Fe/Thiol Cooperative Hydrogen Atom Transfer Olefin Hydrogenation: Mechanistic Insights That Inform Enantioselective Catalysis.

Asymmetric hydrogenation of activated olefins using transition metal catalysis is a powerful tool for the synthesis of complex molecules, but traditional metal catalysts have difficulty with enantioselective reduction of electron-neutral, electron-rich, and minimally functionalized olefins. Hydrogenation based on radical, metal-catalyzed hydrogen atom transfer (mHAT) mechanisms offers an outstanding opportunity to overcome these difficulties, enabling the mild reduction of these challenging olefins with selectivity that is complementary to traditional hydrogenations with H2. Further, mHAT presents an opportunity for asymmetric induction through cooperative hydrogen atom transfer (cHAT) using chiral thiols. Here, we report insights from a mechanistic study of an iron-catalyzed achiral cHAT reaction and leverage these insights to deliver stereocontrol from chiral thiols. Kinetic analysis and variation of silane structure point to the transfer of hydride from silane to iron as the likely rate-limiting step. The data indicate that the selectivity-determining step is quenching of the alkyl radical by thiol, which becomes a more potent H atom donor when coordinated to iron(II). The resulting iron(III)-thiolate complex is in equilibrium with other iron species, including FeII(acac)2, which is shown to be the predominant off-cycle species. The enantiodetermining nature of the thiol trapping step enables enantioselective net hydrogenation of olefins through cHAT using a commercially available glucose-derived thiol catalyst with up to 80:20 enantiomeric ratio. To the best of our knowledge, this is the first demonstration of asymmetric hydrogenation via iron-catalyzed mHAT. These findings advance our understanding of cooperative radical catalysis and act as a proof of principle for the development of enantioselective iron-catalyzed mHAT reactions.

Chemoselective Decarboxylative Protonation Enabled by Cooperative Earth-Abundant Element Catalysis.

Decarboxylative protonation is a general deletion tactic to replace polar carboxylic acid groups with hydrogen or its isotope. Current methods rely on the pre-activation of acids, non-sustainable hydrogen sources, and/or expensive/highly oxidizing photocatalysts, presenting challenges to their wide adoption. Here we show that a cooperative iron/thiol catalyst system can readily achieve this transformation, hydrodecarboxylating a wide range of activated and unactivated carboxylic acids and overcoming scope limitations in previous direct methods. The reaction is readily scaled in batch configuration and can be directly performed in deuterated solvent to afford high yields of d-incorporated products with excellent isotope incorporation efficiency; characteristics not attainable in previous photocatalyzed approaches. Preliminary mechanistic studies indicate a radical mechanism and kinetic results of unactivated acids (KIE=1) are consistent with a light-limited reaction.

Diverse Synthesis of Natural Trehalosamines and Synthetic 1,1'-Disaccharide Aminoglycosides.

A general strategy for the diverse synthesis of ten disaccharide aminoglycosides, including natural 2-trehalosamine (1), 3-trehalosamine (2), 4-trehalosamine (3), and neotrehalosyl 3,3'-diamine (8) and synthetic aminoglycosides 4-7, 9, and 10, has been developed. The aminoglycoside compounds feature different anomeric configurations and numbers of amino groups. The key step for the synthesis was the glycosylation coupling of a stereodirecting donor with a configuration-stable TMS glycoside acceptor. Either the donor or acceptor could be substituted with an azido group. The aminoglycosides prepared in the present study were characterized by 1D and 2D NMR spectroscopy.

Unusually Stable Picoloyl-Protected Trimethylsilyl Glycosides for Nonsymmetrical 1,1'-Glycosylation and Synthesis of 1,1'-Disaccharides with Diverse Configurations.

Nonsymmetrical 1,1'-disaccharides and related derivatives constitute structural components in various glycolipids and natural products. Some of these compounds have been shown to exhibit appealing biological properties. We report a direct yet stereoselective 1,1'-glycosylation strategy for the synthesis of nonsymmetrical 1,1'-disaccharides with diverse configurations and sugar components. The strategy is based on the joined forces of a new class of configurationally stable glycoside acceptors and stereodirecting thioglycoside donors. The new glycoside acceptors feature a picoloyl (Pico) protecting group at the remote C4/C3 position that confers unusual stability on TMS glycosides under acidic conditions.

Vitamin B12 and hydrogen atom transfer cooperative catalysis as a hydride nucleophile mimic in epoxide ring opening.

Epoxide ring-opening reactions have long been utilized to furnish alcohol products that are valuable in many subfields of chemistry. While many epoxide-opening reactions are known, the hydrogenative opening of epoxides via ionic means remains challenging because of harsh conditions and reactive hydride nucleophiles. Recent progress has shown that radical chemistry can achieve hydrogenative epoxide ring opening under relatively mild conditions; however, these methods invariably require oxophilic metal catalysts and sensitive reagents. In response to these challenges, we report a new approach to epoxide ring-opening hydrogenation using bio-inspired Earth-abundant vitamin B12 and thiol-centric hydrogen atom transfer (HAT) co-catalysis to produce Markovnikov alcohols under visible light irradiation. This powerful reaction system exhibits a broad substrate scope, including a number of electrophilic and reductively labile functionalities that would otherwise be susceptible to reduction or cleavage by hydride nucleophiles, and preliminary mechanistic experiments are consistent with a radical process.

Photocatalytic hydrofluoroalkylation of alkenes with carboxylic acids.

Incorporation of fluoroalkyl motifs in pharmaceuticals can enhance the therapeutic profiles of the parent molecules. The hydrofluoroalkylation of alkenes has emerged as a promising route to diverse fluoroalkylated compounds; however, current methods require superstoichiometric oxidants, expensive/oxidative fluoroalkylating reagents and precious metals, and often exhibit limited scope, making a universal protocol that addresses these limitations highly desirable. Here we report the hydrofluoroalkylation of alkenes with cheap, abundant and available fluoroalkyl carboxylic acids as the sole reagents. Hydrotrifluoro-, difluoro-, monofluoro- and perfluoroalkylation are all demonstrated, with broad scope, mild conditions (redox neutral) and potential for late-stage modification of bioactive molecules. Critical to success is overcoming the exceedingly high redox potential of feedstock fluoroalkyl carboxylic acids such as trifluoroacetic acid by leveraging cooperative earth-abundant, inexpensive iron and redox-active thiol catalysis, enabling these reagents to be directly used as hydroperfluoroalkylation donors without pre-activation. Preliminary mechanistic studies support the radical nature of this cooperative process.

Decatungstate-photocatalysed C(sp3)-H azidation.

C-H Azidation is an increasingly important tool for bioconjugation, materials chemistry, and the synthesis of nitrogen-containing natural products. While several approaches have been developed, these often require exotic and energetic reagents, expensive photocatalysts, or both. Here we report a simple and general C-H azidation reaction using earth-abundant tetra-n-butylammonium decatungstate as a photocatalyst and commercial p-acetamidobenzenesulfonyl azide (p-ABSA) as the azide source. This system can azidate a variety of unactivated C(sp3)-H bonds in moderate to good yields and excellent turnover numbers. Preliminary mechanistic experiments implicate a radical mechanism proceeding VIA photo-hydrogen atom transfer (photo-HAT).

Rapid and scalable synthesis of fluoroketones via cerium-mediated C-C bond cleavage.

Ketones with remote fluorination are an important motif in the synthesis of bioactive molecules. Here we demonstrate that ceric ammonium nitrate (CAN) is able to produce this functionality under incredibly mild conditions and short reaction times (30 min) while eliminating the need for precious metals in previous methods. Importantly, this method allows the efficient synthesis of a wide variety of γ-fluoroketones and is highly scalable. Preliminary mechanistic studies suggest this reaction proceeds through a radical pathway.

Associations Between Using Chinese Herbal Medicine and Long-Term Outcome Among Pre-dialysis Diabetic Nephropathy Patients: A Retrospective Population-Based Cohort Study.

Background: Chronic kidney disease (CKD) has become a worldwide burden due to the high co-morbidity and mortality. Diabetic nephropathy (DN) is one of the leading causes of CKD, and pre-dialysis is one of the most critical stages before the end-stage renal disease (ESRD). Although Chinese herbal medicine (CHM) use is not uncommon, the feasibility of using CHM among pre-dialysis DN patients remains unclear. Materials and methods: We analyzed a population-based cohort, retrieved from Taiwan's National Health Insurance Research Database, to study the long-term outcome of using CHM among incident pre-dialysis DN patients from January 1, 2004, to December 31, 2007. All patients were followed up to 5 years or the occurrence of mortality. The risks of all-cause mortality and ESRD were carried out using Kaplan-Meier and competing risk estimation, respectively. Further, we demonstrated the CHM prescriptions and core CHMs using the Chinese herbal medicine network (CMN) analysis. Results: A total of 6,648 incident pre-dialysis DN patients were analyzed, including 877 CHM users and 5,771 CHM nonusers. With overlap weighing for balancing all accessible covariates between CHM users and nonusers, we found the use of CHM was associated with lower all-cause mortality (0.22 versus 0.56; log-rank test: p-value <0.001), and the risk of mortality was 0.42 (95% CI: 0.36-0.49; p-value <0.001) by adjusting all accessible covariates. Further, the use of CHM was associated with a lower risk of ESRD (cause-specific hazard ratio: 0.59, 95%CI: 0.55-0.63; p-value <0.001). Also, from the 5,901 CHM prescriptions, we found Ji-Sheng-Shen-Qi-Wan, Astragalus mongholicus Bunge or (Astragalus membranaceus (Fisch.) Bge.), Plantago asiatica L. (or Plantago depressa Willd.), Salvia miltiorrhiza Bunge, and Rheum palmatum L. (or Rheum tanguticum (Maxim. ex Regel) Balf., Rheum officinale Baill.) were used as core CHMs for different CHM indications. Use of core CHMs was associated with a lower risk of mortality than CHM users without using core CHMs. Conclusions: The use of CHM seemed feasible among pre-dialysis DN patients; however, the beneficial effects still need to be validated by well-designed clinical trials.

Identifying the Chinese Herbal Medicine Network and Core Formula for Allergic Rhinitis on a Real-World Database.

MATERIALS AND METHODS: Patients with a primary diagnosis of AR (ICD-9-CM code: 477.9) in 2010 were included, and the National Health Insurance Research Database in Taiwan was used as the data source. Association rule mining and social network analysis were used to establish and explore the CHM network. Possible molecular pathways of the CHM network were summarized and compared with commonly used western medicine (WM) by conducting overrepresentation analysis in the Reactome pathway database. The potential proteins acted by CHMs were obtained from the CHM ingredient-protein databases, including STITCH, TCMSP, TCMID, and TCM@Taiwan. RESULTS: There were 89,148 AR subjects found in 2010, and a total of 33,507 patients ever used CHM. On an average, 5.6 types of CHMs were utilized per prescription. Xin-Yi-Qing-Fei-Tang was used most frequently (25.5% of 222,279 prescriptions), while Xiao-Qing-Long-Tang with Xin-Yi-San was the most commonly prescribed CHM-CHM combination. Up to six distinctive clusters could be found among the CHM network, and core CHMs could be found for AR, such as Xiao-Qing-Long-Tang and Xin-Yi-Qing-Fei-Tang. A total of 140 molecular pathways were covered by the CHM network (2,432 ingredients from 31 kinds of CHMs), while 39 WMs covered 55 pathways. Among pathways responding to the immune system, WM mainly acted on cytokine signaling-related pathways, while CHM mostly acted on neutrophil/macrophage-related innate pathways and dendritic cell-related adaptive immunity pathways. CONCLUSION: Our study demonstrated and analyzed the CHM network for AR. Core CHM for AR and possible molecular pathways were presented as well, and this information is crucial for researchers to select candidates for CHM-related studies.