New synthetic technology for efficient construction of alpha-hydroxy-beta-amino amides via the Passerini reaction.
[reaction: see text] The Passerini reaction of N-protected amino aldehydes, isonitriles, and TFA using pyridine-type bases proceeds under mild conditions and directly affords alpha-hydroxy-beta-amino amide derivatives in moderate to high yields. These adducts are readily hydrolyzed to alpha-hydroxy-beta-amino carboxylic acids. Application of these key intermediates to concise syntheses of P(1)-alpha-ketoamide protease inhibitors is illustrated.
Semple
J E
JE
Department of Medicinal Chemistry, Corvas International, Inc., 3030 Science Park Road, San Diego, California 92121, USA. ed_semple@corvas.com
Owens
T D
TD
Nguyen
K
K
Levy
O E
OE
D000577:Amides / Q000138:chemical synthesis*; D000596:Amino Acids / Q000737:chemistry; D005449:Fluorenes / Q000737:chemistry; D007651:Keto Acids / Q000138:chemical synthesis; D007930:Leucine / Q000031:analogs & derivatives* / Q000138:chemical synthesis; D011480:Protease Inhibitors / Q000138:chemical synthesis; D013329:Structure-Activity Relationship
D000577:Amides; D000596:Amino Acids; D005449:Fluorenes; D007651:Keto Acids; C016456:N(alpha)-fluorenylmethyloxycarbonylamino acids; D011480:Protease Inhibitors; D007930:Leucine; C012211:ubenimex