Synthesis of 13 (R)-Hyd roxy-7Z,10Z,13R,14E,16Z,19Z Docosapentaenoic Acid (13R-HDPA) and Its Biosynthetic Conversion to the 13-Series Resolvins

Specialized pro-resolving lipid mediators are biosynthesized during the resolution phase of acute inflammation from n-3 polyunsaturated fatty acids. Recently, the isolation and identification of the four novel mediators denoted 13-series resolvins, namely, RvT1 (1), RvT2 (2), RvT3 (3) and RvT4 (4), were reported, which showed potent bioactions characteristic for specialized pro-resolving lipid mediators. Herein, based on results from LC/MS-MS metabololipidomics and the stereoselective synthesis of 13(R)-hydroxy-7Z,10Z,13R,14E,16Z,19Z docosapentaenoic acid (13R-HDPA, 5), we provide direct evidence that the four novel mediators 1−4 are all biosynthesized from the pivotal intermediate 5. The UV and LC/MS-MS results from synthetic 13R-HDPA (5) matched those from endogenously and biosynthetically produced material obtained from in vivo infectious exudates, endothelial cells, and human recombinant COX-2 enzyme. Stereochemically pure 5 was obtained with the use of a chiral pool starting material that installed the configuration at the C-13 atom as R. Two stereoselective Z-Wittig reactions and two Z-selective reductions of internal alkynes afforded the geometrically pure alkene moieties in 5. Incubation of 5 with isolated human neutrophils gave all four RvTs. The results presented herein provide new knowledge on the biosynthetic pathways and the enzymatic origin of RvTs 1−4

Safe Synthesis of Alkylhydroxy and Alkylamino Nitramines

Three different protocols for the syntheses of hydroxyalkylnitramines are presented and compared. Safety issues regarding the synthesis of nitramines are also discussed.Safe Synthesis of Alkylhydroxy and Alkylamino NitraminespublishedVersio

Enantioselective Organocatalyzed Bromolactonizations: Applications in Natural Product Synthesis

Asymmetric bromolactonization reactions of δ-unsaturated carboxylic acids have been investigated in the presence of 10 chiral squaramide hydrogen-bonding organocatalysts. The best catalyst enabled the cyclization of several 5-arylhex-5-enoic acids into the corresponding bromolactones with up to 96% ee and in high to excellent chemical yields. The reported catalysts are prepared in a straightforward manner in two steps from dimethyl squarate. The utility of the developed protocol was demonstrated in highly enantioselective syntheses of the sesquiterpenoids (−)-gossoronol and (−)-boivinianin B. Both natural products were obtained in ≥99% enantiomeric excess

Safe Synthesis of Alkylhydroxy and Alkylamino Nitramines

Three different protocols for the syntheses of hydroxyalkylnitramines are presented and compared. Safety issues regarding the synthesis of nitramines are also discussed

A Modular Strategy for the Synthesis of Dothideopyrones E and F, Secondary Metabolites from an Endolichenic Fungus

Endolichenic fungi are a rich source of natural products with a wide range of potent bioactivities. Herein, syntheses of the two naturally occurring α-pyrones dothideopyrone E and F are presented. These natural products were isolated from a culture of the endolichenic fungus Dothideomycetes sp. EL003334. The outlined strategy includes a Fu–Suzuki akyl–alkyl cross-coupling, a MacMillan α-oxyamination, and a Sato’s pericyclic cascade process to construct the 4-hydroxy-2-pyrone ring system. All the obtained data on the synthesized compounds matched with that of the isolated material

Stereoselective Synthesis and Structural Confirmation of the Specialized Pro-Resolving Mediator Resolvin E4

Herein, we report the stereoselective and convergent synthesis of resolvin E4, a newly identified specialized pro-resolving mediator. This synthesis proves the absolute configuration and exact olefin geometry. Key elements of the successful strategy include a highly stereoselective MacMillan organocatalytic oxyamination, a Midland Alpine borane reduction, and the use of a 1,4-pentadiyne unit as a linchpin building block. The application of reaction telescoping in several of the synthetic transformations enabled the preparation of the resolvin E4 methyl ester in 10% yield over 10 steps (longest linear sequence). The physical property (UV–Vis and LC–MS/MS) data of synthetic resolvin E4 matched those obtained from biologically produced material

Synthesis, Biological Investigation, and Structural Revision of Sielboldianin A

The two <i>ar</i>-bisabol sesquiterpenoids (+)-sielboldianin A (<b>1</b>) and (+)-sielboldianin B (<b>2</b>) were isolated from the stem bark of the plant <i>Fraxinus sielboldiana</i> and belong to a medicinally interesting class of natural products used in traditional Chinese medicine. Herein the total synthesis of the proposed structure of (+)-sielboldianin A (<b>1</b>) is reported using an organocatalyzed enantioselective bromolactonization protocol. X-ray analysis of a key intermediate together with specific rotation values and NOESY data of the synthesized product enabled the revision of the absolute configuration of the natural product (+)-sielboldianin A to (7<i>R</i>,10<i>R</i>). Studies on the antioxidant effects using two cell-based assays were conducted. These studies revealed that the enantiomer of <b>1</b> exhibited antioxidant effects with IC₅₀ values of 18 ± 3 μM in a cellular lipid peroxidation antioxidant activity assay. Moreover, (−)-<b>1</b> showed strong protective effects against reactive oxygen species in a cell-based antioxidant activity assay (IC₅₀ = 31 ± 5 μM). In addition, the two <i>ar</i>-sesquiterpenoids (−)-boivinianin B and (−)-gossoronol showed no effect in either assay. No cytotoxic activity in the K562 cancer cell line was observed for the three sesquiterpenoids tested (IC₅₀ > 50 μM)

Synthesis and biological evaluations of marine oxohexadecenoic acids: PPARα/γ dual agonism and anti-diabetic target gene effects

Obesity and associated disorders such as metabolic syndrome and type 2 diabetes (T2D) have reached epidemic proportions. Several natural products have been reported as Peroxisome Proliferator-Activated Receptor (PPAR) agonists, functioning as lead compounds towards developing new anti-diabetic drugs due to adverse side effects of existing PPAR drugs. We recently isolated and identified (7E)-9-oxohexadec-7-enoic acid (1) and (10E)-9-oxohexadec-10-enoic acid (2) from the marine algae Chaetoceros karianus. Herein we report the total synthesis, pharmacological characterization, and biological evaluations of these naturally occurring oxo-fatty acids (oFAs). The syntheses of 1 and 2 afforded sufficient material for extensive biological evaluations. Both oFAs show an appreciable dose-dependent activation of PPARα and -γ, with EC50 values in the micromolar range, and an ability to regulate important PPAR target genes in hepatocytes and adipocytes. Moreover, both 1 and 2 are able to drive adipogenesis when evaluated in the Simpson-Golabi-Behmel syndrome (SGBS) pre-adipocyte cell model, but with lowered expression of adipocyte markers and reduced lipid accumulation compared to the drug rosiglitazone. This seems to be caused by a transient upregulation of PPARγ and C/EBPα expression. Importantly, whole transcriptome analysis shows that both compounds induce anti-diabetic gene programs in adipocytes by upregulating insulin-sensitizing adipokines and repressing pro-inflammatory cytokines

Protectin D1(n-3 DPA) and resolvin D5(n-3 DPA) are effectors of intestinal protection

William Harvey Research Foundation (T.G. and M.P.). J.D. received funding from the European Research Council under the European Union’s Horizon 2020 Programme for Research and Innovation (Grant 677542) and a Sir Henry Dale fellowship, jointly funded by the Wellcome Trust and the Royal Society (Grant 107613/Z/ 15/Z). C.N.S. is supported by National Institutes of Health Grant P01GM095467. N.V. is supported by the European Research Council (Grant ERC-2012-StG- 20111109)