An asymmetric synthesis of the C-homoterpenoid (+)-Greek tobacco lactone is developed starting from readily available (R)-linalool. The synthesis is comprised of four operations and features a diastereoablative epoxidation and an oxidative tetrahydropyran formation using vanadium-, palladium-, and selenium-catalyzed cyclizations.

A diastereodivergent approach to highly substituted bicyclo[3.1.0]hexanes has been developed through a transannular alkylation reaction that builds up the bicyclic core employing asymmetric organocatalysis as the tool for the installation of all stereocenters. On one hand, a Michael/Michael cascade process between enals and 4-alkenyl sulfamidate imines under the iminium/enamine activation manifold provides an oxathiazole-2,2-dioxide-fused cyclohexane adduct that, after isolation, is subsequently engaged in a transannular alkylation/hydrolysis through enamine activation by the use of a primary amine. On the other hand, the corresponding C-2 epimers are directly obtained from the same starting materials in a single operation through a cascade Michael/Michael/transannular alkylation/hydrolysis sequence through sequential iminium/enamine/enamine combination of aminocatalytic activation manifolds.

4-Alkenyl-5H-1,2,3-oxathiazole 2,2-dioxides undergo Michael/Michael cascade reaction with enals through iminium/enamine activation.

The asymmetric synthesis of substituted pyrrolidines has been accomplished using a novel organocatalytic cyclization reaction promoted by a Cinchona alkaloid based primary amine. The reaction proceeds smoothly yielding pyrrolidine-2,2-dicarboxylates after in situ diastereoselective reduction with high levels of enantioselection. Furthermore, these adducts could be easily transformed into N-protected disubstituted prolines through the base-promoted diastereoselective C → N alkoxycarbonyl transfer reaction.

The pyrrolidine framework is present as key structure in many natural products with interesting biological and pharmaceutical activities.1 It is also used in organic chemistry playing different roles such as ligand, organocatalyst or building block in chiral pool synthesis.2 Furthermore, these properties are very often influenced by the configuration of the stereogenic center present in the molecule. For this reason, new and efficient routes are required to synthesize chiral proline derivatives in a stereocontrolled way. With this in mind, our group has established a good approach to this scaffold employing as key steps an organocatalytic cascade process based on a Michael addition/imine formation sequence and a novel base-promoted rearrangement reaction (Scheme 1). Therefore, the reaction between enones and aminomalonates has been studied using a chiral primary amine as catalyst, due to the known ability of the latter to activate α,β-unsaturated ketones as Michael acceptors under iminium ion formation.3 A sequential diastereoselective reduction leads to enantiopure 1,3-disubstituted pyrrolidines in good yield and enantioselectivity, which are transformed into the desired trisubstituted proline derivatives through a base-promoted rearrangement/deprotection reactions under mild conditions.