Mechanistic elucidation of the tandem Diels-Alder/(3 + 2) cycloadditions in the design and syntheses of heterosteroids.

The potential of azasteroids as novel drug candidates has prompted numerous studies towards the syntheses of heterosteroidal skeletons. The 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 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 1a2 and 1b2 with phenyl azide (3) under the experimental conditions. We extended the scope of these tandem cycloaddition reactions by studying several variants of 1a1, 1b1, and 1c1 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 1a1, 1b1, and 1c1 decrease the barrier of the rds while electron-donating substituents substantially increase the barrier of the rds. The parent reaction (1a1) selectively proceeds via transition states T5Exa to give tandem adduct 5Exa, the experimentally observed tandem product. In the case of 1b1 and 1c1, 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 barrier of the rds, the direct opposite is true for electron-donating groups. A plot of electrophilicity indices against activation energies obtains a favorable correlation. We also investigated the unreported reactivity of a furylcinnamate (2-1a2) with several nitrile imines. Such a reaction is found to proceed through a similar mechanism as those seen for the phenyl azide. It is observed that di-substituted nitrile imines react with furylcinnamate (2-1a2) at favorable energetics than phenyl azide. Calculated GEDT values unveil that the non-polar solvent (toluene) will stabilize the non-polar reaction through van der waals interactions.