Synthesis of pyrazole containing α-amino acids via a highly regioselective condensation/aza-Michael reaction of β-aryl α,β-unsaturated ketones

Gilfillan, Lynne; Artschwager, Raik; Harkiss, Alexander H.; Liskamp, Rob M. J.; Sutherland, Andrew

doi:10.1039/c5ob00364d

Cited by 28 publications

(24 citation statements)

References 44 publications

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“…could be considered as potential scaffold for syntheses of unnatural aromatic amino acids for tuning the peptide structures. [10] In repertoire of unnatural aromatic amino acids, herein we report the syntheses of rationally designed aminopyrazolonyl amino acid (APA) derivatives ( Figure 1b) and their roles in structural organization of native dipeptides. [9] Recently, Sutherland and co-workers have reported the new class of conjugated unnatural α-amino acid containing 5-arylpyrazole residue as probe of serine proteases ( Figure 1a).…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Conformational Analysis of Aminopyrazolonyl Amino Acid (APA)/Peptides

Bollu

Sharma

2019

Eur J Org Chem

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Pyrazole, pyrazolone, and aminopyrazolone derived molecules are bioactive molecules and considered as potential therapeutic drug candidates because of their unique structural properties. These molecules have abilities to interact with several bio‐macromolecules via non‐covalent interactions such as hydrogen bonding and π–π interactions. In structural organization of dipeptides, pyrazole containing aromatic amino acid/dipeptides have been explored and considered as potential amino acid residue. In repertoire of unnatural aromatic amino acids, this report describes the synthesis of 4‐aminopyrazolonyl containing amino acids and their crystal structures. The incorporation of 4‐aminopyrazolonyl at N‐terminal of native amino acid/dipeptides influences the conformational changes of respective peptide which induces the formation of distinctive supramolecular self‐assembly structures such as β‐sheet and α‐helices in their solid‐state crystal. The structural conformation of those peptides, here, are also demonstrated in solution phase by 1H‐NMR (1D/2D) and [D6]DMSO titration methods which support the formation of inter‐/intramolecular hydrogen bonding in solution. Hence, these unnatural amino acid analogues can tune the secondary structure of natural amino acid/peptides by introducing at N‐terminal via amide bond.

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Section: Introductionmentioning

confidence: 99%

Synthesis and Conformational Analysis of Aminopyrazolonyl Amino Acid (APA)/Peptides

Bollu

Sharma

2019

Eur J Org Chem

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“…JC-F 22.0 Hz, 2 × CH), 125.3 (CH), 128.2 (2 × CH), 128.3 (CH), 128.7 (2 × CH), 130.5(C), 130.5 (d,3 JC-F 8 5. Hz, 2 × CH), 136.4 (C), 142.9 (CH), 156.2 (C), 164.4 (d, 1 JC-F 252.6 Hz, C), 171.7 (C), 197.4 (C); MS (ESI) m/z 408 (M+Na + , 100); HRMS (ESI) calcd for C21H20FNNaO5 (M+Na + ) 408.1218, found 408.1201.Methyl (2S,5E)-2-[(benzyloxycarbonyl)amino]-6-(2',4'-dinitrophenyl)-4-oxohex-5-enoate (5i).The reaction was carried out according to the above procedure for the synthesis of methyl (2S,5E)-2-[(benzyloxycarbonyl)amino]-4-oxonon-5-enoate (5a) using methyl (2S,5E)-6-(2',4'-dinitrophenyl)-4oxo-2-(tritylamino)hex-5-enoate (4i) (0.620 g, 1.10 mmol).…”

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confidence: 99%

Synthesis and Fluorescent Properties of β-Pyridyl α-Amino Acids

et al. 2019

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RESULTS AND DISCUSSIONThe first stage of the synthesis of the -pyridyl -amino acids involved the preparation of suitably protected enone-derived -amino acids (Scheme 1). Initially, N-trityl protected phosphonate ester 3 was prepared in three-steps (92% overall yield) from L-aspartic acid 1. 13 Following protection of the amino and carboxylic acid groups, the key step involved the highly regioselective reaction of the anion of dimethyl methylphosphonate with the sterically accessible -methyl ester of 2 to give phosphonate ester 3. Horner-Wadsworth-Emmons reaction of 3 with a wide range of aldehydes under mild conditions, gave enones 4a-j, exclusively as the E-isomers. 14,15 The focus of this project was to prepare aryl substituted pyridyl side-chains and therefore, benzaldehyde derivatives were mainly used to explore the scope of this reaction. As expected, the majority of these gave high yields of the E-enones (66-95%), although highly electron-rich aldehydes required longer reaction times (120 h) and gave more modest yields (e.g. 4e). Scheme 1. Synthesis of Enone-Derived -Amino Acids 4a-j a a Isolated yields are shown. peptide synthesizer using Rink Amide ChemMatrix® resin as the polymer support 22 and routine SPPS methodology (Scheme 3). On coupling Fmoc-L-Lys(Boc)-OH onto the polymer support using HCTU activation, successive rounds of piperidine-mediated N-deprotection and coupling using the next amino acid gave the pentapeptide. Following a subsequent N-terminal Fmoc-deprotection, the Fmoc-protected version of -pyridyl -amino acid 8d, compound 9 was coupled onto the polymer-supported pentapeptide. 23 After a final Fmoc-deprotection step, the N-terminus was acetyl capped and a TFA cleavage cocktail that included triisopropylsilane (TIPS) as a cation scavenger was used to remove the side-chain protecting groups and release the peptide from the polymer support. The resulting hexapeptide, 10 was purified by reverse phase-HPLC (>95% purity) and characterized by high-resolution electrospray ionization mass spectrometry (see Supporting Information for data). Scheme 3. SPPS of a -Pyridyl -Amino Acid Containing HexapeptideAs the -amino acids contained -deficient pyridine moieties, it was proposed that electron-rich conjugating groups may confer fluorescent properties through a charge-transfer (push-pull) mechanism. 24 Accordingly, the optical properties of -pyridyl -amino acids 8a-l were measured. As expected, pyridines with non-conjugating or electron-deficient substituents showed weak fluorescence, while compounds with electron-rich substituents showed strong fluorescence (Figure 2b and Table 1). In

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“…In the final stage of this project, we wanted to further demonstrate the compatible nature of the mild benzotriazole forming process for the synthesis of functionalized, biologically relevant targets. We have an interest in the development of new synthetic methods for the preparation of novel heterocycle‐containing α‐amino acids for biological applications, and so the mild activation and cyclization process was investigated for the synthesis of a benzotriazole‐containing α‐amino acid (Scheme ). Initially, the known L‐3‐aminoalanine derivative 7 , was subjected to an S N Ar reaction with 4‐fluoro‐3‐nitrotoluene under basic conditions, which gave coupled product 8 in 62 % yield .…”

Section: Resultsmentioning

confidence: 99%

Synthesis of Structurally Diverse Benzotriazoles via Rapid Diazotization and Intramolecular Cyclization of 1,2‐Aryldiamines

et al. 2019

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An operationally simple method has been developed for the preparation of N‐unsubstituted benzotriazoles by diazotization and intramolecular cyclization of a wide range of 1,2‐aryldiamines under mild conditions, using a polymer‐supported nitrite reagent and p‐tosic acid. The functional group tolerance of this approach was further demonstrated with effective activation and cyclization of N‐alkyl, ‐aryl, and ‐acyl ortho‐aminoanilines leading to the synthesis of N1‐substituted benzotriazoles. The synthetic utility of this one‐pot heterocyclization process was exemplified with the preparation of a number of biologically and medicinally important benzotriazole scaffolds, including an α‐amino acid analogue.

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Synthesis of pyrazole containing α-amino acids via a highly regioselective condensation/aza-Michael reaction of β-aryl α,β-unsaturated ketones

Cited by 28 publications

References 44 publications

Synthesis and Conformational Analysis of Aminopyrazolonyl Amino Acid (APA)/Peptides

Synthesis and Conformational Analysis of Aminopyrazolonyl Amino Acid (APA)/Peptides

Synthesis and Fluorescent Properties of β-Pyridyl α-Amino Acids

Synthesis of Structurally Diverse Benzotriazoles via Rapid Diazotization and Intramolecular Cyclization of 1,2‐Aryldiamines

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