Equilibration studies of S-allyl glycosyl sulfoxides and binding of hindered bases to boron trifluoride.

Equilibration studies of S-allyl glycosyl sulfoxides and binding of hindered bases to boron trifluoride

Stereoselective Formation of Glycosyl Sulfoxides and Their Subsequent Equilibration: Ring Inversion of an α-Xylopyranosyl Sulfoxide Dependent on the Configuration at Sulfur

A series of four S-allyl d-thiopyranosides, α- and β-manno and xylo, were oxidized with MCPBA at low temperature to give seven of the eight possible sulfoxides, whose configuration at sulfur was determined either directly by X-ray crystallography or by correlation with closely related structures. For the axial thioglycosides oxidation leads very predominantly to the (R)S-diastereomer in the xylo series and exclusively so in the manno series; the configuration at C2 is of little importance in determining the stereoselectivity of oxidation of axial thioglycopyranosides. In the equatorial series the configuration at C2 has a significant effect on the outcome of the reaction as, although both series favored the (S)S-sulfoxide, selectivity was significantly higher in the case of the β-mannoside than of the β-xyloside. The two α-xylo sulfoxides have different conformations of the pyranoside ring with the (R)S-isomer adopting the 1C4 chair and the (S)S-diastereomer the 4C1. Each pair of diastereomeric sulfoxides was thermally equilibrated in C6D6 and in CD3OD. In the mannose series the kinetic isomers are also thermodynamically preferred. In the xylose series, on the other hand, the nature of the thermodynamic isomer in both the α- and β-anomers is a function of solvent with a switch observed on going from C6D6 to CD3OD. The results are rationalized in terms of the exo-anomeric effect, steric shielding provided by H3 and H5 in the axial series, the interaction of the C2−O2 and sulfoxide dipoles, and increased steric interactions on hydrogen bonding of the sulfoxides to CD3OD

Stereoselective Formation of Glycosyl Sulfoxides and Their Subsequent Equilibration: Ring Inversion of an α-Xylopyranosyl Sulfoxide Dependent on the Configuration at Sulfur

A series of four S-allyl d-thiopyranosides, α- and β-manno and xylo, were oxidized with MCPBA at low temperature to give seven of the eight possible sulfoxides, whose configuration at sulfur was determined either directly by X-ray crystallography or by correlation with closely related structures. For the axial thioglycosides oxidation leads very predominantly to the (R)S-diastereomer in the xylo series and exclusively so in the manno series; the configuration at C2 is of little importance in determining the stereoselectivity of oxidation of axial thioglycopyranosides. In the equatorial series the configuration at C2 has a significant effect on the outcome of the reaction as, although both series favored the (S)S-sulfoxide, selectivity was significantly higher in the case of the β-mannoside than of the β-xyloside. The two α-xylo sulfoxides have different conformations of the pyranoside ring with the (R)S-isomer adopting the 1C4 chair and the (S)S-diastereomer the 4C1. Each pair of diastereomeric sulfoxides was thermally equilibrated in C6D6 and in CD3OD. In the mannose series the kinetic isomers are also thermodynamically preferred. In the xylose series, on the other hand, the nature of the thermodynamic isomer in both the α- and β-anomers is a function of solvent with a switch observed on going from C6D6 to CD3OD. The results are rationalized in terms of the exo-anomeric effect, steric shielding provided by H3 and H5 in the axial series, the interaction of the C2−O2 and sulfoxide dipoles, and increased steric interactions on hydrogen bonding of the sulfoxides to CD3OD

Improved Synthesis of Chiral Pyrrolidine Inhibitors and Their Binding Properties to Neuronal Nitric Oxide Synthase

We report an efficient synthetic route to chiral pyrrolidine inhibitors of neuronal nitric oxide synthase (nNOS) and crystal structures of the inhibitors bound to nNOS and to endothelial NOS. The new route enables versatile structure–activity relationship studies on the pyrrolidine-based scaffold, which can be beneficial for further development of nNOS inhibitors. The X-ray crystal structures of five new fluorine-containing inhibitors bound to nNOS provide insights into the effect of the fluorine atoms on binding

Improved Synthesis of Chiral Pyrrolidine Inhibitors and Their Binding Properties to Neuronal Nitric Oxide Synthase

We report an efficient synthetic route to chiral pyrrolidine inhibitors of neuronal nitric oxide synthase (nNOS) and crystal structures of the inhibitors bound to nNOS and to endothelial NOS. The new route enables versatile structure activity relationship studies on the pyrrolidine-based scaffold, which can be beneficial for further development of nNOS inhibitors. The X-ray crystal structures of three new fluorine-containing inhibitors bound to nNOS provide insights into the effect of the fluorine atoms on binding

Cyclopropyl- and methyl-containing inhibitors of neuronal nitric oxide synthase

Inhibitors of neuronal nitric oxide synthase have been proposed as therapeutics for the treatment of different types of neurological disorders. On the basis of a cis-3,4-pyrrolidine scaffold, a series of trans-cyclopropyl- and methyl-containing nNOS inhibitors have been synthesized. The insertion of a rigid electron-withdrawing cyclopropyl ring decreases the basicity of the adjacent amino group, which resulted in decreased inhibitory activity of these inhibitors compared to the parent compound. Nonetheless, three of them exhibited double-digit nanomolar inhibition with high nNOS selectivity on the basis of in vitro enzyme assays. Crystal structures of nNOS and eNOS with these inhibitors bound provide a basis for detailed structure-activity relationship (SAR) studies. The conclusions from these studies will be used as a guide in the future development of selective NOS inhibitors