Computational Exploration of Anomalous Regioselectivities in Cycloadditions of Ketenes to Oxazolines.

Thermal (2 + 2) cycloadditions of several -carboalkoxy ()-2--butyldihydrooxazoles with ketenes have been studied experimentally by the Ghosez group. Contrary to results from Seebach and co-workers that the electrophilic addition of acylating agents occurs β to dihydrooxazole nitrogen, Ghosez found major cycloadducts resulting from an attack of ketene carbonyl carbon β to oxygen. We investigate the potential energy surface for the cycloaddition of diphenyl- and phenylchloroketenes to two ()-2--butyldihydrooxazoles with ωB97X-D and mPW1PW91 density functional theory and DLPNO-CCSD(T) wave function theory.

Productive Syntheses of Privileged Scaffolds Inspired by the Recognition of a Diels-Alder Pattern Common to Three Classes of Natural Products.

Identification of a common Diels-Alder pattern in three classes of bioactive natural products led us to study the synthesis and cycloaddition of a new class of cyclic dienes readily available from β,γ-unsaturated lactams. A practical and readily scalable route to the parent p-methoxybenzyl-protected 6- and 7-membered β,γ-unsaturated lactams was developed. These were readily transformed into the corresponding O-silylated dienes, which were reacted with dimethyl and diethyl fumarate to yield stereoselectively highly functionalized bicyclic adducts.

Mechanisms and Conformational Control of (4 + 2) and (2 + 2) Cycloadditions of Dienes to Keteniminium Cations.

Selectivities in (4 + 2) and (2 + 2) cycloadditions of keteniminium cations with 1,3-dienes studied experimentally by Ghosez et al. were explored with ωB97X-D density functional theory. Reactions of keteniminium cations with 1,3-dienes are influenced by the -cis or -trans nature of the diene.

Discovery of a subnanomolar and selective spirocyclic agonist of the glucocorticoid receptor.

Pure diastereomeric spirocyclic analogs of fluorocortivazol were conveniently prepared by a short and efficient synthetic sequence recently developed in our laboratory. The structures and conformations of several key products were confirmed by single crystal X-ray diffraction analysis. Conformational assignments were also supported by DFT calculations.