Barberou

Dictionnaire Gustave Flaubert, sous la direction d’Éric Le Calvez [avec la collaboration d’A. Carrico, M. F. Davì Trimarchi, S. Dord-Crouslé, A. Herschberg Pierrot, C. Ippolito, É. Le Calvez, B. Magaudda, S. Mangiapane, K. Matsuzawa, R. M. Palermo Di Stefano, F. Pellegrini, N. Petibon, T. Poyet, J. Thomas et F. Vatan] ; Classiques Garnier, 2017 ; coll. Dictionnaires et synthèses ; 1259 page

Stereospecific Approach to the Synthesis of Ring‑A Oxygenated <i>Sarpagine</i> Indole Alkaloids. Total Synthesis of the Dimeric Indole Alkaloid <i>P</i>‑(+)-Dispegatrine and Six Other Monomeric Indole Alkaloids

The first regio- and stereocontrolled total synthesis of the bisphenolic, bisquaternary alkaloid (+)-dispegatrine (<b>1</b>) has been accomplished in an overall yield of 8.3% (12 reaction vessels) from 5-methoxy-d-tryptophan ethyl ester (<b>17</b>). A crucial late-stage thallium­(III) mediated intermolecular oxidative dehydrodimerization was employed in the formation of the C9–C9′ biaryl axis in <b>1</b>. The complete stereocontrol observed in this key biaryl coupling step is due to the asymmetric induction by the natural <i>sarpagine</i> configuration of the monomer lochnerine (<b>6</b>) and was confirmed by both the Suzuki and the oxidative dehydrodimerization model studies on the tetrahydro β-carboline (<b>35</b>). The axial chirality of the lochnerine dimer (<b>40</b>) and in turn dispegatrine (<b>1</b>) was established by X-ray crystallography and was determined to be <i>P</i>(S). Additionally, the first total synthesis of the monomeric indole alkaloids (+)-spegatrine (<b>2</b>), (+)-10-methoxyvellosimine (<b>5</b>), (+)-lochnerine (<b>6</b>), lochvinerine (<b>7</b>), (+)-sarpagine (<b>8</b>), and (+)-lochneram (<b>11</b>) were also achieved via the common pentacyclic intermediate <b>16</b>

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

Design, Synthesis, and Molecular Modeling of Novel Pyrido[2,3‑<i>d</i>]pyrimidine Analogues As Antifolates; Application of Buchwald–Hartwig Aminations of Heterocycles

Opportunistic infections caused by Pneumocystis jirovecii (P. jirovecii, <i>pj</i>), Toxoplasma gondii (T. gondii, <i>tg</i>), and Mycobacterium avium (M. avium, <i>ma</i>) are the principal causes of morbidity and mortality in patients with acquired immunodeficiency syndrome (AIDS). The absence of any animal models for human Pneumocystis jirovecii pneumonia and the lack of crystal structures of <i>pj</i>DHFR and <i>tg</i>DHFR make the design of inhibitors challenging. A novel series of pyrido­[2,3-<i>d</i>]­pyrimidines as selective and potent DHFR inhibitors against these opportunistic infections are presented. Buchwald–Hartwig coupling reaction of substituted anilines with pivaloyl protected 2,4-diamino-6-bromo-pyrido­[2,3-<i>d</i>]­pyrimidine was successfully explored to synthesize these analogues. Compound <b>26</b> was the most selective inhibitor with excellent potency against <i>pj</i>DHFR. Molecular modeling studies with a <i>pj</i>DHFR homology model explained the potency and selectivity of <b>26</b>. Structural data are also reported for <b>26</b> with <i>pc</i>DHFR and <b>16</b> and <b>22</b> with variants of <i>pc</i>DHFR

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

Design, Synthesis, and Preclinical Evaluation of 4‑Substituted-5-methyl-furo[2,3‑<i>d</i>]pyrimidines as Microtubule Targeting Agents That Are Effective against Multidrug Resistant Cancer Cells

The design, synthesis, and biological evaluations of eight 4-substituted 5-methyl-furo­[2,3-<i>d</i>]­pyrimidines are reported. Synthesis involved <i>N</i>⁴-alkylation of <i>N</i>-aryl-5-methylfuro­[2,3-<i>d</i>]­pyrimidin-4-amines, obtained from Ullmann coupling of 4-amino-5-methylfuro­[2,3-<i>d</i>]­pyrimidine and appropriate aryl iodides. Compounds <b>3</b>, <b>4</b>, and <b>9</b> showed potent microtubule depolymerizing activities, while compounds <b>6</b>–<b>8</b> had slightly lower potency. Compounds <b>4</b>, <b>6</b>, <b>7</b>, and <b>9</b> inhibited tubulin assembly with IC₅₀ values comparable to that of combretastatin A-4 (CA-4). Compounds <b>3</b>, <b>4</b>, and <b>6</b>–<b>9</b> circumvented Pgp and βIII-tubulin mediated drug resistance, mechanisms that can limit the efficacy of paclitaxel, docetaxel, and the vinca alkaloids. In the NCI 60-cell line panel, compound <b>3</b> exhibited GI₅₀ values less than 10 nM in 47 of the cell lines. In an MDA-MB-435 xenograft model, compound <b>3</b> had statistically significant antitumor effects. The biological effects of <b>3</b> identify it as a novel, potent microtubule depolymerizing agent with antitumor activity

Base-Mediated Stereospecific Synthesis of Aryloxy and Amino Substituted Ethyl Acrylates

The stereospecific synthesis of aryloxy and amino substituted <i>E</i>- and <i>Z</i>-ethyl-3-acrylates is of interest because of their potential in the polymer industry and in medicinal chemistry. During work on a copper-catalyzed cross-coupling reaction of ethyl (<i>E</i>)- and (<i>Z</i>)-3-iodoacrylates with phenols and <i>N</i>-heterocycles, we discovered a very simple (nonmetallic) method for the stereospecific synthesis of aryloxy and amino substituted acrylates. To study this long-standing problem on the stereoselectivity of aryloxy and amino substituted acrylates, a series of <i>O-</i> and <i>N-</i>substituted nucleophiles was allowed to react with ethyl (<i>E</i>)- and (<i>Z</i>)-3-iodoacrylates. Screening of different bases indicated that DABCO (1,4-diazabicyclo[2.2.2]­octane) afforded successful conversion of ethyl (<i>E</i>)- and (<i>Z</i>)-3-iodoacrylates into aryloxy and amino substituted ethyl acrylates in a stereospecific manner. Herein are the details of this DABCO-mediated stereospecific synthesis of aryloxy and amino substituted <i>E-</i> or <i>Z-</i>acrylates