Enantioselective Synthesis of 1‑Dihydrobenzazepines through Rh₂(II)-Catalyzed Cycloisomerization of 1,6-Enyne

The 1-dihydrobenzazepine skeleton has emerged as a privileged structural motif in bioactive molecules. However, due to a lack of asymmetric methodology, access to chiral 1-dihydrobenzazepines has remained limited. Herein, we report the first intermolecular asymmetric cycloisomerization of benzo-fused enynes for the synthesis of chiral 1-dihydrobenzazepines via dirhodium catalysis. This methodology features high efficiency (up to 98% yield), high enantioselectivity (up to 99% ee), and broad scope of nucleophiles, including oxygen nucleophiles (alcohols, phenols, and carboxylic acids) and carbon nucleophiles (silyl enol ethers). Theoretical and experimental mechanistic studies reveal that the reaction pathway encompasses an asymmetric cycloisomerization, which gives rise to a dirhodium carbene containing a donor–acceptor (D-A) cyclopropane moiety, followed by a ring-opening process and stereoselective nucleophilic attack by external nucleophiles on the cyclopropyl ring. Control experiments demonstrate the pivotal role of the terminal group capped on the alkynyl group of substrates in achieving good efficiency.