Hydroxy propionic acids pyridines

More recently, some AMPA agonists showing unusual stereostructure-activity have been compared using the commercial docking package Glide (21). These include the enantiomers of 2-amino-3-(3-hydroxy-l,2,5-thiadiazol-4-yl)propionic acid (TDPA) and 2-amino-3-hydroxy-5-phenyl-4-isoxazolyl propionic acid (APPA) (28), as well as 3-hydroxy-4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine-5-carboxylic acid (5-HPCA). 

Prien et al. [18] have synthesized 3-hydroxy-2-methylidene propionic acids on hydrox-yethyl resin via a Baylis-Hillman reaction by using aldehydes bearing electron-withdrawing groups, for example nitrobenzaldehyde, trifluoromethylbenzaldehyde and pyridine-carboxaldehyde. 

Preparation by hydrolysis of 2-(2-hydroxy-4,6-dimethoxy-phenyl)-2-oxoethyl benzoate in pyridine with aqueous sodium hydroxide under nitrogen atmosphere at r.t. for 1 h (80%) [5118]. Also obtained by degradation of 2-[2-(2-hydroxy-4,6-dimethoxyphenyl)-2-oxoethoxy]-2-methyl-propionic acid in refluxing mixture of concentrated hydrochloric acid/methanol (1 vol/5 vol) for 1 h (42%) [5119]. 

To a solution of the (+)-methyl 2-[2-(N-phenylsulfonyl)indolyl]-2-hydroxy-3-[3-(N-allyl-5-ethyl-l,2,3,6-tetrahydropyridine)]propionate (a mixture of diastereomers at C-2) in dry dimethoxyethane at -50°C under argon was added sodium naphthalenide (1 M in THF). The mixture was quenched with trifluoroacetic acid, and extracted with ethyl acetate (3 times 10 ml). The extract was washed with saturated aqueous NaHC03 solution, dried (MgS04) and evaporated in vacuo to give the (+)-methyl 2-(2-indolyl)-2-hydroxy-3-[3-(N-allyl-5-ethyl-l,2,3,6-tetrahydro-pyridine )]propionate. The mixture of diastereomers was not separated but chromotagraphed over silica gel eluting with hexane/ethyl acetate/10% aqueous NH4OH/MeOH (5 1 1) to remove more polar impurities. 

D-Phenyl propionates of methyl esters of racemic hydroxy acids were prepared by Hammarstrom and Hamberg [190] and used for the separation of enantiomers of these compounds on QF-1. The separation was successful with methyl 3-, 15-, 16- and-17-hydroxyoctadecanoates, whereas diastereoisomers of methyl 4-, 7- and 13-hydroxyocta-decanoic acids were not separated. The derivatives were prepared at room temperature reaction of the ester of the hydroxy acid with D-2-phenylpropionyl chloride in the presence of pyridine for 2 h. 

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