Iridium-Catalyzed Asymmetric Cascade Allylation/[1,4]-Phospha-Brook Rearrangement Reaction

Abstract

Chiral δ-carbonyl phosphates and their derivatives represent important structural units frequently found in natural products and biologically active molecules and have been extensively employed as key intermediates in organic synthesis. Herein, an unprecedented iridium-catalyzed asymmetric cascade allylation/[1,4]-phospha-Brook rearrangement of β-keto phosphonates with vinyl ethylene carbonate was established, offering an efficient synthetic strategy to access highly functionalized chiral δ-carbonyl phosphates that are difficult to access via known methods. This protocol features easily available starting materials, mild reaction conditions, high chemo-/regio-/enantioselectivity, and a wide substrate scope. Notably, this methodology can be extended to various β-functionalized phosphonates. The gram-scale reaction, diverse functional transformations, and stereodivergent synthesis of chiral δ-hydroxyl phosphates containing two nonadjacent stereocenters demonstrated the synthetic potential of this method. The synthetic utility of this cascade reaction was further confirmed in the concise formal synthesis of natural products hormosirene, dictyopterene A, and biologically active (R)-MCPA-CoA. Control experiments and density field theory computational mechanistic studies revealed that this transformation undergoes asymmetric allylation via kinetic resolution followed by a unique [1,4]-phospha-Brook rearrangement. Ligand–substrate interactions were identified to rationalize the kinetic resolution and chiral induction. The stronger σ-bond of P–O than that of O–C makes the [1,4]-phospha-Brook rearrangement kinetically and thermodynamically favorable.