A practical entry to β-aryl-β-alkyl amino alcohols: application to the synthesis of a potent BACE1 inhibitor.
The 1,2-addition of alkyl Grignard reagents to readily available N-tert-butanesulfinyl ketimines, bearing an α-silyloxy substituent, proceeds in high yields and excellent diastereocontrol. The utility of the present method was demonstrated by the synthesis, in enantiomerically pure form, of one recently disclosed β-secretase (BACE1) inhibitor.
Janssen Research and Development, Neuroscience Medicinal Chemistry Department, Toledo, Spain. odelgad1@its.jnj.com
Oscar
O
Delgado
Antonio
A
Monteagudo
Michiel
M
Van Gool
Andrés A
AA
Trabanco
Santos
S
Fustero
D000544:Alzheimer Disease / Q000188:drug therapy; D000605:Amino Alcohols / Q000138:chemical synthesis* / Q000737:chemistry; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D006801:Humans; D007097:Imines / Q000138:chemical synthesis / Q000737:chemistry; D009570:Nitriles / Q000138:chemical synthesis / Q000737:chemistry
D000605:Amino Alcohols; D004791:Enzyme Inhibitors; D007097:Imines; D009570:Nitriles; C542835:ketimine; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human