Synthesis of (±)-4-Demtthoxy-7 11-Dideoxydaungmy-Cinone

Our continued interest in the total synthesis of natural and unnatural antitumor anthracyclines¹ especially the aglycones such as daunomycinone (1)² and 4-demethoxydaunomycinone (2),³ 11-deoxydaunomycinone(3)⁴ and 4-demethoxy-11-deoxydau-nomycinone (4)⁵ led us to investigate various methods for obtaining these products. Recently we have reported the synthesis of 4-demethoxy-7, 11-dideoxydaunomycinone (5) from 5-methoxy-1-tetralone. Now we wish to report the synthesis of 5 starting from 5-methoxy-1-tetralone (9) which was prepared from 1,6-dimethoxy-naphthalene(8). Umezawa⁷ et al. have reported the total synthesis of 4-demethoxy-ll-deoxydaunomycin(6) and 4-demethoxy-11-deoxy-adriamycin (7) from 5-methoxy-2-tetralone.     

Sugar-assisted ligation in glycoprotein synthesis

Sugar-assisted ligation (SAL) presents an attractive strategy for the synthesis of glycopeptides, including the synthesis of cysteine-free beta-O-linked and N-linked glycopeptides. Here we extended the utility of SAL for the synthesis of alpha-O-linked glycopeptides and glycoproteins. In order to explore SAL in the context of glycoprotein synthesis, we developed a new chemical synthetic route for the alpha-O-linked glycoprotein diptericin epsilon. In the first stage of our synthesis, diptericin segment Cys(Acm)37-Gly(52) and segment Val(53)-Phe(82) were assembled by SAL through a Gly-Val ligation junction. Subsequently, after Acm deprotection, diptericin segment Cys(37)-Phe(82) was ligated to segment Asp(1)-Asn(36) by means of native chemical ligation (NCL) to give the full sequence of diptericin epsilon. In the final synthetic step, hydrogenolysis was applied to remove the thiol handle from the sugar moiety with the concomitant conversion of mutated Cys(37) into the native alanine residue. In addition, we extended the applicability of SAL to the synthesis of glycopeptides containing cysteine residues by carrying out selective desulfurization of the sulfhydryl-modified sugar moiety in the presence of acetamidomethyl (Acm) protected cysteine residues. The results presented here demonstrated for the first time that SAL could be a general and useful tool in the chemical synthesis of glycoproteins.     

Synthesis of diaminopimelic acid containing peptidoglycan fragments and tracheal cytotoxin (TCT) and investigation of their biological functions

Bacterial cell wall peptidoglycan (PGN) is a potent immunostimulator and immune adjuvant. The PGN of Gram-negative bacteria and some Gram-positive bacteria contain meso-diaminopimelic acid (meso-DAP), and we have recently shown that the intracellular protein Nod1 is a PGN receptor and recognizes DAP-containing peptides. In this study, we achieved the synthesis of DAP-containing PGN fragments, including the first chemical synthesis of tracheal cytotoxin (TCT), GlcNAc-(beta1-4)-(anhydro)MurNAc-L-Ala-gamma-D-Glu-meso-DAP-D-Ala, and a repeating-unit of DAP-type PGN, GlcNAc-(beta1-4)-MurNAc-L-Ala-gamma-D-Glu-meso-DAP-D-Ala. For the synthesis of PGN fragments, we first established a new synthetic method for an orthogonally protected meso-DAP derivative, and then we constructed the glycopeptide structures. The ability of these fragments to stimulate human Nod1, as well as differences in Nod1 recognition of the variety of synthesized ligand structures were examined. The results showed that the substitution of the N terminus of iE-DAP is necessary for stronger Nod1 recognition, but the structure of the substituent seems not to be strictly recognized. The importance of the carboxyl group at the 2-position of DAP for human Nod1 stimulation was also shown.     

Secretion of adenylate kinase 1 is required for extracellular ATP synthesis in C2C12 myotubes

Extracellular ATP (exATP) has been known to be a critical ligand regulating skeletal muscle differentiation and contractibility. ExATP synthesis was greatly increased with the high level of adenylate kinase 1 (AK1) and ATP synthase beta during C2C12 myogenesis. The exATP synthesis was abolished by the knock-down of AK1 but not by that of ATP synthase beta in C2C12 myotubes, suggesting that AK1 is required for exATP synthesis in myotubes. However, membrane-bound AK1beta was not involved in exATP synthesis because its expression level was decreased during myogenesis in spite of its localization in the lipid rafts that contain various kinds of receptors and mediate cell signal transduction, cell migration, and differentiation. Interestingly, cytoplasmic AK1 was secreted from C2C12 myotubes but not from C2C12 myoblasts. Taken together all these data, we can conclude that AK1 secretion is required for the exATP generation in myotubes.     

Effect of sildenafil citrate on interleukin-1beta-induced nitric oxide synthesis and iNOS expression in SW982 cells

The purpose of this study was to identify the effect of sildenafil citrate on IL-1β-induced nitric oxide (NO) synthesis and iNOS expression in human synovial sarcoma SW982 cells. IL-1β stimulated the cells to generate NO in both dose- and time-dependent manners. The IL-1β-induced NO synthesis was inhibited by guanylate cyclase (GC) inhibitor, LY83583. When the cells were treated with 8-bromo-cGMP, a hydrolyzable analog of cGMP, NO synthesis was increased upto 5-fold without IL-1β treatment suggesting that cGMP is an essential component for increasing the NO synthesis. Synoviocytes and chondrocytes contain strong cGMP phosphodiesterase (PDE) activity, which has biochemical features of PDE5. When SW982 cells were pretreated with sildenafil citrate (Viagra), a PDE5 specific inhibitor, sildenafil citrate significantly inhibited IL-1β-induced NO synthesis and iNOS expressions. From this result, we noticed that PDE5 activity is required for IL-1β-induced NO synthesis and iNOS expressions in human synovial sarcoma cells, and sildenafil citrate may be able to suppress an inflammatory reaction of synovium through inhibition of NO synthesis and iNOS expression by cytokines.     

Asymmetric total synthesis of fredericamycin A: an intramolecular cycloaddition pathway

The asymmetric total synthesis of the potent antitumor antibiotic fredericamycin A ((S)-1) was achieved by the intramolecular [4+2] cycloaddition of the silylene-protected styrene derivative (S)-7 followed by the aromatic Pummerer-type reaction of the sulfoxide (S)-5. Although we had already succeeded in the total synthesis of racemic 1 by the same approach, synthesis of its asymmetric version was more complicated than we had expected due to the difficulties involved in constructing the quaternary carbon center and the tendency of this center to undergo facile racemization. Racemization of this center during the installation of the acetylene moiety on the dione (R)-8 was the most serious aspect. Systematic studies of its DE-ring analogue (R)-25 revealed that racemization of the quaternary carbon center proceeded by a retro-aldol-aldol reaction of the initial adduct, (1R)-39 a-Li, and that the degree of racemization was dependent on the reaction temperature. The racemization process could be completely depressed by keeping the reaction temperature at -78 degrees C. The construction of the stereogenic quaternary carbon center was achieved by the lipase-catalyzed desymmetrization of the prochiral 1,3-diol 9 a bearing the DEF-ring moiety. These studies enabled us to attain the asymmetric total synthesis of (S)-1 while completely retaining the chiral integrity created by the enzymatic reactions.     

Facile Synthesis of (z)-5-Methyl-3-Phenoxymethylene 4,5-Dihydrofuran-2-One

(z)-α-Alkylidene-α-butyrolactone has been reported as a good plant growth regulator^[1] and as an important intermediate to the synthesis of natural product^[2] in literature. There was no report in the literature for the stereoselective synthesis of α-alkylidene lactones in exocyclic double with the (z)-configuration. Herein, we reported a facile synthesis of (z)-5-methyl-3-(phenoxymethylene)-4,5-dihydrofuran-2-one 4 from a readily available starting material 5-phenoxypent-3-yn-2-one 1 via three-step in good yield. The synthetic route is shown as below (scheme 1).     

New Dendrimers: Synthesis and Characterization of Popam - Pamam Hybrid Dendrimers

Recently developed multifunctional cancer therapeutic nano-device production is based on poly(amidoamine) PAMAM generation 5 (G5) dendrimer as a carrier 1-5. Scale up synthesis of this nano-device is limited because of long reaction sequence (12 reaction steps) and long and not easy work up of the products after each reaction step. Combination of poly(propyle-imine) and poly(amidoamine) synthesis can improve the production of the drug carrier.In this paper we give a general overview of the synthesis and characterization of a series of novel hybrid dendrimers which we coined as novel POMAM hybrid dendrimers, constructed from poly(propylene-imine) (PPI or POPAM) core and poly(amidoamine) PAMAM shells. The synthesis was accomplished by a divergent reiterating method involving repeating subsequent Michael addition and amidation reactions. Each generation of the newly synthesized dendrimer was characterized by using HPLC, GPC, NMR and AFM.     

Convenient Syntheses of Some C4 Chiral Building Blocks Starting From (S)-Malic Acid

In the field of chiral technology, the synthesis of chiral intermediates and chiral building blocks occupies an important position. Chiral building blocks bearing double and / or multiple functionalities is particularly useful for the synthesis of chiral pharmaceuticals and chiral agrochemicals. In the recent years, we have been engaged in the development of synthetic methodology based on (S)-malic acid1-s. In these studies, malimide 2, easily accessible from (S)-malic acid, was shown to be a useful multifunctional building block in the asymmetric synthesis of natural products and chiral drugs (Scheme 1).     

Ruthenium nanoparticles in ionic liquids: structural and stability effects of polar solutes

Ionic liquids are a stabilizing medium for the in situ synthesis of ruthenium nanoparticles. Herein we show that the addition of molecular polar solutes to the ionic liquid, even in low concentrations, eliminates the role of the ionic liquid 3D structure in controlling the size of ruthenium nanoparticles, and can induce their aggregation. We have performed the synthesis of ruthenium nanoparticles by decomposition of [Ru(COD)(COT)] in 1-butyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide, [C(1)C(4)Im][NTf(2)], under H(2) in the presence of varying amounts of water or 1-octylamine. For water added during the synthesis of metallic nanoparticles, a decrease of the solubility in the ionic liquid was observed, showed by nanoparticles located at the interface between aqueous and ionic phases. When 1-octylamine is present during the synthesis, stable nanoparticles of a constant size are obtained. When 1-octylamine is added after the synthesis, aggregation of the ruthenium nanoparticles is observed. In order to explain these phenomena, we have explored the molecular interactions between the different species using (13)C-NMR and DOSY (Diffusional Order Spectroscopy) experiments, mixing calorimetry, surface tension measurements and molecular simulations. We conclude that the behaviour of the ruthenium nanoparticles in [C(1)C(4)Im][NTf(2)] in the presence of 1-octylamine depends on the interaction between the ligand and the nanoparticles in terms of the energetics but also of the structural arrangement of the amine at the nanoparticle's surface.     

3, 4-二氢嘧啶-2-酮衍生物合成研究进展

综述了近十年来3,4-二氢嘧啶-2-酮衍生物合成的研究进展,包括催化合成、固相合成、微波促进合成及天然产物合成中的一些最新研究进展。     

Study of the total synthesis of (-)-exiguolide

In this article, we disclose the various routes and strategies we had to explore before finally achieving the total synthesis of (-)-exiguolide ((-)-1). Two first types of approaches were set, both relying on the Trost's domino ene-yne coupling/oxa-Michael reaction that we choose for its ability to control the geometry of the methylacrylate-bearing tetrahydropyrane ring B. In our first approach, we expected to assemble the two main fragments (C14-C21 and C1-C13) by creating the C13-C14 bond through a palladium(0)-catalyzed cross-coupling, but this step failed, unfortunately. In the second approach, which was more linear, we created the C16-C17 bond through condensation of a lithium acetylide on a Weinreb amide, and we assembled the C1-C5 and C6-C21 subunits through Trost's domino ene-yne coupling/oxa-Michael reaction. These two approaches served us to design an ameliorated third strategy, which finally led to the total synthesis of (-)-exiguolide.     

High light inhibits chlorophyll biosynthesis at the level of 5-aminolevulinate synthesis during de-etiolation in cucumber (Cucumis sativus) cotyledons

Using the vascular plant Cucumis sativus (cucumber) as a model, we studied the effects of high (intense and excess) light upon chlorophyll biosynthesis during de-etiolation. When illuminated with high light (1500-1600 microE/m2/s), etiolated cucumber cotyledons failed to synthesize chlorophyll entirely. However, upon transfer to low light conditions (40-45 microE/m2/s), chlorophyll biosynthesis and subsequent accumulation resumed following an initial 2-12 h delay. Duration of high light treatment negatively correlated with chlorophyll biosynthetic activity. Specifically, we found that high light severely inhibited 5-aminolevulinic acid (ALA) synthesis. This effect partly could be because of the decrease in protein level of glutamyl-tRNA reductase (GluTR) observed. Protein level of glutamate-1-semialdehyde (GSA-AT) remained unchanged. It was also found that high light did not suppress HEMA 1 expression. Therefore, we speculated that this significant inhibition of ALA synthesis might have occurred mainly because of concomitant inactivation of GluTR and/or inhibition of complex formation between GluTR and GSA-AT. Our further observation that both methyl viologen and rose bengal similarly inhibit ALA synthesis under low light conditions suggested that reactive oxygen species (ROS) could be responsible for the inhibition of ALA synthesis in cotyledons exposed to high light conditions.     

An efficient way to 1,7-enynes and ethyl 8-yn-2-enoates from aldohexoses and to polyhydroxylated 1-vinylcyclohexenes

In this paper, we report the synthesis of carbohydrate-derived 1,7-enynes and subsequent metathesis to yield polyhydroxylated 1-vinylcyclohexenes. For example, we converted D-glucose 2 to the (6,7)-dideoxy-D-gluco-hept-6-ene-pyranose 7, which led to the desired 1,7-enyne 16. The ring-closing metathesis of this 1,7-enyne 16 with the second generation Grubbs catalyst, under Mori's conditions, gave the corresponding polyhydroxylated 1-vinylcyclohexene 25 in 76% yield. The conversion of several aldohexoses into polyhydroxylated 1-vinylcyclohexenes was carried out with satisfying yields. We report also the synthesis of two carbohydrate-derived ethyl 8-yn-2-enoates from D-glucose derivatives.     

First Total Synthesis of the (±)-Preverecynarmin

The preverecynarmin(12), (+)-(1E,3E,7E,11E)-cembra-3,7,11-tetraen-6yl acetate,was first isolated in 1990 from both Armina maculata and its prey,the pennatulacean coral Veretillum cynomorium with other there briarane diferpenoids and cembene-C((1E,3E,7E,11E)-cembra-l,3,7,11-tetraen¹. As far as we known, the bioactive test and total synthesis of ¹² have not been reported yet. Herein we wish to describe the first total synthesis of (±)-preverecynarmin (12).     

Enantioselective formal total synthesis of the antitumor macrolide bryostatin 7

A new enantioselective synthesis of Masamune's AB fragment (1) for bryostatin 7 is described. Key steps in the new route include a Meerwein-Ponndorf-Verley reduction to set the O(7) stereocenter and an alkylative union between the dithiane 6 and iodide 5 to construct the C(9)-C(10) bond. Because we have previously published a synthesis of Masamune's C-ring phenyl sulfone 2, our new route to 1 constitutes a formal total synthesis of bryostatin 7; it also corrects the previously reported spectral data for 1 in CDCl3.     

Asymmetric Total Synthesis of Onoseriolide,Bolivianine, and Isobolivianine

In this article, we describe our efforts on the total synthesis of bolivianine ( 1 ) and isobolivianine ( 2 ), involving the synthesis of onoseriolide ( 3 ). The first generation synthesis of bolivianine was completed in 21 steps by following a chiral resolution strategy. Based on the potential biogenetic relationship between bolivianine ( 1 ), onoseriolide ( 3 ), and β‐(E)‐ocimene ( 8 ), the second generation synthesis of bolivianine was biomimetically achieved from commercially available (+)‐verbenone in 14 steps. The improved total synthesis features an unprecedented palladium‐catalyzed intramolecular cyclopropanation through an allylic metal carbene, for the construction of the ABC tricyclic system, and a Diels–Alder/intramolecular hetero‐Diels–Alder (DA/IMHDA) cascade for installation of the EFG tricyclic skeleton with the correct stereochemistry. Transformation from bolivianine to isobolivianine was facilitated in the presence of acid. The biosynthetic mechanism and the excellent regio‐ and endo selectivities in the cascade are well supported by theoretical chemistry based on the DFT calculations.     

Design and the synthesis of 1-heteroaryl-1,2,3-triazoles connected to coumarins via ether linker

In this paper, we report an efficient and versatile methodology for the synthesis of a series of novel heteroaryl-1,2,3-triazoles connected to 4-methylcoumarin (4-methyl-2H-chromen-2-one) via oxymethylene linker. The desired molecules were accessed by both two-step synthesis and the one-pot copper catalyzed cycloaddition reaction of heteroaromatic azides with coumarin containing acetylenes. The developed protocol was found to be facile and effective for preparing a series of novel heteroaryl-1,2,3-triazole-coumarin conjugates in excellent yields. Practical utility of one-pot protocol has been confirmed by the successful gram-scale synthesis of 1,3-Dimethyl-6-(4-[([4-methyl-2-oxo-2H-chromen-7-yl]oxy)methyl]-1H-1,2,3-triazol-1-yl)pyrimidine-2,4(1H,3H)-dione.     

Total synthesis of everninomicin 13,384-1--Part 1: retrosynthetic analysis and synthesis of the A1B(A)C fragment

In this first of a series of four articles we introduce everninomicin 13,384-1 (1), a powerful antibiotic effective against drug resistant bacteria, as a target for total synthesis and discuss its retrosynthetic analysis. From the three defined fragments required for the synthesis (2: A1B(A)C fragment; 4: DE fragment; 5: FGHA2 fragment), we describe herein two approaches to the A1B(A)C block. The first strategy relied on an olefin metathesis reaction to construct a common intermediate for rings B and C, but was faced with final protecting group problems. The second, and successful approach, involved a 1,2-phenylsulfeno migration and a sulfur directed glycosidation procedure to link rings B and C, as well as an acyl fluoride intermediate to install the sterically hindered aryl ester moiety (ring A1). The final stages of the synthesis of the required 2-phenylseleno glycosyl fluoride 2 required introduction of a phenylseleno group at C-1 of ring C followed by a novel, DAST-promoted 1,2-migration to produce the desired 2-beta-phenylseleno glycosyl fluoride moiety.