Enantioselective Synthesis of Chiral 1-Amino-3-silatetralins via Palladium-Catalyzed 4 + 2 Annulation of Benzosilacyclobutenes with N -Allenamides

While silicon incorporation is a compelling strategy in drug discovery due to its bioisosteric properties and the chiral 1-aminotetralin is a privileged scaffold, the synthesis of enantiopure silicon-bridged 1-aminotetralin analogues poses significant challenges and has thus far hampered their medicinal exploration. Herein, we present the strategy for the enantioselective synthesis of 1-amino-3-silatetralins via a palladium-catalyzed asymmetric 4 + 2 annulation of benzosilacyclobutenes with N-allenamides by employing a chiral phosphoramidite ligand. Notably, this protocol leverages the dual role of N-allenamides as both a two-carbon synthon and a nitrogen donor, enabling efficient assembly of structurally diverse chiral 1-amino-3-silatetralins in good yields and high enantioselectivity with broad functional group tolerance. The reaction proceeds with exclusive proximal C═C bond insertion of N-allenamides and selective Si−C(sp2) bond cleavage of benzosilacyclobutenes, a regioselectivity well supported by DFT calculations. This methodology thereby provides access to inaccessible three-dimensional architectures, facilitating drug discovery efforts focused on silicon-based bioisosteres.