An improved asymmetric synthetic route to a novel triple uptake inhibitor antidepressant (2S,4R,5R)-2-benzhydryl-5-((4-methoxybenzyl)amino)tetrahydro-2H-pyran-4-ol (D-142)

Triple monoamine reuptake inhibitors have been implicated in the development of a new generation of antidepressants with higher efficacy than the currently existing therapies. In this paper, we have developed an alternative efficient synthetic route for triple monoamine reuptake inhibitor D-142 in 18.5% overall yield in 11 steps starting from diphenylmethane. D-142 was developed by us recently. The key step of the present synthetic strategy is the preferential formation of a bromohydrin from olefin via a cis-bromonium intermediate, which introduced significant efficiency in the overall synthesis. Furthermore, we have developed an efficient way to recycle the optically active intermediate diol back to the desired chiral epoxide.

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(R)-2-BenzhydryloxiraneC15H14O[α]D25=+10.1 (c 1.0, CH3OH)Source of chirality: hydrolytic kinetic resolutionAbsolute configuration: (R)

(S)-3,3-Diphenylpropane-1,2-diolC15H16O2[α]D25=+48.0 (c 1.0, CH3OH)Source of chirality: hydrolytic kinetic resolutionAbsolute configuration: (S)

(S)-3-((tert-Butyldimethylsilyl)oxy)-1,1-diphenylpropan-2-olC21H30O2Si[α]D25=+31.6 (c 1.0, CH3OH)Source of chirality: hydrolytic kinetic resolutionAbsolute configuration: (S)

(S)-3-((tert-Butyldimethylsilyl)oxy)-1,1-diphenylpropan-2-yl methanesulfonateC22H32O4SSi[α]D25=-40.4 (c 0.5, CH3OH)Source of chirality: hydrolytic kinetic resolutionAbsolute configuration: (S)

(S)-3-Hydroxy-1,1-diphenylpropan-2-yl methanesulfonateC16H18O4S[α]D25=-38.8 (c 0.5, CH3OH)Source of chirality: hydrolytic kinetic resolutionAbsolute configuration: (S)

(S)-1,1-Diphenylpent-4-en-2-olC17H18O[α]D25=-36.6 (c 0.5, CH3OH)Source of chirality: hydrolytic kinetic resolutionAbsolute configuration: (S)

(S)-(2-(Allyloxy)pent-4-ene-1,1-diyl)dibenzeneC20H22O[α]D25=+23.6 (c 1.0, CH3OH)Source of chirality: hydrolytic kinetic resolutionAbsolute configuration: (S)

(S)-2-Benzhydryl-3,6-dihydro-2H-pyranC18H18O[α]D25=-94.6 (c 0.5, CH3OH)Source of chirality: hydrolytic kinetic resolutionAbsolute configuration: (S)

(2S,4R,5R)-2-Benzhydryl-5-bromotetrahydro-2H-pyran-4-olC18H19BrO2[α]D25=-114.4 (c 0.5, CH3OH)Source of chirality: hydrolytic kinetic resolutionAbsolute configuration: (2S,4R,5R)

(1S,4S,6R)-4-Benzhydryl-3,7-dioxabicyclo[4.1.0]heptaneC18H18O2[α]D25=-58.6 (c 0.5, CH3OH)Source of chirality: hydrolytic kinetic resolutionAbsolute configuration: (1S,4S,6R)

(2S,4R,5R)-2-Benzhydryl-5-((4-methoxybenzyl)amino)tetrahydro-2H-pyran-4-olC26H29NO3[α]D25=-72.6 (c 0.5, CH3OH)Source of chirality: hydrolytic kinetic resolutionAbsolute configuration: (2S,4R,5R)