Michio Iwaoka

Design of optically active selenium reagents having a chiral tertiary amino group and their application to asymmetric inter- and intramolecular oxyselenenylations

Abstract A new class of chiral selenium reagents 4–7 was synthesized on the basis of the concept that the strong intramolecular interaction between an electrophilic selenium and an optically modified tertiary amine (Se…N interaction) would induce asymmetric induction in the reaction between the selenium reagent and olefins. When 7, which showed the most powerful asymmetric induction, was applied to asymmetric methoxyselenenylation of (E)-phenylpropene under optimum reaction conditions, the highest diastereomeric excess (d.e.) of the trans-addition product was obtained (97 % d.e.). The same reaction conditions were employed in asymmetric methoxyselenenylation of various olefins (up to 97 % d.e.) and also in asymmetric intramolecular oxyselenenylation of terminal olefins (up to 59 % d.e.) and internal olefins (up to 98 % d.e.). The results show that this class of selenium reagents with a strong Se…N interaction is useful for asymmetric organic synthesis.

Hypervalent nonbonded interactions of a divalent sulfur atom. Implications in protein architecture and the functions.

In organic molecules a divalent sulfur atom sometimes adopts weak coordination to a proximate heteroatom (X). Such hypervalent nonbonded S···X interactions can control the molecular structure and chemical reactivity of organic molecules, as well as their assembly and packing in the solid state. In the last decade, similar hypervalent interactions have been demonstrated by statistical database analysis to be present in protein structures. In this review, weak interactions between a divalent sulfur atom and an oxygen or nitrogen atom in proteins are highlighted with several examples. S···O interactions in proteins showed obviously different structural features from those in organic molecules (i.e., πO → σS* versus nO → σS* directionality). The difference was ascribed to the HOMO of the amide group, which expands in the vertical direction (πO) rather than in the plane (nO). S···X interactions in four model proteins, phospholipase A2 (PLA2), ribonuclease A (RNase A), insulin, and lysozyme, have also been analyzed. The results suggested that S···X interactions would be important factors that control not only the three-dimensional structure of proteins but also their functions to some extent. Thus, S···X interactions will be useful tools for protein engineering and the ligand design.

Direct Observation of Intramolecular Interaction between a Divalent Selenium and a Tertiary Amine by Means of Single Crystal X-Ray Analysis and NMR Spectroscopy

Abstract Intramolecular interaction between a divalent selenium and a tertiary amino moiety has been observed in the solid state for 2,2′-diselenobis(N-cyclohexyl-N-methylbenzyl amine) (1). A similar interaction between an electrophilic selenium and a tertiary amine has also been observed in solution for the corresponding selenenyl bromide (6).

Applications of Water-Soluble Selenides and Selenoxides to Protein Chemistry

Two water-soluble organic selenides, 3,3′-selenodipropanonic acid and 2-selenanecarboxylic acid, were synthesized and reversibly converted to the corresponding selenoxides in deuterium oxide by the sequential treatment with stoichiometric amounts of hydrogen peroxide and then dithiothreitol. The antioxidative catalytic activity of 3,3′-selenodipropanonic acid was subsequently investigated by NMR spectroscopy in the reaction of hydrogen peroxide with dithiothreitol, cysteamine, and benzyl mercaptan in deuterated methanol. For all thiol substrates, the selenide exhibited the distinct catalytic activity. However, the activity was remarkably higher for the dithiol substrate (i.e., dithiothreitol). These results suggested that water-soluble selenides are good glutathione peroxidase mimics, in particular when polythiols are employed as the substrate. It was also suggested that water-soluble selenoxides are efficient oxidizing reagents for protein disulfide-bond formation.

Asymmetric methoxyselenenylation of olefins using an optically active diaryl diselenide derived from d-mannitol

Abstract The diastereomeric excess (d.e.) in asymmetric methoxyselenenylation of trans - β -methylstyrene was significantly enhanced by employing the selenohexafluoro-phosphate of an optically active diaryl diselenide derived from d -mannitol (97 %d.e.). The procedure was applied to the asymmetric methoxyselenenylation of various olefins.

Rapid and Quantitative Disulfide Bond Formation for a Polypeptide Chain Using a Cyclic Selenoxide Reagent in an Aqueous Medium

To elucidate the reaction mechanism of the disulfide (SS) bond formation reaction of a polypeptide molecule with a water-soluble selenoxide reagent, trans-3,4-dihydroxyselenolane oxide (DHS(ox)), short-term oxidation experiments were carried out for the reduced state (R) of a recombinant hirudin CX-397 variant at pH 7.0 and 25 °C. In the reaction, R was oxidized sequentially to one-SS, two-SS, and three-SS intermediate ensembles within 1 min. The kinetic analysis revealed that the three second-order rate constants for the SS formation are proportional to the number of thiol groups existing in the reactant SS intermediates, indicating the stochastic nature of the SS formation. Ab initio calculation at the HF/6-31++G(d,p) level in water by using the polarizable continuum model suggested that the SS formation reaction is highly exothermic and proceeds via a reactive thioselenurane intermediate with a distorted linear O-Se-S linkage. The results clearly demonstrated that the rate-determining step of the SS formation reaction is the first bimolecular process between a thiol substrate and DHS(ox) rather than the subsequent process to release a SS product.

Structural characteristics of areneselenenyl bromide and areneselenenyl chloride stabilized by hypervalent coordination with a halide anion in the solid state

Abstract Solid-state molecular structures of 2-[(N-cyclohexyl-N-methylamino)methyl]benzeneselenenyl bromide (ArSeBr) and chloride (ArSeCl), stabilized by hypervalent coordination with a halide anion (Br− or Cl−, respectively), were determined by X-ray diffraction method. By comparing bond parameters of the observed hypervalent BrSe⋯Br fragment with those reported previously for other organoselenium compounds, which have a similar T-shaped selenium fragment, it was revealed that there is decent hyperbolic relationship between the two linear SeBr atomic distances in the solid state, reflecting the possibility of a pathway for the addition reaction of benzeneselenenyl bromide (PhSeBr) in solution. In addition, the existence of significant bond-shortening (∼0.1 A) due to intermolecular weak packing interactions was strongly suggested by comparison of the extrapolated SeBr covalent bond length (2.220 A) in the solid state with that reported for PhSeBr (2.325 A) in the gas phase. Ab initio molecular orbital calculations at the RHF/6-31G(d,p) level using Ahlrichs pVDZ basis sets for Se and Br estimated the perturbation energy in the solid state to be roughly 1.5 kcal mol−1 independent of the packing structure.

Synthesis of Selenocysteine and Selenomethionine Derivatives from Sulfur‐Containing Amino Acids

Selenium‐containing amino acids have attracted increasing interest from view points of the importance as active centers of several selenoenzymes, the biological synthesis, the metabolism, and the use for structure determination of proteins. In this article, our recent progresses in the transformation from sulfur‐containing amino acids to selenocysteine (SeCys) and selenomethionine (SeMet) derivatives are reviewed along with the surveys of general organic methodologies for the synthesis of SeCys and SeMet derivatives in the literature. The S→Se modification (i.e., the chemical atomic mutation) would be a useful approach to peptide synthesis involving selenoamino acid residues.

Asymmetric Trans-Addition Reactions Using Chiral Selenobinaphthyls

Abstract Asymmetric trans-addition reactions of (E)-phenylpropene, a mechanistically novel reactions, have been achieved by using chiral selenium-containing binaphthyl derivatives. Introduction of an amide group at 2′-position in the binaphthyl skeleton enhances considerably the diastereomeric excess (d.e.) of the asymmetric reaction presumably due to attractive interaction between the nitrogen lone pair and the seleniranium intermediate. Introduction of another chiral center in the amide group further enhances the d.e. as high as 79 %, which is the highest asymmetric induction ever achieved in the asymmetric trans-addition reaction.

Synthesis and structures of host molecules containing an Se–Se bond. Intramolecular hypervalent nature of selenium atoms in the crystal state

The first host molecules containing an Se–Se bond, 5,13,20,28-tetraoxo-3,4 : 14,15 :18,19 : 29,30-tetrabenzo-6,9,12,21,24,27-hexaoxa-1,2,16,17-tetraselenacyclotriaconta-3,14,18,29-tetraene (1) and 2,9-dioxo-3,4:7,8-dibenzo-13,15,21,24-tetraoxa-5,6-diselena-1,10-diazabicyclo[8.8.8]hexacosa-3,7-diene (2), have been synthesized and their structures have been determined by X-ray analysis.