Diastereoselective Synthesis of and Mechanistic Understanding for the Formation of 2-Piperidinones from Imines and Cyano-Substituted Anhydrides.

2-Piperidinones are synthesized in a single step from imines and 2-cyano glutaric anhydrides. The reaction provides the products in good diastereoselectivity and generates a quaternary stereogenic center. Substitutions on the anhydride skeleton are well tolerated to provide 2-piperidinones with three stereogenic centers from a single transformation. The pertinent transition structures have also been computed using quantum mechanics and reveal the key interactions controlling the stereochemical outcome of the reaction.

Construction of Stereogenic α,α-Disubstituted Cycloalkanones via 1° Amine Thiourea Dual Catalysis: Experimental Scope and Computational Analyses.

The mechanistic exploration and an expanded experimental discussion of the organocatalyzed, asymmetric Pfau-d'Angelo reaction by exploiting a bifunctional 1° amine thiourea catalyst system is disclosed. Notable breadth in substrate scope has been demonstrated on both the cyclic ketone moiety and the α,ß-unsaturated electrophile. Exploration into the matched and mismatched selectivity of this process with a ketone containing pre-existing stereocenters has been demonstrated. Computational analyses of the reaction mechanism are reported. In concert with kinetic isotope effect (KIE) experiments, these computational results provide a detailed understanding of the likely mechanism, including the aspects of the organocatalyst scaffold that are critical for stereoselectivity.

Towards theory driven structure elucidation of complex natural products: mandelalides and coibamide A.

The effectiveness of computational tools in determining relative configurations of complex molecules is investigated, using natural products mandelalides A-D and coibamide A, towards a generalized recipe for the scientific community at large. Ultimately, continuing efforts in this vein will accelerate and strengthen relative structure elucidation of complex molecules, such as natural products. Molecular mechanics conformational search, quantum mechanical NMR chemical shift predictions, and DP4 analyses led to confirmation of the revised structures of mandelalides A-D and coibamide A. All chiral centers in the northern hemisphere of mandelalides A-D are inverted with respect to the originally proposed structures, in agreement with recent total syntheses of mandelalide A by Ye, Fürstner & Carter. In the case of coibamide A, it was found that Fang & Su's revision, in which both the macrocycle [MeAla(11)] and the side chain [HIV(2)] residues are inverted from l to d, was consistent with the authentic natural product and computations.