Synthesis and configurational assignment of chiral salicylic aldehydes: Novel building blocks for asymmetric catalysis

We report the synthesis of three novel and chiral salicylic aldehyde building blocks 6-8, each in both enantiomerically pure forms. Two of these salicylic aldehydes were prepared from (+)-camphene and each bear a [2.2.1]bicycloheptyl substituent ortho to the salicylic hydroxy group. In the third case, the chiral element at the 6-position is a (1-phenylethyl) group. The synthetic sequences consisted of ortho-alkylation of para-cresol with either camphene or styrene and subsequent ortho-formylation of the product phenols. The chromatographic separation of enantiomers was accomplished through the diastereomeric imines obtained from condensation of the racemic salicylic aldehydes with (R)-phenylglycinol. Finally, the absolute configurations of two of the salicylic aldehydes were established by X-ray crystallography. For this purpose, the (1-phenylethyl)-substituted salicylic aldehyde was condensed with L-valinamide, and the relative configuration of the resulting Schiff base diastereomer 12 was determined. In the second case, the racemic intermediate phenol rac-15 was separated by HPLC on a chiral stationary phase, ortho-brominated, and analyzed by anomalous X-ray scattering. (C) Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002.