Takuhei Yamamoto

A novel electrochemical deprotection method for acetals, ketals and dithioacetals was developed, yielding carbonyl compounds. LiClO ₄ acts as both an electrolyte and oxygen source, while 1,3,5-trioxane enhances reaction efficiency as a Li activator.

Disulfide bonds of 2-isocyanatophenyl methyl disulfide and 2-endo-isocyanato-6-endo-(methyldisulfanyl)bicyclo[2.2.1]heptane showed neighboring group participation in the formation of thiocarbamates. Natural Bond Orbital (NBO) analyses revealed that the unusual nucleophilicity requires a rigid through-space interaction between a lone pair of the disulfide bond and an antibonding orbital of isocyanate.

The substrate selectivities of three endonucleases were studied quantitatively using capillary zone electrophoresis to find one giving N²-ethyl(Et)-2′-deoxyguanosine-5′-monophosphate (5′-dGMP) and cyclic 1,N²-propano(CPr)-5′-dGMP from DNAs damaged by acetaldehyde (AA). Six 2′-deoxyribonucleoside-5′-monophosphates to be quantified in the hydrolysis solutions of DNAs, namely, Et-5′-dGMP, CPr-5′-dGMP, and four authentic ones, were completely separated using a 100 mM borate running buffer solution having an optimized pH of 9.67. Using the present method, nuclease reactions of nuclease S1 (NS1), nuclease P1 (NP1), and nuclease Bal 31 to 2′-deoxyribonucleoside-5′-monophosphates from damaged Calf thymus (CT-) DNAs were monitored. The CT-DNAs were prepared by treatment with AA to generate Et-guanine or CPr-guanine internally. Bal 31 hydrolyzed the damaged CT-DNAs to yield Et-5′-dGMP and CPr-5′-dGMP quantitatively. The two 5′-dGMP adducts were not detected in the hydrolysis solutions using NS1 or NP1. Bal 31 can be a suitable nuclease for analyzing DNA damages caused by AA.

The electrochemical oxidation of thioethers is shown to be facilitated by neighboring amide participation. ¹H NMR spectroscopic analysis in acetonitrile solution of two conformationally constrained compounds with such facilitation shows that two-electron participation by the amide π₂ orbital can occur to stabilize the developing sulfur radical cation.

Electronic absorption spectra and quantum chemical calculations of the radical cations of m-terphenyl tert-butyl thioethers, where the S–t-Bu bond is forced to be perpendicular to the central phenyl ring, show the occurrence of through-space [π···S···π]⁺ bonding interactions which lead to a stabilization of the thioether radical cations. In the corresponding methyl derivatives there is a competition between delocalization of the hole that is centered on a p-AO of the S atom into the π-system of the central phenyl ring or through space into the flanking phenyl groups, which leads to a mixture of planar and perpendicular conformations in the radical cation. Adding a second m-terphenyl tert-butyl thioether moiety does not lead to further delocalization; the spin and charge remain in one of the two halves of the radical cation. These findings have interesting implications with regard to the role of methionines as hopping stations in electron transfer through proteins.

Reductive cleavage of disulfide bonds is an important step in many biological and chemical processes. Whether cleavage occurs stepwise or concertedly with electron transfer is of interest. Also of interest is whether the disulfide bond is reduced directly by intermolecular electron transfer from an external reducing agent or mediated intramolecularly by internal electron transfer from another redox-active moiety elsewhere within the molecule. The electrochemical reductions of 4,4′-bipyridyl-3,3′-disulfide (1) and the di-N-methylated derivative (2²⁺) have been studied in acetonitrile. Simulations of the cyclic voltammograms in combination with DFT (density functional theory) computations provide a consistent model of the reductive processes. Compound 1 undergoes reduction directly at the disulfide moiety with a substantially more negative potential for the first electron than for the second electron, resulting in an overall two-electron reduction and rapid cleavage of the S–S bond to form the dithiolate. In contrast, compound 2²⁺ is reduced at less negative potential than 1 and at the dimethyl bipyridinium moiety rather than at the disulfide moiety. Most interesting, the second reduction of the bipyridinium moiety results in a fast and reversible intramolecular two-electron transfer to reduce the disulfide moiety and form the dithiolate. Thus, the redox-active bipyridinium moiety provides a low energy pathway for reductive cleavage of the S–S bond that avoids the highly negative potential for the first direct electron reduction. Following the intramolecular two-electron transfer and cleavage of the S–S bond the bipyridinium undergoes two additional reversible reductions at more negative potentials.

Methionine residues have been shown to function as efficient "hopping" sites in long-range electron transfer in model polyprolyl peptides. We suggest that a key to this ability of methionine is stabilization of the transient sulfur radical cation by neighboring proline amide participation. That is, in a model system a neighboring pyrrolidine amide lowers the oxidation potential of the thioether by over 0.5 V by formation of a two-center three-electron SO bond.