Photochemical Synthesis of 2-Azabicyclo[3.2.0]heptanes: Advanced Building Blocks for Drug Discovery. Synthesis of 2,3-Ethanoproline

Abstract

Intramolecular photochemical [2 + 2]-cyclization of acetophenone enamides gave 2-azabicyclo[3.2.0]heptanes, advanced building blocks for drug discovery. Synthesis of a conformationally restricted analogue of proline, 2,3-ethanoproline, was performed.

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.…”

The Right Light: De Novo Design of a Robust Modular Photochemical Reactor for Optimum Batch and Flow Chemistry

“…Sensitized intermolecular and intramolecular [2+2]‐cycloadditions have recently been reported by Mykhailiuk et al . Two of the intermolecular substrates ( 8 and 9 , Scheme ) and one of the intramolecular substrates ( 11 , Scheme ) reported were selected for comparison in PHIL.…”

Synthesis of 3‐Azabicyclo[3.2.0]heptane‐Derived Building Blocks via [3+2] Cycloaddition

“…Several approaches to the construction of 3‐azabicyclo[3.2.0]heptane core are described in the literature, mostly being represented by intra‐ and intermolecular [2+2]cycloaddition reactions. Each of these methods usually require the use of transition‐metal catalysis or UV irradiation, except for the case of intramolecular cycloaddition of keteniminium salts,, thus typically being limited in substrate scope.…”

“…To synthesize 1‐substituted 3‐azabicyclo[3.2.0]heptane derivatives, the flavin‐mediated and copper(I)‐catalyzed [2+2] photocycloadditions were applied, providing 1‐phenyl and 1‐methyl‐substituted analogues, respectively. To date, all the aforementioned methods were not adopted for the preparation of bifunctional 1‐substituted 3‐azabicyclo[3.2.0]heptanes, although its isomer – 2‐azabicyclo[3.2.0]heptane‐1‐carboxylic acid has been obtained using a similar transformation, followed by oxidation of the furan ring with NaIO 4 /RuCl 3 . Other known methods for the synthesis of various 3‐azabicyclo[3.2.0]heptane derivatives include imide formation from cyclobutanedicarboxylic acid anhydride,, multicomponent cascade reactions of α,β‐unsaturated aldehydes, N ‐benzylaminocrotonate and secondary amines, and [3+2] cycloadditions.…”