CHEMOENZYMATIC SYNTHESIS OF OPTICALLY PURE PLANAR CHIRAL (S)-(-)-5-FORMYL-4-HYDROXY[2.2]PARACYCLOPHANE

The synthesis of optically pure (S)-5-formyl-4-hydroxy[2.2]paracycloph ane (S)-3 (ee > 99 %) was achieved by a three-step chemoenzymatic proc edure consisting of (i) kinetic enzymatic resolution of (R,S)-4-acetox y[2.2]paracyclophane (R,S)-1 to produce optically pure starting materi al, which after (ii) hydrolysis was subjected to (iii) stereoselective ortho-formylation with an overall yield of 51 %. All attempts to use a biocatalyst directly for the preparation of optically pure disubstit uted [2.2]paracyclophanes failed because of either total lack of activ ity (bioreduction) or low enantioselectivities of the enzymes screened (hydrolases). Using the chemoenzymatic approach from (R,S)-1, optical ly pure (S)-1 and after subjecting (S)-1 to hydrolysis and finally to formylation (S)-3 was obtained. As confirmed by chiral GC, hydrolysis and formylation took place without racemization. During the optimizati on of the enzymatical part of the synthesis a strong influence of both the nature of the cosolvent and the pH of the buffer-phase on the ena ntioselectivity value E were observed. Using a two-phase system consis ting of diethyl ether and phosphate buffer an E value higher than 100 was achieved at a pH of 7.0 and at room temperature.