1. Studies toward the Large-Scale Synthesis of the HIV Proteinase Inhibitor Ro 31-8959
- Author
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David J. Bushnell, Joseph A. Martin, Michelle P. Gunn, Stephen J. Dunsdon, Robert W. Lambert, Kevin E. B. Parkes, Andrew C. Freeman, Richard A. Hopkins, and Peter H. Crackett
- Subjects
chemistry.chemical_classification ,Sharpless epoxidation ,chemistry.chemical_compound ,Ketone ,chemistry ,Trimethylsilyl ,Acyl chloride ,Stereochemistry ,Organic Chemistry ,Electrophile ,Enantioselective synthesis ,Epoxide ,Chirality (chemistry) - Abstract
Ro 31-8959 (1), a potent and selective inhibitor of HIV proteinase, is currently in phase III clinical trials. Six approaches for the large-scale synthesis of this compound have been studied. All routes employ an initial disconnection to an electrophilic L-phenylalanine homologue equivalent 13 and the decahydroisoquinoline derivative 5. They differ in adopting either an epoxide, a cyclic sulfate, or an aldehyde as the electrophilic entity and develop chirality from L-phenylalanine, dimethyl D-tartrate, or a Sharpless epoxidation. The preferred route starts from N-phthaloyl-L-phenylalaninyl chloride and uses tris((trimethylsilyl)oxy)ethene to effect homologation to hydroxy ketone 30, which is elaborated in a five-step two-pot procedure to N-phthaloyl epoxide 33 and hence 1. Kilogram quantities of Ro 31-8959 have been prepared using this route
- Published
- 1994
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