Chiral phoshoric acid-catalyzed asymmetric synthesis of N,O-acetals comprising quatenary stereogenic center

U ovom radu prikazana je asimetrična priprava N,O-acetala s kvaternim stereogenim centrom katalizirana kiralnim fosfornim kiselinama. Istraživanja su pokazala da kiralni N,Oacetali predstavljaju važne funkcionalne skupine u prirodnim spojevim s antiproliferativnim djelovanjem te stabilizirajućim djelovanjem na mikrotubule. Isoindolinonski derivati N,O-acetala poznati su inhibitori MDM2-p53 protein-protein interakcija. Kondenzacijom ftalimida sa fenilmagnezij bromidom, 2-tienil litijem i (3,5-diklorofenil)magnezij bromidom pripremljeni su spojevi 1, 2 i 3. U reakciji spoja 1 i benzilnog alkohola odnosno cikloheksanola, kataliziranoj fenil fosfinskom kiselinom, pripravljeni su spojevi 5 i 6. U reakcijama benzilnog alkohola sa različitim 3-supstituiranim-3-hidroksiisoindolinonima pripremljeni su spojevi 7-12. Strukture priređenih spojeva potvrđene su 1H i 13C NMR spektroskopijom, te spektrometrijom masa. Stupanj enantioselektivnosti određen je na kiralnim kolonama na HPLC-u.Within this work, asymmetric preparation of N,O-acetals with quaternary stereogenic center catalyzed by chiral phosporic acid is presented. According to previous research, chiral N,O-acetals represent important functional groups in natural compounds with antiproliferative activity and with stabilizing effect on microtubules. Isoindolinone N,O-acetal derivatives are well known inhibitors of MDM2-p53 protein-protein interactions. The condensation of phtalimide with phenylmagnesium bromide, 2-thienyl lithium and (3,5-dichlorophenil)magnesium bromide yielded compunds 1, 2 and 3. In a reaction catalysed by phenyl phospinic acid, compund 1 reacted with benzyl alcohol or cyclohexanol to afford compunds 5 and 6. In reactions of benzyl alcohol with different 3-substituted-3-hydroxyisoindolinones compunds 7-12 were prepared. Structures of prepared compounds were confirmed by 1H i 13C NMR spectroscopy, as well as mass spectrometry. Enantiomeric ratio was determined by chiral HPLC