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.

Xylochemical Synthesis of Cytotoxic 2-Aminophenoxazinone-Type Natural Products Through Oxidative Cross Coupling

Today, the total synthesis of natural products mostly relies on the use of petroleum-based starting materials. The commercial availability of building blocks of this type often deflects attention away from lengthy synthetic routes required for the reintroduction of heteroatom substitution patterns lost in the geological process of kerogenesis. Herein, the use of wood-based starting materials, the so-called xylochemicals, for the synthesis of 2-aminophenoxazinone natural products is presented. The inherent heteroatom substitution patterns as well as chemical functionalities were employed and permitted a short and straightforward synthetic strategy. Moreover, a novel and “green” method for co…

Making natural products from renewable feedstocks: back to the roots?

Covering: up to mid-2019 This review highlights the utilization of biomass-derived building blocks in the total synthesis of natural products. An overview over several renewable feedstock classes, namely wood/lignin, cellulose, chitin and chitosan, fats and oils, as well as terpenes, is given, covering the time span from the initial beginning of natural product synthesis until today. The focus is put on the origin of the employed carbon atoms and on the nature of the complex structures that were assembled therefrom. The emerging trend of turning away from petrochemically derived starting materials back to bio-based resources, just as seen in the early days of total synthesis, shall be demon…

Xylochemicals and where to find them

This article surveys a range of important platform and high value chemicals that may be considered primary and secondary 'xylochemicals'. A summary of identified xylochemical substances and their natural sources is provided in tabular form. In detail, this review is meant to provide useful assistance for the consideration of potential synthetic strategies using xylochemicals, new methodologies and the development of potentially sustainable, xylochemistry-based processes. It should support the transition from petroleum-based approaches and help to move towards more sustainability within the synthetic community. This feasible paradigm shift is demonstrated with the total synthesis of natural …

Anti-inflammatory dihydroxanthones from a Diaporthe species

Abstract In a search for anti-inflammatory compounds from fungi inhibiting the promoter activity of the small chemokine CXCL10 (Interferon-inducible protein 10, IP-10) as a pro-inflammatory marker gene, the new dihydroxanthone methyl (1R, 2R)-1,2,8-trihydroxy-6-(hydroxymethyl)-9-oxo-2,9-dihydro-1H-xanthene-1-carboxylate (2) and the previously described dihydroxanthone AGI-B4 (1) were isolated from fermentations of a Diaporthe species. The structures of the compounds were elucidated by a combination of one- and two-dimensional NMR spectroscopy, mass spectrometry, and calculations using density functional theory (DFT). Compounds 1 and 2 inhibited the LPS/IFNγ induced CXCL10 promoter activity …

Synthesis of 2,3‐Dihydro‐4‐pyridones, 4‐Quinolones, and 2,3‐Dihydro‐4‐azocinones by Visible‐Light Photocatalytic Aerobic Dehydrogenation

Insight into the synthesis of N-methylated polypeptides

The ring-opening polymerization (ROP) of N-carboxy anhydrides (NCAs) is mostly divided into two classes: NCAs of α-substituted amino acids and N-methylated NCAs of α-unsubstituted glycine derivatives (NNCAs). The use of both monomer types offers different mechanistic features and results in a multitude of functional materials. To combine these properties, the synthesis and ROP of α-substituted and N-methylated NCAs (αNNCAs) of several amino acids were investigated. The current study provides insight into the influence of polymerization conditions and the limitations caused by the enhanced steric demand of the amino acid NCA monomers and their N-methylated derivatives. Namely, the effects of…

Vinylcyclopropane [3+2] Cycloaddition with Acetylenic Sulfones Based on Visible Light Photocatalysis

We describe the first intermolecular visible light [3+2] cycloaddition reaction being performed on a meta photocycloadduct employing acetylenic sulfones. The developed methodology exploits the advantages of combining UV and Visible light in a two-step sequence that provides a photogenerated cyclopropane which, through a strain-release process, generates a new cyclopentane ring while increasing significally the molecular complexity. This strategy could be extended to simpler vinylcyclopropanes.

Applications of xylochemistry from laboratory to industrial scale

Xylochemicals and their utilisation in total synthesis and industrial applications are highlighted in this review. This class of chemicals consists of bio-based molecules or building blocks derived from renewable feedstocks like plant-biomass, lignocellulose as well as waste-streams. The advantages over petroleum-based chemicals are presented with the aid of specific examples ranging from the total synthesis of natural products, relevant industrial applications to the exploitation of CO2 as a C1 feedstock. This review contributes to the trend of a “greener” and a more sustainable chemistry.

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…

Antimicrobial secondary metabolites from the medicinal plant Crinum glaucum A. Chev. (Amaryllidaceae)

Abstract Medicinal plants are known as sources of potential antibacterial compounds including alkaloids. The aim of the present study was to evaluate the antibacterial activities of the extract, fractions, and some secondary metabolites isolated from the leaves of Crinum glaucum A. Chev. (Amaryllidaceae). The antibacterial activities were performed with the ethanol (EtOH) extract, as well as with ethyl acetate (EtOAc) and n-butanol (n-BuOH) fractions. Repeated column chromatography of the fractions led to the isolation of several compounds and their structures were elucidated mainly by means of extensive spectroscopic analysis [(one-dimensional (1D) and two-dimensional (2D) nuclear magnetic…

C-28/C-30 oxidized cycloartanes from the leaves and twigs of Caloncoba dusenii Gilg

Abstract Four hitherto unreported cycloartane-type triterpenes (1-4) with C-28/C-30 oxidized methyl groups together with two known compounds (5-6) have been obtained from the leaves and twigs of Caloncoba dusenii Gilg. The compounds were isolated through extraction and silica gel column chromatography. Their structures and relative stereochemistry were determined by extensive use of spectroscopic techniques including IR, 1D and 2D-NMR as well as mass spectrometry. This is the first report of C-28/C-30 oxidized positions in cycloartanes from nature.

Diels–Alder reaction of β-fluoro-β-nitrostyrenes with cyclic dienes

The Diels–Alder reaction of β-fluoro-β-nitrostyrenes with cyclic 1,3-dienes was investigated. A series of novel monofluorinated norbornenes was prepared in up to 97% yield. The reaction with 1,3-cyclohexadiene permits the preparation of monofluorinated bicyclo[2.2.2]oct-2-enes. The kinetic data of the reactions with 1,3-cyclopentadiene and 1,3-cyclohexadiene were used to calculate activation parameters. Furthermore, the synthetic utility of the cycloadducts obtained was demonstrated.

Structure, Biosynthesis, and Bioactivity of Photoditritide from Photorhabdus temperata Meg1

A new cyclic peptide photoditritide (1), containing two rare amino acid d-homoarginine residues, was isolated from Photorhabdus temperata Meg1 after the nonribosomal peptide synthetase encoding gene pdtS was activated via promoter exchange. The structure of 1 was elucidated by HR-MS and NMR experiments. The absolute configurations of amino acids were determined according to the advanced Marfey's method after hydrolysis of 1. Bioactivity testing of 1 revealed potent antimicrobial activity against Micrococcus luteus with an MIC value of 3.0 μM and weak antiprotozoal activity against Trypanosoma brucei rhodesiense with an IC50 value of 13 μM. Additionally, the biosynthetic pathway of 1 was als…

CCDC 1976456: Experimental Crystal Structure Determination

Related Article: Christian Muhl, Lydia Zengerling, Jonathan Groß, Paul Eckhardt, Till Opatz, Pol Besenius, Matthias Barz|2020|Polym.Chem.|11|6919|doi:10.1039/D0PY01055C

CCDC 1976455: Experimental Crystal Structure Determination

Related Article: Christian Muhl, Lydia Zengerling, Jonathan Groß, Paul Eckhardt, Till Opatz, Pol Besenius, Matthias Barz|2020|Polym.Chem.|11|6919|doi:10.1039/D0PY01055C