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Chemistry, Organic

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Biology, Microbiology and Chemistry, Organic

Pactamycin (1), a cytotoxic antibiotic produced by Streptomyces pactum, var. pactum, contains several interesting structural features, including a cyclopentanoid ring, which is rare among natural products, a 6-methylsalicylic acid (6-MSA) unit derived from acetate via a polyketide route, and a m-aminoacetophenone unit, which represents the m-C$\sb7$N unit found in many antibiotics. It was expected that 6-MSA would be an advanced precursor to the corresponding unit on pactamycin, but feeding experiments with 6-methyl (carboxy-$\sp $C) salicylic acid and methyl 6-methyl (carboxy-$\sp $C) salicylate failed to show significant incorporation into either pactamycin or its analogue pactamycate. In addition, these precursors were apparently toxic to S. pactum, causing pronounced acidification of the production medium and substantial reduction of pactamycin production.(DIAGRAM, TABLE OR GRAPHIC OMITTED...PLEASE SEE DAI)

Chemistry, Organic

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Chemistry, Organic and Health Sciences, Immunology

The clinical success of conjugate anticancer and antiviral vaccines critically depends on the identification of, and access to, novel adjuvants with high potency and attenuated toxicity. The QS-21 fraction of Quillaja saponaria extracts comprises an isomeric mixture of complex triterpene saponins and is currently the most promising immunopotentiator in several antitumor and infectious disease vaccine therapies. However, the clinical use of QS-21 has been hindered by the difficulty in obtaining sufficient quantities of homogenous saponin from the natural source as well as by the low-grade toxicity and hydrolytic instability of this adjuvant. In this work, a robust chemical route to the two principal isomeric constituents of QS-21 has been established, and synthetically pure adjuvant has been prepared to fuel several pilot trials. In addition, an improved semisynthetic route to pure QS-saponin adjuvants has been developed, facilitating the discovery of novel immunostimulants with increased potency, stability and attenuated toxicity. This method was applied to the synthesis of the natural product adjuvant QS-7-Api and to non-natural aza-saponins. In this initial foray into designed molecular adjuvants, hydrolytically stable saponins have been discovered that equal or excel QS-21 as immunoadjuvants.

Chemistry, Organic

A general synthetic approach that affords both enantiomers of chiral lactones is described. The key step involves the automated multigram chromatography of diastereomeric derivatives of a racemic intermediate. The generality of the method is demonstrated by the synthesis of ring-saturated lactones of three different ring sizes, a series of bicyclic lactones, (alpha), (beta)-unsaturated lactones, and several examples containing aromatic substituents. Six of these examples occur in nature as pheromones or allomones, and hence are of biological interest. Assignments of absolute configuration to the lactone enantiomers and their precursors typically attend these syntheses. For some lactones, possessing suitable NMR spectra, direct determination of enantiomeric purity is possible using the chiral solvent (R)-(-)-2, 2, 2-trifluoro-1-(9-anthryl) ethanol.

Chemistry, Organic

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Chemistry, Organic

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Chemistry, Organic

The kinetics of the reactions of alkyllithium reagents with ketones and esters in cyclohexane and benzene have been investigated by stopped-flow infrared spectroscopy at 25.0(DEGREES)C. A series of substituted phenyl-sec-butyl ketones (10a-i) and substituted ethyl benzoates (13a-i) along with several aliphatic ketones (14-17) and esters (18,19) were utilized in the study. These compounds were found to form coordination complexes with alkyllithium aggregates. Evidence for this was demonstrated by the appearance of a new carbonyl band in the infrared spectrum of a reacting solution of ester or ketone and alkyllithium reagent immediately after mixing. The new band, which is shifted to lower wave-number relative to the carbonyl band of the carbonyl compound, has been attributed to the formation of a substrate-alkyllithium aggregate complex in rapid equilibrium with the free substrate. Equilibrium constants (K(,c)) for complexation with sec-butyllithium in cyclohexane were determined for several compounds. A trend in the K(,c) values for the substituted phenyl-sec-butyl ketones and ethyl benzoates was observed: the more electron donating the substituent the larger the equilibrium constant of complexation. Further, larger K(,c) values were obtained for the esters, in their reactions with sec-butyllithium, than for the corresponding ketones.

Chemistry, Organic

The (alpha)-silyl-(beta),(gamma)-unsaturated esters were allowed to react with a variety of electrophiles in the presence of TiCl(,4), TiF(,4), BF(,3)(.)OEt(,2), FeCl(,3), or TMSOTf. Ethyl 2-trimethylsilyl-3-methyl-3-butenoate was used as a model substrate to examine the scope and limitations. In all cases, only products resulting from attack of the electrophile (aldehydes, ketones, acid chlorides, ketals, acetals, and chloromethyl phenyl sulfide) at the (gamma)-position were observed; no (alpha)-substituted products could be detected by GLC or ('1)H NMR. High stereoselectivity of ca. 9:1 around the 2,3-double bond is normally observed. Chloromethyl phenyl sulfide, an electrophile shown to give low (gamma):(alpha) ratios when reacted with silyl dienol ethers, also gives clean (gamma)-selectivity, albeit with lower stereoselectivity (E:Z ca 1:1). The model ester appears to have moderate reactivity, and fails to react with those electrophiles that cannot form a well-stabilized carbonium ion. The products isolated from the reactions of the model ester with electrophiles promoted by TiCl(,4), TiF(,4), or FeCl(,3) appeared, in some cases, to arise from subsequent conversion of the initially-formed adducts (chlorination, bis-substitution, and dimerization). In contrast, these further transformations were not observed with acetals and ketals employing TMSOTf as catalyst.

Chemistry, Organic

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