Origin of Enantio- and Chemoselectivity in the Synthesis of Spirocycles via Palladium/Xu-Phos-Catalyzed Cascade Heck/Remote C(sp2)-H Alkylation: A Computational Mechanistic Study.

Density functional theory (DFT) calculations were performed to study the mechanism and factors affecting the enantio-, regio-, and chemoselectivities in the palladium/Xu-Phos-catalyzed cascade Heck/remote C(sp2)-H alkylation reaction. The active catalyst is found to be able to sustain coordination with P and S atoms and can adapt its coordination mode to accommodate the significant steric hindrance between the ligand and substrate, unlike previous findings that showed coordination with P and O atoms. The reaction is established to occur in sequence through the oxidative addition of the aryl iodide to Pd(0), intramolecular alkene insertion, C(sp2)-H bond activation, and C(sp2)-C(sp3) bond reductive elimination. The C(sp2)-C(sp3) bond reductive elimination is identified as the rate-determining step, and the intramolecular alkene insertion as the enantioselectivity-determining step. The high enantioselectivity originates from the stronger electronic interaction between the catalyst and substrate; the exclusive 5-exo-regioselectivity is due to the stronger nucleophilicity of the terminal alkene carbon atom, and the chemoselectivity of C-H activation over carboiodination is driven by thermodynamics.

Density Functional Theory Study of Gold-Catalyzed 1,2-Diarylation of Alkenes: π-Activation versus Migratory Insertion Mechanisms.

Density functional theory calculations are carried out to better understand the first gold-catalyzed 1,2-diarylation reactions of alkenes reported in the recent literature. The calculations on two representative reactions, aryl alkene/aryl iodide coupling pair (the aryl-I bond is located outside the aryl alkene) versus iodoaryl alkene/indole coupling pair (the aryl-I bond is located in the aryl alkene), confirm that the reaction involves a π-activation mechanism rather than the general migratory insertion mechanism in previously known metal catalysis by Pd, Ni, and Cu complexes. Theoretical results rationalize the regioselectivity of the reactions controlled by the aryl-I bond position (intermolecular or intramolecular) and also the ligand and substituent effects on the reactivity.

Mechanism and Origin of MAD-Induced Ni/N-Heterocyclic Carbene-Catalyzed Regio- and Enantioselective C-H Cyclization of Pyridines with Alkenes.

This work presents a DFT-based computational study on the regio- and enantioselective C-H functionalization of pyridines with alkenes at the relatively unreactive C4-position, which was successfully achieved by Shi et al. [J. Am. Chem. Soc. 2019, 141, 5628-5634] using Ni0 /N-heterocyclic carbene (NHC) catalysis under the assistance of an aluminum-based Lewis acid additive (2,6-tBu2 -4-Me-C6 H2 O)2 AlMe (MAD). The calculations indicate that the selective functionalization involves a three-step mechanism in which a unique H-migration assisted oxidation metalation (HMAOM) step is identified as the rate- and enantioselectivity-determining step. The newly proposed mechanism can well rationalize the experimental observation that the preferred product is the endo-type (vs. exo-type), R-configuration (vs. S-configuration) product at the C4 (vs. C2) position, and also unveil the reasons that the NHC ligand and the MAD additive can facilitate the reaction.

Computational Study on Why and How of Nonconventional meta-C-H Arylation of Electron-Rich Arenes via Pd/Quinoxaline-Based Ligand/Norbornene Cooperative Catalysis.

By performing density functional theory (DFT) calculation, this work aims at understanding the nonconventional meta-C-H arylation reaction of electronic-rich arenes with aryl iodide via a Pd/quinoxaline-based ligand/norbornene cooperative catalysis. The reaction is indicated to be initiated either from the ortho-C-H carbopalladation to give the meta-monoarylation product via a sequence of subsequent steps, including norbornene insertion, meta-C-H activation, oxidative addition, and reductive elimination via the Pd(II)/Pd(IV)/Pd(II) redox cycle, norbornene extrusion, and protodepalladation, or from the para-C-H carbopalladation to form the meta-diarylation product via two sequential arylation processes following similar mechanisms. The initial carbopalladation process promoted by the ligand is characterized as the rate-determining step of the reaction. The calculated mechanism shows the distinct role of the norbornene as a transient mediator that enables the final C-H arylation at the same meta-position wherever the initial carbopalladation occurs at either ortho- or para-position. The Pd/ligand/norbornene cooperative catalysis is essential for achieving the exclusive meta-selectivity of the C-H arylation of electron-rich arenes.

Mechanistic Insight into Palladium-Catalyzed γ-C(sp3)-H Arylation of Alkylamines with 2-Iodobenzoic Acid: Role of the o-Carboxylate Group.

Density functional theory calculations were performed to understand the distinctly different reactivities of o-carboxylate-substituted aryl halides and pristine aryl halides toward the PdII-catalyzed γ-C(sp3)-H arylation of secondary alkylamines. It is found that, when 2-iodobenzoic acid (a representative of o-carboxylate-substituted aryl halides) is used as an aryl transfer agent, the arylation reaction is energetically favorable, while when the pristine aryl halide iodobenzene is used as the aryl transfer reagent, the reaction is kinetically difficult. Our calculations showed an operative PdII/PdIV/PdII redox cycle, which differs in the mechanistic details from the cycle proposed by the experimental authors. The improved mechanism emphasizes that (i) the intrinsic role of the o-carboxylate group is facilitating the C(sp3)-C(sp2) bond reductive elimination from PdIV rather than facilitating the oxidative addition of the aryl iodide on PdII, (ii) the decarboxylation occurs at the PdII species instead of the PdIV species, and (iii) the 1,2-arylpalladium migration proceeds via a stepwise mechanism where the reductive elimination occurs before decarboxylation, not via a concerted mechanism that merges the three processes decarboxylation, 1,2-arylpalladium migration, and C(sp3)-C(sp2) reductive elimination into one. The experimentally observed exclusive site selectivity of the reaction was also rationalized well.

Epigenetic regulation of sox30 is associated with testis development in mice.

DNA methylation is involved in tissue-specific and developmentally regulated gene expression. Here, we screened a novel methylation gene Sox30, whose methylation might contribute to its regulation and testis development in mice. Sox30 is a member of Sox transcription factors, and is considered to be involved in spermatogonial differentiation and spermatogenesis. However, the precise function and regulatory expression pattern remain unclear. In the present study, we found that Sox30 is highly expressed in adult testes but not in ovaries. Sox30 expression begins in early development, and in the testes, it is specifically increased coincidentally with development until adulthood. Moreover, Sox30 is expressed not only in testis germ cells, but also in sertoli cells. Sox30 is hypo-methylated in testis, epididymis and lung of adult mice, in which Sox30 is expressed. By contrast, Sox30 is hypermethylated in ovary, heart, brain, liver, kidney, spleen, pancreas, muscle, intestine, pituitary gland, blood and hippocampus of adult mice, in which the Sox30 is absent. Importantly, decreased methylation at CpG islands of Sox30 is observed in mouse developmental testes after birth, which is associated with enhanced Sox30 expression. However, the hypermethylated status of Sox30 is maintained in ovaries that does not express Sox30 during this period. Further, following demethylation treatment using 5-aza-dC, Sox30 expression is restored in GC2, TM3 and TM4 cell lines. This observation convincingly confirms that methylation really contributes to Sox30 silencing. In summary, we show that Sox30 expression is under the control of DNA methylation status, and this expression pattern is associated with testis development in mice.