Thioester

General structure of a thioester.

Thioesters are compounds with the functional group C-S-CO-C. They are the product of esterification between a carboxylic acid and a thiol. Thioesters are widespread in biochemistry, the best-known derivative being acetyl-CoA.

Synthesis

Thioesters have been prepared in many ways,[1] but the main route involves condensation of thiols and carboxylic acids in the presence of dehydrating agents:[2]

RSH + R'CO2H → RSC(O)R' + H2O

A typical dehydration agent is DCC or related reagents.[3] Acid anhydrides and some lactones also react with thiols in the presence of base.

Thioesters can be conveniently prepared from alcohols by the Mitsunobu reaction, using thioacetic acid.[4]

They also arise via carbonylation of alkynes and alkenes in the presence of thiols.[5]

Reactions

The carbonyl center in thioesters is reactive toward nucleophiles, the reactivity being reminiscent of, but milder, than acid chlorides. Thus, thioesters and amines combine to give amides:

Thioesters provide useful chemoselectivity in the synthesis of biomolecules.[6]

A reaction unique to thioesters is the Fukuyama coupling, in which the thioester is coupled with an organozinc halide by a palladium catalyst to give a ketone.

The C-H groups adjacent to the carbonyl in thioesters are mildly acidic (more so than in esters[7][8]) and undergo aldol condensations. This kind of reaction occurs in the biosynthesis of fatty acids.

Thioesters are critical components of the native chemical ligation method for peptide synthesis.

Biochemistry

Structure of acetyl coenzyme A, a thioester that is a key intermediate in the biosynthesis of many biomolecules.

Thioesters are common intermediates in many biosynthetic reactions, including the formation and degradation of fatty acids and mevalonate, precursor to steroids. Examples include malonyl-CoA, acetoacetyl-CoA, propionyl-CoA, and cinnamoyl-CoA. Acetogenesis proceeds via the formation of acetyl-CoA. The biosynthesis of lignin, which comprises a large fraction of the Earth's land biomass, proceeds via a thioester derivative of caffeic acid.[9] These thioesters arise analogously to those prepared synthetically, the difference being that the dehydration agent is ATP. In addition, thioesters play an important role in the tagging of proteins with ubiquitin, which tags the protein for degradation.

Oxidation of the sulfur atom in thioesters (thiolactones) is postulated in the bioactivation of the antithrombotic prodrugs ticlopidine, clopidogrel, and prasugrel.[10][11]

Thioesters and the origin of life

As posited in a "Thioester World," thioesters are possible precursors to life.[12] As de Duve explains:

It is revealing that thioesters are obligatory intermediates in several key processes in which ATP is either used or regenerated. Thioesters are involved in the synthesis of all esters, including those found in complex lipids. They also participate in the synthesis of a number of other cellular components, including peptides, fatty acids, sterols, terpenes, porphyrins, and others. In addition, thioesters are formed as key intermediates in several particularly ancient processes that result in the assembly of ATP. In both these instances, the thioester is closer than ATP to the process that uses or yields energy. In other words, thioesters could have actually played the role of ATP in a "thioester world" initially devoid of ATP. Eventually, [these] thioesters could have served to usher in ATP through its ability to support the formation of bonds between phosphate groups.

Isomeric compounds: thionoesters

Skeletal formula of methyl thionobenzoate

Thionoesters are isomeric with thioesters. In a thionoester, sulfur replaces the carbonyl oxygen in an ester. Methyl thionobenzoate is C6H5C(S)OCH3. Such compounds are typically prepared by the reaction of the thioacyl chloride with an alcohol, but they can also be made by the reaction of Lawesson's reagent with esters.[13]

See also

References

  1. ↑ Fujiwara, S.; Kambe, N. (2005). "Thio-, Seleno-, and Telluro-Carboxylic Acid Esters". Topics in Current Chemistry 251. Berlin / Heidelberg: Springer. pp. 87–140. doi:10.1007/b101007. ISBN 978-3-540-23012-0.
  2. ↑ "Synthesis of thioesters". Organic Chemistry Portal.
  3. ↑ Mori, Y.; Seki, M. (2007). "Synthesis of Multifunctionalized Ketones Through the Fukuyama Coupling Reaction Catalyzed by Pearlman's Catalyst: Preparation of Ethyl 6-oxotridecanoate". Org. Synth. 84: 285.; Coll. Vol. 11, p. 281
  4. ↑ Volante, R. (1981). "A new, highly efficient method for the conversion of alcohols to thiolesters and thiols". Tetrahedron Letters 22 (33): 3119–3122. doi:10.1016/S0040-4039(01)81842-6.
  5. ↑ Bertleff, W.; Roeper, M.; Sava, X. (2005), "Carbonylation", Ullmann's Encyclopedia of Industrial Chemistry, Weinheim: Wiley-VCH, doi:10.1002/14356007.a05_217.pub2
  6. ↑ McGrath, N. A.; Raines, R. T. (2011). "Chemoselectivity in chemical biology: Acyl transfer reactions with sulfur and selenium". Acc. Chem. Res. 44 (9): 752–761. doi:10.1021/ar200081s. PMC 3242736. PMID 21639109.
  7. ↑ Bew, S. P.; Stephenson, G. R.; Rouden, J.; Martinez-Lozano, L.A.; Seylani, H. (2013). "Malonic Acid Half Oxyesters and Thioesters: Solvent-Free Synthesis and DFT Analysis of Their Enols". Org. Lett. 15 (15): 3805–3807. doi:10.1021/ol400804b.
  8. ↑ Bordwell, F. G.; Fried, H. E. (1991). "Heterocyclic Aromatic Anions with 4n + 2 pi-Electrons". J. Org. Chem. 56 (13): 4218–4223. doi:10.1021/jo00013a027.
  9. ↑ Lehninger, A. L.; Nelson, D. L.; Cox, M. M. (2000). Principles of Biochemistry (3rd ed.). New York: Worth Publishing. ISBN 1-57259-153-6.
  10. ↑ Mansuy, D.; Dansette, P. M. (2011). "Sulfenic acids as reactive intermediates in xenobiotic metabolism". Archives of Biochemistry and Biophysics 507 (1): 174–185. doi:10.1016/j.abb.2010.09.015. PMID 20869346.
  11. ↑ Dansette, P. M.; Rosi, J.; Debernardi, J.; Bertho, G.; Mansuy, D. (2012). "Metabolic Activation of Prasugrel: Nature of the Two Competitive Pathways Resulting in the Opening of Its Thiophene Ring". Chemical Research in Toxicology 25 (5): 1058–1065. doi:10.1021/tx3000279.
  12. ↑ de Duve, C. (1995). "The Beginnings of Life on Earth". American Scientist 83 (5): 428–437. Bibcode:1995AmSci..83..428M.
  13. ↑ Cremlyn, R. J. (1996). An Introduction to Organosulfur Chemistry. Chichester: John Wiley and Sons. ISBN 0-471-95512-4.