Prins cyclization: new strategy for the stereoselective total synthesis of Polyrhacitide A.

A highly stereoselective total synthesis of polyrhacitide A, a polyketide natural product, has been accomplished by means of Prins cyclisation. The key precursor i.e. anti-1,3-diol for polyrhacitide A has been prepared from trans-2,6-disubstituted-3,4-dihydropyrans. In this approach, Prins cyclisation has successfully been utilised twice for the construction of 1,3-diol unit of polyrhacitide A. The key steps involved in this approach are Jacobsen hydrolytic kinetic resolution, Mitsunobu inversion, Prins cyclisation and Ring-closing metathesis (RCM).

Total Synthesis and Structural Revision of Greensporone F and Dechlorogreensporone F.

The first asymmetric total syntheses of the real isolation product (2S,5R,8R)-greensporone F and (2S,5R,8R)-dechlorogreensporone F, 14-membered resorcylic acid lactones with a cis-2,5-disubstituted tetrahydrofuran ring system, was accomplished. The synthesis features a late-stage Lewis acid-catalyzed stereoselective intramolecular oxa-Michael reaction, E-selective ring-closing metathesis, De Brabander's esterification, and Jacobsen's hydrolytic kinetic resolution as the key steps. Synthesis of both real isolation and erroneously proposed structure necessitated the revision of the absolute configuration of greensporone F and dechlorogreensporone F. The erroneous representation of (2S,5S,8S)-configuration in greensporone F and dechlorogreensporone F was assigned to be (2S,5R,8R) by comparison with the NMR data and specific rotation of the synthetic compounds with that of the reported data.

Stereoselective Synthesis of the C1-C16 Fragment of the Purported Structure of Formosalide B.

The first stereoselective synthesis of the C1-C16 fragment possessing stereo-enriched fully substituted tetrahydropyran (THP) along with tetrahydrofuran (THF) rings of the proposed structure of formosalide B is described in 12 longest linear steps with 22% overall yield, starting from two cheap and commercially available 1,5-pentanediol and l-glutamic acid, following a convergent approach. The key steps involve in this synthesis are Horner-Wadsworth-Emmons reaction, Sharpless asymmetric dihydroxylation, and acid-mediated ketalization to assemble the substituted THP ring, one-pot Sharpless dihydroxylation-SN2-type cyclization, and Wittig homologation to construct the THF derivative.

Total synthesis and stereochemical revision of relgro and 10'-oxorelgro.

The first asymmetric total synthesis and stereochemical assignments of 10-membered macrolactones relgro and 10'-oxorelgro are disclosed. To this end, palladium-catalyzed Stille coupling, the Mitsunobu reaction, ring-closing metathesis, EDCI promoted coupling and the Jacobsen hydrolytic kinetic resolution are used as key steps. The total synthesis followed by thorough evaluation of the optical rotation and CD spectral data led to the revision of the absolute configuration at C-6' for both relgro and 10'-oxorelgro. Moreover, the 1H as well as 13C NMR data are reported for the first time for relgro.

Total Synthesis and Stereochemical Revision of 4,8-Dihydroxy-3,4-dihydrovernoniyne.

The first asymmetric total synthesis of two possible diastereomers (4S,5R)-4,8-dihydroxy-3,4-dihydrovernoniyne 5 and (4S,5S)-4,8-dihydroxy-3,4-dihydrovernoniyne 5a is accomplished. Salient features of the synthesis involve Cadiot-Chodkiewicz coupling and Sonogashira cross-coupling of terminal acetylenes. Detailed comparison of the 1H and 13C NMR data and specific rotation with that of the natural product led to the revision of the absolute stereochemistry of the natural product as (4S,5S)-4,8-dihydroxy-3,4-dihydrovernoniyne 5a.

Asymmetric Total Synthesis of the Putative Structure of Diplopyrone.

The first asymmetric total synthesis of the putative structure of diplopyrone was achieved in 17 linear steps starting from cis-1,4-butene-diol. The synthetic route features iodine-catalyzed tandem isomerization followed by C-O and C-C bond formation reaction strategy developed by our own group to construct the trans-2,6-disubstituted dihydropyran ring, asymmetric α-aminoxylation reaction, and Still-Gennari (Z)-selective olefination reactions. Careful comparison of 1H and 13C NMR spectroscopic data as well as investigation of the UV and circular dichroism spectrum in trifluoroethanol for compound 2 suggest that the putative structure for diplopyrone {6-[(1S)-1-hydroxyethyl]-2,4a(S),6(R),8a(S)-tetrahydropyran[3,2-b]pyran-2-one} requires revision.

A Convergent Total Synthesis of Balticolid.

A convergent total synthesis of the 12 membered macrolide, Balticolid (1) is described, starting from readily available homoallylic alcohol and 1,3 propane diol The synthetic strategy involves the construction of the 12-membered lactone.

Asymmetric Total Syntheses of Two Possible Diastereomers of Gliomasolide E and Its Structural Elucidation.

The first total syntheses of two possible diastereomers of gliomasolide E, a 14-membered macrolides isolated from the marine sponge Phakellia fusca Thiele, which was collected from the South China Sea, is reported. Highlights of the synthesis include macrolactonization through intramolecular Horner-Wadsworth-Emmons olefination, Yamaguchi-Hirao alkynylation, and base-induced elimination reactions for propargyl alcohol synthesis as the key reactions. Detailed comparison of their 1H and 13C NMR (1D and 2D NMR data) and specific rotation with those of the natural product revealed that the absolute stereochemistry of gliomasolide E should be (2E,5R,7R,9R,13R).

Total Synthesis of a Diacetonide Derivative of Thuggacin A.

A highly stereoselective total synthesis of the diacetonide derivative of the antibiotic thuggacin A has been described. The synthesis features the stereoselective Stille cross-coupling reaction to set up the whole carbon framework, aldol condensation to construct the highly substituted conjugated diene, non-Evans syn aldol, CBS reduction, Hantzsch's thiazole synthesis, Horner-Wadsworth-Emmons reaction, and Shiina's macrolactonization.

Total synthesis of Ivorenolide A following a base-induced elimination protocol.

A concise and stereocontrolled first total synthesis of Ivorenolide A (1) is reported in 16 longest linear steps with a 13.4% overall yield starting from (+)-diethyl tartrate (DET). Key features are base-induced elimination protocol for the construction of chiral propargyl alcohols in both fragments, Pd-catalyzed cross-coupling of terminal acetylenes, and Shiina's 2-methyl-6-nitrobezoic anhydride (MNBA) mediated macrolactonization.

Rugulactone derivatives act as inhibitors of NF-κB activation and modulates the transcription of NF-κB dependent genes in MDA-MB-231cells.

Rugulactone and its analogues were synthesized following Horners-Wadsworth-Emmons and ring-closing metathesis as the key reactions. A library of new rugulactone analogues were designed, synthesized and evaluated for their anticancer activity in breast cancer cells. All analogues have shown anti-proliferative activity, while some of them exhibited significant cytotoxicity. In assays related to cell-cycle distribution, these conjugates induced G1 cell-cycle arrest in MDA-MB-231 cells. The cell cycle arrest nature was further confirmed by examining the effect on Cyclin E and Cdk2 proteins that acts at G1-S phase transition. Immunocytochemistry assay revealed that these compounds inhibited nuclear translocation of NF-κB protein, thereby activation of NF-κB was inhibited. The expression of NF-κB target genes such as Cyclin D1 and Bcl-xL were severely affected. Apart from acting on NF-κB, these compounds also regulate class I Histone deacetylase proteins such as (HDAC-3 and 8) that have a crucial and regulatory role in cell-proliferation. Simultaneously, the apoptotic inducing nature of these compounds was confirmed by activation of PARP protein, a protein that plays a key role in DNA damage and repair pathways. Among all compounds of this series 3g is the most potent compound and can be used for further studies.

Synthesis of acylsilanes via nickel-catalyzed reactions of α-hydroxyallylsilanes.

The redox isomerization processes and tandem isomerization-aldolization reactions, mediated by nickel catalysts, offer new versatile entries to acylsilanes. For the second reaction, high diastereoselectivities, up to 98:2, have been obtained with bulky substituents on silicon.

Plant HDAC inhibitor chrysin arrest cell growth and induce p21WAF1 by altering chromatin of STAT response element in A375 cells.

BACKGROUND: Chrysin and its analogues, belongs to flavonoid family and possess potential anti-tumour activity. The aim of this study is to determine the molecular mechanism by which chrysin controls cell growth and induce apoptosis in A375 cells. METHODS: Effect of chrysin and its analogues on cell viability and cell cycle analysis was determined by MTT assay and flowcytometry. A series of Western blots was performed to determine the effect of chrysin on important cell cycle regulatory proteins (Cdk2, cyclin D1, p53, p21, p27). The fluorimetry and calorimetry based assays was conducted for characterization of chrysin as HDAC inhibitor. The changes in histone tail modification such as acetylation and methylation was studied after chrysin treatment was estimated by immuno-fluorescence and western blot analysis. The expression of Bcl-xL, survivin and caspase-3 was estimated in chrysin treated cells. The effect of chrysin on p21 promoter activity was studied by luciferase and ChIP assays. RESULTS: Chrysin cause G1 cell cycle arrest and found to inhibit HDAC-2 and HDAC-8. Chrysin treated cells have shown increase in the levels of H3acK14, H4acK12, H4acK16 and decrease in H3me2K9 methylation. The p21 induction by chrysin treatment was found to be independent of p53 status. The chromatin remodelling at p21WAF1 promoter induces p21 activity, increased STAT-1 expression and epigenetic modifications that are responsible for ultimate cell cycle arrest and apoptosis. CONCLUSION: Chrysin shows in vitro anti-cancer activity that is correlated with induction of histone hyperacetylation and possible recruitment of STAT-1, 3, 5 proteins at STAT (-692 to -684) region of p21 promoter. Our results also support an unexpected action of chrysin on the chromatin organization of p21WAF1 promoter through histone methylation and hyper-acetylation. It proposes previously unknown sequence specific chromatin modulations in the STAT responsive elements for regulating cell cycle progression negatively via the induction of the CDK inhibitor p21WAF1.

1,3-Dipolar cycloaddition of sugar azides with benzyne: a novel synthesis of 1,2,3-benzotriazolyl glycoconjugates.

Glycosyl azides undergo smooth 1,3-dipolar cycloaddition with benzyne generated in situ from 2-(trimethylsilyl)phenyltrifluoromethanesulfonate and cesium fluoride under mild conditions to furnish 1,2,3-benzotriazole-linked glycoconjugates in excellent yields and with high stereoselectivity. This method provides a novel class of benzotriazole linked glycoconjugates in a single-step reaction. This is the first example of a fluoride- triggered 1,3-dipolar cycloaddition of benzyne with glycosyl azides.

Sub-cellular internalization and organ specific oral delivery of PABA nanoparticles by side chain variation.

BACKGROUND: Organic nanomaterials having specific biological properties play important roles in in vivo delivery and clearance from the live cells. To develop orally deliverable nanomaterials for different biological applications, we have synthesized several fluorescently labelled, self-assembled PABA nanoparticles using possible acid side chain combinations and tested against insect and human cell lines and in vivo animal model. Flurophores attached to nanostructures help in rapid in vivo screening and tracking through complex tissues. The sub-cellular internalization mechanism of the conjugates was determined. A set of physio-chemical parameters of engineered nanoskeletons were also defined that is critical for preferred uptake in multiple organs of live Drosophila. RESULTS: The variability of side chains alter size, shape and surface texture of each nanomaterial that lead to differential uptake in human and insect cells and to different internal organs in live Drosophila via energy dependent endocytosis. Our results showed that physical and chemical properties of C-11 and C-16 acid chain are best fitted for delivery to complex organs in Drosophila. However a distinct difference in uptake of same nanoparticle in human and insect cells postulated that different host cell physiology plays a critical role in the uptake mechanism. CONCLUSIONS: The physical and chemical properties of the nanoparticle produced by variation in the acid side chains that modify size and shape of engineered nanostructure and their interplay with host cell physiology might be the major criteria for their differential uptake to different internal organs.

Stereoselective synthesis of four possible isomers of streptopyrrolidine.

The synthesis of (4R,5R)-streptopyrrolidine (1), (4S,5R)-streptopyrrolidine (2) (4R,5S)-streptopyrrolidine (3) and (4S,5S)-streptopyrrolidine (4) have been achieved in a concise and highly efficient manner via a highly stereoselective aldol type reaction with the trimethylsilyl enolate of ethyl acetate and Lewis acid mediated lactamization as the key reactions in ≈42% yield over six steps starting from D-phenylalanine and L-phenylalanine, respectively. The absolute configuration of the natural product was shown to be (4S,5S) by comparing its spectral and analytical data with the reported values.

Synthesis of (3R,5R)-harzialactone A and its (3R,5S)-isomer.

The total synthesis of (3R,5R)-harzialactone A (1) and its (3R,5S)-isomer (2) is described. Epoxide opening with thioacetal and diastereoselective reductions are used as key reactions.

4-N-pyridin-2-yl-benzamide nanotubes compatible with mouse stem cell and oral delivery in Drosophila.

p-aminobenzoic acid (PABA), a structural moiety of many commercial drugs, is self-assembled with linker alkyl side chains to form tubular nanostructures. The tubes exhibited fluorescence either intrinsic or from fluorescent molecules embedded in the wall during self-assembly. Uptake and inter-cellular delivery of the conjugated nanotubes in human cancer cells and in mouse embryonic stem cells were demonstrated by fluorescence imaging and flow cytometry. Biocompatibility, cytotoxicity and clearance were monitored both ex vivo in mouse multipotent embryonic stem cells and in vivo in adult Drosophila. Accumulation of nanotubes had no adverse effects and abnormalities on stem cell morphology and proliferation rate. A distinct distribution of two separate nanotubes in various internal organs of Drosophila interprets that accumulation of nanomaterials might be interdependent on the side chain modifications and physiological settings of cell or tissue types. Unlike carbon nanomaterials, exposure of PABA nanotubes does not produce any hazards including locomotion defects and mortality of adult flies. Despite differential uptake and clearance from multiple live tissues, the use of self-assembled nanotubes can add new dimensions and scope to the development of dual-purpose oral carriers for the fulfilment of many biological promises.

Gold(III) chloride-catalyzed three-component reaction: a facile synthesis of alkynyl derivatives of 1,2-dihydroquinolines and isoquinolines.

Gold(III) chloride is found to be an effective catalyst for the addition of alkynes on activated quinoline/isoquinolines to produce a series of alkynyl-substituted 1,2-dihydroquinolines and isoquinolines in a single-step operation. The easy availability of starting materials, convenient synthetic procedure, operational simplicity, and high regioselectivity makes this strategy very useful for the preparation of enyne derivatives of aza-aromatic compounds.

Three-component reaction of aldose sugars, aryl amines, and 1,3-diones: a novel synthesis of annulated pyrroles.

Aldose sugars undergo smooth coupling with enamines, generated in situ from aryl amines and 1,3-diketones, in the presence of 10 mol % of InCl3 in water at 80 degrees C to furnish annulated pyrrole derivatives in relatively good to high yields. The use of InCl3, in combination with water, makes this procedure quite simple, more convenient, and environmentally friendly.