A Modular Access to (±)-Tubocurine and (±)-Curine - Formal Total Synthesis of Tubocurarine.

Two consecutive Cu-catalyzed Ullmann-type C–O couplings permitted the first successful entry toward the curare alkaloids (±)-tubocurine and (±)-curine. Starting from vanillin, the synthetic sequence comprises 15 linear steps and includes a total of 24 transformations. In addition, the total synthesis of tubocurine represents a formal total synthesis of the famous arrow poison alkaloid tubocurarine.

Six-Step Gram-Scale Synthesis of the Human Immunodeficiency Virus Integrase Inhibitor Dolutegravir Sodium

This is the accepted manuscript version of the work published in its final form as Dietz, Jule-Philipp; Lucas, Tobias; Groß, Jonathan; Seitel, Sebastian; Brauer, Jan; Ferenc, Dorota; Gupton, B. Frank; Opatz, Till. Organic Process Research & Development; Volume: 25; Issue: 11; Pages: 1898-1910; https://doi.org/10.1021/acs.oprd.1c00139. Deposited by shareyourpaper.org and openaccessbutton.org. We've taken reasonable steps to ensure this content doesn't violate copyright. However, if you think it does you can request a takedown by emailing help@openaccessbutton.org.

The Di-Tert-Butyl Oxymethylphosphonate Route to the Antiviral Drug Tenofovir

<div>The present manuscript describes a simple, two step synthesis of tenofovir from HPA through phosphonomethalation with a novel doubly protected oxymethylphosphonate electrophile. The crystalline electrophile can be prepared in a simple reaction sequence and can be deblocked more easily than its ditehyl analogue involved in the current commercial process for making the drug.</div><div>The approach is general and can also be used for the preparation of related antivirals and the synthesis of adefovir is described as well.<br></div>

Di-tert-butyl Phosphonate Route to the Antiviral Drug Tenofovir

Di-tert-butyl oxymethyl phosphonates were investigated regarding their suitability for preparing the active pharmaceutical ingredient tenofovir (PMPA). First, an efficient and simple access to the crystalline di-tert-butyl(hydroxymethyl)phosphonate was developed. O-Mesylation gave high yields of the active phosphonomethylation reagent. For the synthesis of tenofovir, a two-step sequence was developed using Mg(OtBu)2 as the base for the alkylation of (R)-9-(2-hydroxypropyl)adenine. Subsequent deprotection could be achieved with aqueous acids. (Di-tert-butoxyphosphoryl)methyl methanesulfonate showed to be the most efficient electrophile tested, affording PMPA in 72% yield on a 5 g scale. The …

Total Synthesis of (-)-Oxycodone via Anodic Aryl-Aryl Coupling.

A fully regio- and diastereoselective electrochemical 4a–2′-coupling of a 3′,4′,5′-trioxygenated laudanosine derivative enables the synthesis of the corresponding morphinandienone. This key intermediate is further transformed into (−)-oxycodone through conjugate nucleophilic substitution for E-ring closure and [4 + 2] cycloaddition with photogenerated singlet oxygen to accomplish diastereoselective hydroxylation at C-14. The anodic transformation provides high yields and can be performed under constant current conditions both in a simple undivided cell or in continuous flow.

Synthesis of 5‐Fluorocytosine Using 2‐Cyano‐2‐fluoroethenolate as a Key Intermediate

Back Cover: A Regio- and Diastereoselective Anodic Aryl-Aryl Coupling in the Biomimetic Total Synthesis of (−)-Thebaine (Angew. Chem. Int. Ed. 34/2018)

An Unexpected Three-Component Condensation Leading to Amino(3-oxo-2,3-dihydro-1H-isoindol-1-ylidene)acetonitriles.

The reaction of 2-carboxybenzaldehyde with primary amines in the presence of cyanide leads to the formation of 2-substituted amino(3-oxo-2,3-dihydro-1H-isoindol-1-ylidene)acetonitriles. These compounds originate from the condensation of 2-carboxybenzaldehyde with the amine and two molecules of hydrogen cyanide and represent a novel class of isoindolinones.

An Unexpected Three-Component Condensation Leading to Amino- (3-oxo-2,3-dihydro-1H-isoindol-1-ylidene)- acetonitriles

The reaction of 2-carboxybenzaldehyde with primary amines in the presence of cyanide leads to the formation of 2-substituted amino(3-oxo-2,3-dihydro-1H-isoindol-1-ylidene)acetonitriles. These compounds originate from the condensation of 2-carboxybenzaldehyde with the amine and two molecules of hydrogen cyanide and represent a novel class of isoindolinones.

Eine regio- und diastereoselektive anodische Aryl-Aryl-Kupplung in der biomimetischen Totalsynthese von (−)-Thebain

Simple two-step synthesis of 2,4-disubstituted pyrroles and 3,5-disubstituted pyrrole-2-carbonitriles from enones

The cyclocondensation of enones with aminoacetonitrile furnishes 3,4-dihydro-2H-pyrrole-2-carbonitriles which can be readily converted to 2,4-disubstituted pyrroles by microwave-induced dehydrocyanation. Alternatively, oxidation of the intermediates produces 3,5-disubstituted pyrrole-2-carbonitriles.

Six-Step Gram Scale Synthesis of the HIV Integrase Inhibitor Dolutegravir Sodium

A short and practical synthesis for preparing the active pharmaceutical ingredient dolutegravir sodium was investigated. The convergent strategy developed herein starts from 3-(R)-amino-1- butanol and builds up the BC ring system in 76% isolated yield over four steps. Ring A was constructed by a one-pot 1,4-addition to diethyl-(2E/Z)-2-(ethoxymethylidene)-3-oxobutandioate and subsequent MgBr2·OEt2-mediated regioselective cyclization. Amide formation with 2,4- difluorobenzylamine was either performed from the carboxylic acid or through aminolysis of the corresponding ester precursor. Final salt formation afforded dolutegravir sodium in 48–51% isolated yield (HPLC-purity: 99.7–99.9%) over six…

Ring Contracting Rearrangements of 3-Amino-4-(arylamino)-1H-isochromen-1-ones

Two new ring contracting rearrangements of 3-amino-4-(arylamino)-1H-isochromen-1-ones, leading to 1-(arylamino)-3-oxo-1,3-dihydroisobenzofuran-1-carboxamides and2-aryl-3-oxo-2,3-dihydro-1H-isoindole-1-carboxamides, are described. Both conversions proceed in high yield and no further purification of the products is necessary. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)

Preparation of Indoles from α-Aminonitriles:  A Short Synthesis of FGIN-1-27

α-Aminonitriles derived from 2-aminocinnamic acid esters and amides can be cyclized under basic conditions to furnish substituted indole-3-acetic acid derivatives in quantitative yield. The reaction provides a simple access to a class of biologically active compounds.

Preparation of Indoles from α-Aminonitriles: A Short Synthesis of FGIN-1-27 (VIc).

Chemoenzymatic Synthesis of Functional Sialyl LewisX Mimetics with a Heteroaromatic Core

Functional mimetics of the sialyl Lewis(X) tetrasaccharide were prepared by the enzymatic sialylation of a 1,3-diglycosylated indole and a glycosyl azide, which was subsequently transformed into a 1,4-diglycosylated 1,2,3-triazole, by using the trans-sialidase of Trypanosoma cruzi. These compounds inhibited the binding of E-, L-, and P-selectin-coated nanoparticles to polyacrylamide-bound sialyl-Lewis(X) -containing neighboring sulfated tyrosine residues (sTyr/sLe(X) -PAA) at low or sub-millimolar concentrations. Except for E-selectin, the mimetics showed higher activities than the natural tetrasaccharide.

Facile Preparation of 3-Amino-4-(arylamino)-1H-isochromen-1-ones by a New Multicomponent Reaction

Reactions between 2-formylbenzoic acid, various anilines and HCN result in the formation of 3-amino-4-(arylamino)-1H-isochromen-1-ones in high yield. The mechanism of this three-component condensation involves the intermediate formation of an α-aminonitrile and subsequent cyclization through nucleophilic attack of the ortho-carboxylate at the nitrile carbon. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)

Rücktitelbild: Eine regio- und diastereoselektive anodische Aryl-Aryl-Kupplung in der biomimetischen Totalsynthese von (−)-Thebain (Angew. Chem. 34/2018)

A Regio- and Diastereoselective Anodic Aryl-Aryl Coupling in the Biomimetic Total Synthesis of (-)-Thebaine.

The biosynthesis of thebaine is based on the regioselective, intramolecular, oxidative coupling of (R)-reticuline. For decades, chemists have sought to mimic this coupling by using stoichiometric oxidants. However, all approaches to date have suffered from low yields or the formation of undesired regioisomers. Electrochemistry would represent a sustainable alternative in this respect but all attempts to accomplish an electrochemical synthesis of thebaine have failed so far. Herein, a regio- and diastereoselective anodic coupling of 3',4',5'-trioxygenated laudanosine derivatives is presented, which finally enables electrochemical access to (-)-thebaine.

(Z)-Amino­(2-methyl-3-oxoisoindolin-1-yl­idene)acetonitrile

The asymmetric unit of the title compound, C11H9N3O, contains two independent and nearly identical molecules (A and B). Molecule A can be transformed to B using a rotation of approximately 85° around the [111] direction. Each A molecule is connected to three B molecules via N—H...N and N—H...O hydrogen bonds and vice versa. Centrosymmetrically related molecules of the same residue form π–π interactions with centroid–centroid distances of 4.326 (1) and 3.826 (1) Å for the benzene rings of molecules A and B, respectively.

Facile Preparation of 3-Amino-4-(arylamino)-1H-isochromen-1-ones (IV) by a New Multicomponent Reaction.

CCDC 1831234: Experimental Crystal Structure Determination

Related Article: Alexander Lipp, Dorota Ferenc, Christoph Gütz, Mario Geffe, Nina Vierengel, Dieter Schollmeyer, Hans J. Schäfer, Siegfried R. Waldvogel, Till Opatz|2018|Angew.Chem.,Int.Ed.|57|11055|doi:10.1002/anie.201803887

CCDC 1894341: Experimental Crystal Structure Determination

Related Article: Alexander Lipp, Maximilian Selt, Dorota Ferenc, Dieter Schollmeyer, Siegfried R. Waldvogel, Till Opatz|2019|Org.Lett.|21|1828|doi:10.1021/acs.orglett.9b00419

CCDC 1894340: Experimental Crystal Structure Determination

Related Article: Alexander Lipp, Maximilian Selt, Dorota Ferenc, Dieter Schollmeyer, Siegfried R. Waldvogel, Till Opatz|2019|Org.Lett.|21|1828|doi:10.1021/acs.orglett.9b00419

CCDC 1831233: Experimental Crystal Structure Determination

Related Article: Alexander Lipp, Dorota Ferenc, Christoph Gütz, Mario Geffe, Nina Vierengel, Dieter Schollmeyer, Hans J. Schäfer, Siegfried R. Waldvogel, Till Opatz|2018|Angew.Chem.,Int.Ed.|57|11055|doi:10.1002/anie.201803887

CCDC 1894339: Experimental Crystal Structure Determination

Related Article: Alexander Lipp, Maximilian Selt, Dorota Ferenc, Dieter Schollmeyer, Siegfried R. Waldvogel, Till Opatz|2019|Org.Lett.|21|1828|doi:10.1021/acs.orglett.9b00419

CCDC 1831232: Experimental Crystal Structure Determination

Related Article: Alexander Lipp, Dorota Ferenc, Christoph Gütz, Mario Geffe, Nina Vierengel, Dieter Schollmeyer, Hans J. Schäfer, Siegfried R. Waldvogel, Till Opatz|2018|Angew.Chem.,Int.Ed.|57|11055|doi:10.1002/anie.201803887

CCDC 1831236: Experimental Crystal Structure Determination

Related Article: Alexander Lipp, Dorota Ferenc, Christoph Gütz, Mario Geffe, Nina Vierengel, Dieter Schollmeyer, Hans J. Schäfer, Siegfried R. Waldvogel, Till Opatz|2018|Angew.Chem.,Int.Ed.|57|11055|doi:10.1002/anie.201803887

CCDC 1831235: Experimental Crystal Structure Determination

Related Article: Alexander Lipp, Dorota Ferenc, Christoph Gütz, Mario Geffe, Nina Vierengel, Dieter Schollmeyer, Hans J. Schäfer, Siegfried R. Waldvogel, Till Opatz|2018|Angew.Chem.,Int.Ed.|57|11055|doi:10.1002/anie.201803887