We describe the development and scale-up of a nickel-catalyzed reductive cross-electrophile coupling reaction between a substituted 2-chloropyridine and ethyl 3-chloropropanoate using manganese dust as the terminal reductant. Several additives were screened for the activation of the manganese reductant in situ, and chlorotriethylsilane (TESCl) was found to provide the optimal conversion. A focused beam reflectance measurement (FBRM) probe was utilized to monitor particle attrition as well as manganese activation during the reaction. Modeling was employed to garner an understanding of mixing requirements that would ensure effective suspension of the manganese during scale-up. The process was successfully demonstrated on a 7 kg scale and afforded 2 in 64% yield.

Nucleophilic attack on carbon-based electrophiles is a central reactivity paradigm in chemistry and biology. The steric and electronic properties of the electrophile dictate its reactivity with different nucleophiles of interest, allowing the opportunity to fine-tune electrophiles for use as coupling partners in multistep organic synthesis or for covalent modification of proteins in drug discovery. Reactions that directly transform inexpensive chemical feedstocks into versatile carbon electrophiles would therefore be highly enabling. Herein, we report the catalytic, regioselective oxidative cyanation of conjugated and nonconjugated alkenes using a homogeneous copper catalyst and a bystanding N-F oxidant to furnish branched alkenyl nitriles that are difficult to prepare using existing methods. We show that the alkenyl nitrile products serve as electrophilic reaction partners for both organic synthesis and the chemical proteomic discovery of covalent protein ligands.

A highly efficient method for the enantioselective one-pot synthesis of 1,3-oxazolidines and 1,3-oxazinanes has been reported. The reaction proceeds via the formation of hemiaminal intermediates obtained by the enantioselective addition of respective alcohols to imines catalyzed by a chiral magnesium phosphate catalyst, followed by intramolecular cyclization under mildly basic conditions. A wide range of substrates have been converted to the respective chiral heterocyclic products in high yields and with excellent enantioselectivities using this one-pot procedure.

Axially chiral cyclohexylidene oxime ethers exhibit unique chirality because of the restricted rotation of C=N. The first catalytic enantioselective synthesis of novel axially chiral cyclohexylidene oximes has been developed by catalytic desymmetrization of 4-substituted cyclohexanones with O-arylhydroxylamines and is catalyzed by a chiral BINOL-derived strontium phosphate with excellent yields and good enantioselectivities. In addition, chiral BINOL-derived phosphoric acid catalyzed dynamic kinetic resolution of α-substituted cyclohexanones has been performed and yields versatile intermediates in high yields and enantioselectivities.

A palladium(II)‐catalyzed enantioselective α‐alkylation of azlactones with nonconjugated alkenes is described. The reaction employs a chiral BINOL‐derived phosphoric acid as the source of stereoinduction, and a cleavable bidentate directing group appended to the alkene to control the regioselectivity and stabilize the nucleopalladated alkylpalladium(II) intermediate in the catalytic cycle. A wide range of azlactones were found to be compatible under the optimal reaction conditions to afford products bearing α,α‐disubstituted α‐amino‐acid derivatives with high yields and high enantioselectivity.

A variety of catalytic asymmetric reactions have been realized during the past decade through the combined action of palladium and chiral phosphoric acids (CPAs). This review surveys key examples and examines the underlying mechanisms of stereoinduction.

A palladium(II)‐catalyzed enantioselective α‐alkylation of azlactones with nonconjugated alkenes is described. The reaction employs a chiral BINOL‐derived phosphoric acid as the source of stereoinduction, and a cleavable bidentate directing group appended to the alkene to control the regioselectivity and stabilize the nucleopalladated alkylpalladium(II) intermediate in the catalytic cycle. A wide range of azlactones were found to be compatible under the optimal reaction conditions to afford products bearing α,α‐disubstituted α‐amino‐acid derivatives with high yields and high enantioselectivity.

Axially chiral cyclohexylidene oxime ethers exhibit unique chirality because of the restricted rotation of C=N. The first catalytic enantioselective synthesis of novel axially chiral cyclohexylidene oximes has been developed by catalytic desymmetrization of 4-substituted cyclohexanones with O-arylhydroxylamines and is catalyzedb yachiral BINOLderived strontium phosphate with excellent yields and good enantioselectivities.I na ddition, chiral BINOL-derived phosphoric acid catalyzed dynamic kinetic resolution of a-substituted cyclohexanones has been performed and yields versatile intermediates in high yields and enantioselectivities.The development of novel asymmetric reactions has been one of the prime foci of modern synthetic organic chemistry. Substantial advances have been made in asymmetric synthesis of compounds with central chirality by using transition metals and organocatalytic methods.I na ddition, compounds with axial chirality,p lanar chirality,a nd helical chirality have attracted recent attention because of their importance in synthesis and asymmetric catalysis. [1] Axially chiral compounds,a lso known as atropisomers,e xhibit unique chirality because of the non-coplanar arrangement of groups about an imaginary axis.T his arrangement is attributed to the restricted rotation around either as ingle or double bond. [2] Although the first axially chiral compound was observed in 1910, [3] their importance was not realized until recently as ac onsequence of their occurrence in natural products and their application as chiral ligands. [4] Over the last decade, tremendous progress has been made for the synthesis of axially chiral biaryls,allenes,spiranes,and cyclohexylidenes. [5] However,m ethods for catalytic enantioselective synthesis of cyclohexylidene oximes and its analogues are scarce.Oximes and oxime ethers are versatile intermediates and key structural motifs present in several biologically active compounds which exhibit medicinal properties. [6] Recent progress in CÀHa ctivation proved that oxime ethers are efficient directing groups in several synthetic transformations. [7] Chiral cyclohexylidene oximes contain stereogenic axes which arise from the restricted rotation about the C = N bond and high activation energy barrier for nitrogen inversion. [8] To date,only two reports have described the enantioselective resolution of chiral cyclohexylidene oximes.In1990, Toda first reported the successful isolation of optically active oximes by the conventional second-order asymmetric transformation starting from racemic compounds (Scheme 1a) [9] Later, in 1994, Hoshino et al. demonstrated the kinetic resolution of phenylcyclohexanone oxime esters by lipasecatalyzed transesterification [9b] to give optically active oximes and oxime esters (Scheme 1b). Herein, we report the first enantioselective synthesis of chiral cyclohexylidene oxime ethers by desymmetric condensation of 4-phenylcyclohexanone with aryloxyamine catalyzed by ac hiral BINOL phosphate complex (Scheme 1c). We further applied this methodol...