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.

Transition Metal‐Mediated Functionalization of Isoxazoles: A Review

“…In 2021, Li and co‐workers developed the first palladium‐catalyzed asymmetric [4+4] annulation of anthranils with γ‐methylidene‐δ‐valerolactones in the presence of Et 3 B to afford tetrahydrobenzo[b]‐azocine derivatives with good diastereo‐ and enantioselectivities (Scheme 67). [89b] This catalytic asymmetric cycloaddition reaction which proceeded under mild conditions was found to be scalable and showed wide substrate scope and was used for further functionalization of an array of biologically active compounds. Based on mechanistic studies and control experiments, a plausible reaction mechanism was proposed.…”

“…Intramolecular cyclization of intermediate III followed by elimination of Et 3 B, produces the eight membered cycloadduct along with regeneration of Pd(0) species (Scheme 67). [89b] …”

Recent Advances in the Construction of Quaternary Stereocenters via Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation

“…Recently, our group reported the construction of various highly functionalized tetrahydrobenzo[b]azocine derivatives by Pd-catalyzed IDAAA of -methylidene--valerolactones with anthranils in high efficiency (up to 92% yield, 20:1 dr, 99% ee) (Scheme 24). 60 More than 40 examples, including natural product derived substrates, were well tolerated by using the newly designed phosphoramidite ligand L15. In addition, replacement of the ester group on the GMDVs with cyano afforded the desired product in 75% yield and 94% ee.…”

Stereoselective Synthesis of Azacycles Induced by Group 8–11 Late Transition Metals

“…Li, Liu, and coworkers have used the same palladium catalyst in asymmetric [4 + 4] cycloadditions. [31] Anthranils were reacted with γ-methylidene-δ-valerolactones in the presence of chiral ligand 18 and Et 3 B, furnishing substituted tetrahydrobenzo[b]azocine derivatives. Data in Scheme 24 indicate low to high yields and diastereoselectivities as well as excellent enantioselectivities.…”