Synthesis of 3‐Azabicyclo[3.2.0]heptane Derivatives as γ‐Aminobutyric Acid Analogues through Intermolecular [2+2] Photo­cycloaddition

Abstract

The synthesis of 3‐azabicyclo[3.2.0]heptane‐6‐carboxylic acid and 7‐substituted derivatives was developed as bicyclic analogues of γ‐aminobutyric acid. A sensitized, intermolecular [2+2] photocycloaddition of maleic anhydride with N‐protected 3‐pyrroline served as the key step in these syntheses. Upon transformation of the anhydride function of the primary cycloaddition product, 6‐monosubstituted and 6,7‐disubstituted 3‐azabicyclo[3.2.0]heptane derivatives were obtained.

Recent Advances in the Synthesis of Cyclobutanes by Olefin [2 + 2] Photocycloaddition Reactions

“… 611 Wanner and co-workers prepared product 329 from an N -trifluoroacetyl protected 3-pyrroline en route to γ-aminobutyric acid analogues. 612 Due to the symmetry of maleic anhydride, there is no regioselectivity issue and the relative configuration is cis-anti-cis for cyclic olefins and cis-anti-trans for acyclic olefins. An example for the latter relative configuration is found in photocycloaddition product rac - 330 obtained from 1,4-dichloro-2-butene.…”

Emerging Building Blocks for Medicinal Chemistry: Recent Synthetic Advances

“…[465] Intermolecular photochemical [2 + 2] cycloaddition of maleimides was another efficient approach to 3-azabicyclo[3.2.0] heptanes allowing not only for the preparation of 3,6disubstituted derivatives, but also tricyclic systems of type 102 that can be considered as extended M/P/P analogs (Scheme 59). [466][467][468] One more retrosynthetic disconnection of the 3-azabicyclo [3.2.0]heptane core relied on the [3 + 2] cycloaddition of cyclobutene derivatives and azomethine ylides, used for the construction of 1,3-disubstituted derivatives (Scheme 60). [459] A copper-catalyzed asymmetric version of this transformation leading to polysubstituted 3-azabicyclo[3.2.0]heptanes was also reported.…”

Highly Efficient Visible-Light-Driven [2+2] Cycloaddition of Maleimides to Alkenes and Alkynes for the Synthesis of 3-Aza­bicyclo[3.2.0]heptane-Fused Scaffolds

“…However, presumably due to a lack of practical synthetic methods from easily available starting materials, 3-azabicyclo[3.2.0]heptanes remain somewhat in the shadow compared to other popular cores such as 3-azabicyclo­[3.1.0]hexanes and 3-azabicyclo[3.3.0]octanes. The main approaches to the construction of 3-azabicyclo­[3.2.0]heptanes rely on cyclization reactions, such as intramolecular [2+2] cycloadditions of N -substituted bis-allylamines via metal catalysis 6 or photocatalysis 7 (Scheme 1b ), intermolecular photocycloadditions with ultraviolet-mediated dihydropyrrole analogues (Scheme 1c ), 1b 8 and three-component cascade reactions of α,β-unsaturated aldehydes, N -benzylaminocrotonate, and secondary amines (Scheme 1d ). 9…”