SolidWorks

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Synthetic Studies toward the Tetrapetalones: Diastereoselective Construction of a Putative Intermediate

A strategy toward tetrapetalones was explored including a site-selective ethylenation of the silyl enol ether <b>A</b> to afford a quaternary stereocenter that serves in a stereogenic capacity. Regio- and diastereoselective reactions were observed in conjunction with the oxidative formation of cation <b>B</b>, which included subsequent selective formation of either carbon–oxygen or carbon–carbon bonds at the δ or ζ position on the seven-membered ring. The fourth ring was formed using a Stetter reaction

Mild Construction of 3-Methyl Tetramic Acids Enabling a Formal Synthesis of Palau’imide

A general method to construct 3-methyl-4-<i>O</i>-methylated tetramic acids displaying a C-5 stereocenter is presented. The synthetic sequence employs a SmI₂-mediated cyclization, whereby the chirality of the emerging tetramic acid core is retained from the starting chiral amino acid. Application to palau’imide is discussed

Total Syntheses of <i>ent</i>-Heliespirones A and C

Stereodivergent total syntheses of <i>ent</i>-heliespirone A and C were both completed in 11 vessels and ∼24% combined overall yield (A + C). These syntheses employed an identical inverse demand Diels–Alder reaction between a surrogate for an extendedly conjugated γ–δ unsaturated <i>ortho</i>-quinone methide and l-lactic-acid-derived exocyclic enol ether. Novel reactions of special note include a diastereoselective reduction of a chroman spiroketal by combination of borontrifluoride etherate and triethyl silane, along with oxidative rupture of a chroman etherial ring into the corresponding <i>p</i>-quinone by argentic oxide (AgO). In addition, an unusual <i>intramolecular</i> etherification of a 3° alcohol caused by cerium ammonium nitrate was observed

Total Syntheses of <i>ent</i>-Heliespirones A and C

Stereodivergent total syntheses of <i>ent</i>-heliespirone A and C were both completed in 11 vessels and ∼24% combined overall yield (A + C). These syntheses employed an identical inverse demand Diels–Alder reaction between a surrogate for an extendedly conjugated γ–δ unsaturated <i>ortho</i>-quinone methide and l-lactic-acid-derived exocyclic enol ether. Novel reactions of special note include a diastereoselective reduction of a chroman spiroketal by combination of borontrifluoride etherate and triethyl silane, along with oxidative rupture of a chroman etherial ring into the corresponding <i>p</i>-quinone by argentic oxide (AgO). In addition, an unusual <i>intramolecular</i> etherification of a 3° alcohol caused by cerium ammonium nitrate was observed

Diels–Alder Construction of Regiodifferentiated <i>meta</i>-Amino Phenols and Derivatives

Synthetic access to regiodifferentiated <i>meta</i>-amino phenols is described. The strategy relies upon distinct deprotonation conditions to afford regioisomeric thermodynamic and kinetic dienes that undergo a tandem Diels–Alder and <i>retro</i>-Diels–Alder sequence with assorted acetylenic dienophiles to afford a range of aromatic products

A General Diastereoselective Catalytic Vinylogous Aldol Reaction Among Tetramic Acid-Derived Pyrroles

A catalytic diastereoselective aldol reaction has been developed for <i>N</i>1-arylated/C2-<i>O</i>-silylated/C3-methylated and brominated/C4-<i>O</i>-methylated pyrroles in its reactions with various aldehydes. Syn adducts emerge with regard to the vicinal nitrogen and oxygen heteroatom substituents. The <i>N</i>1-aryl residue undergoes oxidative cleavage, and the C3-bromine atom undergoes palladium-mediated coupling reactions, both without disturbing the newly created stereocenters

A New Strategy for Detection and Development of Tractable Telomerase Inhibitors

Despite intense academic and industrial efforts and innumerable in vitro and cell studies, no small-molecule telomerase inhibitors have emerged as drugs. Insufficient understanding of enzyme structure and mechanisms of interdiction coupled with the substantial complexities presented by its dimeric composition have stalled all progress toward small-molecule therapeutics. Here we challenge the assumption that human telomerase provides the best platform for inhibitor development by probing a monomeric Tetrahymena telomerase with six tool compounds. We find BIBR-1532 (<b>2</b>) and MST-312 (<b>5</b>) inhibit only human telomerase, whereas β-R (<b>1</b>), THyF (<b>3</b>), TMPyP4 (<b>6</b>), and EGCG (<b>4</b>) inhibit both enzymes. Our study demonstrates that some small-molecule scaffolds can be easily surveyed with in vitro studies using Tetrahymena telomerase, a finding that could lead to more tractable inhibitors with a greater potential for development given the more precise insights that can be gleaned from this more easily expressed and assayed monomeric enzyme