From L-Ascorbic Acid to Protease Inhibitors: Practical Synthesis of Key Chiral Epoxide Intermediates for Aspartyl Proteases

• Published in: Bulletin of the Korean Chemical Society Vol. 33; no. 7; pp. 2213 - 2218
• Main Authors: Chang, Sun-Ki, So, Soon-Mog, Lee, Sang-Min, Kim, Min-Kyu, Seol, Kyoung-Mee, Kim, Sung-Min, Kang, Jae-Sung, Choo, Dong-Joon, Lee, Jae-Yeol, Kim, B.-Moon
• Format: Journal Article
• Language: Korean
• Published: 2012
• Subjects: L-Ascorbic acid; Protease inhibitors; Epoxide; Aziridine opening; HIV protease
• ISSN: 0253-2964; 1229-5949

Efficient synthetic routes were developed to prepare a sizable amount (4-15 grams) of the chiral epoxides 4-6 as versatile intermediates for the synthesis of aspartyl protease inhibitors of therapeutic interest such as HIV protease and ${\beta}$-secretase. Oxidative cleavage of the C(2)-C(3) double bond of L-ascorbic acid followed by functional group manipulation led to the preparation of the epoxide 10, which was opened with an azide to yield a common aziridine intermediate 12. Through opening of the aziridine ring of 12 with either a carbon or a sulfur nucleophile, chiral epoxide precursors 4-6 could be prepared for various HIV protease inhibitors. Except for the final low melting epoxides 5 and 6, all intermediates were obtained as crystalline solids, thus the synthetic pathway can be easily applied to a large-scale synthesis of the chiral epoxides.