Enantioselective Synthesis of P(V)-Stereogenic Phosphacycles by N-Heterocyclic Carbene (NHC)-Catalyzed Desymmetric Annulation

Abstract

P(V)-stereogenic compounds show diverse biological properties and remain as a focal point in medicinal chemistry and agrochemicals. Traditional approaches to access enantioenriched P(V)-stereogenic molecules largely depend on chromatographic resolution, chiral auxiliaries, and/or the use of optically active starting materials. In contrast, catalytic strategies have recently advanced, with desymmetric substitution emerging as a powerful method for generating P(V) stereocenters. However, current strategies are mostly limited to acyclic systems, where control is exerted solely over the P(V) stereogenic center. Herein, we report N-heterocyclic carbene (NHC)-catalyzed desymmetric annulation for the enantio- and diastereoselective synthesis of phosphacycles bearing P(V) and C-stereogenic centers at the 1,4-positions. Control over remote chirality and multiple stereogenic centers are the key challenges of the present strategy, which was successfully achieved by choosing the suitable NHC precursor and substrate. DFT studies shed light on the importance of the annulation step, rather than the initial NHC addition to the aldehyde, as the crucial step for the enantio- and diastereoselectivity control of the reaction. The derivatization of the synthesized seven membered phosphacycles emphasizes the practical utility of the present methodology.