Second Generation Catalytic Enantioselective Nucleophilic Desymmetrization at Phosphorus (V): Improved Generality, Efficiency and Modularity.

A broadly improved second generation catalytic two-phase strategy for the enantioselective synthesis of stereogenic at phosphorus (V) compounds is described. This protocol, consisting of a bifunctional iminophosphorane (BIMP) catalyzed nucleophilic desymmetrization of prochiral, bench stable P(V) precursors and subsequent enantiospecific substitution allows for divergent access to a wide range of C-, N-, O- and S- substituted P(V) containing compounds from a handful of enantioenriched intermediates. A new ureidopeptide BIMP catalyst/thiaziolidinone leaving group combination allowed for a far wider substrate scope and increased reaction efficiency and practicality over previously established protocols. The resulting enantioenriched intermediates could then be transformed into an even greater range of distinct classes of P(V) compounds by displacement of the remaining leaving group as well as allowing for even further diversification downstream. Density functional theory (DFT) calculations were performed to pinpoint the origin of enantioselectivity for the BIMP-catalyzed desymmetrization, to rationalize how a superior catalyst/leaving group combination leads to increased generality in our second-generation catalytic system, as well as shed light onto observed stereochemical retention and inversion pathways when performing late-stage enantiospecific SN2@P reactions with Grignard reagents.

Branching out: redox strategies towards the synthesis of acyclic α-tertiary ethers.

Acyclic α-tertiary ethers represent a highly prevalent functionality, common to high-value bioactive molecules, such as pharmaceuticals and natural products, and feature as crucial synthetic handles in their construction. As such their synthesis has become an ever-more important goal in synthetic chemistry as the drawbacks of traditional strong base- and acid-mediated etherifications have become more limiting. In recent years, the generation of highly reactive intermediates via redox approaches has facilitated the synthesis of highly sterically-encumbered ethers and accordingly these strategies have been widely applied in α-tertiary ether synthesis. This review summarises and appraises the state-of-the-art in the application of redox strategies enabling acyclic α-tertiary ether synthesis.