Efficient Regioselective Ring Opening of Oxiranes with Thioacids in the Presence of β‐Cyclodextrin in Water

A mild and convenient synthesis of β‐hydroxy thioesters has been achieved by the regioselective ring opening of oxiranes using thioacetic acid and thiobenzoic acid in the presence of β‐cyclodextrin in water at room temperature. β‐Hydroxy thioesters are realized in high yields, and β‐cyclodextrin can also be recovered and reused.     

Equilibrium shift in the rhodium-catalyzed acyl transfer reactions

Rhodium/phosphine complexes catalyze equilibrium acyl transfer reactions between acid fluorides, aryl esters, acylphosphine sulfides, and thioesters. The use of appropriate co-substrates to accept heteroatom groups shifted the equilibrium to desired products. Acylphosphine sulfides and aryl esters were converted to acid fluorides using benzoylpentafluorobenzene as the fluoride donor, and the fluorination reaction of thioesters employed (4-tolylthio)pentafluorobenzene. Acid fluorides were converted into acylphosphine sulfides and thioesters using diphosphine disulfides and disulfides/triphenylphosphine, respectively. Aryl esters were obtained from acid fluorides and phenols in the presence of triphenylsilane. Aryl esters, acylphosphine sulfides, and thioesters were also interconverted in the presence of rhodium complexes. These rhodium-catalyzed acyl transfer reactions proceeded under neutral conditions without using acid or base. The involvement of acyl rhodium intermediates in these reactions was suggested by the carbothiolation reaction of thioesters and alkynes.     

Rhodium-catalyzed interconversion between acid fluorides and thioesters controlled using heteroatom acceptors

A rhodium complex catalyzed the equilibrium acyl transfer reaction between acid fluorides and thioesters. In the presence of fluoride or thiolate acceptors, the reaction could be shifted to either product. RhH(PPh₃)₄-dppe catalyzed the reaction of acid fluorides and diorgano disulfides in the presence of triphenylphosphine giving thioesters, which was accompanied by triphenylphosphine difluoride. The same complex catalyzed the reaction of aryl thioesters and hexafluorobenzene giving acid fluorides, which was accompanied by 1,4-di(arylthio)-2,3,5,6-tetrafluorobenzenes.     

Solid-phase synthesis of peptide and glycopeptide thioesters through side-chain-anchoring strategies

An efficient new strategy for the synthesis of peptide and glycopeptide thioesters is described. The method relies on the side-chain immobilization of a variety of Fmoc-amino acids, protected at their C-termini, on solid supports. Once anchored, peptides were constructed using solid-phase peptide synthesis according to the Fmoc protocol. After unmasking the C-terminal carboxylate, either thiols or amino acid thioesters were coupled to afford, after cleavage, peptide and glycopeptide thioesters in high yields. Using this method a significant proportion of the proteinogenic amino acids could be incorporated as C-terminal amino acid residues, therefore providing access to a large number of potential targets that can serve as acyl donors in subsequent ligation reactions. The utility of this methodology was exemplified in the synthesis of a 28 amino acid glycopeptide thioester, which was further elaborated to an N-terminal fragment of the glycoprotein erythropoietin (EPO) by native chemical ligation.     

Efficient synthesis of thioesters and amides from aldehydes by using an intermolecular radical reaction in water

The combination of the water-soluble radical initiator, 2,2'-azobis[2-(2-imidazolin-2-yl)propane] dihydrochloride (VA-044) and the surfactant, cetyltrimethyl-ammonium bromide (CTAB), was found to be the most suitable condition for the effective and direct synthesis of useful active thioesters (pentafluorophenyl thioesters) in water. In addition, the direct amidation of aldehydes was achieved by the addition of the amines to the thioesterification reaction mixture in water.     

The direct synthesis of thioesters using an intermolecular radical reaction of aldehydes with dipentafluorophenyl disulfide in water

The combination of the water-soluble radical initiator, 2,2'-azobis[2-(2-imidazolin-2-yl)propane] dihydrochloride (VA-044), and surfactant, cetyltrimethylammonium bromide (CTAB), was found to be the most suitable condition for the effective direct synthesis of useful active thioesters (pentafluorophenyl thioesters) in water.     

Hydrophobic,low-loading and alkylated polystyrene-supported sulfonic acid for several organic reactions in water: remarkable effects of both the polymer structures and loading levels of sulfonic acids

A hydrophobic, low-loading and alkylated polystyrene-supported sulfonic acid (LL-ALPS-SO3H) has been developed for several organic reactions such as the hydrolysis of thioesters, the deprotection of acetals and an acetonide, and the hydration of an epoxide and an alkyne in pure water on the basis of remarkable effects of both the polymer structures and loading levels of the sulfonic acid catalysts.     

Reactions of mixed O,S-esters of acids of trivalent phosphorus with substituted 1-chloroacetylenes

The reactions of mixed O,S-esters oftert-butylthiophosphonous acid and dithiophosphorous acid with 1-chloro-2-organylacetylenes were studied. On the basis of them, a convenient method for the synthesis of thioesters of organylethynylthiophosphinic and dithiophosphonic acids, which are undescribed in the literature, was proposed. A difference was found in the chemical behavior of the methyl ester of S,S-diethyldithiophosphorous acid by comparison with the corresponding complete esters and thioesters of phosphorous acid in reactions with dichloroacetylene.A. E. Arbuzov Institute of Organic and Physical Chemistry, Kazan' Scientific Center, Russian Academy of Sciences, 420083 Kazan'. Translated from Izvestiya Akademii Nauk, Seriya Khimicheskaya, No. 7, pp. 1635–1637, July, 1992.     

Application of Pac Ester in Thioester Method for the Synthesis of Cyclopentapeptides

Thioester method for the synthesis of cyclopeptides is improved by using Pac (Pac = phenacyl, CH2COC6Hs) ester as a protecting group of 3-mercaptopropionic acid. The Pac group is easy to be removed from C-terminal with zinc in acetic acid. The protected glycine thioester and peptide thioesters synthesized by the improved method, are easy to be purified, so the final linear peptides are pure enough for the following cyclization. Furthermore, this method is flexible for peptide chain elongation,either from C-termlnal or from N.terminal. So it is an efficient and practical method for synthesis of bioactive peptides. Two N-protected pentapeptide thioesters, Boc-Pro-Tyr-Leu-Ala-GIySCH2CH2COOPac and Boc-Ala-Tyr-Leu-Ala-Gly-SCH2CH2COOPac were synthesized by the improved thloester method.After deprotecting Pac ester with zinc in aqueous acetic acid and Boc group with trifluoroacetic acid in CH2C12, two free pentapeptide tldoesters were obtained. Ag^ -assisted cyclization in acetate buffered solution afforded two cyclic pentapeptides c(Pro-Tyr-Leu-Ala-Gly) and c(Ala-Tyr-Leu-Ala-Gly).Effects of different buffer pH, different Ag^ concentrations, etc. on the cyclization were studied.     

The reduction of oxidized methionine residues in peptide thioesters with NH4I-Me2S

Oxidized methionine residues in peptide thioesters can be reduced rapidly with NH4I to the corresponding sulfide by using Me2S as coreductant. Comparative reduction studies employing a 28-amino acid peptide thioester with an N-terminal methionine oxide as model system revealed the importance of the Me2S addition to avoid hydrolysis of the reactive thioester functionality. In addition, an NH4I-Me2S containing cleavage cocktail has been used for the global deprotection of various thioesters which revealed no hydrolysis or oxidative side products. These results demonstrate the general applicability of sulfoxides as protecting groups in advanced peptide synthesis techniques by facilitating the preparation and handling of methionine containing peptide thioesters for native chemical ligation (NCL).     

An exceptionally mild catalytic thioester aldol reaction inspired by polyketide biosynthesis

This report details our discovery of a new catalytic ester aldol reaction using malonic acid half thioesters (MAHTs) that directly affords beta-hydroxythioesters. The reaction is catalyzed by combination of a Cu(II) salt and an amine base, and it can be performed under exceptionally mild conditions (23 degrees C, open to the air, wet solvent). Methyl malonic acid half thioesters afforded syn aldol products with distereoselectivities greater than 6:1.     

α-Oxoketene dithioacetals: Versatile substrates for 1,3-carbonyl transpositions

A two step procedure for the conversion of α-oxoketene dithioacetals to β-substituted α, β-unsaturated thioesters or acids is described. The overall transformation represents a 1,3-carbonyl transposition in which the original ketone carbonyl emerges as the carbonyl of an acid or thioester. The resulting thioesters and acids constitute versatile acylating reagents in accord with established procedures.     

9-Fluorenylmethoxycarbonyl-based solid-phase synthesis of peptide α-thioesters

Peptide thioesters play a key role in convergent protein synthesis strategies such as native chemical ligation, traceless Staudinger ligation, and Ag(+) -mediated thioester ligation. The Boc-based solid-phase synthesis provides a very reliable access to peptide thioesters. However, the acid lability of many peptide modifications and the requirements of most parallel peptide synthesizers call for the milder Fmoc-based solid-phase synthesis. The Fmoc-based synthesis of peptide thioesters is more cumbersome and typically proceeds with lower yields than the synthesis of peptide acids and peptide amides. The success of native chemical ligation and related technologies has sparked intensive research effort devoted to the development of new methods. The recent progress in this rapidly expanding field is reviewed.     

DBSA-catalyzed hydrolysis of chain α-oxo ketene dithioacetals in water: Aqueous synthesis of β-ketothioesters

In this paper, we wish to report an environment friendly synthetic method for β-ketothioesters from a dodecylbenzenesulfonic acid (DBSA)-catalyzed hydrolysis reaction of chain α-oxo ketene dithioacetals in water. It was shown that the hydrolysis reaction of chain α-oxo ketene dithioacetals could efficiently occur in the presence of 7.5?mol% DBSA at 100?°C in water, affording the desired β-keto thioesters in excellent yields.     

Copper-catalyzed enantioselective synthesis of trans-1-alkyl-2-substituted cyclopropanes via tandem conjugate addition-intramolecular enolate trapping

Cu-TolBINAP-catalyzed conjugate addition of Grignard reagents to 4-chloro-α,β-unsaturated esters, thioesters, and ketones leads to 4-chloro-3-alkyl-substituted thioesters and ketones in up to 84% yield and up to 96% ee upon protonation of the corresponding enolates at low temperature. Tandem conjugate addition-enolate trapping, however, yields trans-1-alkyl-2-substituted cyclopropanes in up to 92% yield and up to 98% ee. The versatility of this reaction is illustrated by the formation of key intermediates for the formal syntheses of cascarillic acid and grenadamide.     

Direct thioesterification from carboxylic acids and thiols catalyzed by a Brønsted acid

In the presence of a catalytic amount of trifluoromethanesulfonic acid, free carboxylic acids reacted with free thiols directly to afford the corresponding thioesters in high yields.     

Synthesis of thiazolidine thioester peptides and acceleration of native chemical ligation

Thiazolidine thioester peptides were synthesized by reacting bis(2-sulfanylethyl)amido peptides with glyoxylic acid at pH 1. A significant increase in Native Chemical Ligation (NCL) rate was observed with thiazolidine thioesters compared to 3-mercaptopropionic acid-thioester analogues. The method is of particular interest for accelerating valine-cysteine peptide bond formation.     

Separation and identification of organic acid-coenzyme A thioesters using liquid chromatography/electrospray ionization-mass spectrometry

A method has been developed for the direct determination of coenzyme A (CoA) and organic acid-CoA thioesters in mixtures using directly combined liquid chromatography/electrospray ionization-mass spectrometry (LC/ESI-MS). Mixtures of CoA and organic acid-CoA thioesters were analyzed by LC/ESI-MS with detection of protonated molecular ions and characteristic fragment ions for each compound. The identities of the CoA-thioesters were established based on LC retention times and simultaneously recorded mass spectra. Monitoring of the CoA specific fragment ion at m/z 428 throughout the chromatogram provides a unique fingerprint for CoA content in the samples that corroborates the identification of organic acid-CoA thioesters in the mixtures. Furthermore, fragment ions arising from the ester linkage portion of the molecule allow unambiguous identification of the CoA esters in the samples. A second LC elution system was developed that allows the simultaneous separation and identification of 2-hydroxypropionyl-CoA (lactyl-CoA) and 3-hydroxypropionyl CoA (3HP-CoA), which have the same mass and identical MS fragmentation behavior. The utility of LC/ESI-MS employing this elution system is demonstrated by the determination of 3HP-CoA and lactyl-CoA (converted to CoA-thioesters from their corresponding free acids using CoA-transferase) in fermentation broths from Escherichia coli strains engineered for the production of 3-hydroxypropionic acid (3HP). External calibration employing a purified 3HP-CoA standard allowed indirect quantification of 3HP content in the broth with a precision of 1% (RSD). The feasibility of extending the method described above to perform LC/selected reaction monitoring-tandem mass spectrometry for direct determination of organic acid-CoA thioesters in cells was also demonstrated.     

Fe-catalyzed thioesterification of carboxylic esters

Second nature: Starting from shelf-stable aryl esters and thiols, a variety of carboxylic acid esters were transformed into the corresponding thioesters with no racemization of labile stereocenters. The method was successfully applied in a native chemical-ligation-type peptide formation, which suggests that the thiol may act as a co-catalyst for future 1,2-additions of pronucleophiles to carboxylic esters.     

Fmoc-based synthesis of peptide alpha-thioesters using an aryl hydrazine support

C-Terminal peptide thioesters are key intermediates in the synthesis/semisynthesis of proteins and of cyclic peptides by native chemical ligation. They are prepared by solid-phase peptide synthesis (SPPS) or biosynthetically by protein splicing techniques. Until recently, the chemical synthesis of C-terminal alpha-thioester peptides by SPPS was largely restricted to the use of Boc/Benzyl chemistry due to the poor stability of the thioester bond to the basic conditions required for the deprotection of the N(alpha)-Fmoc group. In the present work, we describe a new method for the SPPS of C-terminal thioesters using Fmoc/t-Bu chemistry. This method is based on the use of an aryl hydrazine linker, which is totally stable to conditions required for Fmoc-SPPS. When the peptide synthesis has been completed, activation of the linker is achieved by mild oxidation. This step converts the acyl hydrazine group into a highly reactive acyl diazene intermediate which reacts with an alpha-amino acid alkyl thioester (H-AA-SR) to yield the corresponding peptide alpha-thioester in good yield. This method has been successfully used to prepare a variety of peptide thioesters, cyclic peptides, and a fully functional Src homology 3 (SH3) protein domain.