Jan Kehler

Syntheses and GABA receptor binding properties of 4-amino-1-, 2-, and 3-hydroxybutylphosphinic acids

Abstract Novel racemic 4-amino-1-, 2-, and 3-hydroxybutylphosphinic acids and the corresponding 4-amino-1-, 2-, and 3-hydroxybutyl methylphosphinic acids have been synthesized. The phosphinic acid groups are bioisosteres of the carboxylic acid group, and some of these hydroxy amino acids are GABA B antagonists. The novel phosphinic acids were evaluated for their GABA A and GABA B receptor binding properties using rat brain synaptosomes and were also tested for GABAergic activity in a guinea pig ileum model. None of the phosphinic acids tested were found to be active.

SOLUTION PHASE SYNTHESIS OF DITHYMIDINE PHOSPHOROTHIOATE BY A PHOSPHOTRIESTER METHOD USING NEW S-PROTECTING GROUPS

Abstract ABSTRACT A phosphotriester method for the synthesis of dithymidine phosphorothioates with eight S-protecting groups has been investigated. Three of the S-protecting groups possesed catalytic activity, however side reactions occurred under deprotection. The best S-protecting group was 4-chloro-2-nitrobenzyl which could be removed with a minimum of side reactions (0.3 %). The coupling reagent PyFNOP (11) gave protected dithymidine phosphorothioate in 96% yield after 15 min coupling.

Solution Phase Synthesis of Dithymidine Phosphorodithioate Using New S-Protecting Groups in Combination with a Chemoselective Coupling Reagent (PyNOP)

Abstract ABSTRACT A method for the synthesis of O-thymidin-3′-yl S-alkyl dithiophosphate monomers 1 with different S-protecting groups has been developed. These have been used for solution phase synthesis of dithymidine phosphorodithioate by a new phosphotriester method. Coupling reactions are fast (15 min.) and the products are free from phosphorothioate contaminations.

New solid phase synthesis of oligodeoxythymidine phosphorodithioates by a modified HObt-method

Two new dithiophosphorylating reagents 2a,b have been prepared and shown to give nucleoside monomers 3a,b with reactivities suitable for solid phase synthesis. An octamer and a nonamer deoxythymidine phosphorodithioate were prepared on a TentaGel support with good coupling efficiencies. The products after deblocking are free from phosphorothioate contaminations (detection limit 0.5%).

Solid phase synthesis of oligodeoxynucleoside phosphorodithioates by a phosphotriester method using a chemoselective coupling reagent

Abstract A phosphotriester method has been developed for solid phase synthesis of oligodeoxynucleoside phosphorodithioates. Couplings are performed by chemoselective oxygen activation of protected nucleoside dithiophosphate anions 1, 7, 8, 9 with 4-nitro-6-trifluoromethylbenzotriazol-1-yl-oxy-tris(pyrrolidine)-phosphonium hexafluorophosphate (PyFNOP). Under optimised conditions coupling yields are above 95% for 10 – 20 min couplings, and the products after deblocking are free from phosphorothioate contaminations (detection limit 0.5%).

CHEMOSELECTIVE SYNTHESIS OF DITHYMIDINE PHOSPHOROTHIOATE IN SOLUTION USINGO-PROTECTED THIOPHOSPHATE MONOMERS

Abstract Diastereomerically pure O-protected thymine monothioate nucleotide (I) is efficiently coupled to protected thymidine (II) in a chemoselective, but not stereoselective manner, to give dithymidine phosphorothioates (III).

Syntheses of novel piperidin-4-ylphosphinic acid, and piperidin-4-ylphosphonic acid analogues of the inhibitory neurotransmitter 4-aminobutyric acid (GABA)

Piperidin-4-ylphosphinic acid, methyl(piperidin-4-yl)phosphinic acid and piperidin-4-ylphosphonic acid analogues of the GABAA agonist piperidin-4-ylcarboxylic acid (isonipecotic acid) were synthesised. The acid groups were introduced using a sequential Pudovik addition followed by a Barton deoxygenation procedure and finally followed by acidic hydrolysis. The mild and efficient procedure gave the target amino acids in good yields.

Synthesis of Oligodeoxynucleoside Phosphoro-Monothioates and Phosphorodithioates by a Phosphotriester Method

Abstract A phosphotriester method for the synthesis of dithymidine phosphoromonothoates and phosphorodithioates with new S-protecting groups has been investigated. Four of the S-protecting groups possesed catalytic activity, however side reactions occurred during deprotection. The best S-protecting group was 4-chloro-2-nitlobenzyl which could be removed with a minimum of side reactions (0.3 %). The coupling reagent PyFNOP (14) gave protected dithymidine phosphoromonothioate in 96 % yield after 15 min coupling. Furthermore PyFNOP chemoselectively activates oxygen in nucleoside phosphorodithioate monomers 9 and can be used for the synthesis of oligodeoxynucleoside phosphorodithioates with mixed base sequences.

Syntheses of Methylphosphinic Acids using Tandem Pudovik/Abramov-Barton/McCombie Reactions

Abstract Methylphosphinic acids are very effective and potent carboxylic acid bioisosteres. We have developed a novel mild and eficient method for the syntheses of (sec-alky1)methylphosphinic acids based on tandem Abramov addition of readily available ethyl methylphosphinate, 2, to a ketone, la-lg, followed by a modified Barton-McCombie deoxygenation procedure. The resulting esters, 4a-4g. are readily hydrolyzed. The method gives high yields even for sterically demanding ketones. Using this method we have synthesized several new biologically interesting methylphosphinic acids.