An efficient, stereoselective synthesis of the hydroxyethylene dipeptide isostere core for the HIV protease inhibitor A-792611.
A stereoselective synthesis of the hydroxyethylene dipeptide isostere 1 is described. The route employs a substrate-directed kinetic protonation of an alpha/gamma-substituted lactone to afford the desired stereochemistry. A method for converting the diastereomerically enriched intermediate lactone to the ring-open form with retention of stereochemistry is demonstrated. A novel procedure for utilizing N,N-dibromo-5,5-dimethylhydantoin in Hofmann rearrangements is disclosed. This route was used to prepare amino alcohol 1, the core portion of the HIV protease inhibitor A-792611, in 46% yield from phenylalanine-derived epoxide 2.
Engstrom
Kenneth
K
Department of Process Chemistry, Global Pharmaceutical Research and Development, Abbott Laboratories, 1401 Sheridan Road, North Chicago, IL 60064-6290, USA.
Henry
Rodger
R
Hollis
L Steven
LS
Kotecki
Brian
B
Marsden
Ian
I
Pu
Yu-Ming
YM
Wagaw
Seble
S
Wang
Weifeng
W
D018360:Crystallography, X-Ray; D004151:Dipeptides / Q000138:chemical synthesis* / Q000737:chemistry; D004952:Esters / Q000138:chemical synthesis* / Q000737:chemistry; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D008958:Models, Molecular; D008968:Molecular Conformation; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry; D013237:Stereoisomerism
D004151:Dipeptides; D004952:Esters; D017320:HIV Protease Inhibitors; D011725:Pyridines; C520593:methyl 1-(5-(2-(3-benzyl-2-oxoimidazolidin-1-yl)-3,3-dimethylbutanamido)-4-hydroxy-6-phenyl-1-(4-(pyridin-2-yl)phenyl)hexan-2-ylamino)-3,3-dimethyl-1-oxobutan-2-ylcarbamate