Alkaloid Natural Products Research Articles

General strategies for the stereoselective synthesis of alkaloid natural products

Abstract

ChemInform Abstract: Studies of the Tetrathiafulvalene Mediated Radical‐Polar Crossover Reaction Directed Toward the Total Synthesis of Alkaloid Natural Products.

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Studies of the tetrathiafulvalene mediated radical-polar crossover reaction directed toward the total synthesis of alkaloid natural products

The carbon skeleton of octahydro-1 H-pyrrolo[2,3- d]carbazole ( 4), a tetracylic sub-unit which is common to a wide range of alkaloid natural products has been prepared by two approaches which exploit the one-pot radical-polar crossover chemistry mediated by tetrathiafulvalene. Both approaches proceed with complete stereoselectivity.

Quantitative Capillary Electrophoresis-Ion Spray Mass Spectrometry on a Benchtop Ion Trap for the Determination of Isoquinoline Alkaloids

The quantitative determination of some isoquinoline alkaloid natural products is described using combined capillary electrophoresis-ion trap mass spectrometry (CE/MS). The benchtop ion trap is a previously described modified commercial Varian Saturn II system equipped with an in-house constructed atmospheric pressure ionzation (API) ion source which was operated in the ion spray CE/MS mode. All relevant operational parameters have been optimized for the CE/MS experiments described in this work. A coaxial sheath flow of solvent buffer was used to facilitate ion spray CE/MS operation. Analysis of synthetic mixtures containing nine related isoquinoline alkaloids provided full-scan mass spectra for these compounds with injected quantities as low as 370 attomole

Cell surface oligosaccharide modulation during differentiation: VI. The effect of biomodulation on the senescent and neoplastic cell phenotype

These investigations test the hypothesis developed previously, that there are biomolecules which control and integrate cellular differentiation. Our specific interest in cellular differentiation lies in the area of what we refer to as basal or primitive cellular differentiation mechanisms. These mechanisms are common to all cells, and are required for simple recognition and growth regulation. We have investigated two models, the IMR-90 human fetal lung fibroblast model as a representative of normal growth control, and the CG model, canine glioma cells, a transplantable growth transformed cell line. These two models represent normal, and aberrant cellular differentiation control. In previous studies we have shown that the arrangement of the cell surface oligosaccharide structure on these cell types are predictive of phenotypic transition. We have developed, and partially characterized a series of BIOMODULATORS (BM) which delay the onset of display of neoplastic cells. Three classes of BIOMODULATOR have been explored; (1) a large molecular weight natural product (25–35 kDa), PokeWeed Mitogen (PWM); (2) a small molecular weight natural product (500 Da) Cellular Activator and Differentiator (CAD) and a number of natural and synthetic analogs; and (3) an indolizidine alkaloid natural product, Swainsonine (Sw) which has a known cellular target (oligosaccharide biosynthesis). Preliminary data is presented which structurally links some of these BIOMODULATORS in terms of their effective stereochemistry. These BIOMODULATORS, when used before PDL 38, prevent the cell surface oligosaccharide display changes typical of morphological senescence and delay their onset to PDL 100 or more. These BIOMODULATORS also appear to have regulatory effects on the neoplastic cell models. This re-regulation results in increases in generation time and an increase in the ability of these cells to be recognized by cytotoxic lymphocytes. Proton NMR linewidth measurements of the fraction of ‘bound’ water associated with the cellular surface of treated and untreated cell populations showed induced physical changes in the cell surface related to the use of the BIOMODULATOR and correlated to the oligosaccharide display changes. These data were interpreted as indicating an increase in the organizational display changes. These cells. The data for normal and neoplastic cell populations are compared and contrasted in an effort to form the basis for an analytical approach to the control and integration of differentiation mechanisms.

Substitution reactions of 2-phenylsulphonyl-piperidines and -pyrrolidines with carbon nucleophiles: Synthesis of the pyrrolidine alkaloids norruspoline and ruspolinone

Several 2-phenylsulphonyl-piperidines and -pyrrolidines were prepared from the corresponding N-acyl aminals by treatment with benzenesulphinic acid. On reaction with various carbon nucleophiles these sulphones gave good yields of substitution products. Typical nucleophiles used in these studies were organometallic reagents derived from Grignard reagents and zinc halide together with silyl enol ethers, silyl ketene acetals, allylsilanes and trimethylsilyl cyanide in the presence of a Lewis acid. These methods were employed in the synthesis of two natural product alkaloids; Norruspoline (38) and Ruspolinone (40).

The synthesis of pyrrolizidines and indolizidines by the intramolecular cycloaddition of azides with electron-rich 1,3-dienes. A synthetic equivalent of a nitrene-diene cycloaddition

Alkyl azides were found to undergo intramolecular cycloadditions with certain 1,3-dienes to provide 2,3,5,7a-tetrahydro-1H-pyrrolizines and 3,5,6,7,8,8a-hexahydroindolizines in one operation. The presence of an electron-donating group on the diene (sulfur, selenium, or oxygen) was required to avoid alternative rearrangement processes. The cyclization of chiral azidodienes proceeded with high diastereoselectivity to produce materials that are closely related to several alkaloidal natural products. New methods for the synthesis of the requisite heterosubstituted 1,3-dienes were developed

Synthesis of streptazolin: use of the aza-Ferrier reaction in conjunction with the INOC process to deliver a unique but sensitive natural product

The total synthesis of the unique alkaloid natural product streptazolin is described. The synthetic route makes use of the Ferrier-like reaction of a Δ 2 -piperidinol with alkyltrimethylsilane in combination with the INOC reaction to create the ring skeleton of this product. The extension of the aza-Ferrier reaction to other nucleophiles is discussed. The transformation of isoxazolines with peracids to β-hydroxy ketones or diol monoacetates discovered during the course of these studies is also presented

Direct Substitution of 2-Benzenesulphonylpiperidines and -pyrrolidines by Carbon Nucleophiles: Synthesis of the Pyrrolidine Alkaloid Ruspolinone

Treatment of 2-benzenesulphonylpiperidines and -pyrrolidines with various carbon nucleophiles such as aryl, vinyl, and alkynyl organometallics (5 examples), or alternatively silyl enol ethers or allylsilanes in the presence of a Lewis acid (4 examples), afford the corresponding substitution products in good yield. The method has been used to prepare the pyrrolidine alkaloid natural product Ruspolinone (13).

Antagonism by taxol of effects of microtubule-disrupting agents on lymphocyte cAMP metabolism and cell function.

Several microtubule-disrupting agents (colchicine, demecolcine, vinblastine, vincristine, podophyllotoxin, and nocodazole) have been shown to inhibit lymphocyte-mediated cytolysis. These agents also enhanced the prostaglandin E1-induced rise in cAMP levels in these cytolytic lymphocytes. Taxol, a natural product alkaloid that has been shown to enhance microtubule polymerization and to stabilize microtubules, antagonized both of these effects of the microtubule-disrupting agents in the cytolytic lymphocytes. Taxol also antagonized the enhancement of cAMP increases by colchicine in lymphocytes stimulated by 2-chloroadenosine, isoproterenol, and cholera toxin. The enhancement of the prostaglandin E1-induced cAMP response caused by treatment of the lymphocytes with either cytochalasin B or 3-deazaadenosine in the presence or absence of L-homocysteine was not antagonized by taxol. Taxol, colchicine, or the combination of these two agents did not affect ATP levels in cytolytic lymphocytes. These results support a modulatory role for microtubules in both the cytolytic process and the production of cAMP in these lymphocytes.