Synthesis of cephalosporins carrying isoxazolyl acetamido and related side chains

Starting from 3,5-dimethylisoxazole the carboxylic acids I and V, the amino acids VIII (L-) and IX (D-), and the ureido acids X (L-) and XI (D-) were prepared, which were used for the synthesis of the new cephalosporins XVIIb, XXa-c (L-), and XXIb (D-). Thein vitro antibacterial activity of these semi-synthetic antibiotics was studied. The resorption of XVIIb was investigated in mice.Research Group for Antibiotics of the Hungarian Academy of Sciences, H-4010 Debrecen, P.O. Box 70, Hungary. Published in Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1524–1535, November, 1998.     

Synthesis of cryptophycins via an N-acyl-beta-lactam macrolactonization

An efficient and concise approach to the synthesis of the macrolide core of the cryptophycins has been developed. A novel macrolactonization utilizing a reactive acyl-beta-lactam intermediate incorporates the beta-amino acid moiety within the 16-membered macrolide core. This modular approach, involving a cyanide-initiated acyl-beta-lactam ring opening followed by cyclization, was successfully applied to the total synthesis of cryptophycin-24. The strategy was also used in an efficient synthesis of the 6,6-dimethyl-substituted dechlorocryptophycin-52. In this case, the cyanide-initiated ring opening of the bis-substituted 2-azetidinone followed by macrolactonization was achieved through a catalytic process.     

Palladium-catalyzed synthesis of carcinogenic polycyclic aromatic hydrocarbon epoxide-nucleoside adducts: the first amination of a chloro nucleoside

Pd-catalyzed coupling of the axially constrained, less reactive benzo[a]pyrene bay-region amino benzoates, derived from the tetrahydro and diol epoxides, with C-6 and C-2 halopurine deoxynucleosides offers an efficient approach to the synthesis of the corresponding nucleoside-epoxide adducts. Also reported are the first examples involving the coupling of a 6-chloropurine deoxynucleoside with these amines, a reaction that is difficult by direct halide displacement. Certain mechanistic aspects of this metal-catalyzed C-N bond formation are also discussed. [reaction--see text]     

Accurate quantification of the redox-sensitive GSH/GSSG ratios in the yeast Pichia pastoris by HILIC–MS/MS

A novel method for the simultaneous quantification of both glutathione (GSH) and its oxidized form glutathione disulfide (GSSG) by hydrophilic interaction chromatography–MS/MS has been developed and is critically discussed. Internal standardization based on isotopically labeled standards for both analytes is an absolute prerequisite for accurate quantification of this redox pair. Hence, a highly efficient and selective miniaturized procedure for the synthesis of isotopically labeled GSSG from commercially available glutathione-(glycine-¹³C₂,¹⁵N) was established using H₂O₂ as oxidant and NaI as catalyst. Moreover, a tool is presented to monitor and hence uncover artifactual GSSG formation due to oxidation of GSH during sample preparation, which is the main source of systematic error in GSSG analysis. For this purpose, we propose to monitor the oxidation product formed by reaction of naturally occurring GSH with the isotopically labeled GSH used as internal standard. For the determination of GSH/GSSG ratios in yeast, different extraction methods based on (1) hot extraction with aqueous, acidic, or organic solvents, (2) mechanical cell lysis, and (3) extraction at subambient temperature were investigated in terms of recovery, extraction efficiency, and artifactual formation of GSSG. Total combined uncertainties of as low as 25–30 % (coverage factor?=?2) for the determination of GSH/GSSG ratios without derivatization were made possible by the addition of the internal standards early in the analytical procedure (before extraction) and immediate analysis of the analytes.     

Synthetic studies with 13-deoxybaccatin III

An efficient synthesis of 13-epi-7-O-(triethylsilyl)baccatin III from 13-deoxybaccatin III is described. Oxidation of 13-deoxy-7-O-(triethylsilyl)baccatin III with tert-butyl peroxide, followed by reduction with SmI(2), produced 13-epi-7-O-(triethylsilyl)baccatin III in good overall yield. The preparation of 13-oxo-7-O-(triethylsilyl)baccatin III from 13-epi-7-O-(triethylsilyl)baccatin III using tetrapropylammonium perruthenate and N-methylmorpholine N-oxide is also reported.     

Synthesis of amino acid derived enaminones via Wolff rearrangement using vinylogous amides as carbon nucleophiles

Cyclic enaminones were synthesized in high yields from amino acids in two steps via Wolff rearrangement. The cyclization represents a rare 6-exo-dig cyclization involving a ketene as an electrophile. No racemization was observed during this reaction.     

Ultra-fast HPLC-ICP-MS analysis of oxaliplatin in patient urine

A novel method for rapid HPLC-ICP-MS analysis of oxaliplatin in human urine was developed implementing a stationary HPLC phase with a particle size of 1.8 μm. The method allowed a cycle time of <1 min at a HPLC flow rate of 0.9 mL min⁻¹. Procedural limits of detection of 0.05 μg L⁻¹ oxaliplatin (150 fg on column) were obtained. Analysis of oxaliplatin in patient urine showed that accurate quantification of the intact drug demanded for storage at −80 °C and rapid measurement after thawing.     

Synthesis of fused bicyclic systems with nitrogen atom at the bridgehead, including indolizidines and quinolizidines

Monocyclic as well as fused bicyclic systems with a nitrogen 10 atom at the bridgehead, including indolizidines and quinolizidines, can be prepared in four steps from N-Boc β-lactams. These easily prepared, highly robust, and flexible building blocks allow the incorporation of chirality and structural diversity, rendering the method feasible for diversity- as well as target-oriented synthesis.