Intrinsic reactivities in the alkylations of protected amino acids by (R)- and (S)-methyloxirane

Abstract

A comparative study is described of the reactions between protected amino acids [either N-acetyl-L-cysteine methyl ester (2a), L-valine methyl ester (3a), or N-benzoyl-L-histidine methyl ester (5a)] and the enantiomeric methyloxiranes [R-(1a) or S-(1b)]. At 45 °C in methanol the relative rates of the reactions with either (1a) or (1b) are (5a)∼(3a) > (2a). The reaction of (1a)/(1b) with (2a) is dramatically accelerated ( 100-fold) by triethylamine, because of the conversion of (2a) into its thiolate. The products from (1a)/(1b)+(2a) thiolate are (R, αR)- and (S, αR)-N-acetyl-S-(2-hydroxy-propyl)-L-cysteine methyl ester [(2b) and (2c), respectively]. These products undergo a slow further reaction with methyloxirane leading via a β-elimination to N-acetyldehydroalanine methyl ester and bis-(2-hydroxypropyl) sulphide. The products from (1a)/(1b)+(3a) are (R,αS)- and (S,αS)-N-(2-hydroxypropyl)-L-valine methyl ester [(3b) and (3c), respectively]. These products also undergo a slow further reaction with methyloxirane leading to an NN-bis-(2-hydroxypropyl) valine methyl ester and derived morpholone [e.g. excess of (1a)+(3a)→(R,R,αS)-NN-bis-(2-hydroxypropyl) valine methyl ester (3f) and δ-lactone (3h)]. The reactions of (1a) or (1b) with (5a) give,via the products of mono-N-alkylation in the imidazole ring [e.g.(S,αS)-N^α-benzoyl-N^τ-(2-hydroxypropyl)-L- histidine methyl ester (5d) and its N^π-isomer (5e) from (1b)+(5a)], a mixture [e.g.(S,S,αR/αS)-N^α-benzoyl-N^πN^τ-bis-(2-hydroxypropyl)-L-histidinylimidazolium carboxylates(6d)+(6e) from excess of (1b)+(5a)]. The generation of methoxide during the reactions described is responsible for the β-elimination leading to a dehydroalanine derivative and for the epimerisation during the formation of (6d)+(6e). Kinetic studies show that for none of the substrates (2a), (3a), or (5a) is there significant enantioselectivity in their reactions with the enantiomers of methyloxirane. The relevance of the present study to the toxicology of methyloxiranes is discussed.