Biology-oriented synthesis of stereochemically diverse natural-product-derived compound collections by iterative allylations on a solid support

A strategy aiming at the introduction of stereocenters into polymer-bound natural-product-derived and -inspired compound collections is presented. Treatment of immobilized aldehydes with Brown's pinene-derived allylboranes results in the stereoselective formation of homoallylic alcohols with up to 89% ee (ee=enantiomeric excess). Subsequent iterative ozonolysis-allylation sequences with up to three allylations on a solid support give access to 1,3-polyols with different relative configurations. Esterification with acryloyl chloride and final ring-closing metathesis yields alpha,beta-unsaturated delta-lactones with multiply oxygenated side chains, a substructure found in a group of natural products with a broad range of biological activity. The flexibility of the approach is exemplified by the parallel synthesis of all eight diastereomers of cryptocarya diacetate on a solid support. The individual isomers are obtained in overall yields of 40-60% over 10 steps and with 63-85% diastereoselectivity for the major isomer.