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.     

Synthesis of diaryl ketones via a phosphine-free Fukuyama reaction

The synthesis of unsymmetrical diaryl ketones via the Fukuyama coupling of thioesters and organozinc reagents is described. Typically, the synthesis of diaryl ketones using this methodology provides low yields. The simple complex, Pd(dba)(2), was found to convert a variety of aryl thioesters to diaryl ketones in good yields.     

Direct carbon-carbon bond formation via soft enolization: aldol addition of α-halogenated thioesters

α-Halo thioesters undergo soft enolization and syn-selective direct aldol addition to aldehydes in the presence of MgBr(2)·OEt(2) and i-Pr(2)NEt to produce α-halo-β-hydroxy thioesters.     

Enzymatic resolution of (RS)-2-arylpropionic acid thioesters by Candida rugosa lipase-catalyzed thiotransesterification or hydrolysis in organic solvents

An enzymatic resolution process was developed to produce (S)-naproxen ester, (S)-naproxen or (S)-ibuprofen from the corresponding racemic thioesters by using lipase-catalyzed thiotransesterification or hydrolysis in organic solvents. Enzyme activity is greatly enhanced when activated naproxen thioesters containing an electron-withdrawing group are the substrates. Unlike other lipases, Candida rugosa lipase may discern the sulfur moiety of the thioesters, and yields lower enzyme activity when compared to the corresponding oxygen-containing analogues. Enzyme performances were further compared under various conditions, i.e. different combinations of reaction type (thiotransesterification or hydrolysis), solvent (isooctane or cyclohexane), substrate (naproxen or ibuprofen thioesters) and lipase sources.     

Combined high-performance liquid chromatographic-continuous-flow fast atom bombardment mass spectrometric analysis of acylcoenzyme A compounds

A high-performance liquid chromatographic method for the analysis of coenzyme A thioesters which employs continuous-flow fast atom bombardment mass spectrometric detection is presented. The chromatographic system utilizes gradient elution with reversed-phase conditions using ammonium acetate-acetonitrile from both standard analytical (3.9 mm I.D.) and microbore (1 mm I.D.) columns. Applications to coenzyme A thioesters of various acyl group chain length (C2-C18) and functionality (-COOH, -OH, -C = C-) are described. The system is also applied to an in vitro enzyme reaction (crotonase) to directly follow the disappearance of substrate and appearance of product. The mass spectrometry of coenzyme A thioesters, their chromatographic behavior, system stability, and sensitivity of detection are discussed.     

Facile, fmoc-compatible solid-phase synthesis of peptide C-terminal thioesters

A short route to peptide C-terminal thioesters was developed that does not require the use of special linkers or resins and is compatible with standard Fmoc chemistry. Following conventional solid-phase peptide synthesis, an excess of Me(2)AlCl and EtSH in dichloromethane cleaves peptides from Wang or Pam resins to give the corresponding thioesters directly in good yield and purity.     

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.     

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).     

New molecular markers for prostate tumor imaging: a study on 2-methylene substituted fatty acids as new AMACR inhibitors

The development of prostate carcinoma is associated with alterations in fatty acid metabolism. α‐Methylacyl‐CoA racemase (AMACR) is a peroxisomal and mitochondrial enzyme that catalyses interconversion between the (S)/(R)‐isomers of a range of α‐methylacyl‐CoA thioesters. AMACR is involved in the β‐oxidation of the dietary branched‐chain fatty acids and bile acid intermediates. It is highly expressed in prostate (more than 95 %), colon (92 %), and breast cancers (44 %) but not in the respective normal or hyperplastic tissues. Thus, targeting of AMACR could be a new strategy for molecular imaging and therapy of prostate and some other cancers. Unlabeled 2‐methylenacyl‐CoA thioesters ( 12 a – c ) were designed as AMACR binding ligands. The thioesters were tested for their ability to inhibit the AMACR‐mediated epimerization of (25R)‐THC‐CoA and were found to be strong AMACR inhibitors. Radioiodinated (E)‐¹³¹I‐13‐iodo‐2‐methylentridec‐12‐enoic acid (¹³¹I‐ 7 c ) demonstrated preferential retention in AMACR‐positive prostate tumor cells (LNCaP, LNCaP C4‐2wt and DU145) compared with both AMACR‐knockout LNCaP C4‐2 AMACR‐siRNA and benign BPH1 prostate cell lines. A significant protein‐bound radioactive fraction with main bands at 47 (sum of molecular weights of AMACR plus 12 c ), 70, and 75 kDa was detected in LNCaP C4‐2 wt cells. In contrast, only negligible amounts of protein‐bound radioactivity were found in LNCaP C4‐2 AMACR‐siRNA cells.     

Interaction of thioesters of P(III) with oxygen

The compounds O,O-diethyl- and O,O-diisopropyl-S-benzylthiophosphite, 2-benzyl-thio-4,5-benzo-1,3,2-dioxaphospholane, diphenyl-S-benzylthiophosphinite, and S,S-dibenzylphenyldithiophosphonite were obtained. It was found that the thiophosphites enter into isomerization initiated by oxygen in the air; substitution together with isomerization is thereby observed in the case of thioesters of P(III) with the P-C bond. The interaction of thioesters of P(III) with oxygen is inhibited by spin traps.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 9, pp. 2127–2132, September, 1991.     

Readily available (S)-proline-derived organocatalysts for the Lewis acid-mediated Lewis base-catalyzed stereoselective aldol reactions of activated thioesters

A set of enantiomerically pure Lewis bases containing different diphenyl phosphinyl oxide groups were easily synthesized in a straightforward procedure by reaction of readily available proline-based scaffolds and phosphinoyl chlorides. The newly synthesized derivatives were employed (0.1 mol equiv) as organocatalysts in the Lewis acid-mediated Lewis base-promoted direct stereoselective aldol reactions of activated thioesters with aromatic aldehydes, carried out in the presence of tetrachlorosilane and a tertiary amine. β-Hydroxy thioesters were obtained in moderate to high yields, with very high syn diastereoselectivities (dr up to >98:2), and fair enantioselectivities (ee up to 51%). Theoretical studies were performed in order to elucidate the origin of the stereoselection.     

Diarylcuprates for Selective Syntheses of Multifunctionalized Ketones from Thioesters under Mild Conditions

Ketones were selectively synthesized from thioesters by using diarylcuprates(I) generated in situ from copper(I) salts and aryl Grignard reagents in a 1 : 1.3–1.5 ratio under ambient temperature. During the ketone synthesis, various functional groups, such as carbonyl (ketones, esters, and amides), O-protecting groups, halogens, and heteroarenes, were tolerated to afford multifunctionalized ketones in excellent yields. This copper-mediated ketone synthesis could be applied to the synthesis of not only gluconolactone-derived ketone 6 , a synthetic intermediate in the transformation to the SGLT2 inhibitor canagliflozin, but also thiolactol 8 , a valuable synthetic intermediate for (+)-biotin. Control experiments on an isolated diphenylcuprate(I), [CuPh₂]⁻ ( 12 ), and DFT calculations revealed that this ketone synthesis proceeded by oxidative addition of the C−S bond of thioesters to [CuPh₂]⁻, while reductive elimination from the Cu^III intermediate produced the corresponding ketone and an inactive species [(RS)CuPh]⁻, the latter reacted with [CuPh]₄ ( 11 ) to regenerate the reactive diphenylcuprate(I).     

Highly regioselective thiocarbonylation of conjugated dienes via palladium-catalyzed three-component coupling reactions

Three-component coupling reaction of conjugated dienes, thiols, and carbon monoxide affords an atom-economical thiocarbonylation of the dienes to give beta,gamma-unsaturated thioesters as the sole products. A catalyst system based on [Pd(OAc)(2)] and Ph(3)P showed excellent catalytic activity. The thiocarbonylation was performed under an atmosphere of carbon monoxide (400 psi) at 110 degrees C in CH(2)Cl(2) for 60 h. A wide variety of thioesters were synthesized in good to excellent yields from easily accessible starting materials. The reaction is believed to proceed via a eta(3)-allylpalladium intermediate. The thiocarbonylation, which is applicable to a wide variety of conjugated dienes, occurs in high regioselectivity, the latter dependent on the steric characteristics and stability of the eta(3)-allylpalladium complex.     

Stereoselective Metal‐Free Synthesis of β‐Amino Thioesters with Tertiary and Quaternary Stereogenic Centers

β‐Amino thioesters are important natural building blocks for the synthesis of numerous bioactive molecules. An organocatalyzed Mannich reaction was developed which provides direct and highly stereoselective access to acyclic β²‐ and β^2,3,3‐amino thioesters with adjacent tertiary and quaternary stereocenters. Mechanistic studies showed that the stereochemical course of the reaction can be controlled by the choice of the substrates. The β‐amino thioesters were further functionalized by, for example, stereoselective decarboxylation to access β^2,3‐frameworks. In addition, the value of the β‐amino thioesters was shown in coupling‐reagent‐free peptide synthesis.     

Novel syn intramolecular pathway in base-catalyzed 1,2-elimination reactions of beta-acetoxy esters

As part of a comprehensive investigation of electronic effects on the stereochemistry of base-catalyzed 1,2-elimination reactions, we observed a new syn intramolecular pathway in the elimination of acetic acid from beta-acetoxy esters and thioesters. 1H and 2H NMR investigation of reactions using stereospecifically labeled tert-butyl (2R*,3R*)-3-acetoxy-2,3-2H2-butanoate (1) and its (2R*,3S*) diastereomer (2) shows that 23 +/- 2% syn elimination occurs. The elimination reactions were catalyzed with KOH or (CH3)4NOH in ethanol/water under rigorously non-ion-pairing conditions. By contrast, the more sterically hindered beta-trimethylacetoxy ester produces only 6 +/- 1% syn elimination. These data strongly support an intramolecular (Ei) syn path for elimination of acetic acid, most likely through the oxyanion produced by nucleophilic attack at the carbonyl carbon of the beta-acetoxy group. The analogous thioesters, S-tert-butyl (2R*,3R*)-3-acetoxy-2,3-2H2-butanethioate (3) and its (2R*,3S*) diastereomer (4), showed 18 +/- 2% syn elimination, whereas the beta-trimethylacetoxy substrate gave 5 +/- 1% syn elimination. The more acidic thioester substrates do not produce an increased amount of syn stereoselectivity even though their elimination reactions are at the E1cb interface.     

A facile and efficient direct aldol addition of simple thioesters

[reaction: see text] Simple thioesters undergo direct aldol addition to aldehydes in the presence of MgBr(2).OEt(2) and i-Pr(2)NEt using untreated, reagent-grade CH(2)Cl(2) under atmospheric conditions. The reactions proceed extremely rapidly and in excellent yield.     

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.     

Development of a Chemical Methodology for the Preparation of Peptide Thioesters Applicable to Naturally Occurring Peptides Using a Sequential Quadruple Acyl Transfer System

Peptide thioesters are very useful in protein chemistry, and chemistry- and biochemistry-based protocols are used for the preparation of thioesters. Among such protocols, only a few biochemistry-based approaches have been use for naturally occurring peptide sequences. The development of chemistry-based protocols applicable to natural sequences remains a challenge, and the development of such methods would be a major contribution to protein science. Here, we describe the preparation of peptide thioesters using innovative methodology that features nickel(II)-mediated alcoholysis of a naturally occurring peptide sequence, followed by O−N and N−S acyl transfers. This protocol involves sequential quadruple acyl transfer, termed SQAT. Notably, the SQAT system consists of sequential chemical reactions that allow naturally occurring peptide sequences to be converted to thioesters without requiring an artificial chemical unit.     

Some derivatives of 4-fluorobenzenethiol

Various metallic and organometallic derivatives of 4-fluorobenzenethiol have been prepared directly from the thiol. Its Ag(I), Ni(II) and Pb(II) salts were used to synthesize thioethers thioesters. New compounds have been characterized by elemental analysis, NMR (H-1, F-19 and C-13) and mass spectroscopy.