DBU-Promoted Tandem Michael Additions of Masked Bis-Nucleophiles to 4-Acetoxycyclopent-2-enone: Access to Tetracyclic...

4-Acetoxycyclopent-2-enone is a versatile precursor for constructing polycyclic scaffolds; however, tandem Michael reactions with bis-nucleophiles are often complicated by undesired secondary allylation. Existing asymmetric strategies toward tetracyclic lactams typically require excess reagents, underscoring the need for a more practical approach. Herein, we describe an efficient DBU-mediated tandem Michael addition strategy using masked bis-nucleophiles to access cis-fused [5,5] bicyclic intermediates and their transformation into tetracyclic lactams. Improved tandem Michael reactions were achieved by adding masked bis-nucleophiles to 4-acetoxycyclopent-2-enone. The use of masked bis-nucleophiles prevented the second allylation of the adducts, thereby enabling easy purification of the resulting bicyclic Michael adducts. This strategy afforded a series of cis-fused [5,5] bicyclic products in yields of 38-82% under homogeneous basic conditions mediated by DBU. Subsequent removal of the ester-masked groups, followed by palladium(II)-catalyzed keto α-arylation furnished the corresponding cis-fused tetracyclic lactams in yields of 22-72%. Furthermore, the effects of the solvent and phenyl substitution patterns on the intramolecular cyclization were studied systematically.