Catalytic enantioselective synthesis of the dopamine D1 antagonist ecopipam

A concise asymmetric synthesis of the potent dopamine D1 antagonist, ecopipam, has been accomplished in six steps with 33% overall yield via catalytic enantioselective aziridination and subsequent one-pot Friedel–Crafts cyclization of an in situ generated tethered aziridine with high diastereo- and enantioselectivities.

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(+)-trans-(1R,2S)-N-[1-(4-Chloro-3-methoxy-phenyl)-1,2,3,4-tetrahydro-naphthalen-2-yl]-4-nitro-benzenesulfonamideC23H21ClN2O5See ⩾ 89%[α]D23=+64.2 (c 0.3, DCM)Source of chirality: (S)-bis-oxazoline ligand 10Absolute configuration: (1R,2S)

(+)-trans-(1R,2S)-N-[1-(4-Chloro-3-methoxy-phenyl)-1,2,3,4-tetrahydronaphthalen-2-yl]-4-nitro-benzenesulfonamideC24H23ClN2O5See ⩾ 89%[α]D23=+24.6 (c 0.3, DCM)Source of chirality: asymmetric synthesisAbsolute configuration: (1R,2S)

(+)-trans-(1R,2S)-[1-(4-Chloro-3-methoxy-phenyl)-1,2,3,4-tetrahydronaphthalen-2-yl]-methylamineC18H20ClNOee ⩾ 89%[α]D23=+46.6 (c 1.00, DCM)Source of chirality: asymmetric synthesisAbsolute configuration: (1R,2S)

(+)-trans-(1R,2S)-1-(4-Chloro-3-methoxyphenyl)-N-(2,2-dimethoxyethyl)-1,2,3,4-tetrahydro-N-methyl-2-naphthalenamineC22H28ClNO3ee ⩾ 89%[α]D23=+56.9 (c 1.40, EtOH)Source of chirality: asymmetric synthesisAbsolute configuration: (1R,2S)

trans-(–)-(6aS,13bR)-11-Chloro-6,6a,7,8,9,13b-hexahydro-7-methyl-12-methoxy-5H-benzo[d]naphth[2,1-b]azepineC20H22ClNOee ⩾ 89%[α]D23=-170.9 (c 1.00, EtOH)Source of chirality: asymmetric synthesisAbsolute configuration: (6aS,12bR)

trans-(−)-(6aS,13bR)-11-Chloro-6,6a,7,8,9,13b-hexahydro-7-methyl-5H-benzo[d]naphth-[2,l-b]azepin-l2-olC19H20ClNOee ⩾ 89%[α]D24=-200.9 (c 0.52, DMF)Source of chirality: asymmetric synthesisAbsolute configuration: (6aS,12bR)