Direct catalytic asymmetric aldol reaction of thioamides: a concise asymmetric synthesis of (R)-fluoxetine

A direct catalytic asymmetric aldol reaction of aromatic aldehydes and thioamides is described. A soft Lewis acid/hard Brønsted base cooperative catalyst comprising (R,R)-Ph-BPE/[Cu(CH3CN)4]PF6/Li(OC6H4-p-OMe) promoted the title reaction efficiently, triggered by in situ generation of the active thioamide enolate through a soft–soft interaction of Cu(I) and the thioamide. The aldol product was transformed into (R)-fluoxetine, an antidepressant agent.

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(R)-N,N-Diallyl-3-hydroxy-3-phenylpropanethioamideC15H19NOSEe 79%[α]D23=+105.0 (c 1.2, CHCl3)Absolute configuration: (R)

(R)-N,N-Diallyl-3-hydroxy-3-(naphthalen-2-yl)propanethioamideC19H21NOSEe 79%[α]D23=+92.4 (c 1.1, CHCl3)Absolute configuration: (R)

(R)-N,N-Diallyl-3-hydroxy-3-o-tolylpropanethioamideC16H21NOSEe 67%[α]D23=+92.3 (c 0.9, CHCl3)Absolute configuration: (R)

(R)-N,N-Diallyl-3-hydroxy-3-p-tolylpropanethioamideC16H21NOSEe 79%[α]D23=+95.0 (c 1.2, CHCl3)Absolute configuration: (R)

(R)-N,N-Diallyl-3-hydroxy-3-(3-methoxyphenyl)propanethioamideC16H21NO2SEe 82%[α]D23=+88.1 (c 0.9, CHCl3)Absolute configuration: (R)

(R)-N,N-Diallyl-3-(4-fluorophenyl)-3-hydroxypropanethioamideC15H18FNOSEe 74%[α]D23=+92.1 (c 1.0, CHCl3)Absolute configuration: (R)

(R)-N,N-Diallyl-3-(4-chlorophenyl)-3-hydroxypropanethioamideC15H18ClNOSEe 71%[α]D25=+87.2 (c 1.0, CHCl3)Absolute configuration: (R)

(R)-N,N-Diallyl-3-hydroxy-3-(thiophen-2-yl)propanethioamideC13H17NOS2Ee 91%[α]D25=+110.0 (c 1.1, CHCl3)Absolute configuration: (R)