Enantioselective synthesis of benzomorphan analogues by intramolecular oxa-Pictet–Spengler cyclization

A new strategy toward biologically active enantiomerically pure benzomorphan analogues is described. The key steps in the synthesis are the l-proline catalyzed asymmetric α-aminooxylation of an aldehyde and the titanium tetrachloride promoted intramolecular oxa-Pictet–Spengler cyclization of (4R)-2-(bromomethyl)-4-(2,5-dimethoxybenzyl)-1,3-dioxolane. In the intramolecular oxa-Pictet–Spengler cyclization, cis-pyran 8a (71%) formed over the trans-pyran 8b (14%). Computational modeling studies provided an insight into the stereoselectivity of the products. Docking studies of benzomorphan derivatives indicated that compound 6c had the best binding efficiency, and that it formed extensive hydrogen bonding with TYR148 on transmembrane (TM) helix 3 and HIS297 on TM6 of the μ-opioid receptor, which belong to the G-protein coupled receptor super family.

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(+)-(R)-3-(2,5-Dimethoxyphenyl)propane-1,2-diolC11H16O4ee: 98%[α]D26=+10.4 (c 1, CHCl3)Source of chirality: (S)-ProlineAbsolute configuration: (3R)

(+)-((1S,3R)-1-(Bromomethyl)-5,8-dimethoxyisochroman-3-yl)methanolC13H17BrO4[α]D25=+185.4 (c 1, CHCl3)Source of chirality: (S)-ProlineAbsolute configuration: (1S,3R)

(−)-((1R,3R)-1-(Bromomethyl)-5,8-dimethoxyisochroman-3-yl)methanolC13H17BrO4[α]D23=-23.4 (c 1, CHCl3)Source of chirality: (S)-ProlineAbsolute configuration: (1R,3R)

(+)-(1S,5R)-3-Benzyl-7,10-dimethoxy-1,2,3,4,5,6-hexahydro-1,5-epoxybenzo[d]azocineC20H23NO3[α]D25=+37.5 (c 1, CHCl3)Source of chirality: (S)-ProlineAbsolute configuration: (1S,5R)

(+)-(1S,5R)-3-(3,4-Dichlorobenzyl)-7,10-dimethoxy-1,2,3,4,5,6-hexahydro-1,5-epoxybenzo[d]azocineC20H21Cl2NO3[α]D22.3=+29.4 (c 1, CHCl3)Source of chirality: (S)-ProlineAbsolute configuration: (1S,5R)

(+)-(1S,5R)-3-(2-Chlorobenzyl)-7,10-dimethoxy-1,2,3,4,5,6-hexahydro-1,5-epoxybenzo[d]azocineC20H22ClNO3[α]D26.4=+26.5 (c 0.5, CHCl3)Source of chirality: (S)-ProlineAbsolute configuration: (1S,5R)

(+)-(1S,5R)-3-(4-Fluorobenzyl)-7,10-dimethoxy-1,2,3,4,5,6-hexahydro-1,5-epoxybenzo[d]azocineC20H22FNO3[α]D26=+22.8 (c 1, CHCl3)Source of chirality: (S)-ProlineAbsolute configuration: (1S,5R)

(+)-(1S,5R)-7,10-Dimethoxy-3-(4-methoxybenzyl)-1,2,3,4,5,6-hexahydro-1,5-epoxybenzo[d]azocineC21H25NO4[α]D23=+17.0 (c 1, CHCl3)Source of chirality: (S)-ProlineAbsolute configuration: (1S,5R)

(+)-(1S,5R)-7,10-Dimethoxy-3-(pyridin-4-ylmethyl)-1,2,3,4,5,6-hexahydro-1,5-epoxybenzo[d]azocineC19H22N2O3[α]D26.3=+32.2 (c 1, CHCl3)Source of chirality: (S)-ProlineAbsolute configuration: (1S,5R)

(+)-(1S,5R)-3-(2-(1H-Indol-3-yl)ethyl)-7,10-dimethoxy-1,2,3,4,5,6-hexahydro-1,5-epoxybenzo[d]azocineC23H26N2O3[α]D24=+15.8 (c 1.35, CHCl3)Source of chirality: (S)-ProlineAbsolute configuration: (1S,5R)

(+)-(1S,5R)-3-(3,4-Dimethoxyphenethyl)-7,10-dimethoxy-1,2,3,4,5,6-hexahydro-1,5-epoxybenzo[d]azocineC23H29NO5[α]D23=+3.8 (c 1, CHCl3)Source of chirality: (S)-ProlineAbsolute configuration: (1S,5R)

(+)-(1S,5R)-7,10-Dimethoxy-3-((S)-1-phenylethyl)-1,2,3,4,5,6-hexahydro-1,5-epoxybenzo[d]azocineC21H25NO3[α]D26.7=+27.8 (c 1, CHCl3)Source of chirality: (S)-ProlineAbsolute configuration: (1S,5R) (3S)