Letter to the editor on "Antimicrobial compounds isolated from .

A bisphosphonate recently isolated from Tropaeolum tuberosum is almost certainly a contaminant and not a genuine natural product.

Synthesis of 1-Deoxymannojirimycin from d-Fructose using the Mitsunobu Reaction.

Three different Mitsunobu reactions have been investigated for the synthesis of 1-deoxymannojirimycin (1-DMJ) from d-fructose. The highest yielding and most practical synthesis can be undertaken on a 10 g scale with minimal chromatography. In the key step, ,-di-Boc-hydroxylamine reacts with methyl 1,3-isopropylidene-α-d-fructofuranose under Mitsunobu conditions to give .

Computational discoveries of reaction mechanisms: recent highlights and emerging challenges.

This review examines some of the notable advances and trends that have shaped the field of computational elucidation of organic reaction mechanisms over the last 10-15 years. It highlights the types of mechanistic problems that have recently become possible to study and summarizes the methodological developments that have permitted these new advances. Case studies are taken from three representative areas of organic chemistry-asymmetric catalysis, glycosylation reactions, and single electron transfer reactions-which illustrate themes common to the broader field.

Synthesis of New Triazolopyrazine Antimalarial Compounds.

A radical approach to late-stage functionalization using photoredox and Diversinate chemistry on the Open Source Malaria (OSM) triazolopyrazine scaffold (Series 4) resulted in the synthesis of 12 new analogues, which were characterized by NMR, UV, and MS data analysis. The structures of four triazolopyrazines were confirmed by X-ray crystal structure analysis. Several minor and unexpected side products were generated during these studies, including two resulting from a possible disproportionation reaction.

Genome-Inspired Chemical Exploration of Marine Fungus MF071.

The marine-derived fungus MF071, isolated from sediment collected from the Bohai Sea, China, yielded two new compounds 19,20-epoxy-18-oxotryprostatin A () and 20-hydroxy-18-oxotryprostatin A (), in addition to 28 known compounds (-). The chemical structures were established on the basis of 1D, 2D NMR and HRESIMS spectroscopic data. This is the first report on NMR data of monomethylsulochrin-4-sulphate () and pseurotin H () as naturally occurring compounds.

Mechanistic Aspects of Hydrosilane/Potassium -Butoxide (HSiR/KO Bu)-Mediated Reactions.

The hydrosilane/potassium -butoxide reagent system has attracted significant attention over the last 5 years since the discovery of its ability to silylate heteroarene C-H bonds. Numerous useful HSiR/KO Bu-mediated transformations are now known, including silylation of sp, sp, and sp C-H bonds, reductive cleavage of C-O, C-S, and C-N bonds, reduction of polycyclic arenes, and hydrosilylation and polymerization of styrenes. This mini-review surveys the rich diversity of reaction mechanisms, both ionic and free radical and including hydride transfer, H atom transfer, and electron transfer, that have been uncovered during recent studies on the HSiR/KO Bu reagent system.

Reaction of Papaverine with Baran Diversinates.

The reaction of papaverine with a series of Baran Diversinates is reported. Although the yields were low, it was possible to synthesize a small biodiscovery library using this plant alkaloid as a scaffold for late-stage C-H functionalization. Ten papaverine analogues (-), including seven new compounds, were synthesized.

Design and Synthesis of Natural Product Inspired Libraries Based on the Three-Dimensional (3D) Cedrane Scaffold: Toward the Exploration of 3D Biological Space.

A chemoinformatic method was developed to extract nonflat scaffolds embedded in natural products within the Dictionary of Natural Products (DNP). The cedrane scaffold was then chosen as an example of a nonflat scaffold that directs substituents in three-dimensional (3D) space. A cedrane scaffold that has three orthogonal handles to allow generation of 1D, 2D, and 3D libraries was synthesized on a large scale.

Ionic and Neutral Mechanisms for C-H Bond Silylation of Aromatic Heterocycles Catalyzed by Potassium tert-Butoxide.

Exploiting C-H bond activation is difficult, although some success has been achieved using precious metal catalysts. Recently, it was reported that C-H bonds in aromatic heterocycles were converted to C-Si bonds by reaction with hydrosilanes under the catalytic action of potassium tert-butoxide alone. The use of Earth-abundant potassium cation as a catalyst for C-H bond functionalization seems to be without precedent, and no mechanism for the process was established.

Discovery of new nanomolar inhibitors of GPa: Extension of 2-oxo-1,2-dihydropyridinyl-3-yl amide-based GPa inhibitors.

Glycogen Phosphorylase (GP) is a functionally active dimeric enzyme, which is a target for inhibition of the conversion of glycogen to glucose-1-phosphate. In this study we report the design and synthesis of 14 new pyridone derivatives, and seek to extend the SAR analysis of these compounds. The SAR revealed the minor influence of the amide group, importance of the pyridone ring both spatially around the pyridine ring and for possible π-stacking, and confirmed a preference for inclusion of 3,4-dichlorobenzyl moieties, as bookends to the pyridone scaffold.

2-Oxo-1,2-dihydropyridinyl-3-yl amide-based GPa inhibitors: Design, synthesis and structure-activity relationship study.

Glycogen phosphorylase (GP), which plays a crucial role in the conversion of glycogen to glucose-1-phosphate, is a target for therapeutic intervention in diabetes. In this study, we report the design and synthesis of 29 new derivatives of 2-oxo-1,2-dihydro pyridin-3-yl amides, as potential inhibitors of GP. The hit rate (45%) was high with 13 compounds inhibiting GPa (between 33% at 4.

Direct Mitsunobu monoesterification of N-protected tobramycin competes with intramolecular pyrrolidine formation in ester prodrug synthesis.

Unlike the related aminoglycoside neomycin B, N-protected tobramycin can be selectively esterified at its sole, primary hydroxyl group under Mitsunobu conditions. However, depending on the reaction conditions, the reaction can take a different course with intramolecular cyclization of an N-Boc amine leading to formation of an unusual tobramycin pyrrolidine derivative as the major reaction product.

Synthesis, screening and docking of small heterocycles as glycogen phosphorylase inhibitors.

A series of morpholine substituted amino acids (phenylalanine, leucine, lysine and glutamic acid) was synthesized. A fragment-based screening approach was then used to evaluate a series of small heterocycles, including morpholine, oxazoline, dihydro-1,3-oxazine, tetrahydro-1,3-oxazepine, thiazoline, tetrahydro-1,3-pyrimidine, tetrahydro-1,3-diazepine and hexahydro-1H-benzimidazole, as potential inhibitors of Glycogen Phosphorylase a. Thiazoline 7 displayed an improved potency (IC50 of 25 μM) and had good LE and LELP values, as compared to heterocycles 1, 5, 9-13 and 19 (IC50 values of 1.

Total synthesis of thiaplakortone a: derivatives as metabolically stable leads for the treatment of malaria.

Thiaplakortone A (3a), an antimalarial natural product, was prepared by an operationally simple and scalable synthesis. In our efforts to deliver a lead compound with improved potency, metabolic stability, and selectivity, the synthesis was diverted to access a series of analogues. Compounds 3a-d showed nanomolar activity against the chloroquine-sensitive (3D7) Plasmodium falciparum line and were more active against the chloroquine- and mefloquine-resistant (Dd2) P.

Euodenine A: a small-molecule agonist of human TLR4.

A small-molecule natural product, euodenine A (1), was identified as an agonist of the human TLR4 receptor. Euodenine A was isolated from the leaves of Euodia asteridula (Rutaceae) found in Papua New Guinea and has an unusual U-shaped structure. It was synthesized along with a series of analogues that exhibit potent and selective agonism of the TLR4 receptor.

The glycogen phosphorylase inhibitor 2-(3-benzylamino-2-oxo-1,2-dihydropyridin-1-yl)-N-(3,4-dichlorobenzyl)acetamide.

The molecular structure of the title compound, C21H19Cl2N3O2, a potent glycogen phosphorylase a (GPa) inhibitor (IC50 of 6.3 µM), consists of four distinct conjugated π systems separated by rotatable C-C bonds at the methylene groups. Molecules are linked into dimers disposed about a crystallographic centre of symmetry through a cyclic N-H.

Cyclodehydration of N-(aminoalkyl)benzamides under mild conditions with a Hendrickson reagent analogue.

Methods for the cyclodehydration of N-(aminoalkyl)benzamides are few and employ harsh reaction conditions. We have found that the easily prepared phosphonium anhydrides 1 (Hendrickson reagent) or 2 can be used for cyclodehydration of N-(aminoalkyl)benzamides under very mild conditions (room temperature) to produce five-, six-, and seven-membered cyclic amidines. Good yields are obtained by employing a temporary trityl group protection strategy.

Formation of an unusual four-membered nitrogen ring (tetrazetidine) radical cation.

Treatment of triphenylphosphine (Ph(3)P) with an excess of diisopropyl azodicarboxylate at 0-25 °C resulted in the formation of a symmetrical tetraalkyl tetrazetidinetetracarboxylate radical cation, containing the elusive cyclic N(4) ring system. Electron paramagnetic resonance (EPR) spectroscopy revealed a 9-line spectrum, with hyperfine coupling constants indicative of four almost magnetically equivalent nitrogen atoms. The radical species was surprisingly long-lived, and could still be observed several hours after generation and standing at 25 °C.

rac-3-exo-Ammonio-7-anti-carb-oxy-tricyclo-[2.2.1.0.(2,6)]heptane-3-endo-carboxyl-ate monohydrate.

The racemic title compound, C(9)H(11)NO(4)·H(2)O, a tricyclic rearranged amino-norbornane dicarb-oxy-lic acid, is a conformationally rigid analogue of glutamic acid and exists as an ammonium-carboxyl-ate zwitterion, with the bridghead carb-oxy-lic acid group anti-related. In the crystal, N-H⋯O and O-H⋯O hydrogen bonds involving the ammonium, carb-oxy-lic acid and water donor groups with both water and carboxyl O-atom acceptors give a three-dimensional framework structure.

Synthesis of antitrypanosomal 1,2-dioxane derivatives based on a natural product scaffold.

A short practical synthesis of a new natural product based scaffold (6), based on antitrypanosomal and antimalarial compounds isolated from different Plakortis species is described. The scaffold contains a peroxide unit that is surprisingly stable to chemical manipulation elsewhere in the molecule, enabling it to be elaborated into a small library of derivatives. It is stable to ozonolysis, reductive work-up with dimethylsulfide and the Wittig reaction with stabilized phosphorus ylides.

Glycogen phosphorylase inhibitory effects of 2-oxo-1,2-dihydropyridin-3-yl amide derivatives.

Glycogen phosphorylase (GP) plays a crucial role in the conversion of glycogen to glucose-1-phosphate (and in turn glucose) and is a promising target for therapeutic intervention in diabetes. In this study we synthesized new derivatives of 2-oxo-1,2-dihydropyridin-3-yl amides using a facile aminolysis reaction, in which different alkyl and aryl esters and amides are substituted at N-1 and C-3 of the heterocyclic ring. The in vitro inhibitory activity of compounds against glycogen phosphorylase was evaluated.

The use of phosphonium anhydrides for the synthesis of 2-oxazolines, 2-thiazolines and 2-dihydrooxazine under mild conditions.

Beta-hydroxy amides 6 and 7 were treated with triphenylphosphonium anhydride trifluoromethane sulfonate (3), or the cyclic analogue 4, to generate 2-oxazolines 5 and 8 under mild conditions. The reaction was optimised by examining the number of equivalents of reagents 3 or 4, or diisopropylethyl amine required to best effect cyclisation. The effects of altering the reaction temperature, reaction time, concentration, solvent, and addition rate also were investigated.

Synthesis of four novel natural product inspired scaffolds for drug discovery.

Inspired by the novel spiro structures of a number of bioactive natural products such as the histrionicotoxins, a series of novel spiro scaffolds have been designed and robust syntheses developed. The scaffolds are ready-to-use building blocks and can be easily prepared on a 5-20 g scale. They contain two amino groups (one Boc-protected) and have been designed for ease of conversion to a lead generation library, using either amide formation or reductive amination procedures.

Selective mono reduction of bis-phosphine oxides under mild conditions.

Bis-phosphine oxides can be selectively reduced to bis-phosphine monoxides under exceptionally mild conditions using triflic anhydride and a thiol.

The structure of polymer-supported triphenylphosphine ditriflate: a potentially useful reagent in organic synthesis.

The structure of a polymer-supported version of the Hendrickson "POP" reagent, prepared by the reaction of polymer-supported triphenylphosphine oxide 1 with triflic anhydride, is established as an equilibrium mixture of polymer-supported triphenylphosphine ditriflate 3 (delta 79.4 ppm) and polymer-supported phosphonium anhydride 4 (delta 73.3 ppm).