Application of Isayama–Mukaiyama cobalt catalyzed hydroperoxysilylation for the preparation of ritonavir hydroperoxide. Issue 46 (16th November 2016)

• Record Type: Journal Article
• Authors: Gazal, Sharon; Gupta, Priya; Gunturu, Siva Ramakrishna; Isherwood, Matthew; Voss, Matthew E.
• Is Part Of: Tetrahedron letters. Volume 57:Issue 46(2016)
• Page Start: 5099
• Page End: 5102
• Publication Date: 2016-11-16
• Subjects: Ritonavir hydroperoxide -- Isayama–Mukaiyama hydroperoxysilylation -- TES stoichiometry -- Late stage oxidation -- Cobalt; Chemistry, Organic -- Periodicals; 547.005
• DOI: 10.1016/j.tetlet.2016.10.022
• Languages: English
• ISSNs: 0040-4039

Abstract

Graphical abstract: Highlights: Total synthesis of a hydroperoxide impurity of ritonavir. New conditions were developed for the Isayama–Mukaiyama hydroperoxysilylation reaction. Mild conditions enable hydroperoxy incorporation late in the synthetic sequence. Abstract: We report the preparation of thiazol-5-ylmethyl ((2 S, 3 S, 5 S )-5-(( S )-2-(3-((2-(2-hydroperoxypropan-2-yl)thiazol-4-yl)methyl)-3-methylureido)-3-methylbutanamido)-3-hydroxy-1, 6-diphenylhexan-2-yl)carbamate, a hydroperoxide impurity of ritonavir also known as ritonavir USP impurity G. Due to the complexity of ritonavir's structure and abundance of oxidation susceptible functional groups, forced degradation was found to be a non-selective and inadequate tactic. Therefore, a multistep synthesis was applied. The overall strategy involved initial introduction of a propenyl moiety to the terminal thiazole which enabled selective oxidation using Co(thd)2 (0.1 equiv)/O2 (Isayama–Mukaiyama cobalt catalyzed hydroperoxysilylation) following structural assembly.