Chiral Epoxy-Imine Building Block for Diversity-Oriented Synthesis of Peptidomimetic Aspartic Protease Inhibitors

Anti-1,3-diaminopropan-2-ol is a privileged structural motif in the design of peptidomimetic aspartic protease inhibitors. However, current approaches to the anti-1,3-diaminopropan-2-ol motif are lengthy and therefore ill-suited for rapid introduction of molecular diversity. Herein, we have designed a bifunctional building block for diversity-oriented step economy synthesis of anti-1,3-diaminopropan-2-ol derivatives. The building block comprises chiral epoxide functional group and Ellman’s tert-butanesulfinyl imine handle. The Ellman’s chiral auxiliary effects highly diastereoselective (up to 98:2 d.r.) reaction with a range of magnesium zincate nucleophiles without affecting epoxide moiety. Subsequent epoxide cleavage with a suitable amine delivers anti-1,3-diaminopropan-2-ol derivatives. The suitability of the developed building block for step economy approach to peptidomimetic aspartic protease inhibitors was demonstrated by concise seven-step synthesis of anti-HIV darunavir.