Sharpless asymmetric dihydroxylation as the key step in the enantioselective synthesis of spirocyclic σ1 receptor ligands

The enantioselective synthesis of fluorinated spirocyclic σ1 ligands involved three key steps: (1) the Sharpless asymmetric dihydroxylation of 2-bromostyrene 5 provided enantiomerically pure diols (R)-6 and (S)-6 establishing the stereogenic center; (2) the intramolecular opening of the oxirane ring of (R)-11 and (S)-11, which occurred with excellent regioselectivity and complete inversion of configuration giving access to enantiomerically pure alcohols (S)-7a and (R)-7a; (3) the treatment of alcohols (S)-7b and (R)-7b with DAST, which led to the fluoromethyl derivatives (S)-1 and (R)-1 without racemization. X-ray crystal structure analysis of the tosylate (R)-13 confirmed the absolute configuration of the spirocyclic compounds as well as the enantioselectivity during the Sharpless asymmetric dihydroxylation of 5. The (S)-configured fluoromethyl derivative (S)-1 revealed a high σ1 affinity (Ki = 1.8 nM), high eudismic ratio (factor 8) and high selectivity over the σ2 subtype (667-fold).

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(R)-1-(2-Bromophenyl)ethane-1,2-diolC8H9BrO298.8% ee[α]D20=-63.2 (c 8.0, CH2Cl2)source of chirality: AD-mix-βAbsolute configuration: (R)

(4R)-4-(2-Bromophenyl)-1,3,2-dioxathiolane 2-oxideC8H7BrO3S98.8% ee[α]D20=-7.5 (c 4.6, CH2Cl2)source of chirality: AD-mix-βAbsolute configuration: (4R)

[(R)-2-(2-Bromophenyl)-2-hydroxyethyl] 4-methylbenzenesulfonateC15H15BrO4S98.8% ee[α]D20=-53.6 (c 28.1, CH2Cl2)source of chirality: AD-mix-βAbsolute configuration: (R)

(R)-2-(2-Bromophenyl)oxiraneC8H7BrO98.8% ee[α]D20=-49.9 (c 63.6, CH2Cl2)source of chirality: AD-mix-βAbsolute configuration: (R)

tert-Butyl (R)-3-(hydroxymethyl)-3H-spiro[[2]benzofuran-1,4′-piperidine]-1′-carboxylateC18H25NO495.0% ee[α]D20=-4.3 (c 14.1, CH2Cl2)source of chirality: AD-mix-αAbsolute configuration: (R)

(R)-(1′-Benzyl-3H-spiro[[2]benzofuran-1,4′-piperidin]-3-yl)methanolC20H23NO295.0% ee[α]D20=-5.7 (c 28.2, CH2Cl2)source of chirality: AD-mix-αAbsolute configuration: (R)

(R)-1′-Benzyl-3-(fluoromethyl)-3H-spiro[[2]benzofuran-1,4′-piperidine]C20H22FNO93.0% ee[α]D20=+4.6 (c 4.8, CH2Cl2)source of chirality: AD-mix-αAbsolute configuration: (R)

tert-Butyl (R)-3-[(tosyloxy)methyl]-3H-spiro[[2]benzofuran-1,4′-piperidine]-1′-carboxylateC25H31NO6S95.0% ee[α]D20=-19.3 (c 7.2, CH2Cl2)source of chirality: AD-mix-αAbsolute configuration: (R)