Synthesis of the Lipophilic Antifolate Piritrexim via a Palladium(0)-Catalyzed Cross-Coupling Reaction

Chan, David C.; Rosowsky, A.

doi:10.1021/jo040268z

Cited by 17 publications

(9 citation statements)

References 29 publications

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“…In our attempt to perform diazotization of tyrosine with t- BuONO, we observed the formation of unexpected yellow products. To explore this finding further, we subjected Boc-Tyr-OH ( 1a ) to the nitrite treatment in dichloromethane at room temperature (Scheme ).…”

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confidence: 96%

Chemoselective Nitration of Phenols with tert-Butyl Nitrite in Solution and on Solid Support

2009

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Abstracttert-Butyl nitrite was identified as a safe and chemoselective nitrating agent that provides preferentially mononitro derivatives of phenolic substrates in the presence of potentially competitive functional groups. On the basis of our control experiments, we propose that the reaction proceeds through the formation of O-nitrosyl intermediates prior to C-nitration via homolysis and oxidation. The reported nitration method is compatible with tyrosine-containing peptides on solid support in the synthesis of fluorogenic substrates for characterization of proteases.The technique of Fluorescence Resonance Energy Transfer (FRET) is currently a common method for monitoring structural, functional, or aggregation changes in evaluated biomolecules. 1 Real-time monitoring of hydrolase activity is a particularly useful application of FRET, because the substrate can be chemically modified at sites remote to the scissile bond, minimizing probe interferences with substrate recognition. The 2-aminobenzoic acid (2-Abz) fluorophore and 3-nitrotyrosine quencher pair has been utilized extensively in determining proteolytic activities of endoproteases. 2 As amino acids, these agents represent a convenient fluorophore-quencher combination that can be readily incorporated into a conventional solid phase peptide synthesis protocol. As a part of a program in evolution of site-specific proteases as therapeutic agents, we are interested in developing a flexible and practical platform for kinetic and thermodynamic characterization of evolved enzymes. Thus, we envisioned a unified synthetic strategy for accessing both internally quenched substrates, useful for realtime kinetic analysis of active enzymes, as well as unquenched variants, suitable for fluorescence quenching and anisotropy studies with inactive mutants. We were very keen, therefore, to identify a reagent that could perform a nitration reaction on solid phaseimmobilized peptides containing tyrosines with high efficiency and selectivity. Unfortunately, the existing nitrating agents, such as mixed acids, superacids, and metal nitrates, are not suitable for polymer-supported substrates because of their polymer-reactive or heterogeneous nature. 3,4 In addition, many of the existing reagents can lead to over-nitration of phenols 4a,g,h and ssavinov@purdue.edu. In our attempt to perform diazotization of tyrosine with t-BuONO, 6 we observed the formation of unexpected yellow products. To explore this finding further, we subjected Boc-Tyr-OH (1a) to the nitrite treatment in dichloromethane at room temperature (Scheme 1). After 3 hours of agitation, we detected a complete consumption of 1a and quantitative (>95%) formation of Boc-Tyr(3-NO 2 )-OH (2a) and corresponding N-nitroso derivative 3a (2a:3a 57:43). While there have been reports of C-nitro products emerging from the exposure of electron-rich aromatic compounds to inorganic 7 or organic 8 nitrites, no mechanistic or scope studies have been carried out. In 1 H NMR spectum of the crude reaction mixure we also identified a tra...

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confidence: 96%

Chemoselective Nitration of Phenols with tert-Butyl Nitrite in Solution and on Solid Support

2009

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“…The reaction of 23 in dry THF with 2,5-dimethoxybenzyl- zinc chloride and CH 2 Cl 2 [PdCl 2 (dppf).CH 2 Cl 2 ] provided 2-amino-5-(2,5-dimethoxybenzyl)-4-methyl-3-carbonitrilepyridine ( 25 ). Subsequently, the nonaqueous diazotization of 25 with t-BuONO and SbBr 3 in CH 2 Br 2 gave the bromo nitrile intermediate 26 , which was successfully reacted with guanidine to afford 6-[(2,5-dimethoxyphenyl)methyl]-5-methylpyrido[2,3- d ]pyrimidine-2-amine ( 28 ) ( Scheme 5 ) [ 21 ].…”

Section: Pyridopyrimidines: Therapeutic Potential and Synthesismentioning

confidence: 99%

“… Synthesis of 6-[(2,5-dimethoxyphenyl)methyl]-5-methylpyrido[2,3- d ]pyrimidine-2-amine ( 28 ) by Chan and Rosowsky [ 21 ]. …”

Section: Figures Schemes and Tablementioning

confidence: 99%

“…Biotin dependent carboxylases contain acetyl-CoA carboxylase (ACC), propionyl-CoA carboxylase (PCC), 3-methylcrotonyl-CoA carboxylase (MCC), geranyl-CoA carboxylase (GCC), pyruvate carboxylase (PC), and urea carboxylase (UC). Due to their activity, they are mainly involved in diseases such as type 2 diabetes, obesity and microbial infection [ 21 ]. ACC catalyzes the carboxylation of acetyl-CoA to form malonyl-CoA, which is an intermediate substrate.…”

Section: Introduction: Pyridopyrimidines and Their Scaffoldmentioning

confidence: 99%

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Review on the Synthesis and Therapeutic Potential of Pyrido[2,3-d], [3,2-d], [3,4-d] and [4,3-d]pyrimidine Derivatives

2022

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The objective of this review is to list the structures composed of a pyridopyrimidine moiety which have shown a therapeutic interest or have already been approved for use as therapeutics. We consider all the synthetic protocols to prepare these pyridopyrimidine derivatives. The review is organized into four sections, successively pyrido[2,3-d]pyrimidines, pyrido[3,4-d]pyrimidines, pyrido[4,3-d]pyrimidines and pyrido[3,2-d]pyrimidines. For each compound we present the biological activity and the synthetic route reported. To produce this manuscript, the bibliographic research was done using Reaxys and Scifinder for each kind of pyridopyrimidine.

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“…As per the literature survey, in recent years, the class of "pyrido [2,3-d]pyrimidines" developed as inhibitors that antagonize a variety of biological targets involved in cancer development including cyclin-dependent kinase [8], dihydrofolate reductase [47,48,49], and non-receptor tyrosine kinases [50,51,52].…”

Section: -Chloro-3-pyridine Carboxylic Acid As Precursormentioning

confidence: 99%

Synthesis and Anticancer Perspective of Pyridopyrimidine Scaffold - An Overview

Shetty

Shastry

2021

JPRI

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The core pyridopyrimidines are gaining interest in organic and heterocyclic chemistry in recent days, as this scaffold acts as a building block because of its wide range of biological and pharmacological applications like anticancer, antimicrobial, fungicidal, antiviral, CNS, antibacterial, and anti-inflammatory properties. This review mainly emphasizes the evolution in anticancer properties of pyridopyrimidines since 2008 especially the method of synthesis and anticancer activity of synthesized compounds with reporting of active anticancer scaffolds. Important starting materials which are widely used for the synthesis are 2-thioxopyrimidine, ethyl 2-cyanoacetate, 2-amino-3-cyano-4-trifluoromethyl-6-phenyl-pyridine, 2-amino-4,6-disubstituted nicotinonitrile, 2-chloro-3-pyridine carboxylic acid, in which 2-thioxopyrimidine is found to be mostly employed in the synthesis. Pyridopyrimidines which are synthesized from different starting materials, in which the more active compounds are reported here which may help in further discovery/ development of novel molecules.

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Synthesis of the Lipophilic Antifolate Piritrexim via a Palladium(0)-Catalyzed Cross-Coupling Reaction

Cited by 17 publications

References 29 publications

Chemoselective Nitration of Phenols with tert-Butyl Nitrite in Solution and on Solid Support

Chemoselective Nitration of Phenols with tert-Butyl Nitrite in Solution and on Solid Support

Review on the Synthesis and Therapeutic Potential of Pyrido[2,3-d], [3,2-d], [3,4-d] and [4,3-d]pyrimidine Derivatives

Synthesis and Anticancer Perspective of Pyridopyrimidine Scaffold - An Overview

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