Effect of Substitution and the Counterion on the Structural and Spectroscopic Properties of Cu^II Complexes of Methylated Pyrazoles

<div><p>:</p><p>The coordination chemistry of pyrazole and three of its methyl derivatives with the chloride and nitrate salts of copper(II) under strictly controlled reaction conditions is systematically explored to gain a better understanding of the effect of counterion coordination strength and ligand identity on the structure and electronic absorption spectra of their resulting complexes. Despite the initial 2:1 ligand to metal ratio in water, copper(II) nitrate forms exclusively 4:1 ligand to metal complexes while copper(II) chloride forms a 4:1 ligand to metal complex only with pyrazole, with the methyl derivatives forming 2:1 ligand to metal complexes, as determined by single-crystal XRD. This is attributed to a combination of ligand sterics and stronger coordination of chloride relative to nitrate. Electronic absorption spectroscopy in both water and methanol reveals a surprisingly strong effect of the pyrazole methyl position on the Cu^II d-d transition, with 4-methylpyrazole producing a higher energy d-d transition relative to the other ligands studied. In addition, the number of methyl groups plays a determining role in the energy of the pz πCu^II d_xy LMCT band, lowering the transition energy as more methyl groups are added.</p></div

Expeditious Synthesis, Enantiomeric Resolution, and Enantiomer Functional Characterization of (4-(4-Bromophenyl)-3a,4,5,9b-tetrahydro‑3<i>H</i>‑cyclopenta[<i>c</i>]quinoline-8-sulfonamide (4BP-TQS): An Allosteric Agonist-Positive Allosteric Modulator of α7 Nicotinic Acetylcholine Receptors

An expeditious microwave-assisted synthesis of 4BP-TQS, its enantiomeric separation, and their functional evaluation is reported. Electrophysiological characterization in Xenopus oocytes revealed that activity exclusively resided in the (+)-enantiomer <b>1b</b> (GAT107) and (−)-enantiomer <b>1a</b> did not affect its activity when coapplied. X-ray crystallography studies revealed the absolute stereochemistry of <b>1b</b> to be 3a<i>R</i>,4<i>S</i>,9b<i>S</i>. <b>1b</b> represents the most potent ago-PAM of α7 nAChRs available to date and is considered for further in vivo evaluation

Synthesis of Enantiopure 10-Nornaltrexones in the Search for Toll-like Receptor 4 Antagonists and Opioid Ligands

10-Nornaltrexones (3-(cyclopropylmethyl)-4a,9-dihydroxy-2,3,4,4a,5,6-hexahydro-1<i>H</i>-benzofuro­[3,2-<i>e</i>]­isoquinolin-7­(7a<i>H</i>)-one, <b>1</b>) have been underexploited in the search for better opioid ligands, and their enantiomers have been unexplored. The synthesis of <i>trans</i>-isoquinolinone <b>2</b> (4-aH, 9-<i>O</i>-<i>trans-</i>9-methoxy-3-methyl-2,3,4,4a,5,6-hexahydro-1<i>H</i>-benzofuro­[3,2-<i>e</i>]­isoquinolin-7­(7a<i>H</i>)-one) was achieved through a nonchromatographic optimized synthesis of the intermediate pyridinyl compound <b>12</b>. Optical resolution was carried out on <b>2</b>, and each of the enantiomers were used in efficient syntheses of the “unnatural” 4a<i>R</i>,7a<i>S</i>,12b<i>R</i>-(+)-<b>1</b>) and its “natural” enantiomer (−)-<b>1</b>. Addition of a 14-hydroxy (the 4a-hydroxy) group in the enantiomeric isoquinolinones, (+)- and (−)-<b>2</b>), gave (+)- and (−)-10-nornaltrexones. A structurally unique tetracyclic enamine, (12b<i>R</i>)-7,9-dimethoxy-3-methyl-1,2,3,7-tetrahydro-7,12b-methanobenzo­[2,3]­oxocino­[5,4-<i>c</i>]­pyridine, was found as a byproduct in the syntheses and offers a different opioid-like skeleton for future study

Synthesis of Enantiopure 10-Nornaltrexones in the Search for Toll-like Receptor 4 Antagonists and Opioid Ligands

10-Nornaltrexones (3-(cyclopropylmethyl)-4a,9-dihydroxy-2,3,4,4a,5,6-hexahydro-1<i>H</i>-benzofuro­[3,2-<i>e</i>]­isoquinolin-7­(7a<i>H</i>)-one, <b>1</b>) have been underexploited in the search for better opioid ligands, and their enantiomers have been unexplored. The synthesis of <i>trans</i>-isoquinolinone <b>2</b> (4-aH, 9-<i>O</i>-<i>trans-</i>9-methoxy-3-methyl-2,3,4,4a,5,6-hexahydro-1<i>H</i>-benzofuro­[3,2-<i>e</i>]­isoquinolin-7­(7a<i>H</i>)-one) was achieved through a nonchromatographic optimized synthesis of the intermediate pyridinyl compound <b>12</b>. Optical resolution was carried out on <b>2</b>, and each of the enantiomers were used in efficient syntheses of the “unnatural” 4a<i>R</i>,7a<i>S</i>,12b<i>R</i>-(+)-<b>1</b>) and its “natural” enantiomer (−)-<b>1</b>. Addition of a 14-hydroxy (the 4a-hydroxy) group in the enantiomeric isoquinolinones, (+)- and (−)-<b>2</b>), gave (+)- and (−)-10-nornaltrexones. A structurally unique tetracyclic enamine, (12b<i>R</i>)-7,9-dimethoxy-3-methyl-1,2,3,7-tetrahydro-7,12b-methanobenzo­[2,3]­oxocino­[5,4-<i>c</i>]­pyridine, was found as a byproduct in the syntheses and offers a different opioid-like skeleton for future study

Synthesis of Enantiopure 10-Nornaltrexones in the Search for Toll-like Receptor 4 Antagonists and Opioid Ligands

10-Nornaltrexones (3-(cyclopropylmethyl)-4a,9-dihydroxy-2,3,4,4a,5,6-hexahydro-1<i>H</i>-benzofuro­[3,2-<i>e</i>]­isoquinolin-7­(7a<i>H</i>)-one, <b>1</b>) have been underexploited in the search for better opioid ligands, and their enantiomers have been unexplored. The synthesis of <i>trans</i>-isoquinolinone <b>2</b> (4-aH, 9-<i>O</i>-<i>trans-</i>9-methoxy-3-methyl-2,3,4,4a,5,6-hexahydro-1<i>H</i>-benzofuro­[3,2-<i>e</i>]­isoquinolin-7­(7a<i>H</i>)-one) was achieved through a nonchromatographic optimized synthesis of the intermediate pyridinyl compound <b>12</b>. Optical resolution was carried out on <b>2</b>, and each of the enantiomers were used in efficient syntheses of the “unnatural” 4a<i>R</i>,7a<i>S</i>,12b<i>R</i>-(+)-<b>1</b>) and its “natural” enantiomer (−)-<b>1</b>. Addition of a 14-hydroxy (the 4a-hydroxy) group in the enantiomeric isoquinolinones, (+)- and (−)-<b>2</b>), gave (+)- and (−)-10-nornaltrexones. A structurally unique tetracyclic enamine, (12b<i>R</i>)-7,9-dimethoxy-3-methyl-1,2,3,7-tetrahydro-7,12b-methanobenzo­[2,3]­oxocino­[5,4-<i>c</i>]­pyridine, was found as a byproduct in the syntheses and offers a different opioid-like skeleton for future study

Synthesis and Structural Elucidation of a Pyranomorphinan Opioid and in Vitro Studies

During optimization of the synthesis of the mixed μ opioid agonist/δ opioid antagonist 5-(hydroxy­methyl)­oxy­morphone (UMB425) for scale-up, it was unexpectedly discovered that the 4,5-epoxy bridge underwent rearrangement on treatment with boron tribromide (BBr₃) to yield a novel opioid with a little-studied pyranomorphinan skeleton. This finding opens the pyranomorphinans for further investigations of their pharmacological profiles and represents a novel drug class with the dual profile (μ vs δ) predicted to yield lower tolerance and dependence. The structure was assigned with the help of 1D, 2D NMR and the X-ray crystal structure

Brønsted Acid Mediated Cyclization of Enaminones. Rapid and Efficient Access to the Tetracyclic Framework of the <i>Strychnos</i> Alkaloids

The development of an efficient diastereoselective method that permits rapid construction of the tetracyclic core <b>17</b> of the <i>Strychnos</i>-<i>Aspidosperma</i> alkaloids is described. Enaminone <b>16</b>, synthesized in high yield, has been cyclized under the influence of a Brønsted acid to provide the core tetracyclic framework <b>17</b> of the <i>Strychnos</i> alkaloids in optically active form or alternatively to the β-ketoester tetrahydro-β-carboline (THBC) unit <b>18</b>, by varying the equivalents of acid and the molar concentration. Attempts to utilize <b>18</b> to form the C(7)–C(16) bond of the akuammiline related alkaloids represented by strictamine (<b>22</b>), using metal-carbenoid chemistry, are also described

Configurational Reassignment and Improved Preparation of the Competitive IL-6 Receptor Antagonist 20<i>R</i>,21<i>R</i>-Epoxyresibufogenin-3-formate

20<i>R</i>,21<i>R</i>-Epoxyresibufogenin-3-formate (<b>1</b>) and 20<i>S</i>,21<i>S</i>-epoxyresibufogenin-3-formate (<b>2</b>) were synthesized from commercial resibufogenin (<b>3</b>) using known procedures. The major product (<b>1</b>) was dextrorotatory, as was the major product from the reported synthesis of epoxyresibufogenin-3-formate; however, the literature (+)-compound was assigned the 20<i>S</i>,21<i>S</i>-configuration on the basis of NMR data. We have now unequivocally determined, using single-crystal X-ray structure analyses of the major and minor products of the synthesis and of their derivatives, that the major product from the synthesis was (+)-20<i>R</i>,21<i>R</i>-epoxyresibufogenin-3-formate (<b>1</b>). Our minor synthetic product was determined to have the (−)-20<i>S</i>,21<i>S</i>-configuration (<b>2</b>). The (+)-20<i>R</i>,21<i>R</i>-compound <b>1</b> has been found to have high affinity for the IL-6 receptor and to act as an IL-6 antagonist. A greatly improved synthesis of <b>1</b> was achieved through oxidation of preformed resibufogenin-3-formate. This has enabled us to prepare, from the very expensive commercial resibufogenin, considerably larger quantities of <b>1</b>, the only known nonpeptide small-molecule IL-6 antagonist

Colloidal Stability of Gold Nanoparticles Coated with Multithiol-Poly(ethylene glycol) Ligands: Importance of Structural Constraints of the Sulfur Anchoring Groups

Gold nanoparticles (AuNPs) coated with a series of poly­(ethylene glycol) (PEG) ligands appended with four different sulfur-based terminal anchoring groups (monothiol, flexible dithiol, constrained dithiol, disulfide) were prepared to explore how the structures of the sulfur-based anchoring groups affect the colloidal stability in aqueous media. The PEG-coated AuNPs were prepared by ligand exchange of citrate-stabilized AuNPs with each ligand. The colloidal stability of the AuNPs in different harsh environmental conditions was monitored visually and spectroscopically. The AuNPs coated with dithiol- or disulfide-PEG exhibited improved stability under high salt concentration and against ligand replacement competition with dithiothreitol compared with those coated with their monothiol counterpart. Importantly, the ligands with structurally constrained dithiol or disulfide showed better colloidal stability and higher sulfur coverage on the Au surface compared to the ligands with more flexible dithiol and monothiol. X-ray photoelectron spectroscopy also revealed that the disulfide-PEG ligand had the highest S coverage on Au surface on the Au surface among the ligands studied. This result was supported by energy minimization modeling studies: the structurally more constrained disulfide ligand has the shortest S–S distance and could pack more densely on the Au surface. The experimental results indicate that the colloidal stability of the AuNPs is systematically enhanced in the following order: monothiol < flexible dithiol < constrained dithiol < disulfide. The present study indicates that the colloidal stability of thiolated ligand-functionalized AuNPs can be enhanced by (i) a multidentate chelating effect and (ii) use of the constrained and compact structure of the multidentate anchoring groups

Stereospecific Total Synthesis of the Indole Alkaloid Ervincidine. Establishment of the C‑6 Hydroxyl Stereochemistry

The total synthesis of the indole alkaloid ervincidine (<b>3</b>) is reported. This research provides a general entry into C-6 hydroxy-substituted indole alkaloids with either an α or a β configuration. This study corrects the errors in Glasby’s book (Glasby, J. S. Encyclopedia of the Alkaloids; Plenum Press: New York, 1975) and Lounasmaa et al.’s review (Lounasmaa, M.; Hanhinen, P.; Westersund, M. In The Alkaloids; Cordell, G. A., Ed.; Academic Press: San Diego, CA, 1999; Vol. 52, pp 103–195) as well as clarifies the work of Yunusov et al. (Malikov, V. M.; Sharipov, M. R.; Yunusov, S. Yu. Khim. Prir. Soedin. 1972, 8, 760−761. Rakhimov, D. A.; Sharipov, M. R.; Aripov, Kh. N.; Malikov, V. M.; Shakirov, T. T.; Yunusov, S. Yu. Khim. Prir. Soedin. 1970, 6, 724–725). It establishes the correct absolute configuration of the C-6 hydroxyl function in ervincidine. This serves as a structure proof and corrects the misassigned structure reported in the literature