Copper catalyzed asymmetric propargylation of aldehydes.

The highly enantio- and regioselective copper catalyzed asymmetric propargylation of aldehydes with a propargyl borolane reagent is reported. The methodology demonstrated broad functional group tolerance and provided high enantioselectivities for aliphatic, vinyl, and aryl aldehydes. The utility of the TMS homopropargylic alcohols was demonstrated by the facile conversion to a chiral dihydropyranone.

CDK12-mediated transcriptional regulation of noncanonical NF-κB components is essential for signaling.

Members of the family of nuclear factor κB (NF-κB) transcription factors are critical for multiple cellular processes, including regulating innate and adaptive immune responses, cell proliferation, and cell survival. Canonical NF-κB complexes are retained in the cytoplasm by the inhibitory protein IκBα, whereas noncanonical NF-κB complexes are retained by p100. Although activation of canonical NF-κB signaling through the IκBα kinase complex is well studied, few regulators of the NF-κB-inducing kinase (NIK)-dependent processing of noncanonical p100 to p52 and the subsequent nuclear translocation of p52 have been identified. We discovered a role for cyclin-dependent kinase 12 (CDK12) in transcriptionally regulating the noncanonical NF-κB pathway. High-content phenotypic screening identified the compound 919278 as a specific inhibitor of the lymphotoxin ß receptor (LTßR), and tumor necrosis factor (TNF) receptor superfamily member 12A (FN14)-dependent nuclear translocation of p52, but not of the TNF-α receptor-mediated nuclear translocation of p65. Chemoproteomics identified CDK12 as the target of 919278. CDK12 inhibition by 919278, the CDK inhibitor THZ1, or siRNA-mediated knockdown resulted in similar global transcriptional changes and prevented the LTßR- and FN14-dependent expression of MAP3K14 (which encodes NIK) as well as NIK accumulation by reducing phosphorylation of the carboxyl-terminal domain of RNA polymerase II. By coupling a phenotypic screen with chemoproteomics, we identified a pathway for the activation of the noncanonical NF-κB pathway that could serve as a therapeutic target in autoimmunity and cancer.

Direct, enantioselective α-alkylation of aldehydes using simple olefins.

Although the α-alkylation of ketones has already been established, the analogous reaction using aldehyde substrates has proven surprisingly elusive. Despite the structural similarities between the two classes of compounds, the sensitivity and unique reactivity of the aldehyde functionality has typically required activated substrates or specialized additives. Here, we show that the synergistic merger of three catalytic processes-photoredox, enamine and hydrogen-atom transfer (HAT) catalysis-enables an enantioselective α-aldehyde alkylation reaction that employs simple olefins as coupling partners. Chiral imidazolidinones or prolinols, in combination with a thiophenol, iridium photoredox catalyst and visible light, have been successfully used in a triple catalytic process that is temporally sequenced to deliver a new hydrogen and electron-borrowing mechanism. This multicatalytic process enables both intra- and intermolecular aldehyde α-methylene coupling with olefins to construct both cyclic and acyclic products, respectively. With respect to atom and step-economy ideals, this stereoselective process allows the production of high-value molecules from feedstock chemicals in one step while consuming only photons.

Efficient chiral monophosphorus ligands for asymmetric Suzuki-Miyaura coupling reactions.

A series of novel P-chiral monophosphorus ligands exhibit efficiency in asymmetric Suzuki-Miyaura coupling reactions, enabling the construction of an array of chiral biaryl products in high yields and excellent enantioselectivities (up to 96% ee) under mild conditions. The carbonyl-benzooxazolidinone moiety in these chiral biaryl products allows facile derivatization for further synthetic applications. A computational study has revealed that a π-π interaction between the two coupling partners can enhance the enantioselectivity of the coupling reaction.

Diastereoselective intramolecular Friedel-Crafts alkylation of tetralins.

An efficient and versatile synthesis of cis-hexahydrobenzophenanthridines starting from readily available tetralins has been developed using an intramolecular Friedel-Crafts alkylation as a key step. The substrates were prepared via a highly stereocontrolled rhodium-catalyzed ring-opening reaction of meso-oxabicyclic alkenes and a hydrogenation sequence. Thus, a wide variety of complex tetracyclic compounds have been isolated with a high level of regio-, diastereo-, and enantioselectivity.

Novel, tunable, and efficient chiral bisdihydrobenzooxaphosphole ligands for asymmetric hydrogenation.

A series of novel, efficient, air-stable, and tunable chiral bisdihydrobenzooxaphosphole ligands (BIBOPs) were developed for rhodium-catalyzed hydrogenations of various functionalized olefins such as alpha-arylenamides, alpha-(acylamino)acrylic acid derivatives, beta-(acylamino)acrylates, and dimethyl itaconate with excellent enantioselectivities (up to 99% ee) and reactivities (up to 2000 TON).

Novel and efficient chiral bisphosphorus ligands for rhodium-catalyzed asymmetric hydrogenation.

A series of structurally novel, operationally convenient, and efficient chiral 2-phosphino-2,3-dihydrobenzo[d][1,3]oxaphosphole ligands was developed. Applications of ligands 3a and 3b in rhodium-catalyzed asymmetric hydrogenation of alpha-(acylamino)acrylates and beta-(acylamino)acrylates provided excellent enantioselectivities (up to >99% ee) and reactivities (up to 10,000 TON).