Synthesis of (2S, 4S, 5S)-5-(t-Butoxycarbonylamino)-4-(t-Butyldimethylsilyloxy)-2-Isopropyl-7-Methyl Octanoic Acid

  • Mark A. Lyster
  • Brian G. Conway
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%.

Figure 1


Ethyl Acetate Sodium Chloride Solution Vacuum Distillation Sodium Bicarbonate Solution Potassium Hydroxide Solution 
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  1. 1.
    This work is based on initial efforts by many other labs at The UpJohn Co The authors would like to acknowledge spectftcally Jackson B Hester and his coworkers.Google Scholar
  2. 2.
    This coupling was based on work by Evans, D. A. and Takacs, J. M., (1980) Enantioselective alkylation of chiral enolates Tetrahedron Lett. 21, 4233–4236.CrossRefGoogle Scholar
  3. 3.
    This conversion 1s based on research carried out by Peter G M Wuts at The Upjohn Co.Google Scholar
  4. 4.
    This reduction is based on work by Boyer, S. K., Bach, J., and McKenna, J. (1985) Mild hydrogen-transfer reductions using sodium hypophosphite J. Org. Chem. 50, 3048–3411.CrossRefGoogle Scholar

Copyright information

© Humana Press Inc., Totowa, NJ 1999

Authors and Affiliations

  • Mark A. Lyster
    • 1
  • Brian G. Conway
    • 1
  1. 1.Chemical and Fermentation OperationsPharmacia & Upjohn, Inc.Kalamazoo

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