Ecofriendly Protocol for ipso-Bromination of Arylboronic Acids.

We report a novel and environmentally friendly method for the ipso-bromination of arylboronic acids by exploiting the oxone/KBr system. We discovered that CuBr can catalyze the reaction and increase the yield from 63 to 97%. We believe that CuBr might catalyze the in situ generation of HOBr from oxone/KBr. The mild reaction condition permits tolerance of a diverse array of functional groups with exclusive regio- and chemoselectivity and allows low-cost large-scale reaction without explosion risk.

Aza-Achmatowicz rearrangement coupled with intermolecular aza-Friedel-Crafts enables total syntheses of uleine and aspidosperma alkaloids.

Aspidosperma and uleine alkaloids belong to the large family of monoterpene indole alkaloids with diverse biological activities and thus have attracted extensive synthetic interest. Reported is the development of a new synthetic strategy that allows direct C3-C2' linkage of indoles with functionalized 2-hydroxypiperidines to construct the core common to all aspidoserma and uleine alkaloids. Such indole-piperidine linkage is enabled by coupling aza-Achmatowicz rearrangement (AAR) with indoles via an intermolecular aza-Friedel-Crafts (iAFC) reaction. This AAR-iAFC reaction proceeds under mild acidic conditions with wide tolerance of functional groups (33 examples). The synthetic application of the AAR-iAFC method was demonstrated with collective total syntheses of 3 uleine-type and 6 aspidosperma alkaloids: (+)-3-epi-N-nor-dasycarpidone, (+)-3-epi-dasycarpidone, (+)-3-epi-uleine, 1,2-didehydropseudoaspidospermidine, 1,2-dehydroaspidospermidine, vincadifformine, winchinine B, aspidospermidine, and N-acetylaspidospermidine. We expect that this AAR-iAFC strategy is applicable to other monoterpene indole alkaloids with the C3-C2' linkage of indoles and piperidines.

Bent π-Conjugation within a Macrocycle: Asymmetric Total Syntheses of Spirohexenolides A and B.

Macrocycles with bent π-conjugation motif are extremely rare in nature and synthetically daunting and anticancer haouamines and spirohexenolides were representative of such rare natural products with synthetically challenging bent π-conjugation within a macrocycle. While the total synthesis of haouamines has been elegantly achieved, spirohexenolides remains an unmet synthetic challenge due to the highly strained bent 1,3,5-triene conjugation within C15 macrocycle. Inspired by the chemical synthesis of cycloparaphenylenes (CPPs) and haouamines, herein we devise a synthetic strategy to overcome the highly strained bent 1,3,5-triene conjugation within the macrocycle and achieve the first, asymmetric total synthesis of spirohexenolides A (>20 mg) and B (>50 mg). Our synthesis features strategic design of ring-closing metathesis (RCM) macrocyclization followed by double dehydration to achieve the C15 macrocycle with the deformed nonplanar 1,3,5-triene conjugation. In addition, we have developed a new enantioselective construction of highly functionalized spirotetronate fragment (northeast moiety) through RCM and Ireland-Claisen rearrangement. Our in vitro bioassay studies reveal that both spirohexenolides are cytotoxic against a panel of human cancer cells with IC50 1.2-13.3 µM and spirohexenolide A is consistently more potent (up to 3 times) than spirohexenolide B, suggesting the importance of alcohol for their bioactivity and for medicinal chemistry development.

Nanobead-based single-molecule pulldown for single cells.

Investigation of cell-to-cell variability holds critical physiological and clinical implications. Thus, numerous new techniques have been developed for studying cell-to-cell variability, and these single-cell techniques can also be used to investigate rare cells. Moreover, for studying protein-protein interactions (PPIs) in single cells, several techniques have been developed based on the principle of the single-molecule pulldown (SiMPull) assay. However, the applicability of these single-cell SiMPull (sc-SiMPull) techniques is limited because of their high technical barrier and special requirements for target cells and molecules. Here, we report a highly innovative nanobead-based approach for sc-SiMPull that is based on our recently developed microbead-based, improved version of SiMPull for cell populations. In our sc-SiMPull method, single cells are captured in microwells and lysed in situ, after which commercially available, pre-surface-functionalized magnetic nanobeads are placed in the microwells to specifically capture proteins of interest together with their binding partners from cell extracts; subsequently, the PPIs are examined under a microscope at the single-molecule level. Relative to previously published methods, nanobead-based sc-SiMPull is considerably faster, easier to use, more reproducible, and more versatile for distinct cell types and protein molecules, and yet provides similar sensitivity and signal-to-background ratio. These crucial features should enable universal application of our method to the study of PPIs in single cells.

Design, synthesis and anti-inflammatory activity study of lansiumamide analogues for treatment of acute lung injury.

Acute lung injury (ALI) is an inflammation-mediated respiratory disease with a high mortality rate. Medications with anti-inflammatory small molecules have been demonstrated in phase I and II clinical trials to considerably reduce the ALI mortality. In this study, two series of lansiumamide analogues were designed, synthesized, and evaluated for anti-inflammatory activity for ALI treatment. We found that compound 8n exhibited the best anti-inflammatory activity through inhibiting LPS-induced expression of the proinflammatory cytokines interleukin-6 (IL-6) and interleukin-1ß (IL-1ß) in Raw264.7 cells and activating the Nrf2/HO-1 pathway. Furthermore, we discovered in a LPS-induced ALI mice model that compound 8n significantly reduced the infiltration of inflammatory cells into lung tissue to achieve the effect of protecting lung tissues and improving ALI. Additionally, our mice model study revealed that compound 8n had a good expectorant effect. These results consistently support that lansiumamide analogue 8n represents a new class of anti-inflammatory agents with potential as a lead compound for further development into a therapeutic drug for ALI treatment.

Field observations of C2 and C3 organosulfates and insights into their formation mechanisms at a suburban site in Hong Kong.

Organosulfates (OSs) are formed from volatile organic compounds (VOCs) and their oxidation products in the presence of sulfate particles. While OSs represent an important component in secondary organic aerosol, the knowledge of their formation driving force, mechanisms, and environmental impact remain inadequately understood. In this study, we report ambient observations of C2-3 oxygenated VOCs derived OSs (C2-3 OSs) at a suburban location of Hong Kong during autumn 2016. The C2-3 OSs, including glycolaldehyde sulfate (GS), hydroxyacetone sulfate (HAS), glycolic acid sulfate (GAS), and lactic acid sulfate (LAS), were quantified/semi-quantified using offline liquid chromatography-mass spectrometry analysis of aerosol filter samples. The average sum concentration of C2-3 OSs was 36 ng/m3. Correlation analysis revealed that sulfate, surface area, and liquid water content were important factors influencing C2-3 OS formation. Online measurement with an iodide High-Resolution Time-of-Flight Chemical-Ionization Mass Spectrometer (HR-ToF-CIMS) coupled with the Filter Inlet for Gases and AEROsols (FIGAERO) was also conducted to monitor C2-3 OSs, and their potential oxygenated VOC precursors in both gas- and particle-phase, and aerosol acidity tracer simultaneously. Our measurements support that glycolaldehyde/glyoxal, hydroxyacetone, glycolic acid/glyoxal, and lactic acid/methylglyoxal are likely precursors for GS, HAS, GAS, and LAS, respectively. Additionally, we found strong correlation between C2-3 OSs and H3S2O8-, a marker for aerosol acidity, providing field observational evidence for acid-catalyzed formation of small OSs. Based on both online and offline measurements, acid-catalyzed formation mechanisms in particle/aqueous phase are proposed. Specifically, the unique structure of adjacent carbonyl and hydroxyl groups in the C2-3 oxygenated VOC precursors can facilitate the formation of (1) a five-member ring intermediate via intramolecular hydrogen bond to react with sulfur trioxide through heterogenous reaction or (2) cyclic sulfate intermediate via particle-phase reaction with sulfuric acid to generate C2-3 OSs. These proposed mechanisms provide an alternative pathway for the liquid-phase production of C2-3 OSs.

BiBr3 -Mediated Intramolecular Aza-Prins Cyclization of Aza-Achmatowicz Rearrangement Products: Asymmetric Total Synthesis of Suaveoline and Sarpagine Alkaloids.

An intramolecular aza-Prins cyclization of aza-Achmatowicz rearrangement products was developed in which bismuth tribromide (BiBr3 ) plays a dual role as an efficient Lewis acid and source of the bromide nucleophile. This approach enables the facile construction of highly functionalized 9-azabicyclo[3.3.1]nonanes (9-ABNs), which are valuable synthetic building blocks and a powerful platform for the synthesis of a variety of alkaloid natural products and drug molecules. Suitable substrates for the aza-Prins cyclization include 1,1-disubstituted alkenes, 1,2-disubstituted alkenes, alkynes, and allenes, with good to excellent yields observed. Finally, we showcase the application of this new approach to the enantioselective total synthesis of six indole alkaloids: (-)-suaveoline (1), (-)-norsuaveoline (2), (-)-macrophylline (3), (+)-normacusine B (4), (+)-Na -methyl-16-epipericyclivine (5) and (+)-affinisine (6) in a total of 9-14 steps. This study significantly expands the synthetic utility of the aza-Achmatowicz rearrangement, and the strategy (aza-Achmatowicz/aza-Prins) is expected to be applicable to the total synthesis of other members of the big family of macroline and sarpagine indole alkaloids.

Marine Alkaloid Lepadins E and H Induce Ferroptosis for Cancer Chemotherapy.

Induction of ferroptosis emerges as an effective method for cancer treatment. With massive efforts to elucidate the ferroptosis mechanism, the development of new ferroptosis inducers proceeds rather slowly, with only a few small molecules identified. Herein, we report our discovery of marine alkaloid lepadins E and H as a new class of ferroptosis inducers. Our in vitro studies show that lepadins E and H exhibit significant cytotoxicity, promote p53 expression, increase ROS production and lipid peroxides, reduce SLC7A11 and GPX4 levels, and upregulate ACSL4 expression, all of which consistently support induction of ferroptosis through the classical p53-SLC7A11-GPX4 pathway. Our animal model study of lepadin H confirms its in vivo antitumor efficacy with negligible toxicity to normal organs. This work elucidates the mode of action of lepadins (E and H) and verifies their in vivo efficacy as a new class of ferroptosis inducers for anticancer therapy with translational potential.

[2+2+1+1] Cycloaddition for de novo Synthesis of Densely Functionalized Phenols.

A unique benzannulation strategy for regioselective de novo synthesis of densely functionalized phenols is described. Through metal-mediated formal [2+2+1+1] cycloaddition of two different alkynes and two molecules of CO, a series of densely functionalized phenols were obtained. The benzannulation strategy allows efficient regioselective installation up to five different substituents on a phenol ring. The resulting phenols have a substitution pattern different from those obtained from Dötz and Danheiser benzannulations.

Green Halogenation of Indoles with Oxone-Halide.

Oxidative functionalization of indoles is one of the most widely used approaches to exploit the synthetic utility of indoles. In continuation of our research interest in the green oxidation of indoles, we further explore the oxidation of indoles with oxone-halide and discover that the protecting group on the nitrogen of indoles plays a decisive role in controlling the pathways of indole oxidation with oxone-halide. An electron-withdrawing group on the nitrogen of indoles (N-EWG) enables C2 halogenation with stoichiometric halide, while C3 halogenation could be selectively achieved by using stoichiometric halide without dependence on the electronic property of the protecting group on the indole nitrogen. Different from our previous results obtained by using catalytic halide, these findings lead to the development of an environmentally friendly, efficient, and mild protocol for access to 2- or 3-haloindoles (chloro and bromo). As compared to the previous synthetic methods for 2-/3-haloindoles, our method exploits the in situ-generated reactive halogenating species from oxone-halide for halogenation of indoles and thus eliminates the use of stoichiometric halogenating agents and the production of toxic and hazardous organic byproducts derived from oxidants.

Two Green Protocols for Halogenative Semipinacol Rearrangement.

Semipinacol rearrangement is a special type of Wagner-Meerwein rearrangement that involves carbocation 1,2-rearrangement to provide carbonyl compounds with an α-quaternary carbon center. It has been strategically used for natural product synthesis and construction of highly congested quaternary carbons. Herein, we report a safe and green protocol that uses oxone/halide and Fenton bromide to achieve halogenative semipinacol rearrangement. The key feature of this method is the green in situ generation of reactive halogenating species from oxidation of halide with oxone or H2O2, which produces a nontoxic byproduct (potassium sulfate or water). Easy operation (insensitive to air and moisture) at room temperature without using special equipment adds additional advantage over previous methods.

Ten-step asymmetric total syntheses of potent antibiotics anthracimycin and anthracimycin B.

The increase in antibiotic resistance calls for the development of novel antibiotics with new molecular structures and new modes of action. However, in the past few decades only a few novel antibiotics have been discovered and progressed into clinically used drugs. The discovery of a potent anthracimycin antibiotic represents a major advance in the field of antibiotics. Anthracimycin is a structurally novel macrolide natural product with an excellent biological activity profile: (i) potent in vitro antibacterial activity (MIC 0.03-1.0 µg mL-1) against many methicillin-resistant Staphylococcus aureus (MRSA) strains, Bacillus anthracis (anthrax), and Mycobacterium tuberculosis; (ii) low toxicity to human cells (IC50 > 30 µM); (iii) a novel mechanism of action (inhibiting DNA/RNA synthesis). While the first total synthesis of anthracimycin was elegantly accomplished by Brimble et al. with 20 steps, we report a 10-step asymmetric total synthesis of anthracimycin and anthracimycin B (first total synthesis). Our convergent strategy features (i) one-pot sequential Mukaiyama vinylogous aldol/intramolecular Diels-Alder reaction to construct trans-decalin with high yield and excellent endo/exo selectivity and (ii) Z-selective ring-closing metathesis to forge the 14-membered ring. In vitro antibacterial evaluation suggested that our synthetic samples exhibited similar antibacterial potency to the naturally occurring anthracimycins against Gram-positive strains. Our short and reliable synthetic route provides a supply of anthracimycins for further in-depth studies and allows medicinal chemists to prepare a library of analogues for establishing structure-activity relationships.

Electrochemical oxidative rearrangement of tetrahydro-ß-carbolines in a zero-gap flow cell.

Oxidative rearrangement of tetrahydro-ß-carbolines (THßCs) is one of the most efficient methods for the synthesis of biologically active spirooxindoles, including natural products and drug molecules. Here, we report the first electrochemical approach to achieve this important organic transformation in a flow cell. The key to the high efficiency was the use of a multifunctional LiBr electrolyte, where the bromide (Br-) ion acts as a mediator and catalyst and lithium ion (Li+) acts as a likely hydrophilic spectator, which might considerably reduce diffusion of THßCs into the double layer and thus prevent possible nonselective electrode oxidation of indoles. Additionally, we build a zero-gap flow cell to speed up mass transport and minimize concentration polarization, simultaneously achieving a high faradaic efficiency (FE) of 96% and an outstanding productivity of 0.144 mmol (h-1 cm-2). This electrochemical method is demonstrated with twenty substrates, offering a general, green path towards bioactive spirooxindoles without using hazardous oxidants.

Achmatowicz Rearrangement-Inspired Development of Green Chemistry, Organic Methodology, and Total Synthesis of Natural Products.

The six-membered heterocycles containing oxygen and nitrogen (tetrahydropyrans, pyrans, piperidines) are among the most common heterocyclic structures ubiquitously present in bioactive molecules such as carbohydrates, small-molecule drugs, and natural products. Chemical synthesis of fully functionalized pyrans and piperidines is a research theme of practical importance and scientific significance and, thus, has attracted continuous interest from synthetic chemists. Among the numerous synthetic approaches, Achmatowicz rearrangement (AchR) represents a general and unique strategy that uses biomass-derived furfuryl alcohols as the renewable starting material to obtain fully functionalized six-membered oxygen/nitrogen heterocycles, which provides golden opportunities for organic chemists to address various synthetic challenges.This Account summarizes our 10 years of work on exploiting AchR to address some challenges in organic synthesis ranging from green chemistry and organic methodology to the total synthesis of natural products. We enabled the sustainable and safe use of AchR in a small (academia) or large (industrial) scale by developing two generations of green approaches for AchR (oxone-halide and Fenton-halide), which largely eliminate the use of the most popular, but more toxic and expansive, NBS and m-CPBA. This triggered our intensive interest in developing new green chemistry for important organic reactions, in particular, halogenation/oxidation reactions involving reactive halogenating species with the aim of eliminating the use of commonly used toxic halogen agents such as elemental bromine, chlorine gas, and various N-haloamide reagents (NBS, NCS, and NIS). We successfully employed oxone-halide and Fenton-halide as green alternatives to several mechanistically related organic reactions including arene/alkene halogenation, oxidation or oxidative rearrangement of indoles, oxidation of alcohols/thioacetals, and oxidative halogenation of aldoximes for the in situ generation of nitrile oxide. These green reactions are expected to have a solid impact on the future of organic synthesis in academia and industries.We expanded the synthetic utility of AchR by exploring several new transformations of AchR products and developed a cascade reductive ring expansion, reductive deoxygenation/Heck-Matsuda arylation, palladium-catalyzed C-arylation, and regiodivergent [3 + 2] cycloaddition with 1,3-dicarbonyls. These methodologies offer a new avenue to fully functionalized six-membered heterocycles.The synthetic utility of AchR was demonstrated in our total synthesis of 28 natural products with a pyran/piperidine moiety. The AchR-based strategy endows the total synthesis with scalability, sustainability, and flexibility. The green and scalable approaches developed in our lab for AchR allow us to easily obtain decagrams of synthetically valuable pyrans and/or piperidines with low risk and low cost from biomass-derived furfuryl alcohol/aldehyde.

Environmentally Benign and User-Friendly In Situ Generation of Nitrile Imines from Hydrazones for 1,3-Dipolar Cycloaddition.

Nitrile imines are highly reactive and versatile dipoles and conventionally generated in situ from unstable hydrazonyl halides under basic conditions. Herein, we report the first green and user-friendly protocol for in situ generation of nitrile imines from Oxone-KBr oxidation of hydrazones and base-promoted dehydrobromination. The nitrile imines were demonstrated for 1,3-dipolar cycloaddition with various dipolarophiles, including alkene and alkyne groups. With its green nature, ease of operation, and air and moisture tolerance, we expect our method will find wide applications in organic synthesis.

1,5-Allyl Shift by a Sequential Achmatowicz/Oxonia-Cope/Retro-Achmatowicz Rearrangement.

1,3-Allyl and 1,2-allyl shifts through [3,3]- and [2,3]-sigmatropic rearrangements are well-established and widely used in organic synthesis. In contrast, 1,5-allyl shift through related [3,5]-sigmatropic rearrangement is unknown because [3,5]-sigmatropic rearrangement is thermally Woodward-Hoffmann forbidden. Herein, we report an unexpected discovery of a formal 1,5-allyl shift of allyl furfuryl alcohol through a 2-step sequential rearrangement. Mechanistically, this formal 1,5-allyl shift is achieved through a sequential ring expansion/contraction rearrangement: 1) Achmatowicz rearrangement (ring expansion), and 2) cascade oxonia-Cope rearrangement/retro-Achmatowicz rearrangement (ring contraction). This new 1,5-allyl shift method is demonstrated with >20 examples and expected to find applications in organic synthesis and materials chemistry.

Reinvestigating FeBr3-Catalyzed Alcohol Oxidation with H2O2: Is a High-Valent Iron Species (HIS) or a Reactive Brominating Species (RBS) Responsible for Alcohol Oxidation?

In 2003, Martín et al. reported a green alcohol oxidation with FeBr3(cat.)/H2O2 and proposed a high-valent iron species (HIS) responsible for the alcohol oxidation. Reinvestigating this FeBr3(cat.)/H2O2 method led us to propose a different mechanism that involves a reactive brominating species (RBS) for the oxidation of alcohols. The evidence to support this RBS-based mechanism includes (1) our recent findings of in situ-generated RBS from the related FeBr2/H2O2 or CeBr3/H2O2 systems, (2) our results of a series of controlled experiments, and (3) some related RBS-based precedents (NBS, NBA, or Br2) showing similar high oxidation selectivity of secondary over primary alcohols. These studies enable us to discover that a RBS from CeBr3/H2O2 is much more efficient for the oxidation of secondary and benzylic alcohols, which represents a new green protocol for selective oxidation of alcohols to carbonyls.

Asymmetric Total Synthesis of Indole Diterpenes Paspalicine, Paspalinine, and Paspalinine-13-ene.

Paspaline-derived indole diterpenes (IDTs) are structurally complex mycotoxins with unique tremorgenic activity. Reported are asymmetric total syntheses of three paspaline-derived IDTs paspalicine, paspalinine and paspalinine-13-ene. Our synthesis features a green Achmatowicz rearrangement/bicycloketalization for the efficient construction of FG rings (75 % yield) and a cascade ring-closing metathesis of dienyne for highly regioselective formation of CD rings (72 % yield). Other highlights include four palladium-mediated reactions (Stille, aza-Wacker, Suzuki, and Heck) to forge the BE rings and the installation of two continuous all-carbon quaternary stereocenters via reductive ring-opening of cyclopropane and α-methylation of the conjugate ester. Our new synthetic strategy is expected to be applicable to the chemical synthesis of other paspaline-derived IDTs and will facilitate the bioactivity studies of these agriculturally and pharmacologically important IDTs.

Synthetic Studies toward the Berkeleyacetal Core Architecture.

Berkeleyacetals are structurally complex natural products that have shown potent anti-inflammatory activity. The presence of a highly dense oxygen functionality and a polycyclic ring system presents significant synthetic challenges. Herein, we report an efficient strategy for the construction of the tetracyclic core system of berkeleyacetal. Our synthetic strategy features two cycloadditions ([4+2] and [5+2]) to forge the tetracyclic core and Achmatowicz rearrangement for the preparation of the cyclization substrates containing B and E rings.

Catalytic Asymmetric Alkynylation of 3,4-Dihydro-ß-carbolinium Ions Enables Collective Total Syntheses of Indole Alkaloids.

Chiral tetrahydro-ß-carboline (THßC) is not only a prevailing structural feature of many natural alkaloids but also a versatile synthetic precursor for a vast array of monoterpenoid indole alkaloids. Asymmetric synthesis of C1-alkynyl THßCs remains rarely explored and challenging. Herein, we describe the development of two complementary approaches for the catalytic asymmetric alkynylation of 3,4-dihydro-ß-carbolinium ions with up to 96 % yield and 99 % ee. The utility of chiral C1-alkynyl THßCs was demonstrated by the collective total syntheses of seven indole alkaloids: harmicine, eburnamonine, desethyleburnamonine, larutensine, geissoschizol, geissochizine, and akuammicine.