A Practical and Efficient Total Synthesis of Potent Insulinotropic (2S,3R,4S)-4-Hydroxyisoleucine through a Chiral N-Protected γ-Keto-α-aminoester

✍ Scribed by Sandra De Lamo Marin; Cédric Catala; Sreekantha Ratna Kumar; Alain Valleix; Alain Wagner; Charles Mioskowski

• Publisher: John Wiley and Sons
• Year: 2010
• Tongue: English
• Weight: 145 KB
• Volume: 2010
• Category: Article
• ISSN: 1434-193X
• DOI: 10.1002/ejoc.201000378

✦ Synopsis

Abstract

(2__S__,3__R__,4__S__)‐4‐Hydroxyisoleucine, which exhibits remarkable insulinotropic activity, is expected to be a potent drug to treat type II diabetes. We propose herein a four‐step synthesis of the enantiopure natural product on the basis of successive Mannich condensation, catalytic epimerization, N‐para‐methoxyphenyl deprotection, and diastereoselective reduction. This compact economical and scalable sequence enables to perfectly control three contiguous chiral centers. It does not involve any chromatographic purification, and the desired compound is obtained in >99 % de, >99 % ee, and 22 % overall yield under our optimized conditions.