Enantioselective synthesis of a highly potent selective serotonin reuptake inhibitor. An application of imidazolidinone catalysis to the alkylation of indoles with an alpha,beta-disubstituted alpha,beta-unsaturated aldehyde.
The synthesis of the highly potent and selective serotonin reuptake inhibitor 1 (BMS-594726) is described. In the key construction step, an enantioselective alkylation of the indole nucleus with an alpha-branched alpha,beta-unsaturated aldehyde 7 was accomplished utilizing MacMillan's imidazolidinone catalyst 3b. A rationale is presented for the unexpected stereochemical result, as well as the novel reactivity of the alpha-branched substrate. [reaction: see text]
King
H Dalton
HD
Bristol Myers Squibb, 5 Research Parkway, Wallingford, CT 06492, USA.
Meng
Zhaoxing
Z
Denhart
Derek
D
Mattson
Ronald
R
Kimura
Roy
R
Wu
Dedong
D
Gao
Qi
Q
Macor
John E
JE
D000447:Aldehydes / Q000737:chemistry; D002384:Catalysis; D003517:Cyclopentanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D007093:Imidazoles / Q000737:chemistry*; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D017367:Selective Serotonin Reuptake Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism
D000447:Aldehydes; D003517:Cyclopentanes; D007093:Imidazoles; D007211:Indoles; D017367:Selective Serotonin Reuptake Inhibitors; C510218:BMS-594726