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1.
Artigo em Inglês | MEDLINE | ID: mdl-32686269

RESUMO

A new class of nonplanar metalla-aromatics, diiron complexes 2 bridged by a 1,3-butadienyl dianionic ligand were synthesized in high yields from dilithio reagents and two equivalents of FeBr 2 . Complexes 2 consist of two antiferromagnetically coupled high-spin Fe(II) centers as revealed by magnetometry, Mössbauer spectroscopy and DFT calculations. Furthermore, experimental (X-ray structural analysis) and theoretical analyses (NICS, ICSS, AICD, MOs) suggest that 2 is aromatic. Remarkably, such nonplanar metalla-aromaticity is achieved by an uncommon σ-type overlap between the ligand p and metal d orbitals, in sharp contrast to the intensively studied planar aromatic systems featuring delocalized π-type bonding. Specifically, the σ-type interaction between the two Fe 3d xz orbitals and the butadienyl π orbital results in the formation of a six-electron conjugated system and hence endows the aromatic character to 2 .

2.
Clin Cancer Res ; 26(14): 3608-3615, 2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-32341034

RESUMO

PURPOSE: The recent emergence of radioligand therapies for cancer treatment has increased enthusiasm for developing new theranostic strategies coupling both imaging and cytotoxicity in the same entity. In this study, we evaluated whether CUB domain containing protein 1 (CDCP1), a single-pass transmembrane protein highly overexpressed in diverse human cancers, might be a target for cancer theranostics. EXPERIMENTAL DESIGN: The ectodomain of CDCP1 was targeted using radiolabeled forms of 4A06, a potent and specific recombinant human antibody that we developed. Imaging and antitumor assessment studies were performed in animal models of pancreatic cancer, including two patient-derived xenograft models we developed for this study. For antitumor assessment studies, the endpoints were death due to tumor volume >3,000 mm3 or ≥20% loss in body weight. Specific tracer binding or antitumor effects were assessed with an unpaired, two-tailed Student t test and survival advantages were assessed with a log rank (Mantel-Cox) test. Differences at the 95% confidence level were interpreted to be significant. RESULTS: 89Zr-4A06 detected a broad dynamic range of full length or cleaved CDCP1 expression on seven human pancreatic cancer tumors (n = 4/tumor). Treating mice with single or fractionated doses of 177Lu-4A06 significantly reduced pancreatic cancer tumor volume compared with mice receiving vehicle or unlabeled 4A06 (n = 8; P < 0.01). A single dose of 225Ac-4A06 also inhibited tumor growth, although the effect was less profound compared with 177Lu-4A06 (n = 8; P < 0.01). A significant survival advantage was imparted by 225Ac-4A06 (HR = 2.56; P < 0.05). CONCLUSIONS: These data establish that CDCP1 can be exploited for theranostics, a finding with widespread implications given its breadth of overexpression in cancer.

3.
ACS Chem Biol ; 15(6): 1381-1391, 2020 06 19.
Artigo em Inglês | MEDLINE | ID: mdl-32255605

RESUMO

The complexity of glucocorticoid receptor (GR) signaling cannot be measured with direct tissue analysis in living subjects, which has stifled our understanding of GR's role in human physiology or disease and impeded the development of selective GR modulators. Herein, we report 18F-5-(4-fluorobenzyl)-10-methoxy-2,2,4-trimethyl-2,5-dihydro-1H-chromeno[3,4-f]quinoline (18F-YJH08), a radioligand that enables noninvasive measurements of tissue autonomous GR expression levels in vivo with positron emission tomography (PET). YJH08 potently binds GR (Ki ∼ 0.4 nM) with ∼100-fold selectivity compared to nuclear hormone receptors in the same subfamily. 18F-YJH08 was prepared via Cu(OTf)2(py)4-mediated radiofluorination of an arylboronic acid pinacol ester with ∼12% decay corrected radiochemical yield from the starting 18F-fluoride ion. We applied treatment with the tissue-wide GR agonist dexamethasone and adrenalectomy and generated an adipocyte specific GR knockout mouse to show that 18F-YJH08 specifically binds GR in normal mouse tissues, including those for which aberrant GR expression is thought to drive severe diseases (e.g., brain, adipose tissue, kidneys). Remarkably, 18F-YJH08 PET also revealed that JG231, a potent and bioavailable HSP70 inhibitor, selectively degrades GR only in the adipose tissue of mice, a finding that foreshadows how GR targeted PET might be integrated into drug discovery to screen for selective GR modulation at the tissue level, beyond the historical screening that was performed at the transcriptional level. In summary, 18F-YJH08 enables a quantitative assessment of GR expression levels in real time among multiple tissues simultaneously, and this technology is a first step toward unraveling the daunting complexity of GR signaling and rationally engineering tissue specific therapeutic modulators in vivo.

4.
Mol Cell Proteomics ; 19(2): 294-307, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31792071

RESUMO

Aberrantly high mTORC1 signaling is a known driver of many cancers and human disorders, yet pharmacological inhibition of mTORC1 rarely confers durable clinical responses. To explore alternative therapeutic strategies, herein we conducted a proteomics survey to identify cell surface proteins upregulated by mTORC1. A comparison of the surfaceome from Tsc1 -/- versus Tsc1 +/+ mouse embryonic fibroblasts revealed 59 proteins predicted to be significantly overexpressed in Tsc1 -/- cells. Further validation of the data in multiple mouse and human cell lines showed that mTORC1 signaling most dramatically induced the expression of the proteases neprilysin (NEP/CD10) and aminopeptidase N (APN/CD13). Functional studies showed that constitutive mTORC1 signaling sensitized cells to genetic ablation of NEP and APN, as well as the biochemical inhibition of APN. In summary, these data show that mTORC1 signaling plays a significant role in the constitution of the surfaceome, which in turn may present novel therapeutic strategies.

5.
Angew Chem Int Ed Engl ; 58(28): 9625-9631, 2019 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-31102480

RESUMO

Herein, we present the realization of a class of unprecedented aromatic structures 2: metalla-aromatics with two independent and perpendicular aromatic rings spiro-fused by a transition-metal spiro atom, of which their corresponding organic analogues are impossible. Tetralithio spiro manganacycles 2 are readily synthesized from 1,4-dilithio-1,3-butadienes 1 and MnCl2 in the presence of lithium. The aromaticity of 2 is supported by experimental measurements (X-ray structural analysis, NMR) and theoretical analyses (NICS, ACID, MOs). The spiro atom Mn in 2 uses its 3dxz and 3dxy orbitals to form the two perpendicular manganacycles, which are two independent 6π aromatic systems. Theoretical analyses reveal that the Li cations play an indispensable role in governing their geometric and electronic structures and hence their aromaticity. Therefore, this work contributes not only to enrich the concept of aromaticity, but also to deepen the understanding of the fundamental chemical bonding.

6.
ACS Cent Sci ; 5(4): 727-736, 2019 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-31041393

RESUMO

Redox cycling of iron powers various enzyme functions crucial for life, making the study of iron acquisition, storage, and disposition in the whole organism a worthy topic of inquiry. However, despite its important role in biology and disease, imaging iron in animals with oxidation-state specificity remains an outstanding problem in biology and medicine. Here we report a first-generation reactivity-based probe of labile ferrous iron suitable for positron emission tomography studies in live animals. The responses of this reagent to systemic changes in labile iron disposition were revealed using iron supplementation and sequestration treatments in mice, while the potential of this approach for in vivo imaging of cancer was demonstrated using genetically and pathologically diverse mouse models, including spontaneous tumors arising in a genetically engineered model of prostate cancer driven by loss of PTEN.

7.
Acc Chem Res ; 52(2): 415-424, 2019 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-30707548

RESUMO

Switchable catalysts incorporate stimuli-responsive features and allow synthetic tasks that are difficult or impossible to accomplish in other ways. They mimic biological processes in that they can provide both spatial and temporal control, unlike most reactions promoted by human-made catalysts that usually occur according to carefully optimized conditions. In the area of switchable catalysis, redox-switchable ring-opening polymerization (ROP) has attracted much attention, emerging as a powerful strategy for the development of environmentally friendly biodegradable copolymers, especially those containing blocks with complementary properties. Controlling the sequence and regularity of each copolymeric building block can affect the material properties significantly since they are directly related to the respective microstructures. Such control can be exerted with a well-designed redox-switchable catalyst by timing the oxidation and reduction events. In highly selective systems, one form of the catalyst reacts with a monomer until the redox state of the catalyst is altered, at which point the altered state of the catalyst reacts with another monomer. The reaction time may be varied from one cycle to another to generate various designer multiblock copolymers. The first instance of redox-mediated ROP was described by N. Long and co-workers in 2006. This example, as well as many early reported redox-switchable catalysts, could only achieve an on/off switch of activity toward a single monomer or substrate. However, our efforts brought on a general strategy for designing redox-switchable metal complexes that can catalyze different reactions in two oxidation states. In recent years, our contributions to this research field led to the synthesis of several multiblock copolymers prepared from biorenewable resources. This Account provides an overview of reported redox-switchable polymerization catalysts that allow for complementary reactivity in different oxidation states and highlights the potential of this strategy in preparing biodegradable materials. First, we define the field of redox-switchable catalysis and illustrate the design and significance of our ferrocene-chelating ligands, in which the oxidation state of iron in ferrocene can control the reactivity of the resulting metal complexes remotely. Next, we illustrate recent advances in the synthesis of new biodegradable copolymers including (1) how to tune the activity of the ROP catalysts by exploring various metal centers and ferrocene-based ligand combinations; (2) how to synthesize new multiblock copolymers of cyclic esters, epoxides, and carbonates by redox-switchable ROP; and (3) how to understand the mechanism of these reactions by discussing both experimental and theoretical investigations. By the application and development of redox-switchable strategies, various novel materials and reactions can be expected in the future.

8.
J Clin Invest ; 129(1): 349-363, 2019 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-30530991

RESUMO

While immune checkpoint blockade leads to potent antitumor efficacy, it also leads to immune-related adverse events in cancer patients. These toxicities stem from systemic immune activation resulting in inflammation of multiple organs, including the gastrointestinal tract, lung, and endocrine organs. We developed a dual variable domain immunoglobulin of anti-CTLA4 antibody (anti-CTLA4 DVD, where CTLA4 is defined as cytotoxic T lymphocyte-associated antigen-4) possessing an outer tumor-specific antigen-binding site engineered to shield the inner anti-CTLA4-binding domain. Upon reaching the tumor, the outer domain was cleaved by membrane type-serine protease 1 (MT-SP1) present in the tumor microenvironment, leading to enhanced localization of CTLA4 blockade. Anti-CTLA4 DVD markedly reduced multiorgan immune toxicity by preserving tissue-resident Tregs in Rag 1-/- mice that received naive donor CD4+ T cells from WT C57BL/6j mice. Moreover, anti-CTLA4 DVD induced potent antitumor effects by decreasing tumor-infiltrating Tregs and increasing the infiltration of antigen-specific CD8+ T lymphocytes in TRAMP-C2-bearing C57BL/6j mice. Treg depletion was mediated through the antibody-dependent cellular cytotoxicity (ADCC) mechanism, as anti-CTLA4 without the FcγR-binding portion (anti-CTLA4 DANA) spared Tregs, preventing treatment-induced toxicities. In summary, our results demonstrate an approach to anti-CTLA4 blockade that depletes tumor-infiltrating, but not tissue-resident, Tregs, preserving antitumor effects while minimizing toxicity. Thus, our tumor-conditional anti-CTLA4 DVD provides an avenue for uncoupling antitumor efficacy from immunotherapy-induced toxicities.


Assuntos
Antineoplásicos Imunológicos/farmacologia , Antígeno CTLA-4/antagonistas & inibidores , Imunoterapia , Neoplasias/terapia , Anticorpos de Cadeia Única/farmacologia , Linfócitos T Reguladores/imunologia , Microambiente Tumoral/efeitos dos fármacos , Animais , Antineoplásicos Imunológicos/imunologia , Antígeno CTLA-4/genética , Antígeno CTLA-4/imunologia , Linhagem Celular Tumoral , Células HEK293 , Humanos , Imunidade Celular , Masculino , Camundongos , Camundongos Knockout , Neoplasias/genética , Neoplasias/imunologia , Neoplasias/patologia , Anticorpos de Cadeia Única/imunologia , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
9.
JCI Insight ; 3(21)2018 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-30385712

RESUMO

Noninvasive tools that target tumor cells could improve the management of glioma. Cancer generally has a high demand for Fe(III), an essential nutrient for a variety of biochemical processes. We tested whether 68Ga-citrate, an Fe(III) biomimetic that binds to apo-transferrin in blood, detects glioma in preclinical models and patients using hybrid PET/MRI. Mouse PET/CT studies showed that 68Ga-citrate accumulates in subcutaneous U87MG xenografts in a transferrin receptor-dependent fashion within 4 hours after injection. Seventeen patients with WHO grade III or IV glioma received 3.7-10.2 mCi 68Ga-citrate and were imaged with PET/MR 123-307 minutes after injection to establish that the radiotracer can localize to human tumors. Multiple contrast-enhancing lesions were PET avid, and tumor to adjacent normal white matter ratios were consistently greater than 10:1. Several contrast-enhancing lesions were not PET avid. One minimally enhancing lesion and another tumor with significantly reduced enhancement following bevacizumab therapy were PET avid. Advanced MR imaging analysis of one patient with contrast-enhancing glioblastoma showed that metabolic hallmarks of viable tumor spatially overlaid with 68Ga-citrate accumulation. These early data underscore that high-grade glioma may be detectable with a radiotracer that targets Fe(III) transport.


Assuntos
Neoplasias do Sistema Nervoso Central/diagnóstico por imagem , Citratos/metabolismo , Gálio/metabolismo , Glioma/diagnóstico por imagem , Ferro/metabolismo , Adulto , Animais , Apoproteínas/sangue , Apoproteínas/metabolismo , Neoplasias do Sistema Nervoso Central/metabolismo , Citratos/administração & dosagem , Feminino , Compostos Férricos/metabolismo , Gálio/administração & dosagem , Glioma/metabolismo , Humanos , Espectroscopia de Ressonância Magnética/métodos , Masculino , Camundongos , Pessoa de Meia-Idade , Modelos Animais , Gradação de Tumores , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos/administração & dosagem , Transferrina/metabolismo
10.
iScience ; 7: 120-131, 2018 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-30267674

RESUMO

Neutral zinc alkoxide complexes show high activity toward the ring-opening polymerization of cyclic esters and carbonates, to generate biodegradable plastics applicable in several areas. Herein, we use a ferrocene-chelating heteroscorpionate complex in redox-switchable polymerization reactions, and we show that it is a moderately active catalyst for the ring-opening polymerization of L-lactide, ɛ-caprolactone, trimethylene carbonate, and δ-valerolactone. Uniquely for this type of catalyst, the oxidized complex has a similar polymerization activity as the corresponding reduced compound, but displays significantly different rates of reaction in the case of trimethylene carbonate and δ-valerolactone. Investigations of the oxidized compound suggest the presence of an organic radical rather than an Fe(III) complex. Electronic structure and density functional theory (DFT) calculations were performed to support the proposed electronic states of the catalytic complex and to help explain the observed reactivity differences. The catalyst was also compared with a monomeric phenoxide complex to show the influence of the phosphine-zinc interaction on catalytic properties.

11.
Chem Sci ; 9(8): 2168-2178, 2018 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-29719690

RESUMO

Poly(l-lactide) (PLA) is a bioderived and biodegradable polymer that has limited applications due to its hard and brittle nature. Incorporation of 1,3-trimethylene carbonate into PLA, in a block copolymer fashion, improves the mechanical properties, while retaining the biodegradability of the polymer, and broadens its range of applications. However, the preparation of 1,3-trimethylene carbonate (TMC)/l-lactide (LA) copolymers beyond diblock and triblock structures has not been reported, with explanations focusing mostly on thermodynamic reasons that impede the copolymerization of TMC after lactide. We discuss the preparation of multiblock copolymers via the ring opening polymerization (ROP) of LA and TMC, in a step-wise addition, by a ferrocene-chelating heteroscorpionate zinc complex, {[fc(PPh2)(BH[(3,5-Me)2pz]2)]Zn(µ-OCH2Ph)}2 ([(fcP,B)Zn(µ-OCH2Ph)]2, fc = 1,1'-ferrocenediyl, pz = pyrazole). The synthesis of up to pentablock copolymers, from various combinations of LA and TMC, was accomplished and the physical, thermal, and mechanical properties of the resulting copolymers evaluated.

12.
Oncotarget ; 9(29): 20399-20408, 2018 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-29755660

RESUMO

The glucocorticoid receptor (GR) is an emerging drug target for several common and deadly solid tumors like breast and prostate cancer, and clinical trials studying the antitumor effects of GR antagonists are beginning. Since GR expression can be variable in tumor cells, and virtually all normal mammalian tissues express some GR, we hypothesized that an imaging tool capable of detecting GR positive tumors and/or measuring GR occupancy by drug in tumor and normal tissues could improve the precision application of anti-GR therapies in the clinic. To this end, we developed a fluorine-18 labeled corticosteroid termed GR02 that potently binds the endogenous ligand binding pocket on full length GR. Binding of 18F-GR02 was suppressed in many normal tissues by co-treatment with mifepristone, a GR antagonist in human use, and was elevated in many normal tissues among mice lacking circulating corticosteroids due to adrenalectomy. 18F-GR02 also accumulated in GR positive subcutaneous and subrenal capsule prostate cancer models, and uptake in tumors was competed by mifepristone. Combined with a straightforward and high yielding radiosynthesis, these data establish the foundation for near-term clinical translation of 18F-GR02.

13.
Chem Sci ; 9(3): 560-568, 2018 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-29675144

RESUMO

Metalloaromatic species are unique and important both experimentally and theoretically. Significant progress has been made during the past few decades. New aromatic systems have challenged and extended the concept of aromaticity remarkably. In this perspective, recent results on the study of the dianion aromatic metalloles and their corresponding analogues are reviewed. These include the dilithio group 14 metalloles, group 13 metalloles and transition metal metalloles. X-ray crystallography has made a key contribution to the understanding of the structures. Various theoretical tools, such as NICS and AdNDP, make it possible to measure the aromaticity beyond Hückel's rule. The dianion butadiene skeletons play a key role in these metalloles and can be regarded as non-innocent ligands, which accept the electrons from the metal center and thus form the aromatic rings. By simply changing the central metals to different metals, the metallole analogues such as dicupra[10]annulenes and spiroaromatic palladoles can also be generated, which opens a door to synthesize other metalla-macrocyclic aromatics. Key challenges and envisioned opportunities for the future, such as applying these dianion metalloles as novel ligands of transition metals and generating new types of organometallic aromatic system, are also discussed.

14.
Bioconjug Chem ; 29(1): 96-103, 2018 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-29125731

RESUMO

High sensitivity imaging tools could provide a more holistic view of target antigen expression to improve the identification of patients who might benefit from cancer immunotherapy. We developed for immunoPET a novel recombinant human IgG1 (termed C4) that potently binds an extracellular epitope on human and mouse PD-L1 and radiolabeled the antibody with zirconium-89. Small animal PET/CT studies showed that 89Zr-C4 detected antigen levels on a patient derived xenograft (PDX) established from a non-small-cell lung cancer (NSCLC) patient before an 8-month response to anti-PD-1 and anti-CTLA4 therapy. Importantly, the concentration of antigen is beneath the detection limit of previously developed anti-PD-L1 radiotracers, including radiolabeled atezolizumab. We also show that 89Zr-C4 can specifically detect antigen in human NSCLC and prostate cancer models endogenously expressing a broad range of PD-L1. 89Zr-C4 detects mouse PD-L1 expression changes in immunocompetent mice, suggesting that endogenous PD-1/2 will not confound human imaging. Lastly, we found that 89Zr-C4 could detect acute changes in tumor expression of PD-L1 due to standard of care chemotherapies. In summary, we present evidence that low levels of PD-L1 in clinically relevant cancer models can be imaged with immunoPET using a novel recombinant human antibody.


Assuntos
Antígeno B7-H1/análise , Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Imunoconjugados/química , Imunoglobulina G/química , Neoplasias Pulmonares/diagnóstico por imagem , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons/métodos , Radioisótopos/química , Zircônio/química , Animais , Linhagem Celular Tumoral , Células HEK293 , Humanos , Pulmão/diagnóstico por imagem , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Recombinantes/química
15.
Mol Cancer Res ; 15(9): 1221-1229, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28592703

RESUMO

Noninvasive biomarkers that detect the activity of important oncogenic drivers could significantly improve cancer diagnosis and management of treatment. The goal of this study was to determine whether 68Ga-citrate (which avidly binds to circulating transferrin) can detect MYC-positive prostate cancer tumors, as the transferrin receptor is a direct MYC target gene. PET imaging paired with 68Ga-citrate and molecular analysis of preclinical models, human cell-free DNA (cfDNA), and clinical biopsies were conducted to determine whether 68Ga-citrate can detect MYC-positive prostate cancer. Importantly, 68Ga-citrate detected human prostate cancer models in a MYC-dependent fashion. In patients with castration-resistant prostate cancer, analysis of cfDNA revealed that all patients with 68Ga-citrate avid tumors had a gain of at least one MYC copy number. Moreover, biopsy of two PET avid metastases showed molecular or histologic features characteristic of MYC hyperactivity. These data demonstrate that 68Ga-citrate targets prostate cancer tumors with MYC hyperactivity. A larger prospective study is ongoing to demonstrate the specificity of 68Ga-citrate for tumors with hyperactive MYC.Implications: Noninvasive measurement of MYC activity with quantitative imaging modalities could substantially increase our understanding of the role of MYC signaling in clinical settings for which invasive techniques are challenging to implement or do not characterize the biology of all tumors in a patient. Moreover, measuring MYC activity noninvasively opens the opportunity to study changes in MYC signaling in patients under targeted therapeutic conditions thought to indirectly inhibit MYC. Mol Cancer Res; 15(9); 1221-9. ©2017 AACR.


Assuntos
Genes myc/genética , Tomografia por Emissão de Pósitrons/métodos , Neoplasias da Próstata/genética , Transferrina/metabolismo , Humanos , Masculino
16.
J Am Chem Soc ; 139(14): 5039-5042, 2017 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-28362092

RESUMO

Since the concept of aromaticity represents one of the most fundamental principles in chemistry, the search for unprecedented and exciting aromatic systems, therefore, continues to drive research in this area. Herein we report the synthesis and characterization of spiro metalla-aromatics, in which the transition metal (Pd, Pt, or Rh) is the spiro atom, that cross-conjugates two aromatic five-membered metallacycles. These spiro metalla-aromatics tend to take square planar geometries, with the dihedral angle being influenced by the steric repulsion between the α-positioned substituents. Rationalized and classified via both experimental measurements (X-ray structural analysis, NMR spectroscopy, XPS, etc.) and theoretical analysis (DFT calculation, ISE, AICD, NICS, and CMOs), all these fundamental observations extend the concept of aromaticity and organometallic chemistry.

17.
Angew Chem Int Ed Engl ; 55(47): 14762-14765, 2016 11 14.
Artigo em Inglês | MEDLINE | ID: mdl-27766730

RESUMO

The chemistry of magnesium organocuprates, including their synthesis, structures, and reactions, remains underexplored. In this work, by taking advantage of the high reactivity and ready availability of magnesiacyclopentadienes, a series of magnesiacyclopentadiene-based organocuprates were synthesized and structurally characterized. A variety of CuX salts (X=Cl, Br, I, or alkynyl) were successfully applied to react with magnesiacyclopentadienes. Besides CuX salts, AgX salts (X=Cl, alkynyl) also undergwent the above reaction to afford the corresponding magnesium organoargentates. Single-crystal X-ray structural analysis and DFT calculations of these butadienyl magnesium organocuprates revealed unique structural characteristics and bonding modes. These results are also very useful to understand the transmetalation process, since the product can be viewed as the resting-state intermediate of a transmetalation reaction between organomagnesium compounds and coinage-metal salts. Preliminary information on the reaction chemistry of these magnesium organocuprates is provided by their reactions with allyl bromide, benzoyl chloride, and CO2 .

18.
Chemistry ; 22(10): 3422-3429, 2016 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-26807680

RESUMO

DFT calculations have been performed on the palladium-catalyzed carboiodination reaction. The reaction involves oxidative addition, alkyne insertion, C-N bond cleavage, and reductive elimination. For the alkylpalladium iodide intermediate, LiOtBu stabilizes the intermediate in non-polar solvents, thus promoting reductive elimination and preventing ß-hydride elimination. The C-N bond cleavage process was explored and the computations show that PPh3 is not bound to the Pd center during this step. Experimentally, it was demonstrated that LiOtBu is not necessary for the oxidative addition, alkyne insertion, or C-N bond cleavage steps, lending support to the conclusions from the DFT calculations. The turnover-limiting steps were found to be C-N bond cleavage and reductive elimination, whereas oxidative addition, alkyne insertion, and formation of the indole ring provide the driving force for the reaction.

19.
J Am Chem Soc ; 138(1): 60-3, 2016 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-26708724

RESUMO

Metal-containing aromatic systems (metalla-aromatics) are unique and important both experimentally and theoretically. Among metalla-aromatics, six-membered metallabenzenes and metallabenzynes have attracted much attention in recent years. However, reports on their superior homologues are rare. In this work, the first series of aromatic dicupra[10]annulenes were isolated from the reaction of dilithio reagents and copper salts. Single-crystal X-ray structural analysis revealed dicupra[10]annulenes with averaged bond lengths. (7)Li NMR spectra and theoretical calculations revealed considerable aromatic character. XPS data suggested that the oxidation state of Cu atom in dicupra[10]annulenes was more likely to be Cu(I), indicating that the dilithio moieties in dicupra[10]annulenes participated as noninnocent ligands. This work demonstrates a novel approach to construct macrocyclic metalla-aromatics.

20.
Inorg Chem ; 54(22): 10695-700, 2015 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-26501357

RESUMO

A series of lithium aluminate complexes and alumoles were synthesized from 1,4-dilithio-1,3-butadienes 1 and AlEt2Cl. Their structures were characterized using single-crystal X-ray structural analysis and NMR spectroscopy. The structure of the lithium aluminate complex 2-TMEDA showed that the Al atom adopted a tetra-coordinated mode bonded with two butadienyl Csp2 atoms and two ethyl Csp3 atoms. The lithium cation was located above the alumole ring. The structure of 3a revealed a dimeric 1-ethylalumole in the solid state. Diffusion ordered spectroscopy NMR spectra showed that 3a was also a dimer in C6D6 solvent. However, in tetrahydrofuran (THF) solution, the dimeric 3a dissociated into the 1-ethylalumole-THF adduct. The lithium aluminate complex 2 transformed into 3a-THF when treated with 1.0 equiv of AlEt2Cl. Preliminary reaction chemistry and synthetic applications of the lithium aluminate complex were also investigated.

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