Reactivity of β-Substituted Phosphoenol Pyruvates towards Alkoxides: A Theoretical and Experimental Study

Abstract

A new, practical, synthesis of pyruvic orthoesters relying on the conversion of β-substituted phosphoenol pyruvates by the action of alkoxides is described. Our study of the reaction mechanism was done experimentally and also theoretically. Density functional theory calculations were used to explain the major reaction products found experimentally. Geometry optimisations and atomic charges obtained using different population analyses and the global and local reactivity indices, namely global electrophilicity and the Parr function, were obtained at the B3LYP/6-311G(d) level of theory. The experimental reactivity was correctly reproduced using the Parr function.

Heck Reaction of 2-Oxyacrylates with Aryl Bromides: A Common Route to Monoaryl Pyruvates and Ortho Ester-Protected Monoaryl Pyruvates

“…It was not possible to identify the transition state TS-4 for this reaction, apparently due to the extremely high exergonicity of almost 30 kcal/mol. Interestingly, a similar mechanism was previously proposed for ortho ester formation starting from the phosphoenol pyruvates; however, only the initial step of the nucleophilic attack by the alkoxide was a subject of DFT studies …”

“…These results demonstrate the unique reactivity of 2-pivaloyloxycinnamates toward alkoxide bases for the synthesis of ortho ester-protected pyruvates. The synthesis of ortho esters under basic conditions is novel and preceded by a single example, where a similar transformation was reported starting from phospho-enol pyruvates . Ortho esters are generally synthesized under acid-catalyzed conditions, including the well-known oxabicyclo[2.2.2]­octyl (OBO) ortho ester, a stable protecting group for carboxylic acid originally developed by Corey et al An efficient and practical method for the preparation of OBO-protected pyruvate (three steps) was described recently by Donohoe et al and efficiently used for the synthesis of monoaryl OBO-protected pyruvates .…”

“…Interestingly, a similar mechanism was previously proposed for ortho ester formation starting from the phosphoenol pyruvates; however, only the initial step of the nucleophilic attack by the alkoxide was a subject of DFT studies. 14 This dissociative S N 1-like mechanism can be complemented by a hypothetical synchronous S N 2-like mechanism. Attempts to identify the transition state for the substitution of the pivaloxy group in int-2 by a direct nucleophilic attack of ethoxide were unsuccessful; however, we were able to find the transition state for the ring closing of the rotamer of int-2, which forms methyleneoxirane OX.…”

“…The synthesis of ortho esters under basic conditions is novel and preceded by a single example, where a similar transformation was reported starting from phospho-enol pyruvates. 14 Ortho esters are generally synthesized under acid-catalyzed conditions, including the well-known oxabicyclo[2.2.2]octyl (OBO) ortho ester, a stable protecting group for carboxylic acid originally developed by Corey et al 15 An efficient and practical method for the preparation of OBO-protected pyruvate (three steps) was described recently by Donohoe et al and efficiently used for the synthesis of monoaryl OBO-protected pyruvates. 5 Our approach is more straightforward: it starts from easily prepared 2-oxyacrylates and provides the opportunity to obtain either the monoaryl pyruvate or the corresponding ortho ester depending on the choice of enol protecting group and the reagent used.…”