Computational ligand design in enantio- and diastereoselective ynamide [5+2] cycloisomerization.

Transition metals can catalyse the stereoselective synthesis of cyclic organic molecules in a highly atom-efficient process called cycloisomerization. Many diastereoselective (substrate stereocontrol), and enantioselective (catalyst stereocontrol) cycloisomerizations have been developed. However, asymmetric cycloisomerizations where a chiral catalyst specifies the stereochemical outcome of the cyclization of a single enantiomer substrate--regardless of its inherent preference--are unknown. Here we show how a combined theoretical and experimental approach enables the design of a highly reactive rhodium catalyst for the stereoselective cycloisomerization of ynamide-vinylcyclopropanes to [5.3.0]-azabicycles. We first establish highly diastereoselective cycloisomerizations using an achiral catalyst, and then explore phosphoramidite-complexed rhodium catalysts in the enantioselective variant, where theoretical investigations uncover an unexpected reaction pathway in which the electronic structure of the phosphoramidite dramatically influences reaction rate and enantioselectivity. A marked enhancement of both is observed using the optimal theory-designed ligand, which enables double stereodifferentiating cycloisomerizations in both matched and mismatched catalyst-substrate settings.

Synthesis of malhamensilipin A exploiting iterative epoxidation/chlorination: experimental and computational analysis of epoxide-derived chloronium ions.

We report a 12-step catalytic enantioselective formal synthesis of malhamensilipin A (3) and diastereoisomeric analogues from (E)-2-undecenal. The convergent synthesis relied upon iterative epoxidation and phosphorus(v)-mediated deoxydichlorination reactions as well a titanium-mediated epoxide-opening to construct the C11-C16 stereohexad. The latter transformation occurred with very high levels of stereoretention regardless of the C13 configuration of the parent epoxide, implicating anchimeric assistance of either the γ- or δ-chlorine atoms, and the formation of chloretanium or chlorolanium ions, respectively. A computational analysis of the chloronium ion intermediates provided support for the involvement of chlorolanium ions, whereas the potential chloretanium ions were found to be less likely intermediates on the basis of their greater carbocationic character.