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A series of simplified discodermolide analogues have been designed and synthesized in an attempt to understand the role of the lactone ring. These synthetic efforts have led to an unsubstituted butyrolactone 9 being generated, which shows improved activity over the natural product.
We describe a concise and flexible synthetic avenue for the preparation of compounds with structures relevant to those proposed for the novel marine-derived differential cytotoxins psymberin and irciniastatin A. Our efforts led to their complete stereochemical assignment and the notion that psymberin and irciniastatin A are identical compounds. Our total synthesis features an interesting termini-differentiating lactolization of a dialdehyde obtained from a C2-symmetrical bis-olefin precursor, a mild platinum-catalyzed hydrolysis of an epimerizable nitrile, a novel protocol to prepare sensitive methyl imidates, and a one-pot conversion of these imidates to N-acyl aminals. Starting from fragments 5-7 (prepared in 7-8 steps each, 30-49% overall yield) the synthesis of psymberin/irciniastatin A was completed in an additional 9 steps and 30% yield (17 steps longest linear sequence, 8.9% overall).
The first direct enantioselective organocatalytic intramolecular Diels-Alder reaction has been accomplished. The use of iminium catalysis has provided a new catalytic strategy for the enantioselective [4 + 2] cycloisomerization of a wide variety of tethered diene-enal systems. The use of imidazolidinones 1 and 2 as the asymmetric catalysts has been found to mediate the enantioselective construction of [4.4.0] and [4.3.0] ring systems. Application of this methodology to the highly efficient asymmetric synthesis of the marine metabolite solanpyrone D has also been accomplished. A diverse spectrum of aldehyde substrates can also be accommodated in this new organocatalytic transformation. Importantly, this technology has been utilized to execute the first enantioselective, catalytic Type II IMDA reaction.
An efficient, enantioselective synthesis of apoptolidinone has been completed, demonstrating the versatility of thiazolidinethione auxiliaries. Three propionate aldol additions and two asymmetric glycolate alkylations function to establish 8 of the 12 stereogenic carbon centers. A cross-metathesis reaction is utilized to assemble the C1-C10 trieneoate fragment and the C11-C28 polypropionate region of the molecule.
A new synthetic strategy for the enantioselective synthesis of members of the dolabellane family of marine natural products has been demonstrated for the specific examples beta-araneosene and isoedunol (1 and 2, respectively) by the pathway outlined in Scheme 1. Key steps include (1) diastereoselective alkylation of Seebach's chiral lactate acetal (6) by the iodide derived from 5; (2) Kulinkovich ethylenation of ester 9 to form the cyclopropanol 10; (3) ring expansion of 10 to form 11; (4) pinacol cyclization of keto aldehyde 12 to form 13a; (5) rearrangement of 13b to 14; (6) propenylation of 14 to 2; and (7) reductive pi-transposition to form 1.
Catalytic asymmetric synthesis of the natural antibiotic fostriecin (CI-920) and its analogue 8-epi-fostriecin and evaluation of their biological activity are described. We used four catalytic asymmetric reactions to construct all of the chiral centers of fostriecin and 8-epi-fostriecin; cyanosilylation of a ketone, Yamamoto allylation, direct aldol reaction, and Noyori reduction, two of which were developed by our group. Catalytic enantioselective cyanosilylation of ketone 13 produced the chiral tetrasubstituted carbon at C-8. Both enantiomers of the product cyanohydrin were obtained with high enantioselectivity by switching the center metal of the catalyst from titanium to gadolinium. Yamamoto allylation constructed the C-5 chiral carbon in the alpha,beta-unsaturated lactone moiety. A direct catalytic asymmetric aldol reaction of an alkynyl ketone using LLB catalyst constructed the chirality at C-9 with the introduction of a synthetically versatile alkyne moiety, which was later converted to cis-vinyl iodide, the substrate for the subsequent Stille coupling for the triene synthesis. Noyori reduction produced the secondary alcohol at C-11 from the acetylene ketone 6 with excellent selectivity. Importantly, all the stereocenters were constructed under catalyst control in this synthesis. This strategy should be useful for rapid synthesis of stereoisomers of fostriecin.
Compounds 1 and 2 are novel synthons for bispropionate synthesis, undergoing stereospecific Lewis acid-catalyzed transfer of the bispropionate unit with a variety of aldehydes, including alpha-chiral aldehydes. Thus 1 leads to the E-alkene bispropionate 3 with anti-stereochemistry, whereas diastereomer 2 gives the Z-alkene product 4, under mild conditions and with complete stereospecificity. The efficacy of this methodology is demonstrated in a short synthesis of invictolide beginning with 2 and (R)-2-methylpentanal.
Double diastereoselection in alkaloid-catalyzed acyl halide-aldehyde cyclocondensation (AAC) reactions provides a strategy for realizing syn- or anti-selective propionate aldol additions from a common reaction manifold. Matched AAC homologation of enantioenriched aldehydes afford cis-disubstituted beta-lactones as surrogates for syn aldols; the mismatched AAC reactions provide anti-selective aldols in the form of trans-disubstituted 2-oxetanones. The utility of this reaction technology in synthesis activities is exemplified in a catalytic asymmetric total synthesis of (-)-pironetin.
An enantioselective total synthesis of the apoptosis-inducing natural product, (-)-rasfonin, is described. Camphor lactam-mediated asymmetric alkylation reactions enabled the installation of three stereogenic centers with >95:5 diastereoselectivity. A modified Corey-Peterson olefination was employed in the construction of the (E,E)-diene system. A highly diastereoselective, asymmetric vinylogous Mukaiyama aldol addition was conducted using a chiral cationic oxazaborolidine catalyst. The pyranone core of the natural product was prepared via a DBU-promoted rearrangement of a furanol to its corresponding pyranol with concomitant [1,4]-silyl transfer.
The total synthesis of cytostatin, an antitumor agent belonging to the fostriecin family of natural products, is described in full detail. The convergent approach relied on a key epoxide-opening reaction to join the two stereotriad units and a single-step late-stage stereoselective installation of the sensitive (Z,Z,E)-triene through a beta-chelation-controlled nucleophilic addition. The synthetic route provided rapid access to the C4-C6 stereoisomers of the cytostatin lactone, which were prepared and used to define the C4-C6 relative stereochemistry of the natural product. In addition to the natural product, each of the C10-C11 diastereomers of cytostatin was divergently prepared (11 steps from key convergence step) by this route and used to unequivocally confirm the relative and absolute stereochemistry of cytostatin. Each of the cytostatin diastereomers exhibited a reduced activity toward inhibition of PP2A (>100-fold), demonstrating the importance of the presence and stereochemistry of the C10-methyl and C11-hydroxy groups for potent PP2A inhibition. Extensions of the studies provided dephosphocytostatin, sulfocytostatin (a key analogue related to the natural product sultriecin), 11-deshydroxycytostatin, and an analogue lacking the entire C12-C18 (Z,Z,E)-triene segment, which were used to define the magnitude of the C9-phosphate (>4000-fold), C11-alcohol (250-fold), and triene (220-fold) contribution to PP2A inhibition. A model of cytostatin bound to the active site of PP2A is presented, compared to that of fostriecin, which is also presented in detail for the first time, and used to provide insights into the role of the key substituents. Notably, the alpha,beta unsaturated lactone of cytostatin, like that of fostriecin, is projected to serve as a key electrophile, providing a covalent adduct with Cys269 unique to PP2A, contributing to its potency (> or =200-fold for fostriecin) and accounting for its selectivity.
An intensely orange compound, which has recently been evaluated as one of the main colored compounds formed in Maillard reactions of hexoses, could be unequivocally identified as (Z)-2-[(2-furyl)methylidene]-5,6-di(2-furyl)-6H-pyran-3-one (1) by application of several NMR and LC-MS experiments. To clarify its formation, the effectiveness of certain carbohydrate degradation products as precursors of 1 was studied in a quantitative experiment demonstrating hydroxy-2-propanone, furan-2-aldehyde, and 3-deoxy-2-hexosulose as precursors of the colorant. Site-specific labeling experiments with D-1-[(13)C]glucose and D-6-[(13)C]glucose, respectively, were performed to elucidate the formation pathway of 1 involving a cleavage of the hexose skeleton between carbon atoms C(5) and C(6). In addition, pentoses could be shown to generate 1 via a similar formation pathway involving the 3-deoxy-2-pentosulose.
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On-line techniques were developed to monitor chemical and physical changes occurring during the heating of skim milk powder (SMP). Atmospheric pressure chemical ionization mass spectrometry (APCIMS) followed the generation and release of volatile compounds from SMP in a packed-bed reactor. Operating conditions were optimized to avoid condensation of high boiling compounds such as maltol, and the system was highly reproducible (CV < 7%). Differential scanning calorimetry (DSC) of SMP identified a potential glass transition at an onset temperature of 67.9 degrees C and a series of exothermic events that were related to different stages of the Maillard reaction. No lactose crystallization was found after heating. Using a heated stage reflectance FTIR device, spectra were obtained at different temperatures. Analysis of the data showed a correlation between the intensity ratio at wavenumbers 1017 and 1064 cm(-1) and the glass transition measured by DSC. This FTIR system was not sensitive enough to detect Maillard intermediates. Combining data from the three techniques provides a fuller picture of the physical changes during the Maillard reaction and their effects on the chemical reactions.
A simple and highly sensitive reversed-phase high-performance liquid chromatographic method (RP-HPLC) has been developed for the determination of steviol (SV) using dihydroisosteviol (DHISV) as an internal standard (IS). SV and DHISV were derivatized by reaction of the acids with 4-(bromomethyl)-7-methoxycoumarin in an aprotic solvent (DMF or acetone). The resulting ester derivatives were separated on an ODS column (250 x 4.6 mm i.d., 5 microm particle size) using fluorescence detection with excitation at 321 nm and emission at 391 nm. The mobile phase consisted of acetonitrile/water (80:20 v/v) with a flow rate of 1 mL min(-)(1). A linear relationship was observed for concentrations between 0.5 and 50 microg/mL of SV, and the detection limit was 100 pg. For application of this method to samples of beer fortified with stevioside, a simple procedure for extraction of the beer with diethyl ether and derivatization in DMF was applied. Whereas beer samples spiked with SV gave a linear response over the range 0.1-15 microg/mL beer, no SV could be detected in beer samples enriched in stevioside that had been stored for over 3 years. The application of the method to plant samples involved preparation of an acid fraction containing the SV analyte, derivatization, and sample cleanup using small silica columns and thin-layer chromatography. A sensitive determination of 594 ng of steviol present in 100 mg of dry plant material was performed with high precision and accuracy.
Investigation of the colored products formed by the reaction of d-glucose with butylammonium acetate has been extended. The previously unknown 1-N-butyl-4-hydroxy-5-methyl-2-(N-butyl-3-hydroxy-5-(2-hydroxyethyl)pyrrolyl-2-methylidene)-2H-pyrrolin-3-one (2a) was isolated from the reaction mixture and identified after acylation by spectroscopic data. Butylaminammonium acetate was used as a model compound representing the lysine side chains of proteins.
The phytotoxin epi-radicinol, a diastereomer of radicinol, was isolated from large cultures of Alternaria radicina grown on carrot slices and identified by GC-MS, LC-MS, (1)H NMR, and (13)C NMR. Four strains of A. radicina isolated from rotted carrot produced epi-radicinol as the major metabolite (up to 39414 microg/g) together with radicinol (up to 2423 microg/g), and, to a lesser extent, radicinin when cultured on carrot slices, whereas on rice they mainly produced radicinin (2486-53800 microg/g). Radicinin and epi-radicinol reduced root elongation of germinating carrot seeds at concentrations of 10-20 microg/mL. Carrot samples naturally infected by A. radicina contained detectable quantities of epi-radicinol also in combination with lower levels of radicinin or radicinol. Accumulation of radicinols and radicinin in stored carrots, either naturally contaminated or artificially inoculated with A. radicina, was stimulated by successive temperature rises from 1 to 10 degrees C and from 10 to 20 degrees C, reaching maximum levels of 60 microg/g epi-radicinol and 26 microg/g radicinin. This is the first report on the production of radicinols by A. radicina and its natural occurrence in carrots in association with radicinin.
In this study, an in vitro nitric oxide (*NO)-generating system was used to investigate the *NO-scavenging effects of methanolic extracts of white ginseng (Panax ginseng C.A. Meyer), red ginseng, and sun ginseng and several ginsenosides and phenolic compounds. Sun ginseng extract showed the strongest activity among the three ginseng extracts. None of the ginsenosides used in this experiment showed *NO-scavenging activity, but the phenolic compounds, such as p-coumaric and vanillic acids, and maltol inhibited *NO production in a concentration-dependent manner. Moreover, maltol levels markedly increased by heat processing. Therefore, the enhanced *NO-scavenging activity of ginseng by heat processing was closely related to phenolic acids and the increased content of maltol.
The oviposition pheromone for the pathogen-vectoring mosquitoes in the genus Culex (Diptera: Culicidae), that is, (5R, 6S)-6-acetoxy-5-hexadecanolide, is efficiently synthesized, in admixture with the inactive (5S,6R) enantiomer ( approximately 33% w/w), from the fixed oil extracted from the seeds of the summer cypress plant, Kochia scoparia (Chenopodiaceae), cultivated on an industrial scale. Oviposition bioassays using gravid females of Culex quinquefasciatus, a vector of filariasis in human beings, showed that the product was attractive, with activity comparable to that of a pure synthetic sample containing the same amount of the active enantiomer. Production of the pheromone in the form of a biologically active crude material via a cheap and renewable plant suitable for development as a new industrial crop provides the basis for control of Cx. quinquefasciatus and other congeneric vectors of pathogens in resource-poor areas of the world.