Chiral Resolution and Serendipitous Fluorination Reaction for the Selective Dopamine D3 Receptor Antagonist BAK2-66

  • ACS Med Chem Lett. 2014 Mar 24;5(6):647-51. doi: 10.1021/ml500006v.
Vivek Kumar  1 ,  Ashwini K Banala  1 ,  Erick G Garcia  1 ,  Jianjing Cao  1 ,  Thomas M Keck  1 ,  Alessandro Bonifazi  1 ,  Jeffery R Deschamps  2 ,  Amy Hauck Newman  1
Affiliations
  • 1. Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse-Intramural Research Program, National Institutes of Health , 333 Cassell Drive, Baltimore, Maryland 21224, United States.
  • 2. Naval Research Laboratory , Code 6030, 4555 Overlook Avenue, Washington, D.C. 20375, United States.
PMID: 24944737 DOI: 10.1021/ml500006v
Abstract

The improved chiral synthesis of the selective dopamine D3 receptor (D3R) antagonist (R)-N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3-hydroxybutyl)1H-indole-2-carboxamide (( R )-PG648) is described. The same chiral secondary alcohol intermediate was used to prepare the enantiomers of a 3-F-benzofuranyl analogue, Bak 2-66. The absolute configurations of the 3-F enantiomers were assigned from their X-ray crystal structures that confirmed retention of configuration during fluorination with N,N-diethylaminosulfur trifluoride (DAST). ( R )-BAK2-66 showed higher D3R affinity and selectivity than its (S)-enantiomer; however, it had lower D3R affinity and enantioselectivity than ( R )-PG648. Further, importance of the 4-atom linker length between the aryl amide and 4-phenylpiperazine was demonstrated with the 4-fluorobutyl-product (8).

Keywords
DAST; asymmetric catalysis; dopamine; enantioselectivity.
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