Concise approach to γ-(het)aryl- and γ-alkenyl-γ-aminobutyric acids. Synthesis of vigabatrin.

γ-Aminobutyric acid (GABA) and GABA derivatives have attracted increased attention over the years in the fields of medicinal chemistry and chemical biology due to their interesting biological properties and synthetic relevance. Here, we report a short synthetic route to γ-(het)aryl- and γ-alkenyl-γ-aminobutyric acids, including the antiepileptic drug vigabatrin, from readily available donor-acceptor cyclopropanes and ammonia or methylamine. This protocol includes a facile synthesis of 2-oxopyrrolidine-3-carboxamides and their acid hydrolysis to γ-aryl- or γ-alkenyl-substituted GABAs, which can serve as perspective building blocks for the synthesis of various GABA-based N-heterocycles and bioactive compounds.

Synthesis of 1,5-Substituted Pyrrolidin-2-ones from Donor-Acceptor Cyclopropanes and Anilines/Benzylamines.

We developed a straightforward synthetic route to pharmacologically important 1,5-substituted pyrrolidin-2-ones from donor-acceptor cyclopropanes bearing an ester group as one of the acceptor substituents. This method includes a Lewis acid-catalyzed opening of the donor-acceptor cyclopropane with primary amines (anilines, benzylamines, etc.) to γ-amino esters, followed by in situ lactamization and dealkoxycarbonylation. The reaction has a broad scope of applicability; a variety of substituted anilines, benzylamines, and other primary amines as well as a wide range of donor-acceptor cyclopropanes bearing (hetero)aromatic or alkenyl donor groups and various acceptor substituents can be involved in this transformation. In this process, donor-acceptor cyclopropanes react as 1,4-C,C-dielectrophiles, and amines react as 1,1-dinucleophiles. The resulting di- and trisubstituted pyrrolidin-2-ones can be also used in subsequent chemistry to obtain various nitrogen-containing polycyclic compounds of interest to medicinal chemistry and pharmacology, such as benz[g]indolizidine derivatives.

Expanding Stereoelectronic Limits of endo-tet Cyclizations: Synthesis of Benz[b]azepines from Donor-Acceptor Cyclopropanes.

The importance of intramolecular constraints in cyclic transition-state geometries is especially pronounced in n-endo-tet cyclizations, where the usual backside approach of a nucleophile to the breaking bond is impossible for the rings containing less than eight atoms. Herein, we expand the limits of endo-tet cyclizations and show that donor-acceptor cyclopropanes can provide a seven-membered ring via a genuine 6-endo-tet process. Substrates containing a N-alkyl-N-arylcarbamoyl moiety as an acceptor group undergo Lewis acid-induced cyclization to form tetrahydrobenz[b]azepin-2-ones in high yields. The reaction proceeds with the inversion of the configuration at the electrophilic carbon. In this process, a formally six-membered transition state yields a seven-membered ring as the pre-existing cycle is merged into the forming ring. The stereochemistry of the products can be controlled by the reaction time and by the nature of Lewis acid, opening access to both diastereomers by tuning of the reaction conditions.