Chiral Brønsted Acid-Catalyzed Regio-, Diastereo-, and Enantioselective Formal [2 + 2 + 2] Cycloaddition of 3-Vinyl-1<i>H</i>-indoles with Nitrosobenzenes

A chiral Brønsted acid-catalyzed synthetic method that enables the enantioselective formal [2 + 2 + 2] cycloaddition of 3-vinyl-1H-indoles with nitrosobenzenes is described. Through this previously unknown mode of reactivity of the nitrosoarene, the ring formation protocol offers access to a wide variety of fully substituted 1,2-oxazinanes as a single regioisomer. With four stereogenic centers generated in the product, the N,O-heterocycle was also furnished, in most cases, as a single diastereomer in yields of up to 94% and with enantiomeric excess (ee) values of up to 99%. The synthetic utility of the catalytic method was demonstrated by the 2 mmol scale preparation of one example and its further functional group transformations. Included in this is the selective conversion of the 1,2-oxazinane to either its tetrahydrofuran or a partially hydrogenated pyrrole derivative. Experimental and computational studies based on azaphilic and hydrogen-bonding interactions between the two substrates with the chiral phosphoric acid provide insight into the observed product selectivities.