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The reaction of substituted glycols with catalytic dibutyltin oxide, stoichiometric p-toluenesulfonyl chloride, and triethylamine in CH2Cl2 resulted in the complete and rapid sulfonylation at the primary alcohol. The α-heterosubstituted primary alcohol moiety appeared optimal for best results, supporting the intermediacy of a five-membered chelate. The role of the amine is discussed, in addition to catalyst requirements and solvent effects.

This paper describes a convenient protocol for the regioselective sulfonylation of alpha-chelatable alcohols. Typically, the reaction of alpha-heterosubstituted alcohols with 1 equiv of p-TsCl and 1 equiv of Et(3)N in the presence of 2 mol % of Bu(2)SnO leads to rapid, regioselective, and exclusive monotosylation. The pK(a) of the amine was correlated to the reaction rate. A plausible mechanism for this reaction has been proposed on the basis of (119)Sn NMR studies.

The optimization of the pharmacokinetic performance of various 2-pyridone-containing human rhinovirus (HRV) 3C protease (3CP) inhibitors following oral administration to either beagle dogs or CM-monkeys is described. The molecules described in this work are composed of a 2-pyridone-containing peptidomimetic binding determinant and an alpha,beta-unsaturated ester Michael acceptor moiety which forms an irreversible covalent adduct with the active site cysteine residue of the 3C enzyme. Modification of the ester contained within these compounds is detailed along with alteration of the P(2) substituent present in the peptidomimetic portion of the inhibitors. The pharmacokinetics of several inhibitors in both dogs and monkeys are described (7 h plasma concentrations after oral administration) along with their human plasma stabilities, stabilities in incubations with human, dog, and monkey microsomes and hepatocytes, Caco-2 permeabilities, and aqueous solubilities. Compounds containing an alpha,beta-unsaturated ethyl ester fragment and either an ethyl or propargyl P(2) moiety displayed the most promising combination of 3C enzyme inhibition (k(obs)/[I] 170 000-223 000 M(-1) s(-1)), antiviral activity (EC(50) = 0.047-0.058 microM, mean vs seven HRV serotypes), and pharmacokinetics following oral administration (7 h dog plasma levels = 0.248-0.682 microM; 7 h CM-monkey plasma levels = 0.057-0.896 microM).

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1 -(Dimethylamino)ethyl)phenyl)silatrane and (8-(dimethylamino)-1 -naphthyl)silatrane have been prepared in order to study the possibility of intramolecular coordination at silicon by a nucleophilic atom in the silatrane structure. The structure of the former exhibits no chelation of the NMe2 group; the geometry around the silicon atom remains trigonal bipyramidal. In contrast, the structure of the latter suggests a weak interaction between the silicon atom and the NMe2 group.Species containing a hexacoordinated silicon atom have often been proposed as intermediates or transition states in the course of nucleophilic substitution reactions at silicon.1,2 In all cases, the mechanism proposed involves nucleophilic attack on an anionic or neutral pentacoordinated species.A few years ago, we showed that anionic pentacoordinated silicates3 could undergo nucleophilic displacement at silicon by strong nucleophiles. Interest in nucleophilic attack on anionic pentacoordinated silicon compounds has been further stimulated recently by the determination by X-ray crystallography of the structure (1) (a) Corriu, R.