Enantioselective synthesis of diversely substituted quaternary 1,4-benzodiazepin-2-ones and 1,4-benzodiazepine-2,5-diones.
Benzodiazepines are privileged scaffolds in medicinal chemistry, but enantiopure examples containing quaternary stereogenic centers are extremely rare. We demonstrate that installation of the di(p-anisyl)methyl (DAM) group at N1 of 1,4-benzodiazepin-2-ones and 1,4-benzodiazepine-2,5-diones derived from enantiopure proteinogenic amino acids allows retentive replacement of the C3-proton via a deprotonation/trapping protocol. A wide variety of carbon and nitrogen electrophiles function well in this reaction, providing the corresponding quaternary benzodiazepines with excellent enantioselectivity. Deprotonation/trapping experiments on a pair of diastereomeric 1,4-benzodiazepine-2,5-diones provide evidence for a key role of conformational chirality in these enantioselective reactions. Acidic removal of the DAM group is fast and high-yielding and can be performed selectively in the presence of a N-Boc indole. Thus the synthesis of quaternary benzodiazepines with diverse N1 functionality can now be accomplished.
Carlier
Paul R
PR
Department of Chemistry, Virginia Tech, Blacksburg, Virginia 24060, USA. pcarlier@vt.edu
Zhao
Hongwu
H
MacQuarrie-Hunter
Stephanie L
SL
DeGuzman
Joseph C
JC
Hsu
Danny C
DC
D000478:Alkylation; D001569:Benzodiazepines / Q000138:chemical synthesis* / Q000737:chemistry; D008968:Molecular Conformation; D013237:Stereoisomerism; D013816:Thermodynamics
D001569:Benzodiazepines; C468549:Bz-423