Enantioselective, Catalytic Multicomponent Synthesis of Homoallylic Amines Enabled by Hydrogen-Bonding and Dispersive Interactions

We report a one-step catalytic, enantioselective method for the preparation of homoallylic <i>N</i>-Boc amines directly from acetals. Reactive iminium ion intermediates are generated <i>in situ</i> through the combination of an acetal, a chiral thiourea catalyst, trialkylsilyl triflate, and <i>N</i>-Boc carbamate, and are subsequently trapped by a variety of allylsilane nucleophiles. No homoallylic ether byproducts are detected, consistent with allylation of the iminium intermediate being highly favored over allylation of the intermediate oxocarbenium ion. Acetals derived from aromatic aldehydes possessing a variety of functional groups and substitution patterns yield homoallylic amines with excellent levels of enantiomeric enrichment. Experimental and computational data are consistent with an anchoring hydrogen-bond interaction between the protoiminium ion and the amide of the catalyst in the enantiodetermining transition state, and with stereodifferentiation achieved through specific non-covalent interactions (NCIs) with the catalyst pyrenyl moiety. Evidence is provided that the key NCI in the major pathway is a π-stacking interaction, contrasting with the cation–π interactions invoked in previously studied reactions promoted by the same family of aryl-pyrrolidino-H-bond-donor catalysts.

Enantioselective, Catalytic Multicomponent Synthesis of Homoallylic Amines Enabled by Hydrogen-Bonding and Dispersive Interactions

We report a one-step catalytic, enantioselective method for the preparation of homoallylic <i>N</i>-Boc amines directly from acetals. Reactive iminium ion intermediates are generated <i>in situ</i> through the combination of an acetal, a chiral thiourea catalyst, trialkylsilyl triflate, and <i>N</i>-Boc carbamate, and are subsequently trapped by a variety of allylsilane nucleophiles. No homoallylic ether byproducts are detected, consistent with allylation of the iminium intermediate being highly favored over allylation of the intermediate oxocarbenium ion. Acetals derived from aromatic aldehydes possessing a variety of functional groups and substitution patterns yield homoallylic amines with excellent levels of enantiomeric enrichment. Experimental and computational data are consistent with an anchoring hydrogen-bond interaction between the protoiminium ion and the amide of the catalyst in the enantiodetermining transition state, and with stereodifferentiation achieved through specific non-covalent interactions (NCIs) with the catalyst pyrenyl moiety. Evidence is provided that the key NCI in the major pathway is a π-stacking interaction, contrasting with the cation–π interactions invoked in previously studied reactions promoted by the same family of aryl-pyrrolidino-H-bond-donor catalysts.