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Knappmann, Inga; Lehmkuhl, Kirstin; Köhler, Jens; Schepmann, Dirk; Giera, Martin; Bracher, Franz; Wünsch, Bernhard (2017): Lipase-catalyzed kinetic resolution as key step in the synthesis of enantiomerically pure a ligands with 2-benzopyran structure. In: Bioorganic & Medicinal Chemistry, Vol. 25, No. 13: pp. 3384-3395
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In order to obtain enantiomerically pure csi receptor ligands with a 2-benzopyran scaffold an Oxa-PictetSpengler reaction with the enantiomerically pure 2-phenylethanol derivatives (R)-4 and (S)-4 was envisaged. The kinetic resolution of racemic alcohol (+/-)-4 using Amano Lipase PS-C II and isopropenyl acetate in tert-butyl methyl ether led to the (R)-configured alcohol (R)-4 in 42% yield with an enantiomeric excess of 99.6%. The (S)-configured alcohol (S)-4 was obtained by Amano Lipase PS-C II catalyzed hydrolysis of enantiomerically enriched acetate (S)-5 (76.9% ee) and provided (S)-4 in 26% yield and 99.7% ee. The absolute configuration of alcohol (R)-4 was determined by exciton coupled CD spectroscopy of the bis (bromobenzoate) (R)-7. The next important step for the synthesis of 2-benzopyrans 2 and 3 was the Oxa-Pictet-Spengler reaction of the enantiomerically pure alcohols (R)-4 and (S)-4 with piperidone ketal 8 and chloropropionaldehyde acetal 12. The conformationally restricted spirocyclic 2-benzopyrans 2 revealed higher sigma(1) affinity than the more flexible aminoethyl derivatives 3. The (R)- and (R,R)-configured enantiomers (R)-2 and (R,R)-3 represent the eutomers of this class of compounds with eudismic ratios of 4.8 (2b) and 4.5 (2c). High sigma(1)/sigma(2) selectivity (>49) was found for the most potent sigma(1) ligands (R)-2b, (R)-2c, (R)-2d, and (S)-2d (K-i(sigma(i)) 9-15 nM).