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 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.