Enantioselective Synthesis of Oxazocines via MQ‐Phos Enabled Palladium‐Catalyzed Asymmetric Formal [4+4]‐Cycloadditions

Abstract

Oxazocines are key structural intermediates in the synthesis of natural products and pharmaceutical molecules. However, the synthesis of oxazocines especially in a highly enantioselective manner, is a long‐standing formidable challenge due to unfavorable energetics involved in cyclization. Herein, a series of new PNP‐Ligand P‐chiral stereocenter is first designed and synthesized, called MQ‐Phos, and successfully applied it in the Pd‐catalyzed enantioselective higher‐order formal [4+4]‐cycloaddition of α, β‐unsaturated imines with 2‐(hydroxymethyl)‐1‐arylallyl carbonates. The reaction features mild conditions, excellent regio‐ and enantiocontrol and a broad substrate scope (54 examples). Various medium‐sized rings can be afforded in moderate to excellent yields (up to 92%) and excellent enantioselectivity (up to 99% ee). The newly developed MQ‐Phos is critical for synthesis of the medium‐sized ring in excellent catalytic reactivity and enantioselectivity.