Mechanistic-Insight-Driven Rate Enhancement of Asymmetric Copper-Catalyzed 1,4-Addition of Dialkylzinc Reagents to Enones

The combination of [Cu­(MeCN)4]­TFA·TFAH (TFA = O2CCF3) with Feringa’s phosphoramidite ligand (LA) provides an exceptionally active (0.75 mol %) catalyst for asymmetric conjugate additions of ZnR2 (R = Et and Me at −40 to −80 °C) to enones. Kinetic and other studies of the addition of ZnEt2 to cyclohex-2-en-1-one indicate a transition state stoichiometry composition of (ZnEt2)3(enone)4Cu2(LA)3 that is generated by transmetalation from Et2Zn­(enone)2. Catalyst genesis is significantly slower than turnover (which has limited previous attempts to attain useful kinetic data); in the initial stages, varying populations of catalytically inactive, off-cycle, species are present. These issues are overcome by a double-dose kinetic analysis protocol. A rest state of [LACu­(Et)­(μ-TFA)­(μ-{(enone)­(ZnEt)2(enolate)})­CuLA2]+ (through the equivalence of enolate = enone + ZnEt2) is supported by DFT studies (ωB97X-D/SRSC). Rate-determining ZnEt2(enone)2 transmetalation drives the exceptionally high catalytic activity of this system

Streamlined Synthesis of C(sp³)-Rich <i>N</i>‑Heterospirocycles Enabled by Visible-Light-Mediated Photocatalysis

We report a general visible-light-mediated strategy that enables the construction of complex C­(sp3)-rich N-hetero­spiro­cycles from feedstock aliphatic ketones and aldehydes with a broad selection of alkene-containing secondary amines. Key to the success of this approach was the utilization of a highly reducing Ir-photocatalyst and orchestration of the intrinsic reactivities of 1,4-cyclohexadiene and Hantzsch ester. This methodology provides streamlined access to complex C­(sp3)-rich N-hetero­spiro­cycles displaying structural and functional features relevant to fragment-based lead identification programs

Streamlined Synthesis of C(sp³)-Rich <i>N</i>‑Heterospirocycles Enabled by Visible-Light-Mediated Photocatalysis

We report a general visible-light-mediated strategy that enables the construction of complex C­(sp3)-rich N-hetero­spiro­cycles from feedstock aliphatic ketones and aldehydes with a broad selection of alkene-containing secondary amines. Key to the success of this approach was the utilization of a highly reducing Ir-photocatalyst and orchestration of the intrinsic reactivities of 1,4-cyclohexadiene and Hantzsch ester. This methodology provides streamlined access to complex C­(sp3)-rich N-hetero­spiro­cycles displaying structural and functional features relevant to fragment-based lead identification programs