Overcoming NMR line broadening of nitrogen containing compounds: A simple solution.

This study presents a straightforward solution to the challenge of elucidating the structures of nitrogen containing compounds undergoing isomerization. When spectral line broadening occurs related to isomerization, be it prototropic tautomerism or bond rotations, this poses a significant obstacle to structural elucidation. By adding acids, we demonstrate a simple approach to overcome this issue and effectively sharpen NMR signals for acid stable prototropic tautomers as well as the conformational isomers containing a morpholine or piperazine ring.

Structurally Diverse Bench-Stable Nickel(0) Pre-Catalysts: A Practical Toolkit for In Situ Ligation Protocols.

A flurry of recent research has centered on harnessing the power of nickel catalysis in organic synthesis. These efforts have been bolstered by contemporaneous development of well-defined nickel (pre)catalysts with diverse structure and reactivity. In this report, we present ten different bench-stable, 18-electron, formally zero-valent nickel-olefin complexes that are competent pre-catalysts in various reactions.

Ru-Catalyzed Enantioselective Hydrogenation of 2-Pyridyl-Substituted Alkenes and Substrate-Mediated H/D Exchange.

A highly efficient and enantioselective asymmetric hydrogenation catalyzed by Ru-DTBM-segphos is reported for a broad range of pyridine-pyrroline tri-substituted alkenes. Kinetic, spectroscopic, and computational studies suggest that addition of H is rate-determining and that alkene insertion is the enantio-determining step. These studies also reveal an intriguing Ru-catalyzed H/D exchange process that is facilitated by the substrate at room temperature and low pressure where hydrogenation activity is suppressed.

Kinetic and Thermodynamic Considerations in the Rh-Catalyzed Enantioselective Hydrogenation of 2-Pyridyl-Substituted Alkenes.

The mechanism of asymmetric hydrogenation of 2-pyridyl alkenes catalyzed by chiral Rh-phosphine complexes at ambient temperature is examined using kinetic, spectroscopic, and computational tools. The reaction proceeds with reversible substrate binding followed by rate-determining addition of hydrogen. Substrate binding occurs only through the pyridine nitrogen in contrast to other substrate classes exhibiting stronger substrate direction.

A Process Chemistry Benchmark for sp-sp Cross Couplings.

As sp-sp disconnections gain acceptance in the medicinal chemist's toolbox, an increasing number of potential drug candidates containing this motif are moving into the pharmaceutical development pipeline. This raises a new set of questions and challenges around the novel, direct methodologies available for forging these bonds. These questions gain further importance in the context of process chemistry, where the focus is the development of scalable processes that enable the large-scale delivery of clinical supplies.

P(III) vs P(V): A P(V) Reagent for Thiophosphoramidate Linkages and Application to an Asymmetric Synthesis of a Cyclic Dinucleotide STING Agonist.

A highly stereoselective synthesis of a cyclic dinucleotide (CDN) STING agonist containing two chiral thiophosphoramidate linkages is described. These rare yet key functional groups were, for the first time, installed efficiently and with high diastereoselectivity using a specially designed P(V) reagent. By utilizing this strategy, the CDN was prepared in greater than 16-fold higher yield than the prior P(III) approach, with fewer hazardous reagents and chromatographic purifications.

Meroterpenoids from Neosetophoma sp.: A Dioxa[4.3.3]propellane Ring System, Potent Cytotoxicity, and Prolific Expression.

Six fungal metabolites, of which five were new, including one (1) with a dioxa[4.3.3]propellane ring system, were discovered, identified, and structurally elucidated from Neosetophoma sp.

A Mild, Functional Group Tolerant Addition of Organozinc Nucleophiles to N-Activated Quinolines and Isoquinolines.

An addition of organozinc nucleophiles to N-acyl activated quinolines and isoquinolines is described. Simple transmetalation with the corresponding Grignard reagents using ZnCl forms organozinc compounds which are functional group tolerant and stable to reactive acyl chloride reagents for extended periods. A wide variety of substrates which include reactive electron-withdrawing groups are well tolerated to form 2-substituted dihydroquinolines and dihydroisoquinolines.

Synthesis of HIV-Maturation Inhibitor BMS-955176 from Betulin by an Enabling Oxidation Strategy.

A concise and scalable second generation synthesis of HIV maturation inhibitor BMS-955176 is described. The synthesis is framed by an oxidation strategy highlighted by a Cu mediated aerobic oxidation of betulin, a highly selective PIFA mediated dehydrogenation of an oxime, and a subsequent Lossen rearrangement which occurs through a unique reaction mechanism for the installation of the C17 amino functionality. The synthetic route proceeds in 7 steps with 47% overall yield and begins from the abundant and inexpensive natural product betulin.

Revisiting a Classic Transformation: A Lossen Rearrangement Initiated by Nitriles and "Pseudo-Catalytic" in Isocyanate.

The direct conversion of a hydroxamic acid to an amine has been accomplished in a single step in the synthesis of HIV drug candidate BMS-955176. This process utilizes catalytic base and proceeds under mild conditions (CHCN, cat. DBU, 60 °C), without the need for strong electrophiles required for typical Lossen rearrangements, and can be applied to aliphatic and aromatic hydroxamic acids.

Autoxidation Products of Betulonaldehyde.

Three major degradation products resulted from the exposure of betulonaldehyde (1) to air in solution at room temperature. From HRMS and NMR data, the products, which were isolated by preparative supercritical fluid chromatography (SFC), were identified as betulonic acid (2) and C-17 hydroperoxide epimers 3 (β-OOH) and 4 (α-OOH). For 3 and 4, the H-18 multiplet pattern of the isolated products established the configuration at C-17.

Cytotoxic epipolythiodioxopiperazine alkaloids from filamentous fungi of the Bionectriaceae.

Bioactivity-directed fractionation of the organic extracts of two filamentous fungi of the Bionectriaceae, strains MSX 64546 and MSX 59553 from the Mycosynthetix library, led to the isolation of a new dimeric epipolythiodioxopiperazine alkaloid, verticillin H (1), along with six related analogs, Sch 52900 (2), verticillin A (3), gliocladicillin C (4), Sch 52901 (5), 11'-deoxyverticillin A (6) and gliocladicillin A (7). The structures of compounds 1-7 were determined by extensive NMR and HRMS analyses, as well as by comparisons to the literature. All compounds (1-7) were evaluated for cytotoxicity against a panel of human cancer cell lines, displaying IC(50) values ranging from 1.

Effects of (5Z)-7-oxozeaenol on the oxidative pathway of cancer cells.

Aim: As part of an on going investigation of novel anticancer agents from natural origin, the biological and cellular effects of (5Z)-7-oxozeaenol on cancer cells were investigated.

Materials And Methods: The expression of nuclear factor kappa B (NF-κB), IκB kinase (IKKα), IKKβ and caspase-3 were analyzed by western blot. Reactive oxygen species (ROS) fluorescence and caspase luminescent assays were used to assess the intracellular effects in HeLa cervical and HT-29 colon cancer cell lines.

Effects of (5Z)-7-oxozeaenol on MDA-MB-231 breast cancer cells.

Aim: (5Z)-7-Oxozeaenol was studied to reveal the path through which it exerts its effects on triple-negative MDA-MB-231 breast cancer cells.

Materials And Methods: The apoptotic effect of (5Z)-7-oxozeaenol on MDA-MB-231 cancer cells was analyzed by cell flow cytometry. The effects of (5Z)-7-oxozeaenol on the expression of the nuclear factor kappa B (NF-κB) p65, p50, IκB kinase (IKKα), IKKβ and caspase-7 were analyzed by western blot.

Peptaibols from two unidentified fungi of the order Hypocreales with cytotoxic, antibiotic, and anthelmintic activities.

As part of an ongoing investigation of filamentous fungi for anticancer leads, an active culture was identified from the Mycosynthetix library (MSX 70741, of the order Hypocreales, Ascomycota). The fungal extract exhibited cytotoxic activity against the H460 (human nonsmall cell lung carcinoma) cell line, and bioactivity-directed fractionation yielded peptaibols 1-12 and harzianums A (13) and B (14). Structure elucidation of 1-12 was facilitated by high-resolution MS/MS using higher-energy collisional dissociation and by high field NMR (950 MHz).

Thielavin B methyl ester: a cytotoxic benzoate trimer from an unidentified fungus (MSX 55526) from the Order Sordariales.

As part of our ongoing investigation of filamentous fungi for anticancer leads, an active fungal extract was identified from the Mycosynthetix library (MSX 55526; from the Order Sordariales). Bioactivity-directed fractionation yielded the known ergosterol peroxide (2) and 5α,8α-epidioxyergosta-6,9(11),22-trien-3β-ol(3), and a new benzoate trimer, termed thielavin B methyl ester (1). The structure elucidation of 1 was facilitated by the use of HRMS coupled to an APPI (atmospheric pressure photoionization) source.

Cytotoxic xanthone-anthraquinone heterodimers from an unidentified fungus of the order Hypocreales (MSX 17022).

Two new xanthone-anthraquinone heterodimers, acremoxanthone C (5) and acremoxanthone D (2), have been isolated from an extract of an unidentified fungus of the order Hypocreales (MSX 17022) by bioactivity-directed fractionation as part of a search for anticancer leads from filamentous fungi. Two known related compounds, acremonidin A (4) and acremonidin C (3) were also isolated, as was a known benzophenone, moniliphenone (1). The structures of these isolates were determined via extensive use of spectroscopic and spectrometric tools in conjunction with comparisons to the literature.

Obionin B: An o-pyranonaphthoquinone decaketide from an unidentified fungus (MSX 63619) from the Order Pleosporales.

A fungal extract (MSX 63619), from the Mycosynthetix library of over 50,000 fungi, displayed promising cytotoxicity against a human tumor cell panel. Bioactivity-directed fractionation led to the isolation of an o-pyranonaphthoquinone decaketide, which we termed obionin B (1). The structure of 1 was deduced via spectroscopic and spectrometric techniques.

Resorcylic acid lactones with cytotoxic and NF-κB inhibitory activities and their structure-activity relationships.

As part of our ongoing investigation of filamentous fungi for anticancer leads, an active fungal extract was identified from the Mycosynthetix library (MSX 63935; related to Phoma sp.). The initial extract exhibited cytotoxic activity against the H460 (human non-small cell lung carcinoma) and SF268 (human astrocytoma) cell lines and was selected for further study.

Anthelmintic constituents of Clonostachys candelabrum.

Five diastereomeric polyketide glycosides, roselipins 3A-3E (1-5), have been isolated from the acetone extract of Clonostachys candelabrum on the basis of their positive anthelmintic activity. The structures of these compounds were elucidated by comparison of their NMR and MS data to those of previously reported roselipins and related structures, and were confirmed by 2D-NMR spectral analysis. Known compounds linoleic acid (6) and aurantiogliocladin (7) were also isolated as active anthelmintic components, although much less potent than the roselipins.

Biosynthesis of the aminocyclitol subunit of hygromycin A in Streptomyces hygroscopicus NRRL 2388.

The antibacterial activity of hygromycin A (HA) arises from protein synthesis inhibition and is dependent upon a methylenedioxy bridged-aminocyclitol moiety. Selective gene deletions and chemical complementation in Streptomyces hygroscopicus NRRL 2388 showed that the hyg18 and hyg25 gene products, proposed to generate a myo-inositol intermediate, are dispensable for HA biosynthesis but contribute to antibiotic yields. Hyg8 and Hyg17, proposed to introduce the amine functionality, are essential for HA biosynthesis.

Anthelmintic macrolactams from Nonomuraea turkmeniaca MA7381.

A new macrolactam, fluvirucin B0 (1), and two known macrolactams, Sch 38516/fluvirucin B1 (2) and Sch 39185/fluvirucin B3 (3), have been isolated from an acetone extract of a strain of Nonomuraea turkmeniaca. These compounds were isolated by bioassay-guided fractionation as part of our search for new anthelmintics. The structures of these compounds were elucidated by comparison of their NMR and MS data to those of previously reported fluvirucins, and confirmed by 2D-NMR.

Noreupenifeldin, a tropolone from an unidentified ascomycete.

Noreupenifeldin ( 2), a new monotropolone derivative of the bistropolone eupenifeldin ( 1), was isolated from an unidentified ascomycete by bioassay-guided fractionation as part of our search for new anthelmintics. The structure of 1 was confirmed by comparison with literature data. The structure of 2 was elucidated from MS and 1D and 2D NMR data.

Flavones from Struthiola argentea with anthelmintic activity in vitro.

Parasitic diseases caused by helminthes lead to significant health hazards to animals resulting in enormous economic impact. While a number of anthelmintics are currently available, all are encountering resistance and ones with a mode of action are needed. We report herein bioassay-guided isolation of three anthelmintic flavones 1-3, including the flavone, 5,6,2',5',6'-pentamethoxy-3',4'-methylenedioxyflavone (3) from the methanol extract of Struthiola argentea (Thymelaeaceae).