Ester Surrogates Research Articles

Oxidation and Phenolysis of Peptide/Protein C-Terminal Hydrazides Afford Salicylaldehyde Ester Surrogates for Chemical Protein Synthesis.

With the growing popularity of serine/threonine ligation (STL) and cysteine/penicillamine ligation (CPL) in chemical protein synthesis, facile and general approaches for the preparation of peptide salicylaldehyde (SAL) esters are urgently needed, especially those viable for obtaining expressed protein SAL esters. Herein, we report the access of SAL ester surrogates from peptide hydrazides (obtained either synthetically or recombinantly) via nitrite oxidation and phenolysis by 3-(1,3-dithian-2-yl)-4-hydroxybenzoic acid (SAL(-COOH)PDT). The resulting peptide SAL(-COOH)PDT esters can be activated to afford the reactive peptide SAL(-COOH) esters for subsequent STL/CPL. While being operationally simple for both synthetic peptides and expressed proteins, the current strategy facilitates convergent protein synthesis and combined application of STL with NCL. The generality of the strategy is showcased by the N-terminal ubiquitination of the growth arrest and DNA damage-inducible protein (Gadd45a), the efficient synthesis of ubiquitin-like protein 5 (UBL-5) via a combined N-to-C NCL-STL strategy, and the C-to-N semisynthesis of a myoglobin (Mb) variant.

Synthesis of Carboxylic Acid and Dimer Ester Surrogates to Constrain the Abundance and Distribution of Molecular Products in α-Pinene and β-Pinene Secondary Organic Aerosol.

Liquid chromatography/negative electrospray ionization mass spectrometry [LC/(-)ESI-MS] is routinely employed to characterize the identity and abundance of molecular products in secondary organic aerosol (SOA) derived from monoterpene oxidation. Due to a lack of authentic standards, however, commercial terpenoic acids (e.g., cis-pinonic acid) are typically used as surrogates to quantify both monomeric and dimeric SOA constituents. Here, we synthesize a series of enantiopure, pinene-derived carboxylic acid and dimer ester homologues. We find that the (-)ESI efficiencies of the dimer esters are 19-36 times higher than that of cis-pinonic acid, demonstrating that the mass contribution of dimers to monoterpene SOA has been significantly overestimated in past studies. Using the measured (-)ESI efficiencies of the carboxylic acids and dimer esters as more representative surrogates, we determine that molecular products measureable by LC/(-)ESI-MS account for only 21.8 ± 2.6% and 18.9 ± 3.2% of the mass of SOA formed from ozonolysis of α-pinene and β-pinene, respectively. The 28-36 identified monomers (C7-10H10-18O3-6) constitute 15.6-20.5% of total SOA mass, whereas only 1.3-3.3% of the SOA mass is attributable to the 46-62 identified dimers (C15-19H24-32O4-11). The distribution of identified α-pinene and β-pinene SOA molecular products is examined as a function of carbon number (nC), average carbon oxidation state , and volatility (C*). The observed order-of-magnitude difference in (-)ESI efficiency between monomers and dimers is expected to be broadly applicable to other biogenic and anthropogenic SOA systems analyzed via (-) or (+) LC/ESI-MS under various LC conditions, and demonstrates that the use of unrepresentative surrogates can lead to substantial systematic errors in quantitative LC/ESI-MS analyses of SOA.

The applicability of catalytic esterified biomass-pyrolysis-oil surrogates in diesel engine

Catalytic esterified biomass-pyrolysis-oil is a potential renewable fuel for application in internal combustion engine. Although a number of studies have been conducted on bio-oil production and upgrading, relatively few attention has been paid on the bio-oil application in diesel engine. Here, the aim of this paper is to investigate the performance and emission characteristic of EF (ethyl formate), EA (ethyl acetate), EP (ethyl propionate) in diesel engine. For this purpose, 10% and 20% vol. of the selected ester surrogates were blended with diesel and tested in a diesel engine to check the variation of BSEC (brake specific energy consumption), emission temperature, CO emission, NOx emission and soot opacity along with the increase of load (or power output), and the influence of ester additives on soot morphology was also inspected with a Fourier transform infrared spectroscopy (FTIR) and a field emission scanning electron microscopy (TEM). In the test, EA and EP blended fuels had lower CO, NOx, and soot emissions than diesel, meanwhile, EF blend had the lowest NOx emission but the highest soot opacity among the test four fuels. In addition, the added esters reduced the density of the chemical bonds in soot, and effectively inhibited the formation of crystal structure of soot. The results indicate that EA and EP blended fuels have a better operation and emission performance than diesel. This work reveals that it is possible to operate diesel engine with catalytic esterified biomass-pyrolysis-oil.

Acyl‐Imidazoles: A Privileged Ester Surrogate for Enantioselective Synthesis

AbstractSince the first report by Evans in asymmetric Friedel‐Crafts reactions, the use of acyl‐imidazoles has blossomed as powerful ester/amide surrogates. The imidazole scaffold indeed displays stability and special activation features allowing both better reactivity and selectivity in traditional ester/amide functionalizations: α‐(enolate chemistry), β‐(conjugate additions), α,β‐(cycloadditions) or γ/δ‐(vinylogous). An overview of the contemporary and growing interest in acyl‐imidazoles in metal‐ and organo‐catalyzed transformations (bio‐hybrid catalytic systems will be fully described in a back‐to‐back Minireview) will be highlighted. Moreover, post‐functionalization expediencies are also going to be discussed in this Minireview.

Dioxazolones as masked ester surrogates in the Pd(ii)-catalyzed direct C-H arylation of 6,5-fused heterocycles.

A simple and effective Pd(ii)-catalyzed regioselective C(2)-H arylation of 6,5-fused heterocycles with dioxazolones as a masked ester surrogate under mild conditions is reported. The significance of the arylation is highlighted by the new reactivity demonstrated in dioxazolones via proximal C-H activation of the cyclic carbonate of the hydroxamic acid functionality under protic conditions.

Serine/Threonine Ligation: Origin, Mechanistic Aspects, and Applications.

Synthetic proteins are expected to go beyond the boundary of recombinant DNA expression systems by being flexibly installed with site-specific natural or unnatural modification structures during synthesis. To enable protein chemical synthesis, peptide ligations provide effective strategies to assemble short peptide fragments obtained from solid-phase peptide synthesis (SPPS) into long peptides and proteins. In this regard, chemoselective peptide ligation represents a simple but powerful transformation realizing selective amide formation between the C-terminus and N-terminus of two side-chain-unprotected peptide fragments. These reactions are highly chemo- and regioselective to tolerate the side-chain functionalities present on the unprotected peptides, highly reactive to work with millmolar or submillimolar concentrations of the substrates, and operationally simple with mild conditions and accessible building blocks. This Account focuses on our work in the development of serine/threonine ligation (STL), which originates from a chemoselective reaction between an unprotected peptide with a C-terminal salicylaldehyde (SAL) ester and another unprotected peptide with an N-terminal serine or threonine residue. Mechanistically, STL involves imine capture, 5- endo-trig ring-chain tautomerization, O-to- N [1,5] acyl transfer to afford the N, O-benzylidene acetal-linked peptide, and acidolysis to regenerate the Xaa-Ser/Thr linkage (where Xaa is the amino acid) at the ligation site. The high abundance of serine and threonine residues (12.7%) in naturally occurring proteins and the good compatibility of STL with various C-terminal residues provide multiple choices for ligation sites. The requisite peptide C-terminal SAL esters can be prepared from the peptide fragments obtained from both Fmoc-SPPS and Boc-SPPS through four available methods (a safety-catch strategy based on phenolysis, direct coupling, ozonolysis, and the n + 1 strategy). In the synthesis of proteins (e.g., ACYP enzyme, MUC1 glycopeptide 40-mer to 80-mer, interleukin 25, and HMGA1a with variable post-translational modification patterns), both C-to- N and N-to- C sequential STL strategies have been developed through selection of temporal N-terminal protecting groups and proper design of the switch-on/off C-terminal SAL ester surrogate, respectively. In the synthesis of cyclic peptide natural products (e.g., daptomycin, teixobactin, cyclomontanin B, yunnanin C) and their analogues, intramolecular head-to-tail STL has been implemented on linear peptide SAL ester precursors containing four to 10 amino acid residues with good efficiency and minimized oligomerization. As a thiol-independent chemoselective ligation complementary to native chemical ligation, STL provides an alternative tool for the chemical synthesis of homogeneous proteins with site-specific and structure-defined modifications and cyclic peptide natural products, which lays foundation for chemical biology and medicinal studies of those molecules with biological importance and therapeutic potential.

ChemInform Abstract: Microwave‐Assisted Tandem Organocatalytic Peptide‐Coupling Intramolecular aza‐Michael Reaction: α,β‐Unsaturated N‐Acyl Pyrazoles as Michael Acceptors.

AbstractConjugated N‐acyl pyrazoles are successfully employed in the organocatalytic enantioselective intramolecular aza‐Michael reaction as ester surrogates.

ChemInform Abstract: Trienamine‐Mediated Asymmetric [4 + 2]‐Cycloaddition of α,β‐Unsaturated Ester Surrogates Applying 4‐Nitro‐5‐styrylisoxazoles.

ChemInform Abstract: Trienamine‐Mediated Asymmetric [4 + 2]‐Cycloaddition of α,β‐Unsaturated Ester Surrogates Applying 4‐Nitro‐5‐styrylisoxazoles.

Masked unsaturated esters/amides in asymmetric organocatalysis.

This Concept article summarizes strategies and developments regarding the use of masked unsaturated esters/amides in asymmetric organocatalysis. Useful substrates are categorized by the design of their inherent carboxylate template. This template group not only enables their functionality as ester surrogates, but also define their accessibilities, modes of interactions with catalysts and the simplicity with which they transform back to the parent carboxylates. Both covalent and noncovalent catalytic systems are discussed and examples showing the entire process (from substrates-to-functionalized ester/amides) are given.

Trienamine-mediated asymmetric [4+2]-cycloaddition of α,β-unsaturated ester surrogates applying 4-nitro-5-styrylisoxazoles.

Highly enantioselective organocatalytic [4+2]-cycloaddition of in situ generated trienamines with 4-nitro-5-styrylisoxazoles as α,β-unsaturated ester surrogates is presented. The synthetic utility of this strategy is demonstrated by transforming the formed cycloadducts into optically active carboxylates.

ChemInform Abstract: α‐Ketophosphonates as Ester Surrogates: Isothiourea‐Catalyzed Asymmetric Diester and Lactone Synthesis.

AbstractThe reaction can be scaled up.

Microwave-assisted tandem organocatalytic peptide-coupling intramolecular aza-Michael reaction: α,β-unsaturated N-acyl pyrazoles as Michael acceptors.

Conjugated N-acyl pyrazoles have been successfully employed in the organocatalytic enantioselective intramolecular aza-Michael reaction as ester surrogates. Bifunctional squaramides under microwave irradiation provided the best results in this transformation. Furthermore, this protocol has been combined with a peptide-coupling reaction in a tandem sequence. The final products were easily converted into the corresponding ethyl esters.

Asymmetric Mannich synthesis of α-amino esters by anion-binding catalysis.

We report a scalable, one-pot Mannich route to enantioenriched α-amino esters by direct reaction of α-chloroglycine ester as a practical imino ester surrogate. The reaction is promoted by a chiral aminothiourea, which is proposed to operate cooperatively by generating an iminium ion by chloride abstraction and an enolate by deprotonation, followed by highly stereoselective C–C bond formation between both reactive intermediates associated non-covalently within the catalyst framework.

α-Ketophosphonates as ester surrogates: isothiourea-catalyzed asymmetric diester and lactone synthesis.

Isothiourea HBTM-2.1 catalyzes the asymmetric Michael addition/lactonization of aryl- and alkenylacetic acids using α-keto-β,γ-unsaturated phosphonates as α,β-unsaturated ester surrogates, giving access to a diverse range of stereodefined lactones or enantioenriched functionalized diesters upon ring-opening.

Organosuperbase-catalyzed Direct-type Michael Addition Reactions of Sulfonylimidates as Ester Surrogates

Organosuperbase-catalyzed Direct-type Michael Addition Reactions of Sulfonylimidates as Ester Surrogates

ChemInform Abstract: Microwave‐Assisted Regiospecific Synthesis of Pseudohalohydrin Esters.

AbstractThe reaction of N‐acylbenzotriazoles with epoxides provides products which constitute halohydrin ester surrogates.

ChemInform Abstract: Stereoselective Synthesis of 2,6‐cis‐Substituted Tetrahydropyrans: Broensted Acid‐Catalyzed Intramolecular Oxa‐Conjugate Cyclization of α,β‐Unsaturated Ester Surrogates.

AbstractTreatment of α,β‐unsaturated thioesters, oxazolidinone imides, and pyrrole amides with CSA allows a mild, effective, and stereoselective access to biologically important 2,6‐cis‐substituted tetrahydropyrans.

Microwave-Assisted Regiospecific Synthesis of Pseudohalohydrin Esters

N -Acylbenzotriazoles react regiospecifically with epoxides under palladium catalysis to give novel β-(benzotriazol-1-yl)ethyl esters (52–87%) constituting halohydrin ester surrogates.

Stereoselective Synthesis of 2,6-Cis-Substituted Tetrahydropyrans: Brønsted Acid-Catalyzed Intramolecular Oxa-Conjugate Cyclization of α,β-Unsaturated Ester Surrogates

Intramolecular oxa-conjugate cyclization (IOCC) of α,β-unsaturated carbonyl compounds, triggered by deprotonation with a base, represents a straightforward method for the synthesis of tetrahydropyrans. However, it has been known that stereochemical outcome of IOCC depends on the local structure of substrates and sometimes requires harsh reaction conditions and/or prolonged reaction times for selective formation of 2,6-cis-substituted tetrahydropyrans. These shortcomings limit the feasibility of IOCC in the context of complex natural product synthesis. In this paper, we describe Brønsted acid-catalyzed IOCC of α,β-unsaturated ester surrogates (e.g., α,β-unsaturated thioesters, oxazolidinone imides, and pyrrole amides) under mild reaction conditions, which affords a series of synthetically versatile 2,6-cis-substituted tetrahydropyran derivatives with good to excellent stereoselectivity (dr from 7:1 to >20:1). These α,β-unsaturated carbonyl compounds were found to be more reactive than the corresponding oxoesters that are generally unreactive toward Brønsted acid-catalyzed intramolecular oxa-conjugate additions. The product tetrahydropyrans could be transformed into various derivatives in an efficient manner, highlighting the usefulness of our methodology.

Expanding the Utility of Brønsted Base Catalysis: Biomimetic Enantioselective Decarboxylative Reactions

As a result of the low reactivity of simple esters, the use of them as nucleophiles in direct asymmetric transformations is a long-standing challenge in synthetic organic chemistry. Nature approaches this difficulty through a decarboxylative mechanism, which is used for polyketide synthesis. Inspired by nature, we report guanidine-catalyzed biomimetic decarboxylative C-C and C-N bond-formation reactions. These highly enantioselective decarboxylative Mannich and amination reactions utilized malonic acid half thioesters as simple ester surrogates. It is proposed that nucleophilic addition precedes decarboxylation in the mechanism, which has been investigated in detail through the identification of intermediates by using electrospray ionization (ESI) mass-spectrometric analysis and DFT calculations.