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.

The nature of persistent conformational chirality, racemization mechanisms, and predictions in diarylether heptanoid cyclophane natural products.

Restricted rotations of chemical bonds can lead to the presence of persistent conformational chirality in molecules lacking stereocenters. We report the development of first-of-a-kind predictive rules that enable identification of conformational chirality and prediction of racemization barriers in the diarylether heptanoid (DAEH) natural products that do not possess stereocenters. These empirical rules-of-thumb are based on quantum mechanical computations (SCS-MP2/∞//B3LYP/6-31G*/PCM) of racemization barriers of four representative DAEHs. Specifically, the local symmetry of ring B and the E/Z configuration of the vinylogous acid/ester are critical in determining conformational chirality in the DAEH natural product family.

Synthesis and computational analysis of densely functionalized triazoles using o-nitrophenylalkynes.

Dipolar cylcoadditions with azides using a series of o-nitrophenylethynes and disubstituted alkynes were studied experimentally and computationally. Density functional theory computations reveal the steric and electronic parameters that control the regioselectivity of these cycloadditions. Several new substrates were predicted that would either give enhanced regiocontrol or invert the regiochemical preference. Experimentally, the alkynes were screened in the [3 + 2] cycloaddition with benzyl azide. Of the 11 alkynes screened experimentally, the acetylenes containing halogen substitution directly on the alkyne provided the highest levels of regioselectivity. These haloalkynes were also shown to tolerate variation of the azide moiety with continued good levels of regioselectivity in most cases. Diverse functional groups can be incorporated through the cycloaddition process and their subsequent orthogonal modification was demonstrated.

Stereocontrol in asymmetric γ-lactam syntheses from imines and cyanosuccinic anhydrides.

Computations (SCS-MP2//B3LYP) reveal that the asymmetric synthesis of highly substituted γ-lactams with three stereogenic centers, including one quaternary center, proceeds through a Mannich reaction between the enol form of the anhydride and the E-imine, followed by a transannular acylation. This new mechanistic picture accounts for both the observed reactivity and stereoselectivity. CH-O and hydrogen bonding interactions in the Mannich step and torsional steering effects in the acylation step are responsible for stereocontrol. It is demonstrated that this new mechanistic picture applies to the related reactions of homophthalic anhydrides with imines and presents new vistas for the design of a new reaction to access complex molecular architectures.

Stereoselective synthesis of γ-lactams from imines and cyanosuccinic anhydrides.

A reaction between imines and anhydrides has been developed with chiral disubstituted anhydrides and chiral imines. The synthesis of highly substituted γ-lactams with three stereogenic centers, including one quaternary center, proceeds at room temperature in high yield and with high diastereoselectivity in most cases. Enantiomerically pure alkyl-substituted anhydrides proceed with no epimerization, thus providing access to enantiomerically pure penta-substituted lactam products.