Acyl Transfer Agents Research Articles

N-to-S Acyl Transfer as an Enabling Strategy in Asymmetric and Chemoenzymatic Synthesis.

The observation of thioester-mediated acyl transfer processes in nature has inspired the development of novel protein synthesis and functionalization methodologies. The chemoselective transfer of an acyl group from S-to-N is the basis of several powerful ligation strategies. In this work, we sought to apply the reverse process, the transfer of an acyl group from N-to-S, as a method to convert stable chiral amides into more reactive thioesters. To this end, we developed a novel cysteine-derived oxazolidinone that serves as both a chiral imide auxiliary and an acyl transfer agent. This auxiliary combines the desirable features of rigid chiral imides as templates for asymmetric transformations with the synthetic applicability of thioesters. We demonstrate that the auxiliary can be applied in a range of highly selective asymmetric transformations. Subsequent intramolecular N-to-S acyl transfer of the chiral product and in situ trapping of the resulting thioester provides access to diverse carboxylic acid derivatives under mild conditions. The oxazolidinone thioester products can also be isolated and used in Pd-mediated transformations to furnish highly valuable chiral scaffolds, such as noncanonical amino acids, cyclic ketones, tetrahydropyrones, and dihydroquinolinones. Finally, we demonstrate that the oxazolidinone thioesters can also serve as a surrogate for SNAC-thioesters, enabling their seamless use as non-native substrates in biocatalytic transformations.

Luminescent water dispersible core-shell – (Y/Eu/Li)VO4@APTES@Folate and (Y/Eu/Li)VO4@Fe3O4@PEG nanocomposites: Biocompatibility and induction heating within the threshold alternating magnetic field

Luminescent red-emitting water dispersible core-shell nanocomposites have been synthesized from luminescent (Y/Eu/Li)VO4 and superparamagnetic Fe3O4 nanoparticles. The conjugation of folic acid on the luminescent (Y/Eu/Li)VO4 nanoparticles was achieved by a simpler chemistry via aminopropyl trimethoxysilane (APTES) coating followed by direct conjugation chemistry using dimethylaminopyridine as acyl transfer agent and N,N-disuccinimidyl carbonate as the protecting group in dimethysulfoxide solvent. On the other hand, polyethyleneglycol coated magnetic-luminescent (Y/Eu/Li)VO4@Fe3O4@PEG nanocomposite was also fabricated from the luminescent (Y/Eu/Li)VO4 and superparamagnetic Fe3O4 nanoparticles. The induction heating abilities of the magnetic-luminescent (Y/Eu/Li)VO4@Fe3O4@PEG nanocomposite have been studied within the threshold alternating magnetic field. The alternating magnetic field (Hf) strengths used in the study ranges from 2.15 × 106 to 4.58 × 106 kAm−1 s−1 which are well below the clinical threshold limit of 5 × 106 kAm−1 s−1 for human body. The nanocomposites exhibited good stability of the dispersion and in vitro biocompatibility towards HeLa cell lines. The median lethal dose, LD50 values are found to be 717.90 μg/mL and 677.00 μg/mL for the (Y/Eu/Li)VO4@[email protected] and (Y/Eu/Li)VO4@Fe3O4@PEG nanocomposites respectively. The synthetic methodology may be adopted for the synthesis of functionalized upconversion phosphors in non-invasive infrared assisted bioimaging and magneto-optically guided cancer hyperthermia.

Enantioselective N‐Acylation of Biginelli Dihydropyrimidines by Oxidative NHC Catalysis

The oxidative N‐acylation reaction of 3,4‐dihydropyrimidin‐2‐(1H)‐ones (DHPMs) with enals and N‐heterocyclic carbene (NHC) catalysts is described. The reaction proceeds in the presence of quinone oxidant without additional acyl transfer agents and in the asymmetric variant produces pharmaceutically relevant N3‐acylated products with good‐to‐moderate enantioselectivity.

Base-Promoted Amidation and Esterification of Imidazolium Salts via Acyl C–C bond Cleavage: Access to Aromatic Amides and Esters

Imidazolium salts have been effectively employed as suitable acyl transfer agents in amidation and esterification in organic synthesis. The weak acyl C(O)-C imidazolium bond was exploited to generate acyl electrophiles, which further react with amines and alcohols to afford amides and esters. The broad substrate scope of anilines and benzylic amines and base-promoted conditions are the benefits of this route. Interestingly, phenol, benzylic alcohols, and a biologically active alcohol can also be subjected to esterification under the optimized conditions.

Binary test battery with KeratinoSens™ and h-CLAT as part of a bottom-up approach for skin sensitization hazard prediction

Skin sensitization is one of the key safety endpoints for chemicals applied directly to the skin. Several integrated testing strategies (ITS) using multiple non-animal test methods have been developed to accurately evaluate the sensitizing potential of chemicals, but there is no regulatory-accepted ITS to classify a chemical as a non-sensitizer. In this study, the predictive performance of a binary test battery with KeratinoSens™ and h-CLAT compared to the local lymph node assay (LLNA) and human data was examined using comprehensive dataset of 203 chemicals. When two negative results indicate a non-sensitizer, the binary test battery provided sensitivity of 93.4% or 94.4% compared with the LLNA or human data. Taking into account the predictive limitations (i.e. high log Kow, pre-/pro-haptens and acyl transfer agents (or amine-reactive)), the binary test battery had extremely high sensitivity comparable to that of the 3 out of 3 ITS where three negative results of the DPRA, KeratinoSens™ and h-CLAT indicate a non-sensitizer. Therefore, the data from KeratinoSens™ or h-CLAT may provide partly redundant information on the molecular initiating event derived from DPRA. Taken together, the binary test battery of KeratinoSens™ and h-CLAT could be used as part of a bottom-up approach for skin sensitization hazard prediction.

ChemInform Abstract: Catalytic Insertion of Aldehydes into Dihalonitroacetophenones via Sequential Bond Scission‐Aldol Reaction‐Acyl Transfer.

AbstractIn situ cleavage of dihalonitroacetophenones affords nitronates, which undergo Lewis acid‐catalyzed addition to aldehydes.

One for Many: A Universal Reagent for Acylation Processes

AbstractThis work describes acylation reactions facilitated by a type of heterocycle‐based acyl transfer agent, 2‐acyloxypyridazinone. Reactions of 2‐acyloxypyridazinone with carboxylic acids yield mixed carbonic anhydride intermediates, which are reactive and could be coupled with a wide range of substrates including acids, amines, alcohols, and thiols. The wide substrate scope, ease of operation (no additive or catalyst), storage and handling stability, and atom‐efficiency from recycling the heterocycle carrier make the reported acylating agent attractive for acylation‐based coupling reactions.magnified image

Organocatalytic Kinetic Resolution of Sulfoximines.

An efficient kinetic resolution of sulfoximines with enals was realized using chiral N-heterocyclic carbene (NHC) catalysts. The stereoselective amidation proceeds without additional acyl transfer agent. Both enantiomers of the sulfoximines can be obtained with excellent ee values (up to 99% ee and -97% ee, respectively). Performing the catalysis on a gram scale allowed using the recovered sulfoximine (+)-1j in an asymmetric synthesis of FXa inhibitor F.

Tetra-n-butylammonium Fluoride as an Efficient Transesterification Catalyst for Functionalizing Cyclic Carbonates and Aliphatic Polycarbonates.

We have developed a general method for the functionalization of cyclic carbonate monomers having a pentafluorophenyl ester substituent at the 5-position (MTC-OC6F5), as well as the postpolymerization modification of the subsequent polymer, poly(MTC-OC6F5), with alcohols. The transesterifications are achieved under mild conditions using catalytic tetra-n-butylammonium fluoride (TBAF) as the nucleophilic acyl transfer agent. As an organic-soluble form of fluoride, TBAF loadings as low as 5 mol % were sufficient in bringing about high conversions at room temperature. The mild reaction conditions preserved the integrity of the sensitive carbonate moieties even without the use of Schlenk techniques. In addition to commercial TBAF solutions, we also found solid-supported forms of TBAF to be effective for transesterification, thus enabling facile postreaction workup and purification. More importantly, with only minor adjustments to the reaction conditions, we show that TBAF also promotes the postpolymerization modification of poly(MTC-OC6F5), whereby fluoride-mediated transesterification with various alcohols proceeded quantitatively across the pendant pentafluorophenyl esters. Synthesizing a series of pendant ester-functionalized polycarbonates from a common precursor polymer was previously unattainable with existing methods, an issue that is now resolved by the current work.

ChemInform Abstract: Eco‐Friendly Atom‐Economical Synthesis of 2‐Substituted‐benzo[d]thiazoles and 2‐Substituted‐benzo[d]oxazoles Using 2‐Acylpyridazin‐3(2H)‐ones.

Efficient and green syntheses of heterocycles are of great importance. In this work, we have demonstrated the synthesis of benzo[d]thiazoles and benzo[d]oxazoles using 2-acylpyridazin-3(2H)-ones as acyl transfer agents under transition-metal-free and eco-friendly conditions. It is worthy to note that the reaction is efficient, green, and economical, and will find several applications in organic synthesis, medicinal chemistry, and industrial chemistry.

Eco-friendly atom-economical synthesis of 2-substituted-benzo[d]thiazoles and 2-substituted-benzo[d]oxazoles using 2-acylpyridazin-3(2H)-ones

Efficient and green syntheses of heterocycles are of great importance. In this work, we have demonstrated the synthesis of benzo[d]thiazoles and benzo[d]oxazoles using 2-acylpyridazin-3(2H)-ones as acyl transfer agents under transition-metal-free and eco-friendly conditions. It is worthy to note that the reaction is efficient, green, and economical, and will find several applications in organic synthesis, medicinal chemistry, and industrial chemistry.

Macrocyclisation of Macrodiolide with Dimethylaluminium Methaneselenolate

AbstractDimethylaluminium methaneselenolate (Me2AlSeMe, 1) acts as an acyl transfer agent for esterification. In cases of direct macrolactonisation (n = 10–12), this selenium–aluminium complex preferentially creates symmetric macrodiolides rather than macrolides. The factors determining macrodilactonisation were investigated and applied toward the total synthesis of norpyrenophorin, which result in a macrodilactonisation yield of 64 %.

ChemInform Abstract: Regioselective Acylation of 2′-Deoxynucleosides Through an Enzymatic Reaction with Oxime Esters.

3′-O-Acyl derivatives of 2′-deoxynucleosides are obtained in good yield through an enzymatic reaction using oxime esters as acyl transfer agents.

Mechanism and Stereoselection in a Y-Catalyzed Transacylation Reaction. A Computational Modeling Study

Density functional theory calculations were performed to evaluate the proposed mechanism of a yttrium-salen complex-catalyzed acylation of secondary alcohols using an enol acetate as the acyl-transfer agent. A key step in the proposed mechanism is an intramolecular nucleophilic reaction between the coordinated alcohol and enol ester, brought into close proximity by the yttrium catalyst. The use of the BP86 pure density functional for reproduction of the geometry of the yttrium complex was validated by comparison with the experimental crystal structure. Mapping of the free energy surface of the reaction followed, employing both the BP86 and B3LYP functionals, and results suggest that the proposed mechanism (Org. Lett. 2002, 4, 1607-1610) is a reasonable pathway for the reaction. Reproduction of the experimentally observed enantioselectivity of the reaction was subsequently attempted, with diastereomeric transition states identified for the turnover-limiting step in the reaction, the intramolecular nucleophilic attack of the alcohol into the enol ester reagent. The predicted experimental enantioselectivities were successfully reproduced for the three ligands studied, although the energetic predictions did not perfectly correlate with the experimental enantioselectivities.

ChemInform Abstract: Carbonylation of Aryl Chlorides with Oxygen Nucleophiles at Atmospheric Pressure. Preparation of Phenyl Esters as Acyl Transfer Agents and the Direct Preparation of Alkyl Esters and Carboxylic Acids.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Carbonylation of Aryl Chlorides with Oxygen Nucleophiles at Atmospheric Pressure. Preparation of Phenyl Esters as Acyl Transfer Agents and the Direct Preparation of Alkyl Esters and Carboxylic Acids

A mild, functional group tolerant method of the preparation of phenyl esters from aryl chlorides via palladium-catalyzed carbonylation is described using atmospheric pressure of carbon monoxide. Phenyl esters are shown to be useful acylating agents, delivering libraries of carbonyl derivatives, including alkyl, allyl and thioesters, under very mild conditions. Direct preparation of alkyl esters and carboxylic acids is also demonstrated, providing the first method for the preparation of methyl and ethyl esters from aryl chlorides without pressured reactors.

Lipase‐Catalyzed Monoprotection of 1,4‐Diols in an Organic Solvent Using Vinyl Benzoate as Acyl Transfer Agent.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Lipase-catalyzed monoprotection of 1,4-diols in an organic solvent using vinyl benzoate as acyl transfer agent

Lipase from Mucor miehei (MML) has been selected as the most suitable enzyme to catalyze the efficient monobenzoylation of 1,4-diols using vinyl benzoate as acyl transfer reagent in tert-butyl methyl ether. The regioselectivity of the monobenzoylation of 2-substituted-1,4-diols has been studied as well.

Desymmetrization of meso 1,3- and 1,4-diols with a dinuclear zinc asymmetric catalyst.

A dinuclear asymmetric zinc catalyst generated by mixing a 2:1 ratio of diethylzinc and 2,6-bis[5-2-diarylhydroxy methyl-1-pyrrolidinyl]-4-methylphenol has been contrasted with enzymes for the desymmetrization of some meso diols. The best ligand has a p-biphenylyl group as the aromatic substituent defining the chiral space. A series of 2-substituted propanediols were examined. The best acyl transfer agent proved to be vinyl benzoate. Diacylation normally did not occur. The phenyl substituted substrate gave 91-95% ee which compares favorably with the best ee of 92% reported for an enzymatic desymmetrization. The methyl substituted substrate gave significantly better results with the dinuclear zinc catalyst (89% yield, 82% ee) as compared to the best enzymatic esterification (70% yield, 60% ee). One case of a 1,4-diol, cis-1,2-bis(hydroxymethyl) cyclohexane, also gave much better results with the dinuclear zinc catalysts (93% yield, 91% ee) as compared to the reported enzymatic process (44% yield, 7% ee). A model to rationalize the results is presented.

Polymer-Supported Selenol Esters as Useful Acylating Reagents. Application to α,β-Acetylenic Ketones Synthesis

Three novel polystyrene supported selenol esters were synthesized and used as acyl transfer agents to prepare α,β-acetylenic ketones by reaction with alkynylcoppers.