Synthesis of N-alkyl-N-methyl amino acids. Scope and limitations of base-induced N-alkylation of Cbz-amino acids

Stodulski, Maciej; Młynarski, Jacek

doi:10.1016/j.tetasy.2008.03.025

Cited by 14 publications

(6 citation statements)

References 26 publications

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“…Methylation of 2,2,6-trimethyl-4 H -1,3-dioxin-4-one ( 112 ), phosphination, and oxidative workup provided dioxinone phosphonate 109 in moderate overall yield. Methylation of N -Cbz- d -alanine ( 113 ), ethyl ester formation, and reductive removal of the Cbz protecting group under anhydrous acidic conditions produced hydrochloride salt 111 ·HCl in excellent overall yield.…”

Section: Resultsmentioning

confidence: 99%

Total Synthesis of Aflastatin A

Beiger¹

2022

J. Am. Chem. Soc.

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The total syntheses of aflastatin A and its C3–C48 degradation fragment (6a, R = H) have been accomplished. The syntheses feature several complex diastereoselective fragment couplings, including a Felkin-selective trityl-catalyzed Mukaiyama aldol reaction, a chelate-controlled aldol reaction involving soft enolization with magnesium, and an anti-Felkin-selective boron-mediated oxygenated aldol reaction. Careful comparison of the spectroscopic data for the synthetic C3–C48 degradation fragment to that reported by the isolation group revealed a structural misassignment in the lactol region of the naturally derived degradation product. Ultimately, the data reported for the naturally derived aflastatin A C3–C48 degradation lactol (6a, R = H) were attributed to its derivative lactol trideuteriomethyl ether (6c, R = CD3). Additionally, the revised absolute configurations of six stereogenic centers (C8, C9, and C28–C31) were confirmed.

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Section: Resultsmentioning

confidence: 99%

Total Synthesis of Aflastatin A

Beiger¹

2022

J. Am. Chem. Soc.

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“…This reaction was conducted in the present of K 2 CO 3 ‐TEA mixture and a catalytic amount of tetrabutylammonium bromide (TBAB) in refluxing anhydrous DMF. Pursuant to previous report by Stodulski et al, the similar procedure was applied for the selective mono‐ N ‐alkylation of α‐amino acid [20] . Various α‐amino acids were applied to prepare diverse aryloxy propanol amino acid derivatives which the related structures are shown in Scheme 1.…”

Section: Resultsmentioning

confidence: 99%

Design, Synthesis and In Vivo Cardiovascular Evaluation of Some Novel Aryloxy Propanol Amino Acid Derivatives

et al. 2021

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The design, synthesis and biological evaluation of some aryloxy propanol amino acid derivatives have been described. Synthetic pathways is consisted of the reaction of phenol derivatives with epichlorohydrin and/or epibromohydrin produced the various O‐phenol ether adducts. In continue, the reaction of amino acid with O‐phenol ether adducts generated the new class of β‐blocking agents. The products were evaluated for their cardiovascular property. The 2‐kidney‐1‐clip method was used to induce renovascular hypertension in rats. New analogues of propranolol were evaluated in order to find the most appropriate ones for reducing the hypertension. Our results showed that compound 4 d [i. e.: (2‐hydroxy‐3‐phenoxypropyl) glycine] was effective in blood pressure lowering, even lower than propranolol as a standard drug. All the modelling study was performed at physiological pH (pH∼7.0–7.4).The MEP and docking analysis have shown the appropriate fitting of (2‐hydroxy‐3‐phenoxypropyl) glycine in human β2‐adrenergic receptor active site.

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“…Briefly, L-leucine or heavy isotopic L-leucine was protected at the primary amine with benzyl chloroformate (CbzCl) under basic conditions to yield a secondary amine, derivatized with a single methyl group by reaction with heavy isotopic iodomethane and sodium hydride, then concurrently deprotected and derivatized with the second methyl group by reaction with formaldehyde or heavy isotopic formaldehyde under catalytic hydrogenation conditions with Pd/C in H 2 atmosphere. 32 The three dimethyl leucine 115 and 116 variants were then subjected to 18 O exchange by incubation with acidified H 2 18 O solution (HCl, pH 1) at elevated temperature. Each dimethylleucine product was purified by flash column chromatography, dried in vacuo, and stored at ambient temperature for later use.…”

Section: ■ Materials and Methodsmentioning

confidence: 99%

21-plex DiLeu Isobaric Tags for High-Throughput Quantitative Proteomics

Frost

Feng

2020

Anal. Chem.

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Isobaric tags enable multiplexed quantitative analysis of many biological samples in a single LC-MS/MS experiment. As a cost-effective alternative to expensive commercial isobaric tagging reagents, we developed our own custom N,N-dimethyl leucine 'DiLeu' isobaric tags for quantitative proteomics. Here, we present a new generation of DiLeu tags that achieves 21-plex quantification in high-resolution HCD MS/MS spectra via distinct reporter ions that differ in mass from each other by a minimum of 3 mDa. The 21-plex set retains the compact tag structure and existing isotopologues of the 12-plex set but includes nine new reporter variants formulated with unique configurations of 13 C, 15 N, and 2 H stable isotopes, each synthesized in-house via a stepwise N-monomethylation synthesis strategy using readily available reagents. Thus, multiplexing capacity is expanded significantly while preserving the performance and low cost of the previous implementation. We show that 21-plex DiLeu tags generate strong reporter ions following HCD fragmentation of labeled peptides acquired on Orbitrap platforms at a minimum of 60,000 resolving power (at 400 m/z), and we demonstrate accurate 21-plex quantification of labeled K562 human cell line protein digests via single-shot nanoLC-MS/MS analysis on a Q Exactive HF system.

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Synthesis of N-alkyl-N-methyl amino acids. Scope and limitations of base-induced N-alkylation of Cbz-amino acids

Cited by 14 publications

References 26 publications

Total Synthesis of Aflastatin A

Total Synthesis of Aflastatin A

Design, Synthesis and In Vivo Cardiovascular Evaluation of Some Novel Aryloxy Propanol Amino Acid Derivatives

21-plex DiLeu Isobaric Tags for High-Throughput Quantitative Proteomics

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