Morita-Baylis-Hillman Reaction Accessing GABA Intermediates: Synthesis of New Lipophilic Hydroxylated γ-Nitroesters

The Morita-Baylis-Hillman (MBH) reaction has attracted great attention to generate densely functionalized adducts with promising synthetic utility and biological activities. In this work we demonstrate, for the first time, the synthesis of a series of new lipophilic hydroxylated alpha-alkyl gamma-nitroesters, advanced gamma-aminobutyric acid (GABA) intermediates, using the Morita-Baylis-Hillman (MBH) reaction as key step. The results show that the long-chain MBH adducts can be synthesized in good yields in a metal-free organocatalytic system in the presence of aliphatic aldehydes and activated alkenes, acrylonitrile or methyl acrylate. Followed, the Michael addition of nitromethane to MBH adducts resulted in hydroxylated alpha-alkyl gamma-nitroesters in good yields. Thus, the key MBH reaction led to new lipophilic GABA advanced intermediates in good overall yields from aliphatic aldehydes, demonstrating the potential of this reaction pathway towards the synthesis of new drug molecules for the treatment of psychiatric or neurodegenerative disorders.