Chiral Brønsted\nAcid-Catalyzed Regio‑,\nDiastereo‑, and Enantioselective Formal [2 + 2 + 2] Cycloaddition\nof 3‑Vinyl‑1<i>H</i>‑indoles with Nitrosobenzenes

A chiral Brønsted acid-catalyzed synthetic method\nthat enables\nthe enantioselective formal [2 + 2 + 2] cycloaddition of 3-vinyl-1<i>H</i>-indoles with nitrosobenzenes is described. Through this\npreviously unknown mode of reactivity of the nitrosoarene, the ring\nformation protocol offers access to a wide variety of fully substituted\n1,2-oxazinanes as a single regioisomer. With four stereogenic centers\ngenerated in the product, the <i>N</i>,<i>O</i>-heterocycle was also furnished, in most cases, as a single diastereomer\nin yields of up to 94% and with enantiomeric excess (ee) values of\nup to 99%. The synthetic utility of the catalytic method was demonstrated\nby the 2 mmol scale preparation of one example and its further functional\ngroup transformations. Included in this is the selective conversion\nof the 1,2-oxazinane to either its tetrahydrofuran or a partially\nhydrogenated pyrrole derivative. Experimental and computational studies\nbased on azaphilic and hydrogen-bonding interactions between the two\nsubstrates with the chiral phosphoric acid provide insight into the\nobserved product selectivities.