Iron(ii)-catalyzed asymmetric intramolecular olefin aminochlorination using chloride ion

An iron-catalyzed enantioselective and diastereoselective intramolecular olefin aminochlorination reaction is reported (ee up to 92%, dr up to 15 : 1). In this reaction, a functionalized hydroxylamine and chloride ion are utilized as nitrogen and chlorine sources, respectively. This new method tolerates a range of synthetically valuable internal olefins that are all incompatible with existing asymmetric olefin aminochlorination methods.     

Accurate molecular weight determination of small molecules via DOSY-NMR by using external calibration curves with normalized diffusion coefficients

Determination of the aggregation and solvation numbers of organometallic complexes in solution is an important task to increase insight in reaction mechanisms. Thus knowing which aggregates are formed during a reaction is of high interest to develop better selectivity and higher yields. Diffusion-ordered spectroscopy (DOSY), which separates NMR signals according to the diffusion coefficient, finds increasing use to identify species in solution. However, there still is no simple relationship between diffusion coefficient and molecular weight (MW). Some methods have been developed to estimate the MW but still with a significant error of ±30%. Here we describe a novel development of MW-determination by using an external calibration curve (ECC) approach with normalized diffusion coefficients. Taking the shape of the molecules into account enables accurate MW-predictions with a maximum error of smaller than ±9%. Moreover we show that the addition of multiple internal references is dispensable. One internal reference (that also can be the solvent) is sufficient. If the solvent signal is not accessible, 16 other internal standards (aliphatics and aromatics) are available to avoid signal overlapping problems and provide flexible choice of analytes. This method is independent of NMR-device properties and diversities in temperature or viscosity and offers an easy and robust method to determine accurate MWs in solution.     

Reaction of a diaryldigermyne with ethylene

Reaction of the stable digermyne BbtGeGeBbt (Bbt = 2,6-[CH(SiMe₃)₂]₂-4-[C(SiMe₃)₃]-C₆H₂) with ethylene initially afforded the corresponding 1,2-digermacyclobutene. Depending on the reaction conditions applied, further reaction of this 1,2-digermacyclobutene with ethylene furnished two different reaction products: a 1,4-digermabicyclo[2.2.0]hexane or a bis(germiranyl)ethane. Combined experimental and theoretical results suggested that the 1,4-digermabicyclo[2.2.0]hexane and the bis(germiranyl)ethane are the thermodynamic and kinetic reaction products, respectively. A reaction mechanism in agreement with these results was proposed.     

Diaryldichalcogenide radical cations

One-electron oxidation of two series of diaryldichalcogenides (C₆F₅E)₂ (13a–c) and (2,6-Mes₂C₆H₃E)₂ (16a–c) was studied (E = S, Se, Te). The reaction of 13a and 13b with AsF₅ and SbF₅ gave rise to the formation of thermally unstable radical cations [(C₆F₅S)₂]˙⁺ (14a) and [(C₆F₅Se)₂]˙⁺ (14b) that were isolated as [Sb₂F₁₁]^– and [As₂F₁₁]^– salts, respectively. The reaction of 13c with AsF₅ afforded only the product of a Te–C bond cleavage, namely the previously known dication [Te₄]²⁺ that was isolated as [AsF₆]^– salt. The reaction of (2,6-Mes₂C₆H₃E)₂ (16a–c) with [NO][SbF₆] provided the corresponding radical cations [(2,6-Mes₂C₆H₃E)₂]˙⁺ (17a–c; E = S, Se, Te) in the form of thermally stable [SbF₆]^– salts in nearly quantitative yields. The electronic and structural properties of these radical cations were probed by X-ray diffraction analysis, EPR spectroscopy, and density functional theory calculations and other methods.     

Chelate-free metal ion binding and heat-induced radiolabeling of iron oxide nanoparticles

A novel reaction for chelate-free, heat-induced metal ion binding and radiolabeling of ultra-small paramagnetic iron oxide nanoparticles (USPIOs) has been established. Radiochemical and non-radioactive labeling studies demonstrated that the reaction has a wide chemical scope and is applicable to p-, d- and f-block metal ions with varying ionic sizes and formal oxidation states from 2+ to 4+. Radiolabeling studies found that ⁸⁹Zr–Feraheme (⁸⁹Zr–FH or ⁸⁹Zr–ferumoxytol) can be isolated in 93 ± 3% radiochemical yield (RCY) and >98% radiochemical purity using size-exclusion chromatography. ⁸⁹Zr–FH was found to be thermodynamically and kinetically stable in vitro using a series of ligand challenge and plasma stability tests, and in vivo using PET/CT imaging and biodistribution studies in mice. Remarkably, ICP-MS and radiochemistry experiments showed that the same reaction conditions used to produce ⁸⁹Zr–FH can be employed with different radionuclides to yield ⁶⁴Cu–FH (66 ± 6% RCY) and ¹¹¹In–FH (91 ± 2% RCY). Electron magnetic resonance studies support a mechanism of binding involving metal ion association with the surface of the magnetite crystal core. Collectively, these data suggest that chelate-free labeling methods can be employed to facilitate clinical translation of a new class of multimodality PET/MRI radiotracers derived from metal-based nanoparticles. Further, this discovery is likely to have broader implications in drug delivery, metal separation science, ecotoxicology of nanoparticles and beyond.     

Cobalt-catalysed asymmetric hydrovinylation of 1,3-dienes

In the presence of bidentate 1,n-bis-diphenylphosphinoalkane-CoCl₂ complexes {Cl₂Co[P ∼ P]} and Me₃Al or methylaluminoxane, acyclic (E)-1,3-dienes react with ethylene (1 atmosphere) to give excellent yields of hydrovinylation products. The regioselectivity (1,4- or 1,2-addition) and the alkene configuration (E- or Z-) of the resulting product depend on the nature of the ligand and temperature at which the reaction is carried out. Cobalt(ii)-complexes of 1,1-diphenylphosphinomethane and similar ligands with narrow bite angles give mostly 1,2-addition, retaining the E-geometry of the original diene. Complexes of most other ligands at low temperature (–40 °C) give almost exclusively a single branched product, (Z)-3-alkylhexa-1,4-diene, which arises from a 1,4-hydrovinylation reaction. A minor product is the linear adduct, a 6-alkyl-hexa-1,4-diene, also arising from a 1,4-addition of ethylene. As the temperature is increased, a higher proportion of the major branched-1,4-adduct appears as the (E)-isomer. The unexpectedly high selectivity seen in the Co-catalysed reaction as compared to the corresponding Ni-catalysed reaction can be rationalized by invoking the intermediacy of an η⁴-[(diene)[P ∼ P]CoH]⁺-complex and its subsequent reactions. The enhanced reactivity of terminal E-1,3-dienes over the corresponding Z-dienes can also be explained on the basis of the ease of formation of this η⁴-complex in the former case. The lack of reactivity of the X₂Co(dppb) (X = Cl, Br) complexes in the presence of Zn/ZnI₂ makes the Me₃Al-mediated reaction different from the previously reported hydroalkenylation of dienes. Electron-rich phospholanes, bis-oxazolines and N-heterocyclic carbenes appear to be poor ligands for the Co(ii)-catalysed hydrovinylation of 1,3-dienes. An extensive survey of chiral ligands reveals that complexes of DIOP, BDPP and Josiphos ligands are quite effective for these reactions even at –45 °C and enantioselectivities in the range of 90–99% ee can be realized for a variety of 1,3-dienes. Cobalt(ii)-complex of an electron-deficient Josiphos ligand is especially active, requiring only <1 mol% catalyst to effect the reactions.     

Epoxy resins from novel monomers with a bis‐(9,10‐dihydro‐9‐oxa‐10‐oxide‐10‐phosphaphenanthrene‐10‐yl‐) substituent

A new diepoxide and a new diamine, both bearing bis‐(9,10‐dihydro‐9‐oxa‐10‐oxide‐10‐phosphaphenanthrene‐10‐yl‐)‐substituted methylene linkages, were prepared through the reaction of 9,10‐dihydro‐oxa‐10‐phosphaphenanthrene‐10‐oxide with benzophenone derivatives via a simple addition reaction followed by a dehydration reaction. These two compounds were used as monomers for preparing cured epoxy resins with high phosphorus contents. The resultant epoxy resins showed high glass‐transition temperatures (between 131 and 196 °C). All of the cured epoxy resins exhibited high thermal stability, with 5% weight loss temperatures over 316 °C, and excellent flame retardancy, with limited oxygen index values of 37–50. © 2001 John Wiley & Sons, Inc. J Polym Sci Part A: Polym Chem 40: 359–368, 2002     

Rh-catalyzed reagent-free ring expansion of cyclobutenones and benzocyclobutenones

Here we report a reagent-free rhodium-catalyzed ring-expansion reaction via C–C cleavage of cyclobutenones. A variety of poly-substituted cyclopentenones and 1-indanones can be synthesized from simple cyclobutenones and benzocyclobutenones. The reaction condition is near pH neutral without additional oxidants or reductants. The potential for developing a dynamic kinetic asymmetric transformation of this reaction has also been demonstrated. Further study supports the proposed pathway involving Rh-insertion into the cyclobutenone C–C bond, followed by β-hydrogen elimination, olefin insertion and reductive elimination.     

Catalysis of water oxidation in acetonitrile by iridium oxide nanoparticles

Water oxidation catalysed by iridium oxide nanoparticles (IrO₂ NPs) in water–acetonitrile mixtures using [Ru^III(bpy)₃]³⁺ as oxidant was studied as a function of the water content, the acidity of the reaction media and the catalyst concentration. It was observed that under acidic conditions (HClO₄) and at high water contents (80% (v/v)) the reaction is slow, but its rate increases as the water content decreases, reaching a maximum at approximately equimolar proportions (≈25% H₂O (v/v)). The results can be rationalized based on the structure of water in water–acetonitrile mixtures. At high water fractions, water is present in highly hydrogen-bonded arrangements and is less reactive. As the water content decreases, water clustering gives rise to the formation of water-rich micro-domains, and the number of bonded water molecules decreases monotonically. The results presented herein indicate that non-bonded water present in the water micro-domains is considerably more reactive towards oxygen production. Finally, long term electrolysis of water–acetonitrile mixtures containing [Ru^II(bpy)₃]²⁺ and IrO₂ NPs in solution show that the amount of oxygen produced is constant with time demonstrating that the redox mediator is stable under these experimental conditions.     

Accelerated Hantzsch electrospray synthesis with temporal control of reaction intermediates

Complex chemical reactions can occur in electrosprayed droplets on the millisecond time scale. The Hantzsch synthesis of 1,4-dihydropyridines was studied in this way using on-line mass spectral analysis to optimize conditions and characterize the product mixture. Changing the distance between the nanospray source and the MS inlet allowed exploration of reaction progress as a function of droplet time-of-flight. Desolvation of the charged microdroplets is associated with transformation from starting material to intermediates and eventually to product as the distance is increased. Results of the on-line experiments require a termination step that discontinuously completes the desolvation process and allows the generated gaseous ions to be used to characterize the state of the system at a particular time. The intermediates seen correspond to those known to occur in the bulk solution-phase reaction. Off-line collection of the sprayed reaction mixture allowed the recovery of 250 mg h^–1 of desired reaction product from a single sprayer, permitting characterization by NMR and other standard methods. A thin film version of the accelerated reaction is described and it could be controlled through the temperature of the collection surface.     

Boronic acids facilitate rapid oxime condensations at neutral pH

We report here the discovery and development of boron-assisted oxime formation as a powerful connective reaction for chemical biology. Oximes proximal to boronic acids form in neutral aqueous buffer with rate constants of more than 10⁴ M^–1 s^–1, the largest to date for any oxime condensation. Boron''s dynamic coordination chemistry confers an adaptability that seems to aid a number of elementary steps in the oxime condensation. In addition to applications in bioconjugation, the emerging importance of boronic acids in chemical biology as carbohydrate receptors or peroxide probes, and the growing list of drugs and drug candidates containing boronic acids suggest many potential applications.     

Enantioselective annulation of enals with 2-naphthols by triazolium salts derived from l-phenylalanine

A series of chiral triazolium salts have been synthesized from methyl l-phenylalaninate hydrochloride. The NHCs derived from this class of novel triazolium salts were found to be highly efficient catalysts in the annulation reaction of enals and 2-naphthols. These reactions proceeded with high chemoselectivity and wide substrate scope affording enantioenriched β-arylsplitomicins in good yields with up to 96% ee.     

N-Heterocyclic carbene catalysed redox isomerisation of esters to functionalised benzaldehydes

N-Heterocyclic carbene catalysed redox isomerisation with reduction about the carbonyl has been developed in the transformation of trienyl esters to tetrasubstituted benzaldehydes. The reaction proceeds in good to excellent yield, and in cases that provide 2,2′-biaryls, enantioselectivity is observed. Mechanistic studies demonstrate the intermediacy of a cyclohexenyl β-lactone, while implicating formation of the homoenolate as turnover limiting.     

Enantioselective reductive multicomponent coupling reactions between isatins and aldehydes

A metal-free stereoselective reductive coupling reaction between isatins and aldehydes is reported. The reaction relies on commercial diethyl phosphite (∼€70 kg^–1) as the stoichiometric reductant. Base-catalyzed Pudovik addition and phosphonate/phosphate rearrangement achieved polarity inversion on the isatin, and the derived carbanions were trapped by aldehydes with subsequent dialkoxyphosphinyl migration. Chiral iminophosphoranes were used as basic catalysts to achieve high diastereo- and enantioselectivities with excellent yields.     

Synthesis of 9‐Allyl‐10‐hydroxycamptothecin via Suzuki Reaction

A facile and eco‐friendly approach for synthesizing 9‐allyl‐10‐hydroxycamptothecin ( 2 ), a key intermediate for the preparation of camptothecin analogs, is described. The product was obtained in good yield and high purity (≥99% HPLC) under mild Suzuki reaction condition.     

A convergent total synthesis of ouabagenin

A convergent total synthesis of ouabagenin, an aglycon of cardenolide glycoside ouabain, was achieved by assembly of the AB-ring, D-ring and butenolide moieties. The multiply oxygenated cis-decalin structure of the AB-ring was constructed from (R)-perillaldehyde through the Diels–Alder reaction and sequential oxidations. The intermolecular acetal formation of the AB-ring and D-ring fragments, and combination of the intramolecular radical and aldol reactions, assembled the requisite steroidal skeleton in a stereoselective fashion. Finally, stereoselective installation of the C17-butenolide via the Stille coupling and hydrogenation led to ouabagenin.     

Catalytic asymmetric direct aldol reaction of α-alkyl azlactones and aliphatic aldehydes

An unprecedented highly diastereoselective and enantioselective aldol reaction of α-alkyl azlactones and aliphatic aldehydes was achieved with cinchona alkaloid catalysts. To our knowledge, this reaction provides the first useful catalytic asymmetric access toward β-hydroxy-α-amino acids bearing alkyl substituents, which are structural motifs embedded in many natural products.     

Mechanistic studies on covalent assemblies of metal-mediated hemi-aminal ethers

The use of reversible covalent bonding in a four-component assembly incorporating chiral alcohols was recently reported to give a method for determining the enantiomeric excess of the alcohols via CD spectroscopy. Experiments that probe the mechanism of this assembly, which consists of 2-formylpyridine (2-PA), dipicolylamine (DPA), Zn(ii) and alcohols to yield zinc complexes of tren-like ligands, are presented. The studies focus upon the mechanism of conversion of a hemi-aminal (1) to a hemi-aminal ether (3), thereby incorporating the fourth component. It was found that molecular sieves along with 3 to 4 equivalents of alcohol are required to drive the conversion of 1 to 3. Attempts to isolate an intermediate in this reaction via addition of strong Lewis acids led to the discovery of a five-membered ring pyridinium salt (5), but upon exposure to Zn(ii) and alcohols gave different products to the assembly. This was interpreted to support the intermediacy of an iminium species. Kinetic studies reveal that the conversion of 1 to 3 is zero-order in alcohol in large excesses of alcohol, supporting rate-determining formation of an intermediate prior to reaction with alcohol. Further, the magnitudes of the rate constants for interconversion of 1 and 3 are similar, supporting the notion that there are similar rate-determining steps (rds) for the forward and reverse reactions. Hammett plots show that the rds involves creation of a negative charge (interpreted as the loss of positive charge), supporting the notion that the decomplexation of Zn(ii) from the assemblies to generate apo-forms of 1 and 3 is rate-determining. The individual mechanistic conclusions are combined to create a qualitative reaction coordinate diagram for the interconversion of 1 and 3.     

Chemoselective palladium-catalyzed deprotonative arylation/[1,2]-Wittig rearrangement of pyridylmethyl ethers

Control of chemoselectivity is one of the most challenging problems facing chemists and is particularly important in the synthesis of bioactive compounds and medications. Herein, the first highly chemoselective tandem C(sp³)–H arylation/[1,2]-Wittig rearrangement of pyridylmethyl ethers is presented. The efficient and operationally simple protocols enable generation of either arylation products or tandem arylation/[1,2]-Wittig rearrangement products with remarkable selectivity and good to excellent yields (60–99%). Choice of base, solvent, and reaction temperature play a pivotal role in tuning the reactivity of intermediates and controlling the relative rates of competing processes. The novel arylation step is catalyzed by a Pd(OAc)₂/NIXANTPHOS-based system via a deprotonative cross-coupling process. The method provides rapid access to skeletally diverse aryl(pyridyl)methanol core structures, which are central components of several medications.