Dakin-West Reaction Research Articles

CD, UV, and In Silico Insights on the Effect of 1,3-Bis(1'-uracilyl)-2-propanone on Serum Albumin Structure.

1,3-diaryl-2-propanone derivatives are synthetic compounds used as building blocks for the realization not only of antimicrobial drugs but also of new nanomaterials thanks to their ability to self-assemble in solution and interact with nucleopeptides. However, their ability to interact with proteins is a scarcely investigated theme considering the therapeutic importance that 1,3-diaryl-2-propanones could have in the modulation of protein-driven processes. Within this scope, we investigated the protein binding ability of 1,3-bis(1′-uracilyl)-2-propanone, which was previously synthesized in our laboratory utilizing a Dakin–West reaction and herein indicated as U2O, using bovine serum albumin (BSA) as the model protein. Through circular dichroism (CD) and UV spectroscopy, we demonstrated that the compound, but not the similar thymine derivative T2O, was able to alter the secondary structure of the serum albumin leading to significant consequences in terms of BSA structure with respect to the unbound protein (Δβ-turn + Δβ-sheet = +23.6%, Δα = −16.7%) as revealed in our CD binding studies. Moreover, molecular docking studies suggested that U2O is preferentially housed in the domain IIIB of the protein, and its affinity for the albumin is higher than that of the reference ligand HA 14−1 (HDOCK score (top 1–3 poses): −157.11 ± 1.38 (U2O); −129.80 ± 6.92 (HA 14−1); binding energy: −7.6 kcal/mol (U2O); −5.9 kcal/mol (HA 14−1)) and T2O (HDOCK score (top 1–3 poses): −149.93 ± 2.35; binding energy: −7.0 kcal/mol). Overall, the above findings suggest the ability of 1,3-bis(1′-uracilyl)-2-propanone to bind serum albumins and the observed reduction of the α-helix structure with the concomitant increase in the β-structure are consistent with a partial protein destabilization due to the interaction with U2O.

The Forgotten Pyrazines: Exploring the Dakin-West Reaction.

Pyrazines are an underreported class of N-heterocycles available from nitrogen-rich biomass presenting an interesting functional alternative for current aromatics. In this work, access to pyrazines obtained from amino acids by using the 90 year old Dakin-West reaction was explored. After a qualitative screening several functional proteinogenic amino acids proved good substrates for this reaction, which were successfully scaled to multigram scale synthesis of the corresponding intermediate α-acetamido ketones. Subsequently, the conditions towards pyrazine formation using δ-amino-levulinic acid were optimized, and these were employed to synthesize a relevant set of five functional dimethylpyrazines in high purity. These pyrazines can be considered a versatile toolbox of aromatic building blocks for a wide range of applications, such as in the synthesis of polymers or metal-organic frameworks.

Theoretical model for the design and preparation of a CNT–ursonic acid drug matrix as HIV-gp120 entry inhibitor

Abstract Human Immunodeficiency Virus (HIV) which infection results into Acquired Immunodeficiency Syndrome (AIDS) has claimed the lives of one half of its 70 million victims, a deadly disease that has attracted a global concern. Major challenges associated with modern HIV drugs include side effects, drug resistance, toxicity, patient compliance and lack of curative effect, which necessitated the need for urgent discovery of safer, cheaper and effective alternative drugs from natural plants. Currently, HIV-gp120 entry inhibitors are the most explored, based on the finding that the virus binds to the human CD4 cell via V1/V2 and V3 loops of its glycoprotein-120. The conceptual framework of this report is based on the chemistry that an acid anhydride converts proteins into corresponding acetylaminoalkyl methyl ketones by attacking the N- and C-terminals of the molecules in the presence of a base. Relatively, in this report, an acid anhydride, consisting of carbon nanotubes (CNTs) and ursonic acid (UA) backbone (CNT–UA), is theoretically designed and its expected interaction with HIV-glycoprotein-120 predicted. CNTs are first subjected to acid oxidation using a mixture of HNO3/H2SO4 (3:1) to obtain CNT–COOH moieties followed by acylation with thionyl chloride, SOCl2, to produce the more reactive CNT–COCl species. Refluxing resulting acyl chloride with a solution of UA-pyridine is expected to covalently attach the C-28 of the terpene to yield the desired CNT–UA (acid anhydride) drug matrix. The CNT-AU drug in pyridine base is expected to expend its HIV-gp120 entry inhibition via Dakin–West reaction by attacking the VI/V2 and V3 loops of the virus glycoprotein, converting it into a keto amide in the presence of 4-dimethylaminopyridine catalyst. If this model is intensively explored, it may help towards finding a final cure for HIV/AIDS.

Gram-Scale Synthesis of a β-Secretase 1 (BACE 1) Inhibitor

Development of a scalable synthesis of an oxazine class of β-secretase inhibitor is described. Trifluoromethylated acyloin synthesis by the reaction of a mandelic acid with trifluoroacetic anhydride in the presence of pyridine (Dakin–West reaction) was used as an efficient strategy to install the key trifluoromethyl substituent on the oxazine ring. Diastereoselective addition of methyl magnesium bromide to a cyclic sulfamidate imine and trimethylsilyl trifluoromethanesulfonate catalyzed intramolecular amidine formation to yield oxazine-3-amine are some of the significant, novel synthetic methods developed in this synthesis. These critical transformations allowed a concise 11-step route to the target compound with excellent overall yields.

Diastereoselective Trifluoroacetylation of Highly Substituted Pyrrolidines by a Dakin-West Process.

A robust approach allowing for the efficient trifluoroacetylation of a series of highly substituted pyrrolidines in a diastereoselective manner is reported. The transformation is based on a Dakin-West reaction of advanced pyrrolidine 2-carboxylic acid derivatives that can be assembled stereoselectively in four synthetic steps. Importantly, this work demonstrates how the introduction of lateral substituents on the pyrrolidine scaffold enables the generation of the desired trifluoroacetylation products, which was not possible previously due to the exclusive formation of trifluoromethylated oxazoles (vide infra). In the course of this work we succeeded for the first time in isolating and characterizing (HRMS, IR, 1H, 13C and 19F NMR, X-ray) different intermediates of the Dakin-West reaction allowing us to probe its mechanism.

ChemInform Abstract: The Enantioselective Dakin—West Reaction.

AbstractUsing an adamantane‐anchored methylimidazole‐containing oligopeptide as catalyst, the first examples for an enantioselective Dakin—West reaction are reported.

Synthesis and antifungal activity of bile acid-derived oxazoles

Peracetylated bile acids (1a–g) were used as starting materials for the preparation of fourteen new derivatives bearing an oxazole moiety in their side chain (6a–g, 8a–g). The key step for the synthetic path was a Dakin–West reaction followed by a Robinson–Gabriel cyclodehydration. A simpler model oxazole (12) was also synthesized. The antifungal activity of the new compounds (6a–g) as well as their starting bile acids (1a–g) was tested against Candida albicans. Compounds 6e and 6g showed the highest percentages of inhibition (63.84% and 61.40% at 250μg/mL respectively). Deacetylation of compounds 6a–g, led to compounds 8a–g which showed lower activities than the acetylated derivatives.

The Enantioselective Dakin–West Reaction

AbstractHere we report the development of the first enantioselective Dakin–West reaction, yielding α‐acetamido methylketones with up to 58 % ee with good yields. Two of the obtained products were recrystallized once to achieve up to 84 % ee. The employed methylimidazole‐containing oligopeptides catalyze both the acetylation of the azlactone intermediate and the terminal enantioselective decarboxylative protonation. We propose a dispersion‐controlled reaction path that determines the asymmetric reprotonation of the intermediate enolate after the decarboxylation.

The Enantioselective Dakin-West Reaction.

Here we report the development of the first enantioselective Dakin-West reaction, yielding α-acetamido methylketones with up to 58 % ee with good yields. Two of the obtained products were recrystallized once to achieve up to 84 % ee. The employed methylimidazole-containing oligopeptides catalyze both the acetylation of the azlactone intermediate and the terminal enantioselective decarboxylative protonation. We propose a dispersion-controlled reaction path that determines the asymmetric reprotonation of the intermediate enolate after the decarboxylation.

Solvent Effects on the Kinetics of the Dakin-West Reaction

The rate of the Dakin-West reaction have been investigated in Me₂SO, THF and CH₃CN at the temperature range (55–70) are reported. First order rate constants were obtained in each case. A Bronsted slope was found to be equal -0.0277 indicates that the transition state is very reactant-like and the proton has barely moved. Further, the solvent effect was considered from two points of mechanistic view: the thermodynamic transfer function of Me₂SO to CH₃CN and THF where the rate was found to be fast in Me₂SO and slow in THF and CH₃CN and the Kirkwood-Buff preferential solvation with aqueous Me₂SO, CH₃CN and THF. The techniques supported the proposed transition state structure.

Synergic effect of nano-catalyst and continuous flow system: Dakin–West reaction catalyzed by Nafion-H@SPIONs in a microreactor

The expansion of practical processes for superferromagnetic nanocatalysts is a very attractive subject.

Synthesis of β-amino-α.-ketoamides

β-Amino-α-ketoamides 1 are a class of compounds exhibiting biological activity as reversible covalent enzyme inhibitors. The representative examples are clinically approved drugs for the treatment of hepatitis C virus Boceprevir 2 and Telaprevir 3. β-Amino-α- ketoamide substructure is also found in a number of natural products, many of which display a remarkable biological activity. The methods for the synthesis of β-amino-α-ketoamide can be classified based on the key steps of the synthetic routes: from unsaturated amide involving epoxydation followed by a regioselective azidolysis; from esters involving aminohydroxylation; from adehydes via Passerini reaction, cyanohydrin formation, addition of the masked acylcyanide (MAC) reagent or orthothioester; from imines via addition of dithiolane derived from oxoacetic acid, addition of isoxazolyl-4-triflates or via azetidinone formation; from acids via acylation of (cyanomethylene) triphenylphosphorane (the Wasserman procedure), via acylfurane formation or via Dakin-West reaction; from nitroalkanes via Henry reaction. In this review, the information from the scientific literature published within the period from 1990 till 2014 for the synthesis of β-amino-α-ketoamides is covered and systematized according to the above mentioned key steps. Keywords: Azetidinones, cyanohydrins, dakin-west reaction, epoxides, MAC reagent, orthothioesters, henry reaction, passerini reaction, protease inhibitors, wasserman procedure, β-Amino-α-ketoamides.

ChemInform Abstract: The Dakin—West Analogue Reaction: Improvements and Applications

AbstractReview: 88 refs.

The Dakin–West analogue reaction: improvements and applications

This review summarizes the developments in the synthesis of β-amidocarbonyl compounds via the Dakin–West analogue reaction using enolizable ketones and esters in the presence of aldehyde derivatives and nitrile compounds reported since 1988. Several applications of β-amidocarbonyl compounds are also disclosed in the synthesis of biological and pharmacological intermediates. Research on the Dakin–West reaction for the synthesis of β-amidoketones using carboxylic acids and aminocarboxylic acids prior to 1988 has been reviewed elsewhere.

ChemInform Abstract: Synthesis of Amido Carbonyl Compounds Through the Dakin—West Reaction Using Lewis Acid Catalysts

AbstractReview: 40 refs.

Dakin-West Reaction of N-Thioacylprolines Using Trifluoroacetic Anhydride: Novel Access to 5-Trifluoromethylthiazoles

Dakin-West Reaction of N-Thioacylprolines Using Trifluoroacetic Anhydride: Novel Access to 5-Trifluoromethylthiazoles

Trifluoroacetic Acid–Catalyzed Synthesis of N-(1-(3-Chlorophenyl)-3-aryl-3-oxopropyl)-2-(4-nitrophenyl)acetamides via Dakin–West Reaction

A series of novel N-(1-(3-chlorophenyl)-3-aryl-3-oxopropyl)-2-(4-nitrophenyl) acetamides were synthesized using p-nitrophenylacetonitrile, m-chlorobenzaldehyde, and aryl methyl ketones as starting materials and trifluoroacetic acid (TFA) as catalyst. This realized an improved Dakin–West reaction in which p-nitrophenylacetonitrile was involved. The chemical structures of up to 15 target molecules were characterized by 1H NMR, 13C NMR, and high-resolution mass spectrometry. This method provides a facile synthetic protocol under more moderate reaction conditions, smaller dosage (0.40 mol%) and hence lower cost of catalyst, and simpler posttreatment in comparison to other known methods. A reaction mechanism is proposed in which hydroxyacetophenone is first catalytically converted into the corresponding acetoxyacetophenone prior to be involved in the subsequent Dakin–West reaction that eventually leads to hydroxyl-acetylated target compounds. [Supplementary materials are available for this article. Go to the publisher's online edition of Synthetic Communications® for the following free supplemental resource(s): Full experimental and spectral details.]

Synthesis of Amido Carbonyl Compounds through the Dakin–West Reaction using Lewis Acid Catalysts

The synthesis is described of β-amido carbonyl compounds with enolisable ketones and esters in the presence of aldehyde derivatives and nitrile compounds using Lewis acid catalysts.

Trifluoromethanesulfonic acid promoted Dakin–West reaction: An efficient and convenient synthesis of β-acetamido ketones

Trifluoromethanesulfonic acid promoted efficient condensation of an aromatic aldehyde with an acetophenone and acetonitrile in the presence of acetylchloride as an activator producing β-acetamido carbonyl compounds is described. β-Acetamido carbonyls were synthesized by triflic acid promoted Dakin-West reaction of aryl aldehydes, aryl ketones and acetonitrile.

Dakin–West reaction on 1-thyminyl acetic acid for the synthesis of 1,3-bis(1-thyminyl)-2-propanone, a heteroaromatic compound with nucleopeptide-binding properties

This work deals with the Dakin-West synthesis, starting from the nucleoamino acid 1-thyminyl acetic acid, as well the NMR, ESI MS, and X-ray characterization of a heteroaromatic compound denominated by us T(2)CO, comprising two thymine moieties anchored to a 2-propanonic unit, the spectroscopic properties of which were studied by UV as a function of temperature and ionic strength. Preliminary binding-studies with molecules of biomedical interest such as nucleic acids and proteins, performed on samples containing T(2)CO, suggested that this molecule is able to interact very weakly with double-stranded RNA, whereas it does not seem to bind other nucleic acids or proteins. Moreover, by studies with fresh human serum we found that T(2)CO is resistant to enzymatic degradation till 24 h, whereas UV metal binding-studies, performed using solutions of copper (II) chloride dihydrate and nickel (II) chloride hexahydrate, revealed a certain ability of T(2)CO to bind copper (II) cation. Finally, by CD spectroscopy we investigated the influence of T(2)CO on the already described supramolecular networks based on L-serine-containing nucleopeptides. More particularly, we found that T(2)CO is able to increase the level of structuration of the non-covalent supramolecular assembly of the chiral nucleopeptides, which is a feature of remarkable interest for the development of innovative drug delivery tools.