Rafał Kamiński

Measurements of Heavy-Atom Isotope Effects Using 1H NMR Spectroscopy

A novel method for measuring heavy-atom KIEs for magnetically active isotopes using (1)H NMR is presented. It takes advantage of the resonance split of the protons coupled with the heavy atom in the (1)H spectrum. The method is validated by the example of the (13)C-KIE on the hydroamination of styrene with aniline, catalyzed by phosphine-ligated palladium triflates.

Novel synthesis of symmetrical tetra-alkyl monothiopyrophosphates

Abstract The novel highly efficient synthesis of sym-tetra-alkyl monothiopyrophosphates (RO)2P(O)SP(O) (OR′)2 1 based on the condensation of dialkoxyoxophosphoranesulphenyl chlorides 3 with dialkyltrimethylsilyl phosphites 4 is described.

Insights into the Chemical Biology of Selenium

The long-sought pathway by which selenocysteyl-tRNA[Ser]Sec is synthesized in eukaryotes has been revealed. Seryl-tRNA[Ser]Sec is O-phosphorylated and SecS, a pyridoxal phosphate-dependent protein, catalyzes the reaction of O-phosphoseryl-tRNA[Ser]Sec with monoselenophosphate to give selenocysteyl-tRNA[Ser]Sec . 1 H- 77 Se HMQC-TOCSY NMR spectroscopy has been developed to detect the selenium-containing amino acids present in selenized yeast after protease XIV digestion. An archived selenized yeast sample is found to contain the novel amino acid S-(methylseleno)cysteine in addition to selenomethionine. Arsenite and selenite react with GSH to form (GS) 2 AsSe−. The structure of this compound has been determined by EXAFS, 77 Se NMR and Raman spectroscopic and chromatographic studies. Its formation under biological conditions has been demonstrated.

Structure and photochemistry of matrix-isolated o-phthalaldehyde

Two conformers, (EZ) and (EE), were observed in o-phthalaldehyde (1) isolated in nitrogen and argon matrices. The E-enol (5E) generated upon photolysis (λ 313 nm) of the matrix-isolated (1) was stabilized and characterized by UV and IR absorption spectroscopy. Further irradiation of (5E) resulted in intramolecular cyclization (λ > 357 nm) to phthalide (2) or fragmentation (λ= 313 nm) to carbon monoxide and benzaldehyde (7).

Searching for novel scaffold of triazole non-nucleoside inhibitors of HIV-1 reverse transcriptase

Abstract Azoles are a promising class of the new generation of HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs). From thousands of reported compounds, many possess the same basic structure of an aryl substituted azole ring linked by a thioglycolamide chain with another aromatic ring. In order to find novel extensions for this basic scaffold, we explored the 5-position substitution pattern of triazole NNRTIs using molecular docking followed by the synthesis of selected compounds. We found that heterocyclic substituents in the 5-position of the triazole ring are detrimental to the inhibitory activity of compounds with four-membered thioglycolamide linker and this substitution seems to be viable only for compounds with shorter two-membered linker. Promising compound, N-(4-carboxy-2-chlorophenyl)-2-((4-benzyl-5-methyl-4H-1,2,4-triazol-3-yl)sulfanyl)acetamide, with potent inhibitory activity and acceptable aqueous solubility has been identified in this study that could serve as lead scaffold for the development of novel water-soluble salts of triazole NNRTIs.

Influence of the Solvent Description on the Predicted Mechanism of SN2 Reactions

The influence of the implicit solvent model on transition state structures of two S N2 reactions of biochemical importance is presented. In the considered methyl transfer reaction, we show experimentally that the rate constant in blood serum is about 60% slower than in the aqueous solution and that the implicit solvent model with slightly modified parameters for water captures correctly the energetics of this reaction. With the example of the reaction between 4-methyl-1,2,4-triazol-3-thione and ethyl bromoacetate, we show that relative stabilities of the conformationally different transition states depend upon the solvent inclusion strategy.

Reaction of oxophosphorane-sulphenyl and -selenenyl chlorides with dialkyl trimethylsilyl phosphites. Novel synthesis of compounds containing a sulphur or selenium bridge between two phosphoryl centres

A novel highly efficient synthesis of sym-tetra-alkyl monothio- and monoseleno-pyrophosphates (RO)2P(O)XP(O)(OR′)2(X = S,Se) based on the condensation of dialkoxyoxophosphorane-sulphenyl or -selenenyl chlorides (RO)2P(O)XCl (X = S,Se) with dialkyl trimethylsilyl phosphites (RO)2POSiMe3(9) is described. Remarkably selective reaction of a O,O′-dialkyl O″-trimethylsilyl selenophosphate (RO)2P(Se)OSiMe3(13) with sulphuryl dichloride in the presence of an equimolar amount of a phosphite (9) leads to the formation of sym-monoselenopyrophosphates in excellent yield. A new rearrangement in phosphorus chemistry, sym-monoselenopyraphosphates (11) to asym-monoselenopyrophosphates (12), has been observed.

Mechanisms of Isomerization of Sym-Monothiopyrophosphates

Abstract The detailed mechanistic studies of the thiolo-thiono isomerization of monothiopyrophosphate 1 is presented. The application of isotopic tracers and isotopic effects kinetic methods provide evidence for two distinct mechanisms: SN2(P) reaction induced by external anionic species and the dissociative isomerization proceeding via ion pairs and ions.

36S and 18O isotope effects in infrared spectra of monothiopyrophosphates

Abstract Isotope induced shifts of i.r. lines caused by 36 S and 18 O substitution of two isomeric monothiopyrophosphates allowed the characteristic frequencies for PX and PXP linkages (X = S or O) to be recognized.

Measurement and Prediction of Chlorine Kinetic Isotope Effects in Enzymatic Systems

Approaches to determine chlorine kinetic isotope effects (Cl-KIEs) on enzymatic dehalogenations are discussed and illustrated by representative examples. Three aspects are considered. First methodology for experimental measurement of Cl-KIEs, with stress being on FAB-IRMS technique developed in our laboratory, is described. Subsequently, we concentrate our discussion on the consequences of reaction complexity in the interpretation of experimental values, a problem especially important in cases of polychlorinated reactants. The most fruitful studies of enzymatic dehalogenations by Cl-KIEs require their theoretical evaluation, hence the computational focus of the second part of this chapter.