Mechanism of the condensation of homocysteine thiolactone with aldehydes

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Chemical reactivity of homo-cysteine thiolactone (HTL) has been implicated in cardiovascular disease. Owing to its aminoacyl-thioester character, HTL undergoes facile electrophilic and nucleophilic reactions at its amino and activated-carboxyl group, respectively. To gain insight into the mechanism of the reactions involving its amino group, the kinetics of the condensation of homocysteine thiolactone with formaldehyde, acetaldehyde, and pyridoxal phosphate, were analyzed in the pH range from 5 to 10. The reactions were first order with respect to HTL, aldehyde, and hydroxide ion concentrations. Of the two ionicspecies of HTL (pKa = 6.67 ± 0.05), the acid form HTL+ was ∼100-fold more reactive than the base form HTL 0. The reactions of HTL with aldehydes involve intermediate adducts. The conversion of the intermediate carbinolamine to a product, 1,3-tetrahydrothia-zine-4-carboxylic acid or its 2-substituted analogue, occurs in a two-step reaction. The first step involves hydrolysis of the thioester bond in the intermediate, facilitated by anchimeric assistance by the oxygen of the carbinolamine group of the intermediate. The second step involves an attack of the liberated thiolate on the aldehyde-derived carbon of the intermediate, affording 1,3-tetrahydrothiazine-4-carboxylic acid or its 2-substituted analogue. An unusual feature of these reactions is that the formation of the carbinolamine group increases the reactivity of the thioester bond of HTL ∼104-fold. The facile formation of tetrahydrothiazines may contribute to HTL elimination from the human body.

Original languageEnglish (US)
Pages (from-to)8039-8043
Number of pages5
JournalChemistry - A European Journal
Issue number31
StatePublished - Oct 25 2006
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Catalysis
  • Organic Chemistry


  • Aldehydes
  • Atheroscle-rosis
  • Homocysteine thiolactone
  • Reaction mechanisms
  • Tetrahydro-thiazine

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