Preparation of a 990-member chemical compound library of hydantoin- and isoxazoline-containing heterocycles using multipin technology.

Abstract

The development of a useful chemistry for the construction of polyfunctional heterocycles--first through solution and solid phase (resins) and then library production via SynPhase crowns--is reported. Bead-based synthetic work was done on Merrifield resin where treatment with benzylamine in the presence of DBU followed by reaction with 4-chloromethylbenzoyl chloride afforded amide-linked resin 9. Finally, TFA.NH2-polystyrene macro crowns were derivatized with 4-(hydroxymethyl)benzoic acid to afford pin 14 which was coupled with Boc-protected amino acid 2 in the presence of DIC to deliver pin 15. Deprotection and reaction with phenyl isocyanate afforded urea functionalized pin 17 which underwent 1,3-dipolar cycloaddition reaction to give pin 19. Finally, compound 20 was obtained with moderate diastereoselectivity (20:21::8:1) by the reaction of pin 19 with a catalytic amount of Et3N.