Convenient route to γ-nitro-α-amino acids: conjugate addition of nitroalkanes to dehydroalanine derivatives

Abstract

γ-Nitro-α-amino acid derivatives are obtained in good yield from the base-catalysed conjugate addition of nitroalkanes to N-protected dehydroalanine esters (methyl 2-amidoacrylates). The outcome of the reaction is dependent on the N-protecting group (the ease of the product formation correlates with the electron-withdrawing ability and hence stabilising effect on the adduct α-anion of the 2-substituent in the order phthalimido > benzyloxycarbonylamino > acetamido), the nitroalkane, and on the reaction conditions. Conditions were established in reactions of methyl 2-phthalimidoacrylate 4 with nitromethane for selectively obtaining 1∶1-, 2∶1- or 3∶1-adducts. Good yields of the 1∶1-adducts are obtained when the reaction is carried out with an excess of nitroalkane. Restricting the amount of nitromethane gives rise to the higher adducts. Similarly, reactions of 4 with nitroethane can be adjusted to give 1∶1- or 2∶1-adducts selectively. These reactions occur with little or no diastereoselectivity. As a model for a dehydroalanine residue in a peptide chain, the diamide N-cyclohexyl-2-acetamidoacrylamide 7 has been prepared. This dehydroalanine reacts with 2-nitropropane and with nitromethane in refluxing tert-butyl alcohol to give reasonable yields of 1∶1-adducts. As the nitro group of the resultant γ-nitro-α-amino acid derivatives can be transformed into a variety of other functionalities, the methodology described in this paper offers a versatile entry to a range of γ-substituted α-amino acids.