Highly Diastereo- and Enantioselective Synthesis of Tetrahydrobenzo[b]azocines via Palladium-Catalyzed [4+4] Cycloaddition

The construction of N-heterocyclic eight-membered rings with good regio-, stereo-, and enantioselective control remains a formidable challenge in asymmetric catalysis. Herein, we report a palladium-catalyzed asymmetric [4 + 4] cycloaddition of anthranils with gamma-methylidene-delta-valerolactones in the presence of Et3B, delivering highly functionalized tetrahydrobenzo[b]-azocine derivatives in high efficiency with good diastereoselectivities and enantioselectivities (up to 92% yield, 20:1 dr, 99% ee). Moreover, complex substrates derived from natural products (bearing different functionalities) could be well-tolerated in the catalytic asymmetric cycloaddition. The mild reaction conditions, in conjunction with a broad substrate scope (44 examples), and a high level of stereoselectivity, provide great potential to build complex azocine compounds from simple building blocks.

Automated summary

This study presents a palladium-catalyzed asymmetric [4 + 4] cycloaddition, allowing for efficient synthesis of highly stereochemically controlled nitrogen-heterocyclic compounds. The method provides good regio-, stereo-, and enantioselectivity, with the ability to tolerate complex substrates derived from natural products.