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Mikael Bols

Publications and source records attributed to Mikael Bols.

24 records · Page 2Linked to original sources
PubMed2002

Stereoelectronic substituent effects in polyhydroxylated piperidines and hexahydropyridazines.

From the pK(a) values of the conjugate acids of a large series of hydroxylated piperidines and hexahydropyridazines, a consistent difference in basicity was found between stereoisomers having an axial or equatorial hydroxyl (OH) group either beta or gamma to the amine. Compounds with an equatorial OH group in the 3-position were 0.8 pH units more acidic than otherwise identical compounds with an axial OH group, whilst compounds with an equatorial OH group in the 4-position relative to the amine were 0.4 pH units more acidic than the corresponding compound with an axial OH. A similar effect was observed for the COOMe substituent. The difference in electron-withdrawing power of axial and equatorial substituents was explained by a difference in charge-dipole interactions in the two systems. Since this stereoelectronic substituent effect causes differences in basicity in different conformers, certain piperidines and hexahydropyridazines were found to change conformation upon protonation. A method for predicting the pK(a) of piperidines which takes stereochemistry into account is described.

Journal Article↗
PubMed1997

The First Tri- and Tetraalkoxysilanes with Four Different Substituents.

Unsymmetrically substituted tri- and tetraalkoxysilanes were surprisingly found to be configurationally stable and easy to prepare. It was found that compounds of type MeSi(OR)(2)(OR'), MeSi(OR)(OR')(OR"), Si(OR)(2)(OR')(2), Si(OR)(2)(OR')(OR"), Si(OR)(3)(OR'), and even Si(OR)(OR')(OR")(OR) could be obtained by sequential addition of a variety of chiral and achiral alcohols to methyltrichlorosilane or tetrachlorosilane in the presence of pyridine. In the case of MeSi(OR)(OR')(OR") and Si(OR)(OR')(OR")(OR), two types of compounds that have never been prepared before, were obtained in good yield.

Journal Article↗
PubMedDate not supplied

Two- and three dimensional combinatorial chemistry from multicomponent Grignard reagents.

The conjugate addition of five component Grignard reagents to methyl ecgonidine was used to create libraries of 3-substituted tropanes. By variation in the reagent combination in 10 such 5-membered sublibraries, a library of 25 compounds was made in a two-dimensional format. Screening of this library led to identification of two new potent monoamine transporter ligands that were subsequently synthesized. The most potent compound in this library was (1R,2S,3S,5S)-3-(3,4-dimethylphenyl)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylic acid methyl ester, which inhibited dopamine transporter (hDAT) binding and reuptake with a K(i) of 26 and 20 nM, respectively. The conjugate addition to a 5-membered library of methyl ecgonidine analogues with variation of nitrogen substituent was also carried out and used to create 15 sublibraries of 25 compounds, which displayed 125 compounds in a three-dimensional format. From this 3D library, several potent dopamine transport inhibitors were likewise identified and synthesized. The most potent hDAT inhibitor discovered was (1R,2S,3S,5S)-3-(3,4-dimethylphenyl)-8-pentyl-8-azabicyclo[3.2.1]octane-2-carboxylic acid methyl ester. The study also showed that 3-alkyltropanes were poor inhibitors of monoamine transporters.

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