Unique and Efficient Synthesis of [2S-(2R~*,3S~*,4R~*)]-2-Amino-1-cyclohexyl-6-methyl-3,4-heptanediol, a Popular C-Terminal Component of Many Renin Inhibitors

摘要

A new, simple, large scale route to [2S-(2R~*,3S~*,4R~*)]-2-amino-1-cyclohexyl-6-methyl-3,4-heptanediol (9) was established starting from BOC-Phe. Diastereoselectivity was improved by selective crystallization of pure cyano-hydrin diastereomer 4 and using a sodium triacetoxy-borohydride reagent in the reduction of β-amino α-hy-droxy ketone 7. Aggregate and solvation problems dealing with multianionic intermediates in the carboxy-late coupling to β-amino α-hydroxy ketone 7 were overcome by introducing a toluene/LiBr/THF solvent system. The synthetic route consists of eight steps starting from BOC-Phe and results in a 37% overall yield. All but two steps were run on a multikilogram scale. These two steps preparing 4 and 5 worked excellently on a large ( > 150 g) laboratory scale. We have demonstrated a traditional synthetic approach to [2S-(2R~*,3S~*,4R~*)]-2-amino-1-cyclohexyl-6-methyl-3,4-heptanediol (9) by controlling stereochemistry of each additional chiral center starting from a chiral amino acid, BOC-Phe. This overall efficient and practical synthetic strategy should be applicable to a wide variety of 1-amino-2,3-diols utilizing commercially available chiral amino acids as starting materials and varying the lithium alkyl used in the coupling reaction.