Diastereoselective Pd-catalyzed Decarboxylative (4+2) Cycloaddition Reactions of 4-Vinylbenzoxazinanones and 2-Nitro-1,3-enynes.

A formal palladium-catalyzed decarboxylative (4+2) cycloaddition reaction between 4-vinylbenzoxazinanones and 2-nitro-1,3-enynes has been developed to produce highly valuable, densely functionalized tetrahydroquinolines in moderate to excellent yields with high diastereoselectivity under mild reaction conditions. The optimised protocol tolerates a range of substituted 2-nitro-1,3-enynes, which represent an under-utilized class of dipolarophile for transition-metal catalyzed cycloadditions. The employed reaction methodology facilitates efficient cycloaddition with both N-H- and N-Ts-4-vinylbenzoxazinanone dipole precursors. The stereochemistry of the major and minor diastereomeric (4+2) cycloadducts was determined by single crystal X-ray analyses. A mechanistic rationale for the high intrinsic diastereoselectivity and preliminary enantioselective experiments are also presented. The tetrahydroquinoline cycloadduct products feature numerous pendant functionalities, including a vinyl handle, an internal alkyne motif and a nitro functionality (which functions as a latent C-3 nitrogen substituent) for further synthetic manipulations.

Diastereoselective Petasis-Borono-Mannich Crotylation Reactions of Chiral α-Heteroatom (F, OBz, OH) Aldehydes: Rapid Access to Valuable Mono and Bicyclic Heterocyclic Scaffolds.

The crotylation reactions of chiral α-F, α-OBz and α-OH aldehydes under Petasis-borono-Mannich conditions using (E)- or (Z)-crotylboronates and primary amines resulted in γ-addition products in high dr and high er. α-F and α-OBz aldehydes gave 1,2-anti-2,3-syn and 1,2-anti-2,3-anti, products, respectively while an α-OH aldehyde gave 1,2-syn-2,3-syn products. The stereochemical outcomes of reactions of the former aldehydes can be explained using a six-membered ring transition state (TS) model in which a Cornforth-like conformation around the imine intermediate is favoured resulting in 1,2-anti products. The 2,3-stereochemical outcome is dependent upon the geometry of the crotylboronate. These TS models were also supported by DFT calculations. The stereochemical outcomes of reactions employing an α-OH aldehyde can be rationalised as occurring via an open-TS involving H-bonding in the imine intermediate between the α-OH group and the imine N atom. Representative products were converted to highly functionalized 1,2,3,6-tetrahydropyridines and 3H-oxazolo[3,4-a]pyridine-3-ones which will be valuable scaffolds in synthesis.

Nickel Phosphite-Catalyzed Tetradehydro-Diels-Alder Reactions of (E)-3-ene-1,8-diynes.

A nickel-catalyzed tetradehydro-Diels-Alder reaction of (E)-3-ene-1,8-diynes for the preparation of isoindolines, dihydroisobenzofurans, and tetrahydroisoquinolines has been developed. A series of air-stable nickel catalysts were used in this study, including the novel nickel(0)-phosphite catalysts, Ni[P(O-3,5-Me-Ph)3]4, Ni[P(O-1-naphthyl)3]4, and Ni[P(O-2-naphthyl)3]4. To help understand the type of intermediate in the initial cycloisomerization process, the trapping of nickellacycle intermediates with pinacolborane to yield vinyl boronates is also discussed.

Synthesis of the Purported Structure of Glyphaeaside C and Proposed Revisions to the Structures of the Glyphaeaside Alkaloids.

The 10 glyphaeaside alkaloids isolated from the roots of Glyphaea brevis were originally purported as piperidine-based 1-C-alkylated iminosugars, with the A-, B-, and C-type glyphaeasides bearing l-DFJ, DGJ, and DNJ ring configurations, respectively. Subsequent investigations have revealed glyphaeaside C as being a pyrrolidine-based iminosugar with a DMDP ring configuration via total synthesis of the revised structure. In this work, side chain diastereomers of the originally purported structure of glyphaeaside C (10) and two related α-1-C-alkylated DNJ derivatives were synthesized from a common precursor, which was prepared in turn via stereoselective Grignard addition to a protected d-glycosylamine, followed by a reductive amination-cyclization sequence. Glycosidase inhibitory activity studies revealed general structure 10 as having potent inhibition against various α-glucosidases and weak inhibition against almond ß-glucosidase in agreement with similar DNJ-based iminosugars and in contrast to natural glyphaeaside C, suggesting that the (1,2-dihydroxy-3-phenyl)propyl moiety does not play a particularly vital role in the inhibitory modes of action of either compound. Furthermore, the absolute configuration of natural glyphaeaside C was proposed as that of d-DMDP, and the structures of the A- and B-type glyphaeasides were revised as 1-deoxy-DALDP and DALDP derivatives, respectively, based on interpretation of their reported NMR spectroscopic data.

The Roots of Neorautanenia mitis (A. Rich) Verdcourt: Further Evidence of Its Antidiarrhoeal Activity.

Despite the current management options and therapeutics used in the treatment of diarrhoea, in Africa and Asia, diarrhoea remains a major concern, especially in children under the age of 5 years. Traditional knowledge of medicinal plants used in the management of diarrhoea symptoms can be explored for their efficacy. In Nigeria, the TMPs (Traditional Medicine Practitioners) have, over the years, employed medicinal plants in the management of diarrhoea symptoms. In our current and previous studies, we aimed at validating the effectiveness of Neorautanenia mitis in the management of diarrhoea as claimed by the TMPs. Out of the 20 compounds isolated from N. mitis, the compounds neodulin, pachyrrhizine, neotenone and dolineone were the most abundant, and in this study, neodulin showed a pronounced relaxation of the rhythmic contraction of the isolated rabbit jejunum in an organ bath in a concentration-dependent manner, with a complete relaxation at 60 µg/mL. Neotenone and dolineone showed a dose-dependent inhibition of defecation of 65.07%, and 50.01%, respectively, at 20 mg/kg in a castor-oil-induced diarrhoea model. This is a strong indication that compounds from N. mitis possess antidiarrhoeal properties, thereby giving credence to its traditional usage in diarrhoea therapy, and therefore validating its antidiarrhoeal activity and its being worthy of further investigation.

Synthesis of 7α-Methoxy-7-(4-phenyl-1H-1,2,3-triazol-1-yl)acetamino-3'-arylthio-cephalosporic Acid Derivatives from 7-Aminocephalosporic Acid.

The aim of this project was to develop a synthetic protocol for the preparation of a cephamycin scaffold that would readily allow the synthesis of its analogues with variations at the C-7 amino group and the C-3' position. We also aimed to develop a method that avoided the use of toxic and potentially explosive diphenyldiazomethane. These aims were achieved via the synthesis of the novel α-bromo acetamide 18 which allowed functionalization at the α-bromo acetamide position by azide and then the introduction of a 4-phenyl-1H-1,2,3-triazol-1-yl moiety via a Cu(I)-catalysed azide-alkyne cycloaddition reaction with phenylacetylene. Palladium-catalyzed arylthioallylation reactions then allowed the introduction of 3'-arylthiol substituents. We also report for the first time the synthesis of the 4-methoxybenzyl ester of (6R,7S)-3-[(acetyloxy)methyl]-7-amino-7-methoxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid and the use of diphenyl trichloroacetimidate, instead of diphenyldiazomethane, and 4-methoxybenzyl trichloroacetimidate to prepare related 4-methoxybenzyl esters. The chemistry described, and several of the synthetic intermediates reported here, are potentially valuable methods and scaffolds, respectively, for further development of ß-lactam antibiotics.

A Rare Alder-ene Cycloisomerization of 1,6-Allenynes.

Thermally induced cycloisomerization reactions of 1,6-allenynes gives α-methylene-γ-lactams via intramolecular Alder-ene reactions. The mechanism is supported by computational and deuterium labelling studies. This thermal, non-radical method enables the discovery of a hitherto unknown route that proceeds via a divergent mechanism distinct from the previous [2+2] cycloisomerization manifold.

Synthesis of spirocyclic heterocycles from α,ß-unsaturated N-acyliminium ions.

The reactions of α,ß-unsaturated N-acyliminium ions, generated in situ from 4(S)-O-substitutedhydroxy-5-hydroxy-5-vinyl-N-alkylpyrrolidin-2-ones, with allylsilanes and indoles leading to the formation of spirocyclic heterocycles, are reported. Six single crystal X-ray structures and extensive 2D NMR experiments confirmed the structures and stereochemistries of these products. In addition, computational studies provided mechanistic insights and an understanding of the stereochemical outcomes of these reactions.

Five-membered cyclic sulfamidate imines: versatile scaffolds for organic synthesis.

In recent years, five-membered ring cyclic sulfamidate imines (5H-1,2,3-oxathiazole 2,2-dioxides) have received increasing attention as useful precursors for the stereoselective synthesis of many valuable heterocycles. Bearing a reactive N-sulfonyl imine moiety as part of the stereodefined skeleton, this sulfamidate imine platform has been utilised as a substrate in many reactions, including nucleophilic additions and reductions, to prepare highly functionalised cyclic sulfamidates. In addition, cyclic sulfamidate imines can also readily participate as nucleophiles in many chemical transformations, owing to the acidic proton(s) adjacent to the imine moiety. This short review highlights recent developments involving cyclic sulfamidate imines, including their synthesis and reactivity, with a focus on stereoselective processes.

α-Glucosidase inhibitory and nitric oxide production inhibitory activities of alkaloids isolated from a twig extract of Polyalthia cinnamomea.

The first phytochemical investigation of Polyalthia cinnamomea led to the isolation and identification of two new oxoprotoberberine alkaloids, (-)-(13aS)-polyalthiacinnamines A and B, together with eleven known compounds. The structures of the new compounds were elucidated by extensive spectroscopic methods. The absolute configuration of miliusacunine E and consanguine B was established by X-ray diffraction analysis using Cu Kα radiation and ECD spectra, whereas the absolute configurations of polyalthiacinnamines A and B were established by comparison of their ECD spectra and specific rotations with those of miliusacunine E and consanguine B. Compounds 1-4, 6, and 8 exhibited α-glucosidase inhibitory activities (IC50 values ranging from 11.3 to 57.9 µM) better than a positive control (acarbose, IC50 83.5 µM). Compound 2 also exhibited NO production inhibitory activity with an IC50 value of 24.4 µM (indomethacin, a positive control, IC50 = 32.2 µM).

Phloroglucinol Benzophenones and Xanthones from the Leaves of Garcinia cowa and Their Nitric Oxide Production and α-Glucosidase Inhibitory Activities.

Five new compounds-two phloroglucinol benzophenones, garciniacowones F (1) and G (2), and three xanthones, garciniacowones H (3), I (4), and J (5)-together with seven known xanthones (6-12) were isolated from the fresh leaves of Garcinia cowa. Their structures were elucidated by detailed analysis of NMR and MS data. Compounds 1 and 2 are phloroglucinol benzophenones containing a polyprenylated bicyclo[3.3.1]nonane ring system, while compounds 3-5 are rare xanthones having farnesyl (3 and 5) and geranylgeranyl (5) units at C-8. Compounds 1, 3, 4, 7, 8, and 10 exhibited inhibitory effects on NO production in LPS-induced RAW264.7 macrophage cells with IC50 values ranging from 5.4 to 18.6 µM. Compounds 4 and 8 had α-glucosidase inhibitory activities with IC50 values of 15.4 and 11.4 µM, respectively, which were more potent than that of the acarbose control.

1,2-Addition versus homoconjugate addition reactions of indoles and electron-rich arenes to α-cyclopropyl N-acyliminium ions: synthetic and computational studies.

An investigation of the reactivity of α-cyclopropyl N-acyliminium ions towards indoles has resulted in the unprecedented synthesis of 5-cyclopropyl-5-(3-indoyl)pyrrolidin-2-ones via 1,2-addition reactions and, in the case of highly electron deficient indoles and electron rich arenes, spiroheterocycles via sequential homoconjugate and 1,2-addition reactions with often high diastereoselective control at the C-5 quaternary stereocentres. Computational studies provided support for the proposed mechanisms and stereochemical outcome of these reactions, clearly showing that the 1,2-addition pathway is kinetically controlled. In reactions where the 1,2-adduct is destabilised, for example when the arene ring is less nucleophilic, the 1,2-addition is reversible and the thermodynamically preferred homoconjugate addition and subsequent rearrangement and cyclisation reactions become the major pathway.

α-Glucosidase Inhibitory Flavonoids and Oxepinones from the Leaf and Twig Extracts of Desmos cochinchinensis.

Four new flavonoids (1-4), a new benzyl benzoate derivative (5), five new oxepinones (6-10), and 14 known compounds (11-24) were isolated from the leaf and twig extracts of Desmos cochinchinensis. Their structures were established by spectroscopic methods. The structure of 1 was also confirmed by X-ray diffraction data. The absolute configurations of 3, 4, and 6-10 were determined from comparisons of their ECD spectra with those of relevant reported compounds. Compounds 1, 2, 6, 8, 10, 12-15, and 17 showed α-glucosidase inhibitory activities with IC50 values ranging from 0.2 to 4.9 µM.

Dasymaschalolactams A-E, Aristolactams from a Twig Extract of Dasymaschalon dasymaschalum.

Five new aristolactam alkaloids (1-5), dasymaschalolactams A-E, and the first isolation of dasymaschalolactone (17) as a natural product, together with 19 known compounds (6-16 and 18-25) were isolated from the twig extract of Dasymaschalon dasymaschalum. Their structures were elucidated by spectroscopic methods as well as comparisons made from the literature. Compounds 20 and 21 showed α-glucosidase inhibitory activities with IC50 values of 4.5 and 24.7 µM, respectively.

Mallopenins A-E, Antibacterial Phenolic Derivatives from the Fruits of Mallotus philippensis.

The chromatographic separation of the components of the acetone extract of Mallotus philippensis fruits yielded five new phenolic compounds including two chalcones, 1 and 3, a functionalized phloroglucinol, 2, two flavanones, 4 and 5, and six known compounds. The structures of 1-5 were confirmed by NMR and mass analyses. Racemic compounds 1 and 2 were separated by chiral-phase HPLC, and the absolute configuration of (+)-1 was confirmed by X-ray diffraction studies and ECD spectroscopic data. The configurations of the enantiomers of 2 were defined by comparison of its ECD data with those of (+)-1. Compounds 6 and 7 exhibited significant antibacterial activities, with MIC values ranging from 3.8 to 15.5 µM.

Antibacterial and Inhibitory Activities against Nitric Oxide Production of Coumaronochromones and Prenylated Isoflavones from Millettia extensa.

A chemical investigation of leaf and root extracts of Millettia extensa led to the isolation and structural elucidation of four new prenylated isoflavones, millexatins G-J (1-4), and three new coumaronochromones, millexatins K-M (5-7), along with 16 known compounds. The structures of the new compounds were determined on the basis of NMR and MS data. Compound 4 is a rare isoflavone having a 2-hydroxyethyl moiety at C-8, whereas the structures of compounds 5-7 formally arise from a ring closure through HO-2' and C-2. The absolute configurations at the C-2 and C-3 positions of 5 and 6 were determined from their ECD spectra through comparison with those of previously reported compounds. Most of compounds were evaluated for their inhibitory effects against nitric oxide (NO) production on RAW264.7 macrophages and their antibacterial activities. Compounds 18 and 19 inhibited NO production with IC50 values of 8.5 and 14.3 µM, respectively. Compounds 13 and 14 showed antibacterial activity against various Gram-positive bacteria with MIC values ranging from 2 to 8 µg/mL.

Corrected Structure of Natural Hyacinthacine C1 via Total Synthesis.

Hyacinthacines C1 and C4 are natural products that were isolated from Hyacinthoides non-scripta and Scilla socialis in 1999 and 2007, respectively. Despite their different 1H NMR and 13C NMR spectroscopic data, these compounds have been assigned the same structures, including absolute configurations. This work details the total synthesis of natural (+)-hyacinthacine C1, whose structure is confirmed as being the C-6 epimer of that reported. The synthetic strategy focused on inverting the configuration at C-1 of the final hyacinthacines via operating the inversion at the corresponding carbon atom in three previously synthesized intermediates. To do this, the advanced intermediates were subjected to Swern oxidation, followed by a stereoselective reduction with L-Selectride. This approach led to the synthesis of (+)-5 -epi-hyacinthacine C1 (15), the corrected structure for (+)-hyacinthacine C1 (19), (+)-6,7-di- epi-hyacinthacine C1 (23), and (+)-7- epi-hyacinthacine C1 (29). Glycosidase inhibition assays revealed that (+)-hyacinthacine C1 (19) proved the most active, with IC50 values of 33.7, 55.5, and 78.2 µM, against the α-glucosidase of rice, human lysosome, and rat intestinal maltase, respectively.

Polyoxygenated Cyclohexenes and Their Chlorinated Derivatives from the Leaves of Uvaria cherrevensis.

The chemical study of leaf extracts from Uvaria cherrevensis resulted in the identification of 11 new polyoxygenated cyclohexenes, cherrevenols A-K (1-11), and a new seco-cyclohexene derivative, cherrevenol L (12). Nine known compounds (13-21) were also isolated. Three of the isolated compounds are chlorinated polyoxygenated cyclohexenes. The structures of these compounds were determined using spectroscopic methods and, in some cases (compounds 2, 6, 8, and 10), single-crystal X-ray crystallographic structural analysis or chemical correlation (compounds 6 and 7). Compounds 6 and 7 were both isolated as scalemic mixtures (ee 23-24%).

Amides and Flavonoids from the Fruit and Leaf Extracts of Melodorum siamensis.

Four new chalcones (1, 10, 13, and 14), a new flavanone, (9), a new amide (8), and 19 known compounds were acquired from Melodorum siamensis. The structures were established by NMR and MS data analyses. Compounds 1 (er 1.4:1) and 2 (er 1.1:1) were scalemic and were resolved to yield (-)-1 and (+)-1 and (-)-2 and (+)-2, respectively. The absolute configurations of these compounds were determined from experimental and calculated ECD data. The structures and configurations of (-)-2 and (+)-8 were identified by single-crystal X-ray diffraction analysis. Compound 11 showed nuclear factor-κB inhibitory effects (IC50 = 9 µM) in a pancreatic ß cell line (MIN-6 cells).

Utilization of electrocoagulation for the isolation of alkaloids from the aerial parts of Stemona aphylla and their mosquitocidal activities against Aedes aegypti.

The electrocoagulation (EC) technique is an alternative method of isolating natural products with the advantage of minimizing the amounts of organic solvents required for this process, which are often harmful to the environment. In this research, the EC and the conventional solvent extraction methods were used in the isolation of Stemona alkaloids from the aerial parts of Stemona aphylla. A comparison was made between the amounts of the isolated alkaloids and the solvents used. The isolated alkaloids were evaluated for their larvicidal, ovicidal and oviposition-deterrent activities against the dengue vector, Aedes aegypti. The morphology and histopatology of the alkaloid treated larvae were also investigated. Two Stemona alkaloids, (2'S)-hydroxystemofoline and stemofoline, were isolated from both the EC and the conventional method. The amounts of (2'S)-hydroxystemofoline from the EC method was about the same as that obtained from the conventional method. However, the amounts of stemofoline obtained from the EC method were about two times larger than those obtained from the conventional method. Importantly, the EC method required six times less total organic solvents. The larvicidal activity assays of (2'S)-hydroxystemofoline and stemofoline showed that these were highly effective against Aedes aegypti larvae with LC50 values of 3.91 µg/ml and 4.35 µg/ml, respectively. Whereas, the crude EC extract (LC50 = 11.86 µg/ml) showed greater larvicidal activity than the crude extract obtained from the conventional extraction method (LC50 = 53.40 µg/ml). The morphological observations of the (2'S)-hydroxystemofoline and the stemofoline treated larvae revealed that the anal gills were the sites of aberrations. A histopathological study showed that larvae treated with these alkaloids had cytopathological alterations to the epithelial cells of the midgut. At a concentration 40 µg/ml (2'S)-hydroxystemofoline showed 100% ovicidal activity on 24 h old eggs while stemofoline showed 97.2%. Furthermore, the oviposition-deterrent effects of (2'S)-hydroxystemofoline and stemofoline, at a concentration of 80 µg/ml were 99.5% and 97.2%, respectively.