Directed reductive amination of beta-hydroxy-ketones: convergent assembly of the ritonavir/lopinavir core.
An efficient procedure for the directed reductive amination of beta-hydroxy-ketones (3) for the stereoselective preparation of 1,3-syn-amino alcohols (6) is reported. The operationally simple protocol uses Ti(iOPr)4 for coordination of the intermediate imino alcohol (5) and PMHS as the reducing agent. The method was expanded to an asymmetric aldol reductive amination sequence to allow a highly convergent synthesis of the hydroxy-amine core of the HIV-protease inhibitors ritonavir and lopinavir. [reaction: see text].
Menche
Dirk
D
Gesellschaft für Biotechnologische Forschung mbH, Medizinische Chemie, Mascheroder Weg 1, D-38124 Braunschweig, Germany. dirk.menche@helmholtz-hzi.de
Arikan
Fatih
F
Li
Jun
J
Rudolph
Sven
S
D000586:Amination; D000605:Amino Alcohols / Q000138:chemical synthesis* / Q000737:chemistry; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D007659:Ketones / Q000737:chemistry*; D061466:Lopinavir; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000737:chemistry; D010084:Oxidation-Reduction; D011744:Pyrimidinones / Q000138:chemical synthesis* / Q000737:chemistry; D019438:Ritonavir / Q000138:chemical synthesis* / Q000737:chemistry; D013237:Stereoisomerism; D014025:Titanium / Q000737:chemistry
D000605:Amino Alcohols; D017320:HIV Protease Inhibitors; D007659:Ketones; D009942:Organometallic Compounds; D011744:Pyrimidinones; D061466:Lopinavir; D014025:Titanium; D019438:Ritonavir