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

Abstract

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 γ-methylidene-δ-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.