Enantioselective and Regiodivergent Synthesis of Dihydro-1,2-oxazines from Triene-Carbamates via Chiral Phosphoric Acid-Catalysis
Emma Naulin, Marine Lombard, Vincent Gandon, Pascal Retailleau, Elsa Van Elslande, Luc Neuville, Géraldine Masson
Abstract
Conjugated trienes are fascinating building blocks for the rapid construction of complex polycyclic compounds. However, limited success has been achieved due to the challenging regioselectivity control. Herein, we report an enantio- and diastereoselective process allowing to regioselectively control the functionalization of N H-triene-carbamates. Synthesis of chiral cis -3,6-dihydro-2 H -1,2-oxazines is achieved by a chiral phosphoric acid catalyzed Nitroso-Diels–Alder cycloaddition involving [(1 E,3 E,5 E )-hexa-1,3,5-trien-1-yl]carbamates. Moreover, modular access to three different regioisomers with excellent diastereoselectivities and high to excellent enantioselectivities is obtained by a careful choice of the reaction conditions. A computational study reveals that the regioselectivity is influenced by the steric demand of the substituents at the 6-position of the triene, as well as noncovalent interactions between the two cycloaddition partners. Utility of each regioisomeric cycloadduct is highlighted by a variety of synthetic transformations.