Concise Strategy Research Articles

Concise Synthesis of the Antiplasmodial Isocyanoterpene 7,20‐Diisocyanoadociane

AbstractThe flagship member of the antiplasmodial isocyanoterpenes, 7,20‐diisocyanoadociane (DICA), was synthesized from dehydrocryptone in 10 steps, and in 13 steps from commercially available material. Our previous formal synthesis was reengineered, leveraging only productive transformations to deliver DICA in fewer than half the number of steps of our original effort. Important contributions, in addition to the particularly concise strategy, include a solution to the problem of axial nucleophilic methylation of a late‐stage cyclohexanone, and the first selective synthesis and antiplasmodial evaluation of the DICA stereoisomer with both isonitriles equatorial.

Solventless ketalization of glycerol to solketal with acetone over the ionic liquid [P(C4H9)3C14H29][TsO

Abstract The ketalization of glycerol with acetone was conducted over an ionic liquid [P(C4H9)3C14H29][TsO] (TTPT) in a batch reactor. A scheme to obtain the purified product using TTPT as a homogeneous catalyst is proposed and a maximum solketal yield of 86% is achieved at acetone/glycerol molar ratio of 6/1, reaction time of 0.5 h, reaction temperature of 303 K, catalyst amount of 5 wt% of glycerol. TTPT was recycled and reused for ten times without obvious losses in terms of quantity and activity. Furthermore, effects of various experimental parameters (stirring speed, catalyst loadings, temperature and reactant composition) on the reaction kinetics are investigated. In terms of kinetics modeling, Kγ is fitted by reactant composition at the temperature range 298 K–323 K, which was a concise strategy that showed good precision in the kinetics fitting. The activation energy for this ketalization reaction was evaluated to be 28.2 kJ·mol−1. In addition, the kinetics of the reaction at a temperature exceeding the boiling point of acetone were also studied. We believe that all the results are important for further development of a technology for the continuous synthesis of solketal.

Total Synthesis of Caesalpinnone A and Caesalpinflavan B: Evolution of a Concise Strategy.

The total syntheses of caesalpinnone A (1) and its putative biosynthetic precursor caesalpinflavan B (3) are described. Herein, we describe the evolution of a synthetic strategy toward 1 and 3, which entails a convergent Barluenga coupling that quickly delivers a heavily functionalized benzopyran containing the core carbon framework and exploration of two distinct synthetic routes for forging the flavanoid C-ring by reducing a sterically encumbered embedded alkene: one via a stepwise approach and a second, more direct and atom-economical, enabled by a Shenvi-HAT hydrogenation. The latter strategy allowed access to caesalpinflavan B in 6 steps after Pd-mediated deallylation. A late-stage dearomative phenolic oxidation and deallylation/oxa-Michael cascade was implemented to access caesalpinnone A (1) in 7 steps. We also describe an enantioselective total synthesis and stereochemical revision of (-)-caesalpinflavan B, as well as a formal enantioselective synthesis of (-)-caesalpinnone A, by implementing an enantioselective Pd-catalyzed conjugate addition developed by Stoltz.

Modular Syntheses of Phenanthroindolizidine Natural Products.

A highly concise strategy for the total synthesis of phenanthroindolizidines was developed. The one-pot iterative Suzuki-Miyaura reaction of aryl boronic acids with ortho-bromoaryl N-methyliminodiacetate (MIDA) boronate followed by a second Suzuki-Miyaura reaction with a suitable pyridyl bromide provided ortho-aza-terphenyls. Subsequent saturation of the triple bond, treatment with mesyl chloride, and reduction of the resulting dihydroindolizidinium ring afforded the hexahydroindolizines. A final vanadium-catalyzed oxidative electrocyclization provided the desired alkaloids in only three column-separation operations.

A Concise Total Synthesis of (-)-Himalensine A.

The daphniphyllum alkaloids are a structurally fascinating and remarkably diverse family of natural products. General strategies for the chemical synthesis of their challenging architectures are highly desirable for efficiently accessing these intriguing alkaloids and addressing their pharmaceutical potential. Herein, a concise strategy designed to provide general and diversifiable access to various daphniphyllum alkaloids is described and utilized in the asymmetric synthesis of (-)-himalensine A, which was accomplished in 14 steps. Key features of this strategy include a Cu-catalyzed nitrile hydration, a Heck reaction to construct the challenging 2-azabicyclo[3.3.1]nonane motif, a Meinwald rearrangement reaction, six, pot-economic reactions, and the minimal use of protecting groups, which significantly improved the overall synthetic efficiency.

A Concise Total Synthesis of (−)‐Himalensine A

AbstractThe daphniphyllum alkaloids are a structurally fascinating and remarkably diverse family of natural products. General strategies for the chemical synthesis of their challenging architectures are highly desirable for efficiently accessing these intriguing alkaloids and addressing their pharmaceutical potential. Herein, a concise strategy designed to provide general and diversifiable access to various daphniphyllum alkaloids is described and utilized in the asymmetric synthesis of (−)‐himalensine A, which was accomplished in 14 steps. Key features of this strategy include a Cu‐catalyzed nitrile hydration, a Heck reaction to construct the challenging 2‐azabicyclo[3.3.1]nonane motif, a Meinwald rearrangement reaction, six, pot‐economic reactions, and the minimal use of protecting groups, which significantly improved the overall synthetic efficiency.

Quick Access to Pyridines through 6π-3-Azatriene Electrocyclization: Concise Total Synthesis of Suaveoline Alkaloids

Pyridine is a prevalent structural heterocyclic motifs in natural products, pharmaceuticals, and advanced materials. Several different methodologies have been developed for the synthesis of these kinds of molecules. However, a sustainable and efficient procedure for the synthesis of pyridines is still highly desirable. In this Synpacts article, we highlight our recent approach to the construction of highly substituted pyridines though a tandem condensation/alkyne isomerization/6π-3-azatriene electrocyclization sequence. The present protocol was used to synthesize a series of polysubstituted pyridines (30 examples) in moderate to good yields. The process also permitted the development of a concise strategy for collective total syntheses of suaveoline, norsuaveoline, and macrophylline.

A Practical General Method for the Preparation of Long Acenes.

The field of long acenes, the narrowest of the zig-zag graphene nanoribbons, has been an area of significant interest in the past decade because of its potential applications in organic electronics, spintronics and plasmonics. However the low solubility and high reactivity of these compounds has so far hindered their preparation on large scales. We report here a concise strategy for the synthesis of higher acenes through Diels-Alder condensation of arynes with a protected tetraene ketone. After deprotection by cleavage of the ketal, the obtained monoketone precursors cleanly yield the corresponding acenes through quantitative cheletropic thermal decarbonylation in the solid state, at moderate temperatures of 155 to 205 °C. This approach allows the preparation of heptacene, benzo[a]hexacene, cis- and trans-dibenzopentacene and offers a valuable new method for the synthesis of even larger acenes.

Iron-Catalyzed Synthesis of (E)-β-Vinylsilanes via a Regio- and Stereoselective Hydrosilylation from Terminal Alkynes

A concise strategy for the synthesis of vinylsilanes from an iron-catalyzed regio- and stereoselective hydrosilylation of terminal alkynes has been developed. The catalyst and reagents are commercially available and easy to handle, providing a simple and practical method for iron-catalyzed anti-Markovnikov hydrosilylation with a good functional group tolerance.

Directed C-H Bond Functionalization: A Unified Approach to Formal Syntheses of Amorfrutin A, Cajaninstilbene Acid, Hydrangenol, and Macrophyllol.

Formal syntheses of natural products amorfrutin A, cajaninstilbene acid, hydrangenol, and macrophyllol have been accomplished on the basis of successive C-H bond functionalization of ready-stock benzoic acids. This concise strategy involves transition-metal-catalyzed directed C-H olefination, C-H hydroxylation, and acid-mediated C-H prenylation as key steps.

Copper-Catalyzed Synthesis of Substituted 4-Acylpyrazole Derivatives through a Cascade Transformation from N-Propargylic Sulfonylhydrazones and Diaryliodonium Salts

A concise strategy for the synthesis of substituted 4-acylpyrazole derivatives from N-propargylic sulfonylhydrazones and diaryliodonium salts has been developed. The pyrazole derivatives are formed through a five-step cascade sequence that includes intramolecular cyclization, hydroxylation, elimination, copper-catalyzed aerobic oxidation, and intramolecular rearrangement.

Facile, Stereocontrolled Synthetic Route towards Bis-functionalised Pyrrolizidines

A simple and convenient method for the synthesis of bis-functionalised pyrrolizidines starting from readily available N-Cbz-l-prolinal is described. This aldehyde was converted within two concise steps to the corresponding aminoepoxides, which were separately subjected to regioselective cyclisation induced by a reductive cleavage of the Cbz protecting group. The versatile and concise strategy holds great potential for practical application in the straightforward preparation of pyrrolizidine-based drugs and natural products.

Accelerating evaluation of converged lattice thermal conductivity

High-throughput computational materials design is an emerging area in materials science, which is based on the fast evaluation of physical-related properties. The lattice thermal conductivity (κ) is a key property of materials for enormous implications. However, the high-throughput evaluation of κ remains a challenge due to the large resources costs and time-consuming procedures. In this paper, we propose a concise strategy to efficiently accelerate the evaluation process of obtaining accurate and converged κ. The strategy is in the framework of phonon Boltzmann transport equation (BTE) coupled with first-principles calculations. Based on the analysis of harmonic interatomic force constants (IFCs), the large enough cutoff radius (rcutoff), a critical parameter involved in calculating the anharmonic IFCs, can be directly determined to get satisfactory results. Moreover, we find a simple way to largely (~10 times) accelerate the computations by fast reconstructing the anharmonic IFCs in the convergence test of κ with respect to the rcutof, which finally confirms the chosen rcutoff is appropriate. Two-dimensional graphene and phosphorene along with bulk SnSe are presented to validate our approach, and the long-debate divergence problem of thermal conductivity in low-dimensional systems is studied. The quantitative strategy proposed herein can be a good candidate for fast evaluating the reliable κ and thus provides useful tool for high-throughput materials screening and design with targeted thermal transport properties.

Caryophyllene driven diversity in an one-pot rearrangement of oxidation and transanular reactions

Diversity oriented synthesis starting from natural products is a newly coming strategy to build diverse skeletons to meet the demands of high throughput screening in drug development. Caryophyllene was being considered as an ideal starting point to build divers natural-like sesquiterpenes due to its rich sources and build-in reactivity. In this paper, six new natural-like products (2–7) were synthesized form the natural cryophyllene oxide via cascade oxidation and transannular reactions in a one-pot procedure. Their structures were elucidated by exhaustive spectra method including 2D NMR and X-ray diffraction. Of the products, compounds 6 and 7 possess very similar skeleton to natural products. Our findings demonstrated that one-pot cascade reactions on macrocyclic natural products is a concise strategy to create diverse natural-like skeletons.

Doxorubicin-conjugated Escherichia coli Nissle 1917 swimmers to achieve tumor targeting and responsive drug release

The use of bacteria as drug carriers meets several challenges, such as biocompatibility, motility deterioration after drug loading and lack of in vivo verification. Escherichia coli Nissle 1917 (EcN) is one of the best studied probiotic strains, and doxorubicin (DOX) is conjugated onto EcN in the current study via acid-labile linkers of cis-aconitic anhydride (EcN-ca-Dox), realizing the bacteria-directed accumulation and acid-responsive release of anticancer drugs in tumors. The drug conjugation has maintained the bacterial motion profiles of over 9μm/s and cell viability of over 70%. After 3h and 3days of intravenous injection of EcN-ca-Dox, DOX accumulations in tumors are determined as 12.9% and 6.4% of the injected doses per gram of tissue, respectively, which are much higher than the commonly used nanocarriers. Compared with free DOX and DOX-conjugated EcN via stable linkers of succinic anhydride, the EcN-ca-Dox treatment improves the antitumor efficacy with respect to the tumor growth inhibition, prolongation of animal survivals, and apoptosis induction of tumor cells. In addition, EcN has been cleaned off from tumors and other tissues after antimicrobial treatment. Thus, the acid-labile EcN conjugates provide a safe and concise strategy to enhance the temporal and spatial controllability of anticancer drugs.

Cu-Catalyzed Cascade Annulation of Alkynols with 2-Azidobenzaldehydes: Access to 6H-Isochromeno[4,3-c]quinoline.

A copper-catalyzed cascade reaction of alkynols and 2-azidobenzaldehydes has been achieved, giving 6H-isochromeno[4,3-c]quinoline in yields of 40-81%. This reaction provides a novel, concise strategy for rapidly constructing compounds with fused N- and O-containing heterocycles. In contrast to previously reported reactions of alkynols in which the first step is intramolecular cycloisomerization, the first step in this novel reaction of alkynols is entropically unfavorable intermolecular addition. The resulting hemiacetal intermediate then undergoes intramolecular cyclization and aromatization to afford the product.

An eco-compatible strategy for the diversity-oriented synthesis of macrocycles exploiting carbohydrate-derived building blocks.

An efficient, eco-compatible diversity-oriented synthesis (DOS) approach for the generation of library of sugar embedded macrocyclic compounds with various ring size containing 1,2,3-triazole has been developed. This concise strategy involves the iterative use of readily available sugar-derived alkyne/azide–alkene building blocks coupled through copper catalyzed azide–alkyne cycloaddition (CuAAC) reaction followed by pairing of the linear cyclo-adduct using greener reaction conditions. The eco-compatibility, mild reaction conditions, greener solvents, easy purification and avoidance of hazards and toxic solvents are advantages of this protocol to access this important structural class. The diversity of the macrocycles synthesized (in total we have synthesized 13 macrocycles) using a set of standard reaction protocols demonstrate the potential of the new eco-compatible approach for the macrocyclic library generation.

ChemInform Abstract: Iron Nitrate/TEMPO‐Catalyzed Aerobic Oxidative Synthesis of Quinazolinones from Alcohols and 2‐Aminobenzamides with Air as the Oxidant.

A highly efficient, iron nitrate/TEMPO-catalyzed approach for the synthesis of quinazolinones has been achieved via a one-pot, tandem aerobic oxidative cyclization of primary alcohols with 2-aminobenzamides. This practical reaction tolerates a broad scope of substrates and could afford a variety of desirable products in good to excellent yields with air as the terminal green oxidant. Thus, the present synthetic protocol provides an efficient and concise strategy for the synthesis of quinazolinones.

ChemInform Abstract: A General, Concise Strategy That Enables Collective Total Syntheses of over 50 Protoberberine and Five Aporhoeadane Alkaloids within Four to Eight Steps.

AbstractA 4‐step approach is developed which allows the access to the 13‐methylprotoberberine skeleton [cf.

ChemInform Abstract: Unparalleled Ease of Access to a Library of Biheteroaryl Fluorophores via Oxidative Cross‐Coupling Reactions: Discovery of Photostable NIR Probe for Mitochondria.

The development of straightforward accesses to organic functional materials through C–H activation is a revolutionary trend in organic synthesis. In this article, we propose a concise strategy to construct a large library of donor–acceptor-type biheteroaryl fluorophores via the palladium-catalyzed oxidative C–H/C–H cross-coupling of electron-deficient 2H-indazoles with electron-rich heteroarenes. The directly coupled biheteroaryl fluorophores, named Indazo-Fluors, exhibit continuously tunable full-color emissions with quantum yields up to 93% and large Stokes shifts up to 8705 cm–1 in CH2Cl2. By further fine-tuning of the substituent on the core skeleton, Indazo-Fluor 3l (FW = 274; λem = 725 nm) is obtained as the lowest molecular weight near-infrared (NIR) fluorophore with emission wavelength over 720 nm in the solid state. The NIR dye 5h specifically lights up mitochondria in living cells with bright red luminescence. Typically, commercially available mitochondria trackers suffer from poor photostabilit...