Study of nucleophilicity of an enol tosylate fragment of alpha-formylglycine (alpha-FGly-OTs)

Sitaram Bhavaraju, University of Rhode Island


In this dissertation the synthesis and reactions of an enol tosylate fragment of α-Formylglycine is presented. The α-Formylglycine (α-FGly) amino acid fragment is present at the active center of enzyme sulphatases in both eukaryotes and prokaryotes. In humans this class of enzymes regulates the degradation of sulfate esters that are accumulated at various substrate sites. Impaired desulfation at these sites leads to several associated disorders. It has been proposed that α-FGly plays an important role in this mode of desulfation. ^ Endiamines are a modified form of the α-FGly fragment. Endiamines are proposed to introduce conformational rigidity to the molecular structure of peptides, as in the case of a recently isolated marine metabolite Callynormine A. Literature attempts to make endiamines by reacting the enol tosylate of α-FGly with amines were unsuccessful except when the enol tosylate fragment is linear or has the support of an ester functionality. The reactions of amines with an enol tosylate of α-FGly, that has the support of a cyclic amide, with amines have been reported to be unfavorable. This thesis focuses on the reactivity of neutral nucleophiles like 10-, 2 0- and 30 -amines with the E-enol tosylate of an α-FGly that has the support of a cyclic amide to give stereoselectively the E-endiamines. Most of these reactions occurred at room temperature thereby enabling us to monitor the reaction using NMR. Time course NMR studies of these reactions revealed interesting intermediates that gave us a hint at the reaction mechanism. Consequently we propose that the α-FGly fragment reacts with neutral nucleophiles, like 10- or 20-amines and thiols, via a nulceophilic substitution mechanism. The 30 amine DABCO yields a unique product via an elimination mechanism. These mechanistic proposals are the cornerstones for description of events at the molecular level thereby laying a strong foundation for a major portion of work attempted in this dissertation. ^ The relationship between the concentration of amines and substrate enol tosylate has been examined. Good linear rate plots were obtained demonstrating a pseudo first order dependence at higher concentrations of amines while bimolecular kinetic rate dependence was observed when reactions were done at equivalent concentration of amine and substrate enol tosylate. ^

Subject Area

Chemistry, Organic

Recommended Citation

Sitaram Bhavaraju, "Study of nucleophilicity of an enol tosylate fragment of alpha-formylglycine (alpha-FGly-OTs)" (2007). Dissertations and Master's Theses (Campus Access). Paper AAI3292101.