Efficient Synthesis of (2S,3S)-2-Ethyl-3-methylvaleramide Using (1S,2S)-Pseudoephedrine as a Chiral Auxiliary

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An efficient and scaleable synthesis of (2S,3S)-2-ethyl-3-methylvaleramide (1) has been developed starting from inexpensive and readily available l-isoleucine. The key step in this process is an asymmetric alkylation using (1S,2S)-pseudoephedrine as a chiral auxiliary. A practical procedure was developed to remove the sterically hindered pseudoephedrine auxiliary from the amide. The process consists of eight chemical steps and five isolations without any chromatographic purification. It has been successfully implemented to prepare several multikilogram batches of the target compound 1 in 41% overall yield.