The first Cu-catalyzed asymmetric borylative cyclization of cyclohexadienone-containing 1,6-enynes is achieved through a tandem process: selective β-borylation of propargylic ether and subsequent conjugate addition to cyclohexadienone. The reaction proceeds with excellent regioselectivity and enantioselectivity to afford an optically pure cis-hydrobenzofuran framework bearing alkenylboronate and enone substructures. Furthermore, the resulting bicyclic products could be converted to bridged and tricyclic ring structures. This method extends the realm of Cu-catalyzed asymmetric tandem reactions using bis(pinacolato)diboron (B2pin2).

Two tunable arylative cyclizations of cyclohexadienone-containing 1,6-enynes are reported via rhodium(III)-catalyzed C-H activation of O-substituted N-hydroxybenzamides. The use of different O substituents, i.e. O-Piv and O-Me, on the directing group allows the formation of either tetracyclic isoquinolones through an Ⓝ-Michael addition process or hydrobenzofurans through a Ⓒ-Michael addition process. Mechanistic investigations of these two cascade reactions clearly indicated that the C-H bond cleavage process was involved in the turnover-limiting step. Furthermore, the cyclization products could be subjected to various transformations for elaborating the pharmaceutically and synthetically valuable potential. This is the first example of a rhodium(III)-catalyzed arylative cyclization reaction of 1,6-enynes, and the results extend the application realm of Cp*Rh(III)-catalyzed C-H activation cascade reactions.

Herein we describe a protocol for the unprecedented stereodivergent synthesis of tertiary fluoride-tethered allenes bearing a stereogenic center and stereogenic axis via Cu/Pd synergistic catalysis. A broad scope of conjugated enynes are coupled with various α-fluoroesters in high yields with high diastereoselectivities and generally >99% ee. In addition, the four stereoisomers of the allene products ensure precise access to the corresponding four stereoisomers of the fluorinated hydrofurans via a novel stereodivergent axial-to-central chirality transfer process.

Although much effort has been spent on the enantioselective synthesis of tertiary alkyl fluorides, the synthesis of compounds containing such a stereogenic center within an array of stereocenters, particularly two vicinal ones, remains a synthetic challenge, and no method to control the configuration of each stereogenic center independently has been reported. We describe a strategy to achieve such a stereodivergent synthesis of vicinal stereogenic centers, one containing a fluorine atom, by forming the connecting carbon− carbon bond with a catalyst system comprising an iridium complex that controls the configuration at the electrophilic carbon and a copper catalyst that controls the configuration at the nucleophilic fluorine-containing carbon. These reactions occur with alkyl-and aryl-substituted allylic esters and the unstabilized enolates of azaaryl ketones, esters, and amides in high yield, diastereoselectivity, and enantioselectivity (generally >90% yield, >20:1 dr, 97−99% ee). Access to all four stereoisomers of products demonstrates the precise control of the two configurations independently. This methodology extends to the stereodivergent construction of vicinal quaternary and tertiary stereocenters in similarly high yield and selectivity. DFT calculations uncover the origin of stereoselectivity of copper enolate in allylic substitution.

A methyl group on an arene, despite its small size, can have a profound influence on biologically active molecules. Typical methods to form a methylarene involve strong nucleophiles or strong and often toxic electrophiles. We report a strategy for a new, highly efficient, copper and iodide co-catalyzed methylation of aryl- and heteroarylboronic esters with the mild, nontoxic reagent trimethylphosphate, which has not been used previously in coupling reactions. We show that it reacts in all cases tested in yields that are higher than those of analogous copper-catalyzed reactions of MeOTs or MeI. The combination of C−H borylation and this methylation with trimethylphosphate provides a new approach to the functionalization of inert C−H bonds and is illustrated by late-stage methylation of four medicinally active compounds. In addition, reaction on a 200 mmol scale demonstrates reliability of this method. Mechanistic studies show that the reaction occurs by a slow release of methyl iodide by reaction of PO(OMe)3 with iodide catalyst, rather than the typical direct oxidative addition to a metal center. The low concentration of the reactive electrophile enables selective reaction with an arylcopper intermediate, rather than nucleophilic groups on the arylboronate, and binding of tert-butoxide to the boronate inhibits reaction of the electrophile with the tert-butoxide activator to form methyl ether.

The Cu-catalyzed asymmetric conjugate hydroboration reaction of β-substituted α-dehydroamino acid derivatives has been established, affording enantioenriched syn- and anti-β-boronate-α-amino acid derivatives with excellent combined yields (83-99%, dr ≈ 1:1) and excellent enantioselectivities (92-98% ee). The hydroboration products were expediently converted into valuable β-hydroxy-α-amino acid derivatives, which were widely used in the preparation of chiral drugs and bioactive molecules.

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Chiral cis-hydrobenzofurans represent a unique motif existing in numerous natural products, for instance, isoambrox, [1] haterumaimide I, [2] rosenonolactone, [3] incarviditone, [4] and millingtonine A [5] (Scheme 1 a). Owing to their diverse biological activities, [1][2][3][4][5] a great deal of attention has been paid to the development of efficient methods toward their enantioselective syntheses. One of the most straightforward and powerful ways to construct such a framework is the catalytic asymmetric desymmetrization of cyclohexadienones (Scheme 1 b). In recent elegant reports, Rovis and co-workers demonstrated the feasibility of using chiral-NHC-catalyzed intramolecular Stetter reactions for the asymmetric desymmetrization of cyclohexadienones to prepare chiral cis-hydrobenzofuranones. [6] Very recently, Sasai and co-workers described the use of bifunctional chiral phosphinothiourea catalysts in a intramolecular Rauhut-Currier reaction for the enantioselective discrimination of cyclohexadienones. [7] Although these protocols [6][7][8] proved to be highly effective, their efforts were mainly focused on the application of chiral organocatalysts in intramolecular reactions with a limited substrate scope. Moreover, transition metal catalyzed asymmetric desymmetrization of cyclohexadienones is quite scarce. [9] During our continuous efforts in exploring rhodium/chiral diene-catalyzed asymmetric arylation, [10] we envisioned that a rhodium-catalyzed tandem arylrhodation/conjugate addition reaction of cyclohexadienone-containing [13,14] 1,6-dienynes, [11,12] which are accessible from dearomatization of corresponding phenols, [15] would provide a novel approach to these enantioenriched cis-hydrobenzofurans (Scheme 1 c). However, two major concerns need to be addressed in this rhodium-catalyzed asymmetric desymmetrization process.One is the competitive reaction between the arylrhodation of the carbon-carbon triple bond and two conjugate addition reactions of the cyclohexadienone with the arylboronic acid. The other is whether the chiral ligand coordinating to rhodium could efficiently discriminate between the mesocyclohexadienones in the cyclization step.With this in mind, several varieties of chiral ligands (Scheme 2) were evaluated for this rhodium-catalyzed asymmetric tandem arylrhodation/conjugate addition of (4-Scheme 1. Catalytic asymmetric desymmetrization of cyclohexadienones for preparing chiral cis-hydrobenzofurans. a) cis-Hydrobenzofurans as structural motifs in natural products. b) Organocatalytic asymmetric desymmetrization of cyclohexadienones. c) Our approach to enantioenriched cis-hydrobenzofurans.