Lewis Base-Boryl Radicals Enabled Borylation Reactions and Selective Activation of Carbon-Heteroatom Bonds.

ConspectusThe past decades have witnessed tremendous progress on radical reactions. However, in comparison with carbon, nitrogen, oxygen, and other main group element centered radicals, the synthetic chemistry of boron centered radicals was less studied, mainly due to the high electron-deficiency and instability of such 3-center-5-electron species. In the 1980s, Roberts and co-workers found that the coordination of a Lewis base (amines or phosphines) with the boron center could form 4-center-7-electron boryl radicals (Lewis base-boryl radicals, LBRs) that are found to be more stable. However, only limited synthetic applications were developed. In 2008, Curran and co-workers achieved a breakthrough with the discovery of N-heterocyclic carbene (NHC) boryl radicals, which could enable a range of radical reduction and polymerization reactions. Despite these exciting findings, more powerful and valuable synthetic applications of LBRs would be expected, given that the structures and reactivities of LBRs could be easily modulated, which would provide ample opportunities to discover new reactions. In this Account, a summary of our key contributions in LBR-enabled radical borylation reactions and selective activation of inert carbon-heteroatom bonds will be presented.Organoboron compounds have shown versatile applications in chemical society, and their syntheses rely principally on ionic borylation reactions. The development of mechanistically different radical borylation reactions allows synthesizing products that are inaccessible by traditional methods. For this purpose, we progressively developed a series of NHC-boryl radical mediated chemo-, regio-, and stereoselective radical borylation reactions of alkenes and alkynes, by which a wide variety of structurally diverse organoboron molecules were successfully prepared. The synthetic utility of these borylated products was also demonstrated. Furthermore, we disclosed a photoredox protocol for oxidative generation of NHC-boryl radicals, which enabled useful defluoroborylation and arylboration reactions.Selective bond activation is an ideal way to convert simple starting materials to value-added products, while the cleavage of inert chemical bonds, in particular the chemoselectivity control when multiple identical bonds are present in similar chemical environments, remains a long-standing challenge. We envisaged that finely tuning the properties of LBRs might provide a new solution to address this challenge. Recently, we disclosed a 4-dimethylaminopyridine (DMAP)-boryl radical promoted sequential C-F bond functionalization of trifluoroacetic acid derivatives, in which the α-C-F bonds were selectively snipped via a spin-center shift mechanism. This strategy enables facile conversion of abundantly available trifluoroacetic acid to highly valuable mono- and difluorinated molecules. Encouraged by this finding, we further developed a boryl radical enabled three-step sequence to construct all-carbon quaternary centers from a range of trichloromethyl groups, where the three C-Cl bonds were selectively cleaved by the rational choice of suitable boryl radical precursors in each step. Furthermore, a boryl radical promoted dehydroxylative alkylation of α-hydroxy carboxylic acid derivatives was achieved, allowing for the efficient conversion of some biomass platform molecules to high value products.

[Relationship between Blood Glucose and Lipid Levels and Intestinal Bifidobacteriumin Middle-Aged and Older Adults in Chengdu].

Objective: To explore characteristics of the species structure of the genus Bifidobacterium at different levels of blood glucose and lipid in middle-aged and older adults in Chengdu so as to provide research basis for applying bifidobacteria in the prevention and treatment of hyperglycemia and dyslipidemia. Methods: A total of 289 middle-aged and older adults of 45 and older were recruited in Chengdu between April and August 2018. They were divided into the healthy group, the dyslipidemia group, the hyperglycemia group, and the combination group (of subjects with both dyslipidemia and hyperglycemia). The levels of their fasting blood glucose (GLU), total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) were examined. In addition, stool samples were collected and real-time fluorescence quantitative PCR was used for quantitative analysis of the genus Bifidobacteriumand the 8 bifidobacteria most commonly found in human intestines, the results of which were then examined to identify their correlation to blood glucose and lipid levels. Results: A total of 289 samples were collected and findings of inter-group comparison of the species structure of Bifidobacterium were as follows: 1) findings regarding the Bifidobacterium species examined--there was no significant difference between groups in the detection rate and the number of species detected; the quantity of B. angulatum was significantly higher in the dyslipidemia group than that in the healthy group and that in the combination group, the quantify of B. catenulatum was significantly higher in the hyperglycemia group than that in the healthy group, and the quantity of B. dentium was significantly higher in the dyslipidemia group than that in the combination group. 2) Findings regarding the correlation between the quantity of bifidobacteria and blood glucose and lipid--at the genus level, only the dyslipidemia group showed negative correlation (r=-0.346) between Bifidobacterium and TC. At the species level, B. bifidum was negatively correlated with TG (r=-0.761), B. breve was negatively correlated with GLU, TC, and LDL-C (r=-0.256, r=-0.261, and r=-0.362), B.dentium was positively correlated with GLU (r=0.206), and B. infantis was negatively correlated with TC (r=-0.334) in the healthy group. In the hyperglycemia group, B. catenulatum and B. infantis were both positively correlated with HDL-C (r=0.307 and r=0.525). In the combination group, B. bifidum was negatively correlated with HDL-C (r=-0.828), while B. breve was positively correlated with TG and HDL-C (r=0.427 and r=0.375). Conclusion: Middle-aged and older adults with dyslipidemia and/or hyperglycemia were significantly different from healthy subjects in their testing results for Bifidobacterium. Compared with the structure of Bifidobacterium species, the changes in the number of Bifidobacterium species detected were more closely correlated to the levels of blood glucose and blood lipid, showing unique characteristics in different situations, which may indicate potential application as indicators for glucose and lipid metabolism.

Dehydroxylative Alkylation of α-Hydroxy Carboxylic Acid Derivatives via a Spin-Center Shift.

A strategically distinct dehydroxylative alkylation reaction of α-hydroxy carboxylic acid derivatives with alkenes is developed. The reaction starts with the attack of a 4-dimethylaminopyridine (DMAP)-boryl radical to the carbonyl oxygen atom, followed by a spin-center shift (SCS) to trigger the C-O bond scission. The resulting α-carbonyl radicals couple with a wide range of alkenes to furnish various alkylated products. This strategy allows for the efficient conversion of a wide array of α-hydroxy amides and esters derived from several biomass molecules and natural products to value-added compounds. Experimental and computational studies verified the reaction mechanism.

Boryl Radical-Promoted Dehydroxylative Alkylation of 3-Hydroxyoxindole Derivatives.

A boryl radical-promoted dehydroxylative alkylation of 3-hydroxy-oxindole derivatives is achieved. The reaction starts from addition of 4-dimethylaminopyridine (DMAP)-boryl radical to the amide carbonyl oxygen atom, which induces a spin-center shift process to promote the C-O bond cleavage. The elimination of a hydroxide anion from a free hydroxy group is also accomplished. Capture of the generated carbon radical with alkenes furnishes a variety of C-3 alkylated oxindoles. This method features a simple operation and broad substrate scope.

Sequential C-F bond functionalizations of trifluoroacetamides and acetates via spin-center shifts.

Defluorinative functionalization of readily accessible trifluoromethyl groups constitutes an economical route to partially fluorinated molecules. However, the controllable replacement of one or two fluorine atoms while maintaining high chemoselectivity remains a formidable challenge. Here we describe a general strategy for sequential carbon-fluorine (C-F) bond functionalizations of trifluoroacetamides and trifluoroacetates. The reaction begins with the activation of a carbonyl oxygen atom by a 4-dimethylaminopyridine-boryl radical, followed by a spin-center shift to trigger the C-F bond scission. A chemoselectivity-controllable two-stage process enables sequential generation of difluoro- and monofluoroalkyl radicals, which are selectively functionalized with different radical traps to afford diverse fluorinated products. The reaction mechanism and the origin of chemoselectivity were established by experimental and computational approaches.