Enantioselective Synthesis of All‐Carbon Quaternary Stereogenic Centers by Catalytic Asymmetric Conjugate Additions of Alkyl and Aryl Aluminum Reagents to Five‐, Six‐, and Seven‐Membered‐Ring β‐Substituted Cyclic Enones

Catalytic asymmetric conjugate addition (ACA) reactions of carbon-based nucleophiles to β,β-disubstituted enones present an efficient approach to enantioselective synthesis of all-carbon quaternary stereogenic centers[1] that reside adjacent to synthetically versatile enolates [Eq. (1)]. In spite of recent advances involving catalytic ACA reactions of alkyl metal (mostly dialkyl zinc) reagents,[2–5] a number of critical short-comings remain unaddressed. One noteworthy challenge concerns transformations of β-substituted cyclopentenones, processes that are often less efficient[6, 7] (vs. reactions of larger rings) but can deliver products that may be used in enantioselective syntheses of a variety of biologically active natural products.[8] Previously reported approaches, involving zinc-based reagents, are only effective with five-memberedring substrates when the enone bears an additional activating substituent.[4] Additions of trialkyl aluminum reagents to β-substituted cyclopentenones catalyzed by chiral copper phosphoramidites have been shown to proceed in three cases. In only a single instance, however, is high selectivity observed (ACA with Et3Al; 96.5:3.5 e.r., 93% ee).[5a] Herein, we disclose an efficient set of protocols for catalytic ACA reactions of alkyl and aryl aluminum reagents with a range of unactivated β-substituted cyclic enones, including cyclopentenones. Reactions, promoted in the presence of a chiral bidentate N-heterocyclic carbene (NHC) copper complex (5 mol%), are efficient (up to 97% yield) and highly selective (up to >99: <1 e.r., greater than 98% ee). In the case of transformations involving additions of aryl units, the requisite aluminum-based reagents are prepared in situ from commercially available dimethylaluminum chloride and the corresponding aryl lithium compounds.