Acyl Transfer Catalyst Research Articles

Enantioselective construction of stereogenic-at-sulfur(IV) centres via catalytic acyl transfer sulfinylation.

Chiral sulfur pharmacophores are crucial for drug discovery in bioscience and medicinal chemistry. While the catalytic asymmetric synthesis of sulfoxides and sulfinate esters with stereogenic-at-sulfur(IV) centres is well developed, the synthesis of chiral sulfinamides remains challenging, which has primarily been attributed to the high nucleophilicity and competing reactions of amines. In this study, we have developed an efficient methodology for the catalytic asymmetric synthesis of chiral sulfinamides and sulfinate esters by the sulfinylation of diverse nucleophiles, including aromatic amines and alcohols, using our bifunctional chiral 4-arylpyridine N-oxides as catalysts. The remarkable results are a testament to the efficiency, versatility and broad applicability of the developed synthetic approach, serving as a valuable tool for the synthesis of sulfur pharmacophores. Mechanistic experiments and density functional theory calculations revealed that the initiation and stereocontrol of this reaction are induced by an acyl transfer catalyst. Our research provides an efficient approach for the construction of optically pure sulfur(IV) centres.

Catalytic covalent inhibition of cyclooxygenase-1 by a biomimetic acyltransferase

Covalent binding enzyme inhibitors have grown in acceptance in therapeutic discovery. Several recent examples of protein-targeting acyl-transfer catalysts covalently modify protein targets in cellular systems but generally do not affect protein function. In this study, a small molecule has been developed for the first time that can achieve catalytic covalent inhibition of the inflammatory response enzyme, cyclooxygenase-1, in cells using only endogenous acetyl-CoA as a co-substrate. By utilizing a catalytic inhibitor which can self-regenerate, a sustained inhibitory response is achieved in cells compared to the analogous non-catalytic covalent cyclooxygenase antagonist, acetylsalicylic acid (aspirin).

Calibrating Catalytic DNA Nanostructures for Site-Selective Protein Modification.

Many biomedical fields rely on proteins that are selectively modified. These can be attached using reactive or catalytic moieties, but the position where these moieties are attached is often poorly controlled. We assessed how catalyst position affects the efficiency and selectivity of protein modification. For this, we anchored a template DNA strand to three different proteins, which were subsequently hybridized to DNA strands that contained catalysts at different positions. We found a strong correlation between the catalyst‐to‐protein distance and the efficiency of protein modification for acyl transfer catalysts, which operate via a covalently bound reactant intermediate. Additionally, we found that the catalyst's distance and orientation with respect to the protein surface, also influences its site‐selectivity. A catalyst operating with unbound reactant intermediates showed only enhanced efficiency. Our results are rationalized using computational simulations, showing that one‐point anchoring of the DNA construct leads to notable differences in the site of modification.

Energy Decomposition Analysis Reveals the Nature of Lone Pair-π Interactions with Cationic π Systems in Catalytic Acyl Transfer Reactions.

Lone pair-π (LP-π) interactions between Lewis basic heteroatoms, such as oxygen and sulfur, and electron-deficient π systems are important noncovalent interactions. However, they have seldom been used to control catalyst-substrate interactions in catalysis. We performed density functional theory calculations to investigate the strengths of LP-π interactions between different lone pair donors and cationic π systems, and in different complexation geometries. Energy decomposition analysis calculations indicated that the dominant stabilizing force in LP-π complexes is electrostatic interaction and the electrostatic potential surface of the π system predicts the most favorable site for forming LP-π complexes. Benzotetramisole (BTM) is revealed as a privileged acyl transfer catalyst that promotes LP-π interactions because the positive charge of the acylated BTM is delocalized onto the dihydroimidazole ring, which binds strongly with a variety of oxygen and sulfur lone pair donors.

Development of a triazinedione-based dehydrative condensing reagent containing 4-(dimethylamino)pyridine as an acyl transfer catalyst.

A new triazinedione-based reagent, (N,N'-dialkyl)triazinedione-4-(dimethylamino)pyridine (ATD-DMAP) was developed for the operationally simple dehydrative condensation of carboxylic acids. This reagent comprises an ATD core and DMAP as the leaving group, which is liberated into the reaction system to accelerate acyl transfer reactions. Upon adding ATD-DMAP to a mixture of carboxylic acids and alcohols in the presence of an amine base, the corresponding esters were formed rapidly at room temperature. Moreover, dehydrative condensation between carboxylic acids and amines using ATD-DMAP proceeded in high yield.

Site-selective and inducible acylation of thrombin using aptamer-catalyst conjugates.

Two acyl-transfer catalysts were conjugated to thrombin-binding DNA aptamers to acylate thrombin. Modification occurred site-selectively on Lys (≫Ser) residues proximal to the respective aptamer-thrombin interface, was selective for thrombin in the presence of other proteins, and the activity of both DNA-catalysts could be controlled by an external trigger.

Rational Design of 2-Substituted DMAP-N-oxides as Acyl Transfer Catalysts: Dynamic Kinetic Resolution of Azlactones.

A novel concept that conversion of chiral 2-substituted DMAP into its DMAP-N-oxide could significantly enhance the catalytic activity and still be used as an acyl transfer catalyst is presented. A new type of chiral 2-substituted DMAP-N-oxides, derived from l-prolinamides, has been rationally designed, facilely synthesized, and applied in the dynamic kinetic resolution of azlactones. Using simple MeOH as the nucleophile, various l-amino acid derivatives were produced in high yields (up to 98% yield) and enantioselectivities (up to 96% ee). Furthermore, α-deuterium labeled l-phenylalanine derivative was also obtained. Experiments and DFT calculations revealed that in 2-substituted DMAP-N-oxide, the oxygen atom acted as the nucleophilic site and the N-H bond functioned as the H-bond donor. High enantioselectivity of the reaction was governed by steric factors, and the addition of benzoic acid reduced the activation energy by participating in the construction of a H-bond bridge. The theoretical chemical study indicated that only when attack directions of the chiral catalyst were fully considered could the correct calculation results be obtained. This work paves the way for the utilization of the C2 position of the pyridine ring and the development of chiral 2-substituted DMAP-N-oxides as efficient acyl transfer catalysts.

Tropolonate Salts as Acyl-Transfer Catalysts under Thermal and Photochemical Conditions: Reaction Scope and Mechanistic Insights

Acyl-transfer catalysis is a frequently used tool to promote the formation of carboxylic acid derivatives, which are important synthetic precursors and target compounds in organic synthesis. Howeve...

Chiral DMAP-N-oxides as Acyl Transfer Catalysts: Design, Synthesis, and Application in Asymmetric Steglich Rearrangement.

A DMAP-N-oxide, featuring an α-amino acid as the chiral source, was developed, synthesized and applied in asymmetric Steglich rearrangement. A series of O-acylated azlactones afforded C-acylated azlactones possessing a quaternary stereocenter in high yields (up to 97 % yield) and excellent enantioselectivities (up to 97 % ee). Compared to the widespread use of pyridine nitrogen, which serves as the nucleophilic site in the asymmetric acyl transfer reaction, we discovered that chiral DMAP-N-oxides, in which the oxygen now acts as the nucleophilic site, are efficient acyl transfer catalysts. Our finding might open a new door for the development of chiral DMAP-N-oxides for asymmetric acyl transfer reactions.

Chiral DMAP‐N‐oxides as Acyl Transfer Catalysts: Design, Synthesis, and Application in Asymmetric Steglich Rearrangement

AbstractA DMAP‐N‐oxide, featuring an α‐amino acid as the chiral source, was developed, synthesized and applied in asymmetric Steglich rearrangement. A series of O‐acylated azlactones afforded C‐acylated azlactones possessing a quaternary stereocenter in high yields (up to 97 % yield) and excellent enantioselectivities (up to 97 % ee). Compared to the widespread use of pyridine nitrogen, which serves as the nucleophilic site in the asymmetric acyl transfer reaction, we discovered that chiral DMAP‐N‐oxides, in which the oxygen now acts as the nucleophilic site, are efficient acyl transfer catalysts. Our finding might open a new door for the development of chiral DMAP‐N‐oxides for asymmetric acyl transfer reactions.

Kinetic Resolution of Racemic 2-Hydroxyamides Using a Diphenylacetyl Component as an Acyl Source and a Chiral Acyl-Transfer Catalyst.

Various optically active 2-hydroxyamide derivatives are produced based on the kinetic resolution of racemic 2-hydroxyamides with a diphenylacetyl component and (R)-benzotetramisole ((R)-BTM), a chiral acyl-transfer catalyst, via asymmetric esterification and acylation. It was revealed that a tertiary amide can be used with this novel protocol to achieve high selectivity (22 examples; s-value reaching over 250). The resulting chiral compounds could be transformed into other useful structures while maintaining their chirality.

Synthesis of Histidine-Containing Oligopeptides via Histidine-Promoted Peptide Ligation.

Histidine-containing peptides are valuable therapeutic agents for a treatment of neurodegenerative diseases. However, the synthesis of histidine-containing peptides is not trivial due to the potential of imidazole sidechain of histidine to act as a nucleophile if unprotected. A peptide ligation method utilizing the imidazole sidechain of histidine has been developed. The key imidazolate intermediate that acts as an internal acyl transfer catalyst during ligation is generated by deprotonation. Transesterification with amino acids or peptides tethered with C-terminal thioester followed by N→N acyl shifts led to the final ligated products. A range of histidine-containing dipeptides could be synthesized in moderate to good yields via this method without protecting the imidazole sidechain. The protocol was further extended to tripeptide synthesis via a long-range N→N acyl transfer, and tetrapeptide synthesis.

Acylative kinetic resolution of racemic aromatic β-hydroxy esters catalyzed by chiral nucleophilic N-(1-arylethyl)benzoguanidines

An efficient acylative kinetic resolution of racemic aromatic β-hydroxy esters with cyclohexanecarboxylic anhydride was achieved using newly designed (R)-N-methylbenzoguanidine ((R)-NMBG) derivatives. A series of (R)-NMBG derivatives was synthesized by modifying the original (R)-NMBG catalyst with the introduction of branched N-substituents containing a stereogenic center, and their catalytic performance was evaluated. (R,R)-N-(1-(β-1-Naphthyl)ethyl)benzoguanidine [(R,R)-NβNpEtBG] was found to function as an efficient acyl transfer catalyst for the reaction of a broad variety of substrates, regardless of the substituent type and substitution pattern.

(R)-(+)-N-Methylbenzoguanidine ((R)-NMBG) catalyzed acylative kinetic resolution of racemic 3-hydroxy-3-aryl-propanoates

(R)-(+)-N-methylbenzoguanidine ((R)-NMBG) functioned as an efficient acyl transfer catalyst for the acylative kinetic resolution of racemic β-hydroxy esters using cyclohexane carboxylic anhydride under mild reaction conditions. A tert-butyl ester moiety is necessary to achieve a high selectivity. The effects of the substituents on the aromatic rings of the substrates were systematically investigated, and diverse substrates participated in the reaction with good s-values (>20) irrespective of the type of substituents and their patterns, except for o-methoxy group.

Antagonizing the Androgen Receptor with a Biomimetic Acyltransferase.

The Androgen Receptor (AR) remains the leading target of advanced prostate cancer therapies. Thiosalicylamide analogs have previously been shown to act in cells as acyltransfer catalysts that are capable of transferring cellular acetate, presumably from acetyl-CoA, to HIV NCp7. Here we explore if the cellular acetyl-transfer activity of thiosalicylamides can be redirected to other cellular targets guided by ligands for AR. We constructed conjugates of thiosalicylamides and the AR-binding small molecule tolfenamic acid, which binds the BF-3 site of AR, proximal to the coactivator "FXXLF" binding surface. The thiosalicylamide-tolfenamic acid conjugate, YZ03, but not the separate thiosalicylamide plus tolfenamic acid, significantly enhanced acetylation of endogenous AR in CWR22Rv1 cells. Further analysis confirms that Lys720, a residue critical to FXXLF coactivator peptide binding, is a site of acyl-YZ03 acetylation. Under acyl-transfer conditions, YZ03 significantly enhances the ability of BF-3 site binding ligands to inhibit AR-coactivator peptide association. These data suggest that biomimetic acyltransferases can enhance protein-protein interaction inhibitors through covalent modification of critical interfacial residues.

Nonenzymatic, Enantioconvergent Dynamic Kinetic Resolution (DKR) of Racemic 2-(1H-Pyrrol-1-yl)alkanoic Acids as α-Amino Acid Equivalents

Abstract We report an effective dynamic kinetic resolution (DKR) system of racemic 2-(1H-pyrrol-1-yl)alkanoic acids, which consists of a rapid racemization step via an activating substrate and an enantio-discriminating step via catalytic esterification. The combination of pivalic anhydride as an activating agent, bis(α-naphthyl)methanol as an achiral alcohol, (R)-BTM as a chiral acyl-transfer catalyst, and Hünig’s base converted racemic 2-(1H-pyrrol-1-yl)alkanoic acids to the corresponding chiral carboxylates, which can be transformed into chiral α-amino acid derivatives with maintained high enantiopurity.

Kinetic resolution of α-methylene-β-hydroxy esters catalyzed by acyl transfer catalyst An-PIQ.

A highly efficient nonenzymatic kinetic resolution of a series of structurally diverse racemic α-methylene-β-hydroxy esters utilizing the acyl transfer catalyst An-PIQ and propionic anhydride is reported. This procedure provides recovered alcohols with extremely high ee's (up to >99%) in reasonable conversions and excellent selectivity factors (S up to 108). Several synthetically important substrates were resolved in gram-scale reactions, and highly optically pure α-methylene-β-hydroxy esters were obtained with excellent S values and good yields.

Nonenzymatic kinetic resolution of α-aryl substituted allylic alcohols catalyzed by acyl transfer catalyst Np-PIQ

Chiral α-aryl substituted allylic alcohols are important versatile synthetic intermediates. We report here an effective nonenzymatic kinetic resolution of racemic α-aryl substituted allylic alcohols by introducing different aryl groups with acyl transfer catalyst Np-PIQ and propionic anhydride, providing moderate to good selectivity factors (S=12–37).

Phenolic Ester Mediated Oligopeptide Synthesis Promoted by HOBt

Although substituted phenolic ester mediated peptide synthesis is an efficient and well established method, the same via totally unsubstituted phenyl ester is not preferred due to the extremely slow rate of aminolysis. We have investigated the scope of the unsubstituted phenyl ester as an intermediate in peptide bond formation and found that it may be useful for the design of chemoselective peptide ligation when HOBt is used as an acyl transfer catalyst. The scope of HOBt catalyzed, oxo ester mediated ligation is explored for the synthesis of oligopeptides containing a cysteine, serine and threonine at the N-terminus of the ligating peptide.

An Adventurous Synthetic Journey with MNBA from Its Reaction Chemistry to the Total Synthesis of Natural Products

Abstract After initially establishing a novel cyclization reaction of ω-hydroxycarboxylic acids (seco-acids) using 4-trifluoromethylbenzoic anhydride (TFBA) and Lewis acid catalysts to form the corresponding lactones, we discovered a more advanced method for this transformation using 2-methyl-6-nitrobenzoic anhydride (MNBA) as a coupling reagent with nucleophilic catalysts. The latter lactonization is promoted by acyl-transfer catalysts, such as 4-(dimethylamino)pyridine (DMAP), 4-pyrrolidinylpyridine (PPY), and 4-(dimethylamino)pyridine N-oxide (DMAPO). (+)-Ricinelaidic acid lactone ((+)-2) was first synthesized by the TFBA-mediated cyclization with Lewis acid catalysts, while the threo-aleuritic acid lactone (20) was alternatively synthesized by the MNBA-mediated cyclization with acyl-transfer catalysts. Using this effective lactonization technology to form the ester linkage under mild conditions, we then demonstrated the preparation of various large-, medium-, and small-sized natural and unnatural lactones including (−)-cephalosporolide D ((−)-3), (−)-octalactin A ((−)-4), (−)-octalactin B ((−)-25), 2-epibotcinolide (49), (−)- and (+)-2-hydroxytetracosanolides ((−)-77 and (+)-77), (−)- and (+)-2-hydroxy-24-oxooctacosanolides ((−)-78 and (+)-78), (−)-tetrahydrolipstatin ((−)-THL, (−)-117), and the erythromycin A skeletons 103b, 103c, 104c, and 105b. The transition structures involved in the formation of the β-lactones from the corresponding 3-hydroxycarboxylic acids were then determined using DFT calculations at the B3LYP/6-31G*//B3LYP/6-31G* level, and the reactivity of several seco-acids was successfully predicted on the basis of the calculated thermodynamic properties of the transition structures.