Details

Autor(en) / Beteiligte

• Dhake, Kushal
• Woelk, Kyla J.
• Becica, Joseph
• Un, Andy
• Jenny, Sarah E.
• Leitch, David C.

Titel

Beyond Bioisosteres: Divergent Synthesis of Azabicyclohexanes and Cyclobutenyl Amines from Bicyclobutanes

Ist Teil von

• Angewandte Chemie International Edition, 2022-07, Vol.61 (27), p.e202204719-n/a

Auflage

International ed. in English

Ort / Verlag

Germany: Wiley Subscription Services, Inc

Erscheinungsjahr

2022

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• The development of two divergent and complementary Lewis acid catalyzed additions of bicyclobutanes to imines is described. Microscale high‐throughput experimentation was integral to the discovery and optimization of both reactions. N‐arylimines undergo formal (3+2) cycloaddition with bicyclobutanes to yield azabicyclo[2.1.1]hexanes in a single step; in contrast, N‐alkylimines undergo an addition/elimination sequence to generate cyclobutenyl methanamine products with high diastereoselectivity. These new products contain a variety of synthetic handles for further elaboration, including many functional groups relevant to pharmaceutical synthesis. The divergent reactivity observed is attributed to differences in basicity and nucleophilicity of the nitrogen atom in a common carbocation intermediate, leading to either nucleophilic attack (N‐aryl) or E1 elimination (N‐alkyl). By exploiting the divergent reactivity of bicyclobutanes undergoing addition to imines, highly‐functionalized and stereochemically‐defined azabicyclohexanes and cyclobutenyl amines are easily accessible. These modular syntheses provide new and selective methods to prepare Csp3‐rich scaffolds with potential beyond bioisosteric replacements in medicinal chemistry.