Synthesis of (2S, 4S, 5S)-5-(t-Butoxycarbonylamino)-4-(t-Butyldimethylsilyloxy)-2-Isopropyl-7-Methyl Octanoic Acid
Part of the Methods in Molecular Medicine™ book series (MIMM, volume 23)
In an effort to produce renm mhibttory peptides, the preparation of (2S,4S,5S)-5-(t-Butoxycarbonylamino)-4-(t-butyldimethylsilyloxy)-2-isopropyl-7-methyl octanotc acid, 15, was carried out (1). This pseudo-dipeptide was used to replace combinattons of leucme coupled with valine in pepttde sequences. The preparation described is the final method developed, after many early less successful attempts. The synthesis mvolves (Fig. 1) the coupling of 1-bromo-5-methyl-2-hexene 3 and N-isovaleryl-l-prolmol 4 using the opttcal activity of the l-prolmol to induce optical activrty at the C-2 posmon of 5, a key intermediate (2). After purifying this intermediate through the formatron of its benzoate, the functionalizatlon of the C-4 and C-5 positions is carried out through an epoxtdation to give two stereoisomers. After mesylation and separation of the undesired isomer, 12, it is converted to the desired isomer, 11, through a hydrolysis/lactomzation process, which inverts the C-4 and C-5 centers (3). After formatron of the mesylate, from the recycled material the amine function is introduced through azrde displacement of the mesylate, followed by reduction (4) and protectron with the t-BOC group. Finally, the lactone is opened and the hydroxyl group is protected as the t-butyldtmethylsilyl ether to give the title compound, 15. As can be seen in the procedure, this synthesis was carried out on a large-scale producing 4 8 kg of 15 through a 15-step sequence in an overall yield of 18.5%.
KeywordsEthyl Hexane Acetonitrile CDCl3 Sulfuric Acid
© Humana Press Inc., Totowa, NJ 1999