Formation of Heterosteroid Type Skeletons: Mechanistic Elucidation of the Diels-Alder/(3 + 2) Cycloadditions in the Design and Synthesis of Novel Azasteroids

The potential of azasteroids as novel drug candidates has prompted numerous studies towards the syntheses of heterosteroidal skeletons. Preparation of novel azasteroidal compounds and the modification of substituents on their steroidal skeletons might provide excellent congeners with useful biological properties. We present herein, a computational investigations on the Diels-Alder/(3 + 2) tandem sequential cycloaddition reaction of 21 distinctive derivatives of furylcinnamate with phenyl azides. First, we performed the computational study on the originally reported reaction of ester-substituted furylcinnamate derivatives 1a and 1b with phenyl azide (3) under the experimental conditions. We extended the scope of this tandem cycloaddition reactions by studying several variants of 1a, 1b and 1c and their reactivity towards 3. In all instances of tandem reactions considered in this study, the Diels-Alder cycloaddition step is the rate determining step (rds). Electron withdrawing-substituted 1a, 1b, and 1c decreases the rds whiles electron donating substituents substantially increase the rds. The parent reaction (1a) selectively proceeds via transition states T5Exa to give tandem adduct 5Exa, the experimentally observed tandem product. In the case of 1b and 1c, the reaction is competitively favored via T4Ex and T5Ex to give corresponding 4Ex and 5Ex (the experimentally observed tandem adducts). The various substituents studied demonstrate that the tandem adduct obtained is highly dependent on the substituents on the Diels-Alder intermediate. Whereas electron withdrawing groups substantially decrease the rds, the direct opposite is true for electron donating groups. A plot of electrophilicity indices and chemical hardness against activation energies gives a good correlation.