The Spiro mode. Efficient and highly selective synthesis of azapropellanes

A new variant of the tandem inter [4 + 2]/intra [3 + 2] nitroalkene cycloaddition has been developed. Intermolecular [4 + 2] cycloaddition of a 2-nitroalkene (bearing an unsaturated ester moiety, the dipolarophile) with a vinyl ether produces a cyclic nitronate substituted at C(3) wherein the only stereogenic center is the anomeric carbon C(6). Since the dipolarophile is attached to a tether extending from the C(3) of the nitronate ([Alpha]-carbon of the nitroalkene), the intramolecular [3 + 2] cycloaddition affords a spiro tricyclic nitroso acetal. The cycloaddition proceeds smoothly for three- and four-atom tethers to afford five- and six-membered rings. Both E- and Z-unsaturated esters serve well as dipolarophiles, but the E-isomers react more selectively. Hydrogenolysis of the nitroso acetals affords the spiro tricyclic [Alpha]-hydroxy lactams in good yield. Remarkably high levels of asymmetric induction are observed with the use of a chiral vinyl ether derived from (1R, 2S)-2phenylcyclohexanol. The origin of asymmetric induction is a combination of the established face selectivity of the enol ether and the preference for a distal fold of the tether away from the substituent on the anomeric carbon. The scope and limitations of this transformation and an analysis of the origin of stereoselectivity are provided.