This article reviews synthetic transformations involving cleavage of a carbon–carbon bond of a four-membered ring, with a particular focus on the examples reported during the period from 2011 to th...

Cleavage of Carbon-Carbon σ-Bonds of Four-Membered Rings.

Reported is an asymmetric reductive dicarbofunctionalization of unactivated alkenes. Under the catalysis of a Ni/BOX system, various aryl bromides, incorporating a pendant olefinic unit, were successfully reacted with an array of primary alkyl bromides in the presence of Zn as a reductant, furnishing a series of benzene-fused cyclic compounds bearing a quaternary stereocenter in high enantioselectivities. Notably, this reaction avoids the use of pregenerated organometallics and demonstrates high tolerance of sensitive functionalities. The preliminary mechanistic investigations reveal that this Ni-catalyzed reaction proceeds as a cascade consisting of migratory insertion and cross-coupling with a nickel(I)-mediated intramolecular 5-exo cyclization as the enantiodetermining step.

Nickel-Catalyzed Asymmetric Reductive Arylalkylation of Unactivated Alkenes.

A highly enantioselective dicarbofunctionalization of unactivated alkenes was implemented by a Pd-catalyzed asymmetric tandem Heck/Suzuki coupling reaction. This reaction represents the first example of a highly enantioselective intramolecular cyclization/cross-coupling of olefin-tethered aryl halides with alkyl-, alkenyl- or arylboronic acids, and provides rapid access to a number of chiral compounds, such as dihydrobenzofurans, indolines, chromanes, and indanes bearing a quaternary stereocenter, in good yields with excellent enantioselectivities. The practicality of this reaction was validated in the modification of biologically complex molecules such as peptides, piperitol, CB2 receptor agonists, etc. Moreover, the synthesis of two enantiomers can be easily realized by simple change in the order of the steps in the coupling sequence.

Enantioselective Dicarbofunctionalization of Unactivated Alkenes by Palladium-Catalyzed Tandem Heck/Suzuki Coupling Reaction.

ConspectusThe oxindole scaffold is a privileged structural motif that is found in a variety of bioactive targets and natural products. Moreover, derivatives of the oxindole structure are widely pre...

Metal-Catalyzed Approaches toward the Oxindole Core.

Transition-metal-catalysed cross-coupling reactions, particularly those mediated by palladium, are some of the most broadly used chemical transformations. The fundamental reaction steps of such cross-couplings typically include oxidative addition, transmetallation, carbopalladation of a π-bond and/or reductive elimination. Herein, we describe an unprecedented fundamental reaction step: a C-C σ-bond carbopalladation. Specifically, an aryl palladium(II) complex interacts with a σ-bond of a strained bicyclo[1.1.0]butyl boronate complex to enable addition of the aryl palladium(II) species and an organoboronic ester substituent across a C-C σ-bond. The overall process couples readily available aryl triflates and organoboronic esters across a cyclobutane unit with total diastereocontrol. The pharmaceutically relevant 1,1,3-trisubstituted cyclobutane products are decorated with an array of modular building blocks, including a boronic ester that can be readily derivatized.

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Carbopalladation of C–C σ-bonds enabled by strained boronate complexes

A palladium-catalyzed enantioselective intramolecular σ-bond cross-exchange between C-I and C-C bonds is realized, providing chiral indanones bearing an alkyl iodide group and an all-carbon quaternary stereocenter. Pd/TADDOL-derived phosphoramidite is found to be an efficient catalytic system for both C-C bond cleavage and alkyl iodide reductive elimination. In addition to aryl iodides, aryl bromides can also be used for this transformation in the presence of KI. Density-functional theory (DFT) calculation studies support the ring-opening of cyclobutanones occuring through an oxidative addition/reductive elimination process involving PdIV species.

Enantioselective Cross-Exchange between C-I and C-C σ Bonds.

The Sonogashira-type cross-coupling reaction is one of the most significant alkynylation transformations in organic chemistry. However, highly enantioselective alkynylation via the Sonogashira-type cross-coupling reaction is rather limited, mainly due to the difficulties in matching the stereoselective induction of chiral ligands with the combinational behavior of Pd/Cu-based bimetallic catalysts. We herein report novel enantioselective palladium/copper-catalyzed alkyl alkynylation of cyclobutanones with terminal alkynes via tandem C–C bond activation/Sonogashira-type cross coupling reaction, in which a novel chiral TADDOL-derived phosphoramidite ligand bearing fluorine and silicon-based bulky groups simplified as TFSi-Phos is found to be an efficient ligand for both C(sp2)–C(sp3) bond cleavage and new C(sp3)–C(sp) bond formation. A wide range of chiral alkynylated indanones bearing an all-carbon quaternary stereocenter are obtained efficiently with up to 97.5 : 2.5 er.

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Enantioselective palladium/copper-catalyzed C-C σ-bond activation synergized with Sonogashira-type C(sp3)-C(sp) cross-coupling alkynylation.

A palladium-catalyzed enantioselective sequential ring-opening/cross-coupling of cyclobutanones is disclosed that provides chiral indanones bearing C3-quaternary stereocenters. The reaction process involves palladium-catalyzed nucleophilic addition of cyclobutanones and aryl halides, enantioselective β-carbon elimination, and intermolecular trapping of a transient σ-alkylpalladium complex with boronic acids. Alternatively, an intramolecular cyclopropanation is realized through C-H bond functionalization in the absence of external coupling reagents, affording chiral cyclopropane-fused-indanones in good yields and enantioselectivity.

Pd-Catalyzed Enantioselective Ring Opening/Cross-Coupling and Cyclopropanation of Cyclobutanones.

A facile synthesis of γ,δ-unsaturated ketones via palladium-catalyzed ring-opening of 2-alkylidenecyclobutanols with organic halides is described. The key step involves Csp3-Csp2 bond cleavage via palladium-catalyzed β-carbon elimination. The desired γ,δ-unsaturated ketones are obtained in good to excellent yields and broad functional group tolerability. Aryl, heteroaryl, benzyl, and alkynyl halides all readily participate to forge tri-substituted carbon-carbon double bond in a stereoselective manner.

Feng-Na Sun

Papers

Enantioselective Cross-Exchange between C-I and C-C σ Bonds.

Enantioselective palladium/copper-catalyzed C-C σ-bond activation synergized with Sonogashira-type C(sp3)-C(sp) cross-coupling alkynylation.

Pd-Catalyzed Enantioselective Ring Opening/Cross-Coupling and Cyclopropanation of Cyclobutanones.

Palladium‐Catalyzed Ring‐Opening of 2‐Alkylidenecyclobutanols: Stereoselective Synthesis of γ,δ‐Unsaturated Ketones by C−C Bond Cleavage

Lewis Acid‐Catalyzed Yne‐Carbonyl Metathesis of Ynamides and Cyclobutanones: Facile Synthesis of Functionalized Alkylidenecyclobutanes