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A stereoselective method for the construction of the C8′-O-C6″ ether of nigricanoside-A: Synthesis of simple models for the C20 lipid chain/galactosyl glycerol segment
Abstract
A method for the stereoselective construction of the C8′–O–C6″ ether of nigricanoside-A, an antimitotic natural product from the green alga Avrainvillea nigricans, has been developed based on chirality-transferring Ireland–Claisen rearrangement. The method was successfully applied to the synthesis of simple models for the C20 lipid chain/galactosyl glycerol segment of the natural product.
... In fact, with all these plakosides in hand, their biological activities were evaluated in three in vitro assays (the mixed-lymphocyte-reaction proliferation (MLR) assay, the concanavalin A response assay, and the murine bone marrow cell proliferation assay). Surprisingly, the authors found that all these compounds (95)(96)(97)(98)(99)(100)(101)(102), and the synthetic plakosides A (87) and B (88), displayed modest immunosuppressive activity compared to the reported activities for the natural compounds. Among them, analogue 95 was the most active in the series, albeit in a modest range, with an IC 50 value of 7.1 µM in the MLR proliferation assay. ...
... Consequently, the total synthesis represents the only means to determine unambiguously the stereochemistry of the chiral centers and to have enough material for further biological screenings. Thus, several synthetic approaches have been initiated for the lipidic fragments [99][100][101], but many of them have not solved the stereochemical assignment problem. In fact, this stereochemical assignment represents a formidable synthetic challenge because of the presence of seven chiral centers in the lipidic unit, which could provide up to 128 possible stereoisomers, assuming that the configuration for the sugar unit and the geometry of the double bonds were correctly established (Scheme 19). ...
... These spectroscopic differences led the authors to propose a C6/C9 syn relationship for the natural product instead of the initially proposed anti relative configuration. Thus, several synthetic approaches have been initiated for the lipidic fragments [99][100][101], but many of them have not solved the stereochemical assignment problem. In fact, this stereochemical assignment represents a formidable synthetic challenge because of the presence of seven chiral centers in the lipidic unit, which could provide up to 128 possible stereoisomers, assuming that the configuration for the sugar unit and the geometry of the double bonds were correctly established (Scheme 19). ...
Glycolipids represent a broad class of natural products structurally featured by a glycosidic fragment linked to a lipidic molecule. Despite the large structural variety of these glycoconjugates, they can be classified into three main groups, i.e., glycosphingolipids, glycoglycerolipids, and atypical glycolipids. In the particular case of glycolipids derived from marine sources, an impressive variety in their structural features and biological properties is observed, thus making them prime targets for chemical synthesis. In the present review, we explore the chemistry and biology of this class of compounds.
... 521 A stereoselective synthesis of the C-8 0 -O-C-6 00 ether of the antimitotic agent nigricanoside A 522 was successfully applied in model systems. 523 Included in the green algal literature for 2013 were reports on the cytotoxic effects of clerosterol from Codium fragile 524 on HTCLs 525 and the spasmolytic effects of caulerpine 526 on guinea pig ileum. 527 ...
This review covers the literature published in 2013 for marine natural products (MNPs), with 982
citations (644 for the period January to December 2013) referring to compounds isolated from
marine microorganisms and phytoplankton, green, brown and red algae, sponges, cnidarians,
bryozoans, molluscs, tunicates, echinoderms, mangroves and other intertidal plants and
microorganisms. The emphasis is on new compounds (1163 for 2013), together with the relevant
biological activities, source organisms and country of origin. Reviews, biosynthetic studies, first
syntheses, and syntheses that lead to the revision of structures or stereochemistries, have been
included.
The Julia–Kocienski olefination is a direct connective synthesis of alkenes via the addition of metalated aryl alkyl sulfones to carbonyl compounds. The activating aromatic group associated with the sulfone must possess electrophilic character, and alkene formation occurs via β‐alkoxy sulfone formation, transfer of the aryl group from sulfur to oxygen via a Smiles rearrangement, and then elimination of sulfur dioxide and an aryloxide anion from the resulting β‐aryloxy sulfinate anion. The olefination process itself and the methods used to prepare the requisite sulfone substrates are tolerant of a wide variety of functional groups, and a variety of alkene targets can be prepared. Stereoselectivity is dependent on the nature of the sulfone, the carbonyl compound, the activating aryl moiety, and the reaction conditions.
This chapter describes theoretical and operational aspects of the Julia–Kocienski olefination such that the reader will be able to obtain optimal results in his/her own research. A detailed mechanistic overview is included to account for the factors that influence stereoselectivity and yield. Methods for introducing sulfone activators into fragments of interest, best practices for generating sulfone anions, and optimal strategies for targeting different classes of alkene targets are discussed. Functional group compatibilities, reaction variants, and a comparison to other methods of alkene synthesis are also presented. Tabular surveys are organized according to type of alkene synthesized, with an emphasis on the degree of substitution and the level of conjugation about the newly formed double bond. The literature is covered from the initial disclosure of the Julia–Kocienski olefination in 1991 to the first quarter of 2016.
Nigricanoside A, isolated from the green alga Avrainvillea nigricans, is a structurally unique natural product in which two fatty acids, galactose, and glycerol are connected with ether linkages. Its dimethyl ester showed potent antitumor activities to cancer cell lines. The structure determination of nigricanoside A has not been solved due to the limited availability of this natural product. In this review, the structure elucidation of nigricanoside A by total synthesis is described.
The unparalleled effectiveness of microtubule-targeting drugs has been validated by the successful use of vincristine, vinblastine, and paclitaxel for the treatment of a wide variety of human cancers. However, drug-resistance, both inherent and acquired, is common because of constant usage of anticancer agents. A worldwide search for compounds with similar mechanisms of action but improved characteristics has been urgent for wide clinical use. The largely unexplored marine world that presumably harbors the most biodiversity has provided inspiration for the development of new chemical classes of anticancer drugs. As such, they have also received considerable attentions from both academic industrial researchers who are interested in their bioactivity and chemistry. In this paper, several classes of typical microtubule-targeting marine natural products with diverse structure and unique bioactivity are summarized, focusing on their chemical and bioactive properties. Particularly, the preclinical and clinical trials of microtubule-targeting marine natural products are also discussed.
The Ireland–Claisen rearrangement of 6-methylene-1,4-oxazepan-2-one-derived boron enolates leads to stereochemically defined, synthetically useful 4-(E)-ethylidene prolines. Detailed computational and experimental studies explain the stereochemical outcome of this transformation and suggest an unusual double-chelated transition state that involves two boron atoms. The scope of the method is also explored.
Nigricanoside A was isolated from green alga its dimethyl ester was found to display potent cytotoxicity. Its scarcity prevented a full structure elucidation, leaving total synthesis as the only means to determine its relative and absolute stereochemistry and to explore its biological activity. Here we assign the stereochemistry of the natural product through enantioselective total synthesis and provide initial studies of its cytotoxicity.
Trimethylsilyldiazomethane (TMSCHN2), known as a stable and safe substitute for highly toxic and explosive diazomethane in the Arndt-Eistert synthesis and homologation of carbonyl compounds, has smoothly reacted with various carboxylic acids in methanolic benzene solution to give the corresponding methyl esters in excellent yields.
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Readily preparable N-methoxy-N-methylamides couple in good yields with Grignard and organolithium reagents to produce ketones, and are reduced with hydrides to afford aldehydes.
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The reagent formed by combining diethyl azodicarboxylate (DEAD) and triphenylphosphine (TPP) could be utilized in the intermolecular dehydration between an alcohol and various acidic components such as carboxylic acids, phosphoric diesters, imides, and active methylene compounds. By the use of DEAD and TPP, diols and hydroxy acids gave cyclic ethers and lactones, respectively. The reaction of nucleosides with DEAD and TPP afforded triphenylphosphoranylnucleosides. Alcohols reacted with 2,6-di-t-butyl-4-nitrophenol in the presence of DEAD and TPP to give aci-nitroesters which converted into the corresponding carbonyl compounds.
The reactions of RuCl2(PPh3)3 with a number of diazoalkanes were surveyed, and alkylidene transfer to give RuCl2(CHR)(PPh3)2 (R = Me (1), Et (2)) and RuCl2(CH-p-C6H4X)(PPh3)2 (X = H (3), NMe2 (4), OMe (5), Me (6), F (7), Cl (8), NO2 (9)) was observed for alkyl diazoalkanes RCHN2 and various para-substituted aryl diazoalkanes p-C6H4XCHN2. Kinetic studies on the living ring-opening metathesis polymerization (ROMP) of norbornene using complexes 3−9 as catalysts have shown that initiation is in all cases faster than propagation (ki/kp = 9 for 3) and that the electronic effect of X on the metathesis activity of 3−9 is relatively small. Phosphine exchange in 3−9 with tricyclohexylphosphine leads to RuCl2(CH-p-C6H4X)(PCy3)2 10−16, which are efficient catalysts for ROMP of cyclooctene (PDI = 1.51−1.63) and 1,5-cyclooctadiene (PDI = 1.56−1.67). The crystal structure of RuCl2(CH-p-C6H4Cl)(PCy3)2 (15) indicated a distorted square-pyramidal geometry, in which the two phosphines are trans to each other, and the alkylidene unit lies in the Cl−Ru−Cl plane. The benzylidenes RuCl2(CHPh)(PR3)2 (R = Cy (cyclohexyl) (10), Cp (cyclopentyl) (17), i-Pr (18)) are quantitatively available via one-pot synthesis with RuCl2(PPh3)3, PhCHN2, and PR3 as reaction components. 10 is an efficient catalyst for metathesis of acyclic olefins: On reaction with excess ethylene, the methylidene complex RuCl2(CH2)(PCy3)2 (19) is formed quantitatively, and various alkylidene compounds RuCl2(CHR)(PCy3)3 (R = Me (20), Et (21), n-Bu (22)) are isolated as the kinetic products from the reaction of 10 with an excess of the corresponding terminal or disubstituted olefins. Metathesis of conjugated and cumulated olefins with 10 results in the formation of vinylalkylidene and vinylidene complexes, as shown by the synthesis of RuCl2(CHCHCH2)(PCy3)2 (23) and RuCl2(CCH2)(PCy3)2 (24) from 1,3-butadiene or 1,2-propadiene, respectively. Also, functional groups such as −OAc, −Cl, and −OH can be introduced into the alkylidene moiety via cross metathesis with the appropriate alkene.
The [3,3] sigmatropic rearrangement of a number of allylic esters (1), as the enolate anions or the corresponding silylketene acetals, produces the γ,δ-unsaturated acids 2 in 66-88% yield. The mild conditions allow rearrangement of acid-sensitive and thermally labile esters. Rearrangement of ester 1g affords (E)-4-decenoic acid (2g) with greater than 99% stereoselectivity. (E)-Crotyl propanoate (12) leads to erythro acid 14 when enolization is carried out in THF, but to the threo acid 15 when the solvent is 23% HMPA-THF. Results with a variety of esters demonstrate that kinetic enolization with lithium diisopropylamide gives selective formation of the geometrical enolate H in THF and the isomeric enolate I in HMPA-THF. Similar results are obtained with 3-pentanone.
Lanthanoid chlorides (LnC13) are efficient catalysts for the regioselective 1,2 reduction of a-enones by NaBH4 in methanol solution. Optimal conditions of this reaction have been determined. A mechanistic interpretation depicting the role of the Ln3+ ions is given. The major effect of Ln3+ is the catalysis of BH4- decomposition by the hydroxylic solvent to afford alkoxyborohydrides, which may be responsible for the observed regioselectivity. The stereoselectivity of the process is also modified by the presence of the Ln3+ ions, in that axial attack of cyclohexano?e systems is enhanced. Since the discovery of the reducing properties of boron hydrides, sodium borohydride has received considerable attention as a se- lective and mild reducing agent of the carbonyl group. A large variety of papers report results of synthetic, mechanistic, or ste- reochemical importance, and reviews have recently been pub- lished.2 The question of the mechanism, especially in an alcoholic solvent, is intriguing and complex since as the reaction proceeds various alkoxyborohydrides 1 are produced, which may react with their own stereo- and regioselectivities. Disproportionation of some or all alkoxyborohydrides to BH, further complicates the situation. The problem has been extensively studied theoretically3 as well as by stereochemical and kinetic appro ache^.^,^ Other studies demonstrate that the usual reaction selectivity of NaBH4 can be substantially modified by addition of various metal salts, such as al~minum,~ cobalt: copper,' nickel: tin? titanium,lo and zinc," to give complex reagents, which are capable of synthetically useful conversions including the reductions of acyl chlorides to aldehydes,' olefins to saturated hydrocarbon,6 and dehalogenation of aryl halides to arene~.~
Mosher's (H-1) method to elucidate the absolute configuration of secondary alcohols was reexamined by use of high-field FT NMR spectroscopy, which enables assignment of most of the protons of complex molecules. There is a systematic arrangement of DELTA-delta (delta-S - delta-R) values obtained for the (R)- and (S)-MTPA esters of (-)-menthol, (-)-borneol, cholesterol, and ergosterol, the absolute configurations of which are known. Analysis of the DELTA-delta values of these compounds led to a rule that could predict the absolute configurations of natural products. When this rule was applied to some marine terpenoids including cembranolides and xenicanes, their absolute configurations were assigned and a part of the results were confirmed by X-ray structural analyses. In the case of sipholenol A, which has a sterically hindered OH group, this rule is inapplicable. But the problem is overcome by inverting the OH group to a less sterically hindered position; the resulting epimer gives systematically arranged DELTA-delta values, which enabled the elucidation of the absolute configuration. Comparison of the present method with Mosher's F-19 method indicates that the latter one using F-19 NMR lacks in reliability.
Plastid envelope membranes play a major role in the biosynthesis of glycerolipids. In addition, plastids are characterized by the occurrence of plastid-specific membrane glycolipids (galactolipids, a sulfolipid). Plant lipid metabolism therefore has unique features, when compared to that of other eukaryotic organisms, such as animals and yeast. However, the glycerolipid biosynthetic pathway in chloroplasts is almost identical to that found in cyanobacteria, and reflects the prokaryotic origin of the chloroplast. Fatty acids generated in the plastid stroma are substrates for a whole set of enzymes involved in the synthesis of polar lipids of plastid membranes such as galactolipids, the sulfolipid, the phosphatidylglycerol. In addition, fatty acids are exported outside the plastid where they are used for extraplastidial polar lipid synthesis (phosphatidylcholine, phosphatidylethanolamine, etc.). Various desaturation steps leading to the formation of polyunsaturated fatty acids occur in various cell compartments, especially in chloroplasts, using fatty acids esterified to polar lipids as substrates. Furthermore, plant glycerolipids can be metabolized by a series of very active envelope enzymes, such as the galactolipid:galactolipid galactosyltransferase and the acyl-galactolipid forming enzyme. The physiological significance of these enzymes is however largely unknown. One of the most active pathways involved in lipid metabolism and present in envelope membranes is the oxylipin pathway: polyunsaturated fatty acids that are released from polar lipids under various conditions (injury, pathogen attack) are converted to oxylipin. Thus, the plastid envelope membranes are also involved in the formation of signalling molecules.
The protected stereoisomer of a trihydroxy unsaturated fatty acid, which could be employed as a potential nigricanoside α-chain building block, was synthesized by using Evans asymmetric alkylation, Sharpless kinetic resolution, and diastereoselective reduction as the key steps.
Two sides of the same coin: Syn and anti 1,4-diols have been synthesized through the regio- and diastereoselective CuI-catalyzed boration of allylic epoxides (see scheme; pin=pinacolato, TES=triethylsilyl). In situ protection of the alcohol allows isolation of syn and anti 1,4- silyloxyboronates. Monoprotected 1,4-diols can be prepared by a one-pot addition-protection-oxidation sequence.
Benzylic ethers and related ArCH(2)OR substrates are oxidatively cleaved by 4-acetamido-2,2,6,6-tetramethylpiperidine-1-oxoammonium tetrafluoroborate (1) in wet CH(3)CN at room temperature to give the corresponding aromatic aldehyde and alcohol in high yield. Primary or secondary alcohol products are further oxidized by 1 to give carboxylic acids and ketones, respectively. The oxidation likely involves a formal hydride abstraction from the benzylic carbon as evidenced by slow reaction of substrates bearing electron-withdrawing substituents.
A new technique to deconvolute complex (1)H NMR spectra of small molecules has been developed that utilizes shape selective pulses to simultaneously decouple multiple protons. A limitation in the assignment of the relative configuration of small molecules is the ability to accurately obtain coupling constants. Other methods such as the E.COSY and the 2D J-resolved are available to obtain complicated coupling constants; the multiple homonuclear decoupling method (MDEC) described is a rapid and simple technique. Three examples of increasing spectral complexity, menthol, cholesteryl acetate and a C(16) fatty acid, demonstrate the utility of the technique. Increasing the experimental utility, the single pulse MDEC experiment can be incorporated in other 1D experiments, such as a 1D-TOCSY to solve specific problems.
Tetra-n-butylammonium fluoride was found to be a mild and efficient base for the elimination reaction of bromoalkenes. Treatment of 1,1-dibromoalkenes, (Z)-1-bromoalkenes, and internal bromoalkenes with 5 equiv of TBAF x 3H2O in DMF yielded terminal and internal alkynes in high yields without undue regard to the presence of water.
Two isomeric icosatrienoic acids with double bonds at positions 5,8,14 and 5,11,14 and their 1-14C- and acetylenic analogues were prepared. The syntheses and characterization of these acids are described.
[reaction in text] A convergent asymmetric synthesis of (-)-ratjadone (1) has been achieved, confirming the assignments of stereochemistry for the naturally occurring antifungal metabolite.
Human pancreatic lipase-related protein 2 (HPLRP2) was found to be expressed in the pancreas, but its biochemical properties were not investigated in detail. A recombinant HPLRP2 was produced in insect cells and the yeast Pichia pastoris and purified by cation exchange chromatography. Its substrate specificity was investigated using pH-stat and monomolecular film techniques and various lipid substrates (triglycerides, diglycerides, phospholipids, and galactolipids). Lipase activity of HPLRP2 on trioctanoin was inhibited by bile salts and poorly restored by adding colipase. In vivo, HPLRP2 therefore seems unlikely to show any lipase activity on dietary fat. In human pancreatic lipase (HPL), residues R256, D257, Y267, and K268 are involved in the stabilization of the open conformation of the lid domain, which interacts with colipase. These residues are not conserved in HPLRP2. When the corresponding mutations (R256G, D257G, Y267F, and K268E) are introduced into HPL, the effects of colipase are drastically reduced in the presence of bile salts. This may explain why colipase has such weak effects on HPLRP2. HPLRP2 displayed a very low level of activity on phospholipid micelles and monomolecular films. Its activity on monogalactosyldiglyceride monomolecular film, which was much higher, was similar to the activity of guinea pig pancreatic lipase related-protein 2, which shows the highest galactolipase activity ever measured. The physiological role of HPLRP2 suggested by the present results is the digestion of galactolipids, the most abundant lipids occurring in plant cells, and therefore, in the vegetables that are part of the human diet.
The methyl esters 3 and 4 of the antimitotic glycolipids nigricanosides A (1) and B (2) have been isolated from extracts of the green alga Avrainvillea nigrans collected in Dominica. The structures of 3 and 4 were elucidated by detailed analysis of MS and NMR data. Nigricanoside A dimethyl ester 3 arrests human breast cancer MCF-7 cells in mitosis with an IC50 of 3 nM. Arrested cells have highly disorganized microtubule spindles, compared with the bipolar spindles of untreated metaphase cells. Ester 3 at 20 mu M stimulates the polymerization of pure tubulin in vitro and it inhibits the proliferation of both MCF-7 and human colon cancer HCT-116 cells with an IC50 approximate to 3 nM. The nigricanosides are the first examples of a new class of ether-linked glycoglycerolipids. The potent antimitotic activity of the nigricanosides and their ability to promote tubulin polymerization is without precedent among previously known glycoglycerolipids.