme 161: C-3 arylation of imidazo[1,2-a]pyridines with aryl bromides catalyzed by Pd(OAc)2.
Scheme 162: Pd(II)-catalyzed C-3 arylations with aryl tosylates and mesylates.
Scheme 163: CDC reaction for the synthesis of imidazo[1,2-a]pyridines.
Scheme 164: Plausible reaction mechanism for Pd(OAc)2-catalyzed synthesis of imidazo[1,2-a]pyridines.
Scheme 165: Pd-catalyzed C–H amination reaction.
Scheme 166: Mechanism for C–H amination reaction.
Scheme 167: One-pot synthesis for 3,6-di- or 2,3,6-tri(hetero)arylimidazo[1,2-a]pyridines.
Scheme 168: C–H/C–H cross-coupling reaction of IPs and azoles catalyzed by Pd(II).
Scheme 169: Mechanistic cycle.
Scheme 170: Rh-catalyzed C–H arylation reaction.
Scheme 171: Mechanistic pathway for C–H arylation of imidazo[1,2-a]pyridine.
Scheme 172: Rh(III)-catalyzed double C–H activation of 2-phenylimidazo[1,2-a]pyridines and alkynes.
Scheme 173: Rh(III)-catalyzed mechanistic pathway.
Scheme 174: Rh(III)-mediated oxidative coupling reaction.
Scheme 175: Reactions showing functionalization of the product obtained by the group of Kotla.
Scheme 176: Mechanism for Rh(III)-catalyzed oxidative coupling reaction.
Scheme 177: Rh(III)-catalyzed C–H activation reaction.
Scheme 178: Mechanistic cycle.
Scheme 179: Annulation reactions of 2-arylimidazo[1,2-a]pyridines and alkynes.
Scheme 180: Two-way reaction mechanism for annulations reaction.
Scheme 181: [RuCl2(p-cymene)]2-catalyzed C–C bond formation reaction.
Scheme 182: Reported reaction mechanism.
Scheme 183: Fe(III) catalyzed C-3 formylation approach.
Scheme 184: SET mechanism-catalyzed by Fe(III).
Scheme 185: Ni(dpp)Cl2-catalyzed KTC coupling.
Scheme 186: Pd-catalyzed SM coupling.
Scheme 187: Vanadium-catalyzed coupling of IP and NMO.
Scheme 188: Mechanistic cycle.
Scheme 189: Selective C3/C5–H bond functionalizations by mono and bimetallic systems.
Scheme 190: rGO-Ni@Pd-catalyzed C–H bond arylation of imidazo[1,2-a]pyridine.
Scheme 191: Mechanistic pathway for heterogeneously catalyzed arylation reaction.
Scheme 192: Zinc triflate-catalyzed coupling reaction of substituted propargyl alcohols.
cis–trans-Amide isomerism of the 3,4-dehydroproline residue, the ‘unpuckered’ proline
- Vladimir Kubyshkin and
- Nediljko Budisa
Beilstein J. Org. Chem. 2016, 12, 589–593, doi:10.3762/bjoc.12.57
- Pro structural analogues, azetidine-2-carboxylic acid (norproline) and pipecolic acid (homoproline) [4], it appears that the high isomerization barrier is a feature associated with the 5-membered pyrrolidine ring of Pro [5]. The pyrrolidine ring of Pro can be found in several conformations, designated
Graphical Abstract
Scheme 1: s-cis–s-trans Amide bond isomerism in an N-acyl-proline fragment.
Figure 1: Amino acids that have been compared in this study.
Figure 2: X-ray crystal structures of compounds 5–9. Carbon- grey, nitrogen – blue, oxygen – red, fluorine – ...
Scheme 2: The relationship between the pKa of the ammonium function in the amino acid and the amide rotationa...
Figure 3: The double bond between C3 and C4 atoms in 3,4-dehydroproline residues induces an increase in the a...
Diversity-oriented synthesis of analogues of the novel macrocyclic peptide FR-225497 through late stage functionalization
- Jyotiprasad Mukherjee,
- Suman Sil and
- Shital Kumar Chattopadhyay
Beilstein J. Org. Chem. 2015, 11, 2487–2492, doi:10.3762/bjoc.11.270
- the trapoxins 2 and 3 contain a 2-amino-8-oxo-9,10-epoxydecanoic acid (Aoe) as the unusual amino acid. The cyclic tetrapeptide scaffold represented by structure III is nearly identical to the compounds 2–4, the difference being in the D-proline/D-pipecolic acid segment. The difference may be
Graphical Abstract
Figure 1: Structure of FR-225497 (4) and related cyclic tetrapeptides.
Figure 2: Synthetic planning for the design of analogues of 4.
Scheme 1: Preparation of the macrocyclic template 13.
Scheme 2: Synthesis of nor-FR225497 (15).
Scheme 3: Synthesis of oxygenated ethyl vinyl ketones.
Scheme 4: Synthesis of analogues of FR-225497.
Streptopyridines, volatile pyridine alkaloids produced by Streptomyces sp. FORM5
- Ulrike Groenhagen,
- Michael Maczka,
- Jeroen S. Dickschat and
- Stefan Schulz
Beilstein J. Org. Chem. 2014, 10, 1421–1432, doi:10.3762/bjoc.10.146
- streptopyridines are biosynthetically produced via a polyketide sequence similar to that reported for streptazolin, involving a pentaketide precursor [13], or whether a specific pyridine precursor, e.g., pipecolic acid, with chain elongation was used. Feeding experiments with 13C2-sodium acetate showed
Graphical Abstract
Figure 1: Alkaloids produced by Streptomyces strain FORM5.
Figure 2: Part of the total ion chromatogram of the headspace extract of Streptomyces sp. FORM5 with the stru...
Figure 3: Mass spectra of a) (E)-2-(pent-3-en-1-yl)pyridine (streptopyridine E, 8), b) (1Z,3E)-penta-1,3-dien...
Scheme 1: Synthesis of streptopyridines A to E (8–12) and the 2-alkylpyridines 6 and 7.
Figure 4: Total ion chromatograms of the product mixtures of isomers 9–12 synthesized under E-selective (a) a...
Figure 5: Structures of piperidine derivatives 20–26.
Figure 6: a) Mass spectrum of streptopyridine A (12), b) mass spectrum of 12 after feeding of 2 mM 13C2-sodiu...
Scheme 2: Proposed biosynthesis of the streptopyridines. PKS: polyketide synthase; red: reduction; ta: transa...
Figure 7: Compounds detected in the headspace of Streptomyces sp. FORM5.
Isocyanide-based multicomponent reactions towards cyclic constrained peptidomimetics
- Gijs Koopmanschap,
- Eelco Ruijter and
- Romano V.A. Orru
Beilstein J. Org. Chem. 2014, 10, 544–598, doi:10.3762/bjoc.10.50
- temperature and the final tetrazoles 158a–c were obtained in moderate to good yields. Six-membered ring constraints Pipecolic acid In the previous section we discussed some important conformational properties of proline derivatives playing an important role in controlling peptide and protein secondary
- structures. Replacement of the proline residue by its six-membered analogue, pipecolic acid, has provided valuable insights in peptide folding and bioactive conformations [128][129]. In particular, pipecolic acid derivatives often find their application as β-turn mimetics [130], and are therefore included in
- several pharmaceutical compounds such as antipsychotics, anticonvulsants, local anaesthetics or analgesics [131]. An interesting diastereoselective multicomponent approach towards such six-membered pipecolic acid-based analogues was described by Maison et al. [128] Although this work is closely related to
Graphical Abstract
Scheme 1: The proposed mechanism of the Passerini reaction.
Scheme 2: The PADAM-strategy to α-hydroxy-β-amino amide derivatives 7. An additional oxidation provides α-ket...
Scheme 3: The general accepted Ugi-mechanism.
Scheme 4: Three commonly applied Ugi/cyclization approaches. a) UDC-process, b) UAC-sequence, c) UDAC-combina...
Scheme 5: Ugi reaction that involves the condensation of Armstrong’s convertible isocyanide.
Scheme 6: Mechanism of the U-4C-3CR towards bicyclic β-lactams.
Scheme 7: The Ugi 4C-3CR towards oxabicyclo β-lactams.
Scheme 8: Ugi MCR between an enantiopure monoterpene based β-amino acid, aldehyde and isocyanide resulting in...
Scheme 9: General MCR for β-lactams in water.
Scheme 10: a) Ugi reaction for β-lactam-linked peptidomimetics. b) Varying the β-amino acid resulted in β-lact...
Scheme 11: Ugi-4CR followed by a Pd-catalyzed Sn2 cyclization.
Scheme 12: Ugi-3CR of dipeptide mimics from 2-substituted pyrrolines.
Scheme 13: Joullié–Ugi reaction towards 2,5-disubstituted pyrrolidines.
Scheme 14: Further elaboration of the Ugi-scaffold towards bicyclic systems.
Scheme 15: Dihydroxyproline derivatives from an Ugi reaction.
Scheme 16: Diastereoselective Ugi reaction described by Banfi and co-workers.
Scheme 17: Similar Ugi reaction as in Scheme 16 but with different acids and two chiral isocyanides.
Scheme 18: Highly diastereoselective synthesis of pyrrolidine-dipeptoids via a MAO-N/MCR-procedure.
Scheme 19: MAO-N/MCR-approach towards the hepatitis C drug telaprevir.
Scheme 20: Enantioselective MAO-U-3CR procedure starting from chiral pyrroline 64.
Scheme 21: Synthesis of γ-lactams via an UDC-sequence.
Scheme 22: Utilizing bifunctional groups to provide bicyclic γ-lactam-ketopiperazines.
Scheme 23: The Ugi reaction provided both γ- as δ-lactams depending on which inputs were used.
Scheme 24: The sequential Ugi/RCM with olefinic substrates provided bicyclic lactams.
Scheme 25: a) The structural and dipole similarities of the triazole unit with the amide bond. b) The copper-c...
Scheme 26: The Ugi/Click sequence provided triazole based peptidomimetics.
Scheme 27: The Ugi/Click reaction as described by Nanajdenko.
Scheme 28: The Ugi/Click-approach by Pramitha and Bahulayan.
Scheme 29: The Ugi/Click-combination by Niu et al.
Scheme 30: Triazole linked peptidomimetics obtained from two separate MCRs and a sequential Click reaction.
Scheme 31: Copper-free synthesis of triazoles via two MCRs in one-pot.
Scheme 32: The sequential Ugi/Paal–Knorr reaction to afford pyrazoles.
Scheme 33: An intramolecular Paal–Knorr condensation provided under basic conditions pyrazolones.
Scheme 34: Similar cyclization performed under acidic conditions provided pyrazolones without the trifluoroace...
Scheme 35: The Ugi-4CR towards 2,4-disubstituted thiazoles.
Scheme 36: Solid phase approach towards thiazoles.
Scheme 37: Reaction mechanism of formation of thiazole peptidomimetics containing an additional β-lactam moiet...
Scheme 38: The synthesis of the trisubstituted thiazoles could be either performed via an Ugi reaction with pr...
Scheme 39: Performing the Ugi reaction with DMB-protected isocyanide gave access to either oxazoles or thiazol...
Scheme 40: Ugi/cyclization-approach towards 2,5-disubstituted thiazoles. The Ugi reaction was performed with d...
Scheme 41: Further derivatization of the thiazole scaffold.
Scheme 42: Three-step procedure towards the natural product bacillamide C.
Scheme 43: Ugi-4CR to oxazoles reported by Zhu and co-workers.
Scheme 44: Ugi-based synthesis of oxazole-containing peptidomimetics.
Scheme 45: TMNS3 based Ugi reaction for peptidomimics containing a tetrazole.
Scheme 46: Catalytic cycle of the enantioselective Passerini reaction towards tetrazole-based peptidomimetics.
Scheme 47: Tetrazole-based peptidomimetics via an Ugi reaction and a subsequent sigmatropic rearrangement.
Scheme 48: Resin-bound Ugi-approach towards tetrazole-based peptidomimetics.
Scheme 49: Ugi/cyclization approach towards γ/δ/ε-lactam tetrazoles.
Scheme 50: Ugi-3CR to pipecolic acid-based peptidomimetics.
Scheme 51: Staudinger–Aza-Wittig/Ugi-approach towards pipecolic acid peptidomimetics.
Figure 1: The three structural isomers of diketopiperazines. The 2,5-DKP isomer is most common.
Scheme 52: UDC-approach to obtain 2,5-DKPs, either using Armstrong’s isocyanide or via ethylglyoxalate.
Scheme 53: a) Ugi reaction in water gave either 2,5-DKP structures or spiro compounds. b) The Ugi reaction in ...
Scheme 54: Solid-phase approach towards diketopiperazines.
Scheme 55: UDAC-approach towards DKPs.
Scheme 56: The intermediate amide is activated as leaving group by acid and microwave assisted organic synthes...
Scheme 57: UDC-procedure towards active oxytocin inhibitors.
Scheme 58: An improved stereoselective MCR-approach towards the oxytocin inhibitor.
Scheme 59: The less common Ugi reaction towards DKPs, involving a Sn2-substitution.
Figure 2: Spatial similarities between a natural β-turn conformation and a DKP based β-turn mimetic [158].
Scheme 60: Ugi-based syntheses of bicyclic DKPs. The amine component is derived from a coupling between (R)-N-...
Scheme 61: Ugi-based synthesis of β-turn and γ-turn mimetics.
Figure 3: Isocyanide substituted 3,4-dihydropyridin-2-ones, dihydropyridines and the Freidinger lactams. Bio-...
Scheme 62: The mechanism of the 4-CR towards 3,4-dihydropyridine-2-ones 212.
Scheme 63: a) Multiple MCR-approach to provide DHP-peptidomimetic in two-steps. b) A one-pot 6-CR providing th...
Scheme 64: The MCR–alkylation–MCR procedure to obtain either tetrapeptoids or depsipeptides.
Scheme 65: U-3CR/cyclization employing semicarbazone as imine component gave triazine based peptidomimetics.
Scheme 66: 4CR towards triazinane-diones.
Scheme 67: The MCR–alkylation–IMCR-sequence described by our group towards triazinane dione-based peptidomimet...
Scheme 68: Ugi-4CR approaches followed by a cyclization to thiomorpholin-ones (a) and pyrrolidines (b).
Scheme 69: UDC-approach for benzodiazepinones.
Scheme 70: Ugi/Mitsunobu sequence to BDPs.
Scheme 71: A UDAC-approach to BDPs with convertible isocyanides. The corresponding amide is cleaved by microwa...
Scheme 72: microwave assisted post condensation Ugi reaction.
Scheme 73: Benzodiazepinones synthesized via the post-condensation Ugi/ Staudinger–Aza-Wittig cyclization.
Scheme 74: Two Ugi/cyclization approaches utilizing chiral carboxylic acids. Reaction (a) provided the product...
Scheme 75: The mechanism of the Gewald-3CR includes three base-catalysed steps involving first a Knoevnagel–Co...
Scheme 76: Two structural 1,4-thienodiazepine-2,5-dione isomers by U-4CR/cyclization.
Scheme 77: Tetrazole-based diazepinones by UDC-procedure.
Scheme 78: Tetrazole-based BDPs via a sequential Ugi/hydrolysis/coupling.
Scheme 79: MCR synthesis of three different tricyclic BPDs.
Scheme 80: Two similar approaches both involving an Ugi reaction and a Mitsunobu cyclization.
Scheme 81: Mitsunobu–Ugi-approach towards dihydro-1,4-benzoxazepines.
Scheme 82: Ugi reaction towards hetero-aryl fused 5-oxo-1,4-oxazepines.
Scheme 83: a) Ugi/RCM-approach towards nine-membered peptidomimetics b) Sequential peptide-coupling, deprotect...
Scheme 84: Ugi-based synthesis towards cyclic RGD-pentapeptides.
Scheme 85: Ugi/MCR-approach towards 12–15 membered macrocycles.
Scheme 86: Stereoselective Ugi/RCM approach towards 16-membered macrocycles.
Scheme 87: Passerini/RCM-sequence to 22-membered macrocycles.
Scheme 88: UDAC-approach towards 12–18-membered depsipeptides.
Figure 4: Enopeptin A with its more active derivative ADEP-4.
Scheme 89: a) The Joullié–Ugi-approach towards ADEP-4 derivatives b) Ugi-approach for the α,α-dimethylated der...
Scheme 90: Ugi–Click-strategy for 15-membered macrocyclic glyco-peptidomimetics.
Scheme 91: Ugi/Click combinations provided macrocycles containing both a triazole and an oxazole moiety.
Scheme 92: a) A solution-phase procedure towards macrocycles. b) Alternative solid-phase synthesis as was repo...
Scheme 93: Ugi/cyclization towards cyclophane based macrocycles.
Scheme 94: PADAM-strategy towards eurystatin A.
Scheme 95: PADAM-approach for cyclotheanamide.
Scheme 96: A triple MCR-approach affording RGD-pentapeptoids.
Scheme 97: Ugi-MiBs-approach towards peptoid macrocycles.
Scheme 98: Passerini-based MiB approaches towards macrocycles 345 and 346.
Scheme 99: Macrocyclic peptide formation by the use of amphoteric aziridine-based aldehydes.
Tertiary alcohol preferred: Hydroxylation of trans-3-methyl-L-proline with proline hydroxylases
- Christian Klein and
- Wolfgang Hüttel
Beilstein J. Org. Chem. 2011, 7, 1643–1647, doi:10.3762/bjoc.7.193
- enzyme was already found in conversions with the 6-ring-analogue of L-proline, i.e., L-pipecolic acid. In that case an approx. 1:1 mixture of the expected cis-5-hydroxypipecolic acid and its cis-3-isomer, which is also the product of cis-P3H_II, was obtained [34]. In general, it can be assumed that the
Graphical Abstract
Scheme 1: Catalytic cycle of α-KG dependent oxygenases.
Scheme 2: Selectivities and relative yields in conversions of (a) L-proline (defined as 100% yield) and (b) t...
Figure 1: Typical HPLC-chromatograms of the conversions of (a) trans-3-methyl-L-proline and (b) L-proline und...
