Harnessing the 1,3-azadiene-anhydride reaction for the regioselective and stereocontrolled synthesis of lactam-fused bromotetrahydropyrans by bromoetherification of lactam-tethered trisubstituted tertiary alkenols.

Halo-cycloetherification of lactam-tethered alkenols enables the construction of oxygen-heterocycles that are fused to nitrogen heterocycles via intramolecular halonium-induced nucleophilic addition. Specifically, tetrahydropyrans (THPs) that are fused to a nitrogen heterocycle constitute the core of several bioactive molecules, including tachykinin receptor antagonists and alpha-1 adrenergic antagonists. Although the literature is replete with successful examples of the halo-cycloetherification of simple mono- or disubstituted primary alkenols, methods for the modular, efficient, regioselective, and stereocontrolled intramolecular haloetherification of sterically encumbered trisubstituted tertiary alkenols are rare. Here, we describe a simple intramolecular bromoetherification strategy that meets these benchmarks and proceeds with exclusive 6-endo regioselectivity. The transformation employs mild and water-tolerant conditions, which bodes well for late-stage diversification. The hindered ethers contain four contiguous stereocenters as well as one halogen-bearing tetrasubstituted stereocenter.

Revisiting the 1,3-azadiene-succinic anhydride annulation reaction for the stereocontrolled synthesis of allylic 2-oxopyrrolidines bearing up to four contiguous stereocenters.

Polysubstituted 2-oxopyrrolidines bearing at least two contiguous stereocenters constitute the core of several pharmaceuticals, including clausenamide (antidementia). Here, we describe a flexible annulation strategy, which unites succinic anhydride and 1,3-azadienes to produce allylic 2-oxopyrrolidines bearing contiguous stereocenters. The approach is chemoselective, efficient, modular, scalable, and diastereoselective. The scalable nature of the reactions offers the opportunity for post-diversification, leading to incorporation of motifs with either known pharmaceutical value or that permit subsequent conversion to medicinally relevant entities.