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Sharpless asymmetric dihydroxylation of styrene derivative 6 afforded chiral triols (R)-7 and (S)-7, which were cyclized with tosyl chloride in the presence of Bu2SnO to provide 2-benzopyrans (R)-4 and (S)-4 with high regioselectivity. The additional hydroxy moiety in the 4-position was exploited for the introduction of various substituents. Williamson ether synthesis and replacement of the Boc protective group with a benzyl moiety led to potent σ1 ligands with high σ1/σ2-selectivity. With exception of the ethoxy derivative 16, the (R)-configured enantiomers represent eutomers with eudismic ratios of up to 29 for the ester (R)-18. The methyl ether (R)-15 represents the most potent σ1 ligand of this series of compounds, with a Ki value of 1.2 nM and an eudismic ratio of 7. Tosylate (R)-21 was used as precursor for the radiosynthesis of [18F]-(R)-20, which was available by nucleophilic substitution with K[18F]F K222 carbonate complex. The radiochemical yield of [18F]-(R)-20 was 18%–20%, the radiochemical purity greater than 97% and the specific radioactivity 175–300 GBq/µmol. Although radiometabolites were detected in plasma, urine and liver samples, radiometabolites were not found in brain samples. After 30 min, the uptake of the radiotracer in the brain was 3.4% of injected dose per gram of tissue and could be reduced by coadministration of the σ1 antagonist haloperidol. [18F]-(R)-20 was able to label those regions of the brain, which were reported to have high density of σ1 receptors.

In order to obtain enantiomerically pure σ 1 receptor ligands with a 2-benzopyran scaffold an Oxa-Pictet-Spengler 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 σ 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 σ 1 /σ 2 selectivity (>49) was found for the most potent σ 1 ligands ( R )- 2b , ( R )- 2c , ( R )- 2d , and ( S )- 2d ( K i (σ 1 ) 9–15 nM). [ABSTRACT FROM AUTHOR]

The Oxa-Pictet–Spengler reaction of methyl 3-hydroxy-4-phenylbutanoate ( 8 ) was explored to obtain novel σ receptor ligands. 1-Acyl protected piperidone ketals 10 and 11 reacted with phenylethanol 8 to yield spirocyclic compounds. Aliphatic aldehyde acetals 19 provided 1,3-disubstituted 2-benzopyrans 20 with high cis -diastereoselectivity. The intramolecular Oxa-Pictet–Spengler reaction of 24 led to the tricyclic compound 25 . The spirocyclic compounds 18 show high σ 1 affinity ( K i 20–26 nM) and σ 1 /σ 2 selectivity (>9-fold), when a large substituent ( n -octyl, benzyl, phenylpropyl) is attached to the piperidine N -atom. Opening of the piperidine ring to yield aminoethyl ( 22 , 23 ) or aminomethyl derivatives ( 21 ) resulted in reduced σ 1 affinity and σ 1 /σ 2 selectivity. [ABSTRACT FROM AUTHOR]

Sharpless asymmetric dihydroxylation of styrene derivative 6 afforded chiral triols (R)-7 and (S)-7, which were cyclized with tosyl chloride in the presence of Bu2SnO to provide 2-benzopyrans (R)-4 and (S)-4 with high regioselectivity. The additional hydroxy moiety in the 4-position was exploited for the introduction of various substituents. Williamson ether synthesis and replacement of the Boc protective group with a benzyl moiety led to potent σ1 ligands with high σ1/σ2-selectivity. With exception of the ethoxy derivative 16, the (R)-configured enantiomers represent eutomers with eudismic ratios of up to 29 for the ester (R)-18. The methyl ether (R)-15 represents the most potent σ1 ligand of this series of compounds, with a Ki value of 1.2 nM and an eudismic ratio of 7. Tosylate (R)-21 was used as precursor for the radiosynthesis of [18F]-(R)-20, which was available by nucleophilic substitution with K[18F]F K222 carbonate complex. The radiochemical yield of [18F]-(R)-20 was 18%-20%, the radiochemical purity greater than 97% and the specific radioactivity 175-300 GBq/μmol. Although radiometabolites were detected in plasma, urine and liver samples, radiometabolites were not found in brain samples. After 30 min, the uptake of the radiotracer in the brain was 3.4% of injected dose per gram of tissue and could be reduced by coadministration of the σ1 antagonist haloperidol. [18F]-(R)-20 was able to label those regions of the brain, which were reported to have high density of σ1 receptors [ABSTRACT FROM AUTHOR]