New regioselective multicomponent reaction: One pot synthesis of spiro heterobicyclic aliphatic rings

In the context of our high-throughput organic synthesis program, we have st udied the reactivity of special beta -keto esters toward the Biginelli reac tion. We have found that a cyclic beta -keto ester reacts with one molecule of urea and two molecules of aldehyde to give a new family of spiro hetero bicyclic aliphatic rings in good yields. Interestingly, the Biginelli produ ct was not detected. After analysis of products using HPLC, LH NMR, and C-1 3 NMR, we have found that the reaction is driven by a regio-specific conden sation of two molecules of aldehyde with the other reagents to afford only products harboring substituents exclusively in cis configuration. Monte Car lo minimization studies using MM2 force field suggest that cis products are energetically more stable than the trans counterparts. Together with previ ously reported data, these results suggest that the trans products were not obtained as result of steric hindrance produced by the equatorial position of one of the ring substituents. This new reaction is useful for high-thro ughput organic synthesis. Indeed, the new scaffold can be used to introduce additional groups in the molecules through remaining functional groups by a "domino strategy".