Stereocontrolled total synthesis of neuroprotectin D1 / protectin D1 and its aspirin-triggered stereoisomer

Neuroprotectin D1 / protectin D1, a potent anti-inflammatory, proresolving, and neuroprotective lipid mediator derived biosynthetically from docosahexaenoic acid, was prepared in enantiomerically pure form via total organic synthesis. The synthetic strategy is highly stereocontrolled and convergent, featuring epoxide opening of glycidol starting materials for the introduction of the 10(R) and 17(S) hydroxyl groups. The desired alkene Z geometry was secured via the cis-reduction of alkyne precursors, while the conjugated E,E,Z triene was introduced at the end, in order to minimize Z/E isomerization. The same strategy, was also employed for the total synthesis of aspirin-triggered neuroprotectin D1 / protectin D1 having the 17(R)-stereochemistry. Synthetic compounds obtained with the reported method were matched with endogenously derived materials, and helped establish their complete stereochemistry.     

Aspirin-triggered metabolites of EFAs

Aspirin triggers the biosynthesis of oxygenated metabolites from arachidonic, eicosapentaenoic, and docosahexaenoic (DHA) acids. In a preceding issue, Serhan et?al. (2011) describe a novel aspirin-triggered DHA pathway for the biosynthesis of a potent anti-inflammatory and proresolving molecule.     

Resolvin D1, protectin D1, and related docosahexaenoic acid-derived products: Analysis via electrospray/low energy tandem mass spectrometry based on spectra and fragmentation mechanisms

Resolvin D1 (RvD1) and protectin D1 (Neuroprotectin D1, PD1/NPD1) are newly identified anti-inflammatory lipid mediators biosynthesized from docosahexaenoic acid (DHA). In this report, the spectra-structure correlations and fragmentation mechanisms were studied using electrospray low-energy collision-induced dissociation tandem mass spectrometry (MS/MS) for biogenic RvD1 and PD1, as well as mono-hydroxy-DHA and related hydroperoxy-DHA. The loss of H2O and CO2 in the spectra indicates the number of functional group(s). Chain-cut ions are the signature of the positions and numbers of functional groups and double bonds. The observed chain-cut ion is equivalent to a hypothetical homolytic-segment (cc, cm, mc, or mm) with addition or extraction of up to 2 protons (H). The alpha-cleavage ions are equivalent to: [cc + H], with H from the hydroxyl through a beta-ene or gamma-ene rearrangement; [cm - 2H], with 2H from hydroxyls of PD1 through a gamma-ene rearrangement, or 1H from the hydroxyl and the other H from the alpha-carbon of mono-HDHA through an alpha-H-beta-ene rearrangement; [mc - H], with H from hydroxyl through a beta-ene or gamma-ene rearrangement, or from the alpha-carbon through an alpha-H-beta-ene rearrangement; or [mm] through charge-direct fragmentations. The beta-ene or gamma-ene facilitates the H shift to gamma position and alpha-cleavage. Deuterium labeling confirmed the assignment of MS/MS ions and the fragmentation mechanisms. Based on the MS/MS spectra and fragmentation mechanisms, we identified RvD1, PD1, and mono-hydroxy-DHA products in human neutrophils and blood, trout head-kidney, and stroke-injury murine brain-tissue.     

A Versatile and Stereocontrolled Total Synthesis of Dihydroxylated Docosatrienes Containing a Conjugated E,E,Z‐Triene

A versatile strategy featuring a Colvin rearrangement, hydrozirconation, a Sonogashira cross‐coupling reaction and a Z‐selective Wittig olefination, was successfully developed for the construction of a conjugated E,E,Z‐triene subunit, flanked on both sides by two Z‐allylic hydroxyl groups. This chemical pattern is found in many endogenous lipid metabolites such as maresin 1 (MaR1), neuroprotectin D1 (NPD1), and its aspirin triggered‐isomer AT‐NPD1, which not only counter‐regulate inflammation but also actively orchestrate (at nanomolar doses) the resolution and termination program of acute inflammation while promoting wound healing, return to homeostasis and neuroprotection. Unlike previous approaches, the advantages of the present strategy are obvious, as it allows us to modify the nonpolar tail, the carboxylated head or both ends of the molecule without repeating the whole synthetic sequence (about 26–34 steps according to the literature). Thus, the first total syntheses of NPD1 methyl ester epimer (which can also be considered as an enantiomer of AT‐NPD1) and its n‐3 docosapentaenoic acid derived analogue were achieved from a highly functionalized and late advanced pivotal intermediate. This innovative route may be easily adapted to gain access to other dihydroxylated metabolites and analogues of polyunsaturated fatty acids containing a conjugated E,E,Z‐triene subunit. Different epimers/diastereoisomers may be obtained by purchasing the suitable optically pure (S)‐ and/or (R)‐1,2,4‐butanetriol(s) as a chiral pool for both stereogenic centers.     

Syntheses of some polyunsaturated sulfur- and oxygen-containing fatty acids related to eicosapentaenoic and docosahexaenoic acids.

With the aim of enhancing selectively the beneficial biological effects of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) a number of polyunsaturated fatty acids containing sulfur or oxygen atoms in the chain has been synthesized starting from EPA and DHA, respectively. Oxidative degradation of these acids led to the corresponding aldehydes all-(Z)-3,6,9,12-pentadecatetraenal and all-(Z)-3,6,9,12,15-octadecapentaenal. Reactions with DBU converted these aldehydes quantitatively into the conjugated isomers (2E,6Z,9Z,12Z)-pentadecatetraenal and (2E,6Z,9Z,12Z,15Z)-octadecapentaenal, respectively. The four aldehydes were transformed by a sequence of reactions comprising reduction to the alcohols, halogenation and substitution with mercapto esters into the corresponding sulfur containing polyunsaturated fatty acid esters. The oxygen containing esters were prepared from the respective alcohol by boron trifluoride catalysed reaction with ethyl diazoacetate.     

Two new potent inhibitors of xanthine oxidase from leaves of Perilla frutescens Britton var. acuta Kudo

A known and a new caffeic ester (1 and 2), new inhibitors of xanthine oxidase (XO), were isolated from leaves of Perilla frutescens var. acuta and their structures have been established as (Z,E)-2-(3,4-dihydroxyphenyl)ethenyl ester (1) and (Z,E)-2-(3,5-dihydroxyphenyl)ethenyl ester (2) of 3-(3,4-dihydroxyphenyl)-2-propenoic acid, respectively, based on detailed spectral studies, including 2D COSY, long range COSY, difference NOE, etc. Both caffeic esters strongly inhibited XO in vitro and especially, the inhibition by 1 was as potent as that by allopurinol. The inhibition mode of 1 was also shown to be non-competitive.     

Resolvin E2: identification and anti-inflammatory actions: pivotal role of human 5-lipoxygenase in resolvin E series biosynthesis

The family of resolvins consists of omega-3 fatty acid-derived mediators, including E series resolvins generated from eicosapentaenoic acid (EPA), and carry potent anti-inflammatory properties. Here, we report the isolation, identification, and bioactions of resolvin E2 (RvE2), which is 5S,18-dihydroxy-eicosapentaenoic acid. RvE2 stopped zymosan-induced polymorphonuclear (PMN) leukocyte infiltration and displayed potent anti-inflammatory properties in murine peritonitis. We also demonstrate that human recombinant 5-lipoxygenase generates RvE2 from a common precursor of E series resolvins, namely, 18-hydroxyeicosapentaenoate (18-HEPE). Furthermore, the initial 5-hydroperoxide intermediate was also converted to a 5(6)-epoxide intermediate in RvE1 formation. These results demonstrate that RvE2, together with RvE1, may contribute to the beneficial actions of omega-3 fatty acids in human diseases. Moreover, they indicate that the 5-lipoxygenase in human leukocytes is a pivotal enzyme that can produce both pro- and anti-inflammatory chemical mediators.     

Cation-recognized photosensitization in E-Z isomerization of 1,2-dichloroethylene by crowned benzophenones

Photosensitized isomerization of 1,2-dichloroethylene with 15- and 18-membered-ring crowned benzophenones (1a and 1b) as triplet sensitizers resulted in the cation-dependent increase in the Z/E isomer ratios up to ca. 10 by addition of alkali and alkaline earth metal ions in comparison with the metal-free reactions (Z/E = 1.5-2.1). The highest Z/E values were attained for 1a with Li+ (2.9) and Mg2+ (5.3), and for 1b with Na+ (8.2) and Ca2+ (9.8), respectively, among each family of alkali and alkaline earth metal ions. It was found that the cation recognized sensitization brought about the change of the inherent triplet energy ET as well as the PhiE/Phiz ratio to raise the Z/E isomer ratio of 1,2-dichloroethylene.     

Antihepatitis B virus constituents of Solanum erianthum

Eleven compounds were isolated from the methanolic extract of the leaves of Solanum erianthum D. Don, including five alpha-linolenic acid analogs, alpha-linolenic acid (1), 13S-hydroxy-9(Z),11(E)-octadecadienoic acid (2), 9S-hydroxy-10(E),12(Z), 15(Z)-octadectrienoic acid (3), 9(Z),11(E)-octadecadienoic acid (4), and octadecanoic acid (5); two benzofuran-type lactones, loliolide (6) and dihydroactinidiolide (7); two steroidal alkaloids, solasonine (8) and solamargine (9); a flavonol glycoside, camelliaside C (10); and a flavone, 5-methoxy-(3,4"-dihydro-3",4"-diacetoxy)-2",2'-dimethylpyrano-(7,8:5",6")-flavone (11). Among these isolated compounds, 9 showed the most potent activity against HBsAg, with an IC50 of 1.57 microM, followed by 8 (IC50 is 5.89 microM). In the testing against HBeAg, 11 was the only active compound with an IC50 of 36.11 microM. Compound 9 also revealed strong inhibition of DNA replication towards HBV and its IC50 was 2.17 microM. However, alpha-linolenic acid (1) showed a prominent selected index (SI), both in anti-HBsAg and inhibition of DNA replication with SI values of 7.75 and 7.18, respectively. This is the first report that unsaturated fatty acid 1, steroidal alkaloid glycoside 9 and flavone 11, all showed excellent activity against HBV. These results provide lead candidates in the development of anti-HBV drugs from natural sources.     

Novel synthesis of alkenes via triethylborane-induced free-radical reactions of alkyl iodides and beta-nitrostyrenes

Reactions of (E)-beta-nitrostyrenes 1 and triethylborane 2 or tricyclohexylborane 4 in THF solution at room temperature in the presence of oxygen in the air as radical initiator generate high yields of trans-alkenes (E)-3 or (E)-5. Medium to high yields of different (E)-alkenes (E)-5, 7, 10, 12, and 14 also can be prepared when 1 reacts with different radicals, prepared from secondary alkyl iodides 6 and 8 or tertiary alkyl iodides 9, 11, and 13, in the presence of 2 and air as radical initiator. The generation of the only product (E)-alkenes can be explained by the generation of the benzylic radical A and/or B as the intermediate only and the mechanism is similar to Scheme 1. Both (E)- and (Z)-16a-c are generated when (E)- and (Z)-15a-c are used to react with adamantyl radical under similar conditions. Only (Z)-16d was observed when either (E)- or (Z)-15d was used to react with adamantyl radical. The generation of the (E)- and/or (Z)-alkenes can be explained by the free rotation of the A and/or B to generate A' and/or B' and vice versa, and the mechanism is proposed to be a free-radical reaction via NO2/alkyl substitution and is shown as Scheme 2.     

Concise syntheses of cystothiazoles A, C, D, and melithiazol B

A convergent synthesis of cystothiazoles C 1 and D 3 was achieved based on Julia coupling between the functionalized aldehyde 5b, corresponding to left half of the final molecule, and aryl sulfone 6 or 7, bearing a bithiazole moiety, corresponding to right half. Methylation of 1 and 3 gave cystothiazole A 2 and melithiazol B 4, respectively. The overall yield (5 steps from (2R,3S)-3-methylpent-4-yne-1,2-diol 10; 57%) of 5b via the present route was improved in comparison to that of the previously reported functionalized aldehyde 5a (7 steps from 10; 13%). By applying the modified Julia coupling method, selectivity (6E/6Z=20 : 1-26 : 1) toward the (6E)-form of the coupled products (15 or 19) against the corresponding (6Z)-form was improved in comparison to the Wittig method (6E/6Z=4 : 1-6.9 : 1).     

Acid-promoted reactions of ethyl linoleate with nitrite ions: formation and structural characterization of isomeric nitroalkene, nitrohydroxy, and novel 3-nitro-1,5-hexadiene and 1,5-dinitro-1, 3-pentadiene products

The reaction of ethyl linoleate (1) with NO(2)(-) in different air-equilibrated acidic media resulted in the formation of complex patterns of products, some of which could be isolated by repeated TLC fractionation and were formulated as the nitroalkenes 2-5, the novel (1E, 5Z)-3-nitro-1,5-hexadienes 6/7, the novel (E,E)-1, 5-dinitro-1,3-pentadiene derivatives 8 and 9, and the nitro alcohols 10/11 and 12/13 by extensive GC-MS and 2D NMR analysis, as aided by 1D Hartmann-Hahn proton mapping experiments. Similar reaction of methyl oleate gave mainly nitroalkene (14/15) and allylic nitro derivatives (16/17). Formation of 2-13 may be envisaged in terms of HNO(2)-mediated nitration pathways in which regioisomeric beta-nitroalkyl radical intermediates derived from attack of NO(2) to the 1,4-pentadiene moiety of 1 evolve through competitive H-atom abstraction and free radical combination routes.     

Total synthesis of (+)- and (-)-duryne: a potent anticancer agent from the marine sponge Cribrochalina dura. Establishment of the central double bond geometry and the absolute configuration of the chiral centers

Duryne is a C30 polyacetylenic alcohol with C2 symmetry. Despite its potent cytotoxicity, its central double bond geometry and the absolute configuration of the chiral centers were not determined. We report the total syntheses of both enantiomers of the anticancer natural product (+)-duryne and the establishment of its stereochemistry by synthesizing both geometric isomers. The natural (+)-duryne is identified as (15Z) and (3S,28S) as shown in structure 1. The autoxidation/Wittig coupling reaction was employed to synthesize the central (Z)-olefin. The stereochemistry of the (E)-alkene isomer was constructed stereoselectively by using LiAlH4 reduction of the corresponding alkyne. The absolute configurations of the chiral centers are established by using Burgess' enzymatic resolution procedure with Pseudomonas AK lipase.     

STUDIES ON PLANT BILE PIGMENTS. II. REGIOSELECTIVE PHOTOCHEMICAL AND ACID CATALYZED Z,E ISOMERIZATION OF DIHYDROBILINDIONE AS PHYTOCHROME MODEL

The (4 Z, 10 Z , 15 E )-2,3-dihydrobilindione 4 , along with the fully unsaturated ( E, Z, Z )-analogue 8 , has been prepared from the corresponding ( Z, Z, Z )-isomer by a variation of Falk's method (Falk et aL, 1980). The photochemical and acid-catalyzed back-reactions have been studied by UV-vis and ¹H-NMR spectroscopy.     

(10Z)- and (10E)-19-fluoro-1alpha,25-dihydroxyvitamin D3: an improved synthesis via 19-nor-10-oxo-vitamin D

An efficient synthetic route to (10Z)- and (10E)-19-fluoro-1alpha,25-dihydroxyvitamin D3 was developed. The key feature of this pathway is the introduction of a 19-fluoromethylene group to a (5E)-19-nor-10-oxo-vitamin D derivative. The 10-oxo-compound was obtained via a 1,3-dipolar cycloaddition reaction of (5E)-1alpha,25-dihydroxyvitamin D with in situ generated nitrile oxide followed by ring cleavage of the formed isoxazoline moiety with molybdenum hexacarbonyl. Conversion of the keto group of (5E)-19-nor-10-oxo-vitamin D to the E and Z fluoromethylene group was achieved through a two-step sequence involving a reaction of lithiofluoromethyl phenyl sulfone followed by the reductive desulfonylation of the alpha-fluoro-beta-hydroxy sulfone. The dye-sensitized photoisomerization of the (5E)-19-fluorovitamin D afforded the desired (5Z)-19-fluorovitamin D derivatives, (10Z)- and (10E)-19-fluoro-1alpha,25-dihydroxyvitamin D3.     

Conformations, protonation sites, and metal complexation of benzohydroxamic Acid. A theoretical and experimental study

A theoretical and experimental study on the structure and deprotonation of benzohydroxamic acid (BHA) has been performed. Calculations at the RHF/cc-pVDZ level, refined by the B3LYP/AUG-cc-pVDZ method, indicate that, in the gas phase, Z amide is the most stable structure of both neutral and deprotonated BHA. (1)H-(1)H nuclear Overhauser enhancement spectroscopy and (1)H-(1)H correlation spectroscopy spectra in acetone, interpreted with ab initio interatomic distances, reveal that BHA is split into the Z and E forms, the [E]/[Z] ratio being 75:25 at -80 degrees C. The formation of E-E, Z-Z, and E-Z dimers has been detected; in the presence of water, the dimers dissociate to the corresponding monomers. The rates of proton exchange within the Z and E forms and between E and Z were measured by dynamic (1)H NMR in the -60 to 40 degrees C temperature range; an increase in water content lowers the rate of exchange of the E isomer. The effect of D(2)O on the NMR signals indicates a fast hydrogen exchange between D(2)O and the E and Z amide forms. The sequence of the acid strength at low temperatures is (N)H(E)) approximately (O)H(E) < (O)H(Z) approximately (N)H(Z). The kinetics of complex formation between BHA and Ni(2+), investigated by the stopped-flow method, show that both neutral BHA and its anion can bind Ni(2+). Whereas the anion reacts at a "normal" speed, the rate of water replacement from Ni(H(2)O)(6)(2+) by neutral BHA is about 1 order of magnitude less than expected. This behavior was interpreted assuming that, in aqueous solution, BHA mainly adopts a closed (hydrogen-bonded) Z configuration, which should open (with an energy penalty) for the metal binding process to occur.     

Design and synthesis of a potent phorboxazole C(11-15) acetal analogue

[structure: see text] We disclose here the design, synthesis, and biological evaluation of simplified Z- and E-C(2-3) alkynyl phorboxazole C(11-15) acetals (+)-7Z and (+)-7E, wherein the Z-isomer proved to be a potent nanomolar cytotoxic agent. Reevaluation of (+)-C(45-46) E-chloroalkenyl phorboxazole A (6) confirms subnanomolar activity across a broad panel of human cancer cell lines.     

A mild and efficient stereoselective synthesis of (Z)- and (E)-allyl sulfides and potent antifungal agent, (Z)-3-(4-methoxybenzylidene)thiochroman-4-one from Morita-Baylis-Hillman acetates

A facile stereoselective synthesis of (Z)- and (E)-allyl sulfides has been accomplished from Morita-Baylis-Hillman acetates in one-pot by treatment with benzene thiol in the presence of catalytic amounts of 15% aqueous NaOH and TBAI in DMSO at room temperature. The method has been applied for the synthesis of (Z)-3-(4-methoxybenzylidene)thiochroman-4-one, a potent antifungal compound.     

Synthesis of (10Z)- and (10E)-19-fluoro-1alpha,25-dihydroxyvitamin D3: compounds to probe vitamin D conformation in receptor complex by 19F-NMR

To study the interaction of vitamin D with its receptor by 19F-NMR, (5Z,10Z)- and (5Z,10E)-19-fluoro-1alpha,25-dihydroxyvitamin D3 were synthesized starting from vitamin D2 via electrophilic fluorination of vitamin D-SO2 adducts as the key step. Regio- and stereoselective electrophilic fluorination at C(19) of vitamin D-SO2 adducts was achieved under the conditions using (PhSO2)2NF and bulky bases. The stereochemistry of the addition and elimination of SO2 of various vitamin D derivatives was studied in detail. SO2 causes Z-E isomerization of the 5,6-double bond of vitamin D and adds to the resulting (5E)-isomer from the sterically less hindered side opposite to the substituent at C(1). Elimination of SO2 from 19-substituted vitamin D-SO2 adducts proceeded exclusively in a suprafacial manner with respect to the diene part under either thermal or reductive conditions. Dye-sensitized photochemical isomerization of 19-fluorovitamin D derivatives was studied in detail. The rapid isomerization at the 5,6-double bond was followed by the slow isomerization at the 10,19-double bond to yield the (5E,10Z)-isomer (by nomenclature of the 1-OH derivatives) as the major product. (10Z)- and (10E)-19-Fluorovitamin Ds were also interconverted thermally probably via the corresponding previtamin D by 1,7-sigmatropic isomerization.     

Structure elucidation of deoxylutein II isomers by on-line capillary high performance liquid chromatography-(1)H nuclear magnetic resonance spectroscopy

Thermal and iodine-catalyzed photochemical (Z/E)-isomerization of deoxylutein II [(3R,6'R)-3-hydroxy-3',4'-didehydro-beta,gamma-carotene, anhydrolutein I] (2), the dehydration product of lutein [(3R,3'R,6'R)-beta,varepsilon-carotene-3,3'-diol] (4), yielded multi-component mixtures of (Z)-isomers. By I(2)-catalyzed photoisomerization, (9Z)-2, (9'Z)-2, (13Z)-2, (13'Z)-2 and (15Z)-2 are generated as main products. In addition, this thermodynamic-equilibrium mixture contains traces of (9Z,9'Z)-2 and other (di-Z)-isomers in minor concentrations. Thirteen isomers are chromatographically separated and detected on-line by UV-vis and mass spectrometry. (all-E)-Deoxylutein II (2) and six of its (Z)-configured isomers are separated by capillary HPLC (acetone-d(6)/D(2)O = 85:15) and detected on-line by (1)H NMR spectroscopy in a microprobe. With the microprobe and the active detection volume of 1.5 microl, it is possible to perform structure elucidation with very small amounts available for various (Z)-isomers of deoxylutein II (2) in the isomerization mixture.