β-Substituted γ-butyrolactams from mucochloric acid: synthesis of (±)-baclofen and other γ-aminobutyric acids and useful building blocks

In the course of our exploration of the application of mucohalic acids in organic synthesis, we reported the synthesis of alpha,beta-dihalo-alpha,beta-unsaturated gamma-butyrolactams by reductive amination of a suitable mucohalic acid and a suitable amine. However, the functionalization of the alpha- and/or beta-halogen was found to be elusive under Suzuki conditions that worked well with the corresponding gamma-lactones. Although the corresponding beta-aryl derivative was obtained under some of the modified Suzuki conditions tried, the yields were found to be very low. Next, the Suzuki coupling was performed on mucochloric acid prior to the reductive amination step. By careful control of the reaction conditions, only beta-substitution was achieved to yield the corresponding beta-aryl mucochloric acid. This could then be converted to the corresponding beta-substituted gamma-butyrolactam by reductive amination with 2,4-dimethoxybenzylamine (DMB-NH2) followed by reduction by nickel boride and subsequent deprotection of the DMB group. The resulting gamma-butyrolactam could either be alkylated or hydrolyzed resulting in the corresponding beta-substituted gamma-aminobutyric acid. This methodology was extended to synthesize (+/-)-baclofen in five steps starting from mucochloric acid.