A Chemobiological Synthesis of Eplerenone

Abstract

This paper will describe an approach to the synthesis of eplerenone, which is being marketed for the treatment of hypertension. The synthesis begins with DHEA available from wild yams and uses a combination of microbiological and chemical transformations to build eplerenone.

Key words

carbonylation - microbial oxidation - hydroformylation - steroids - Ishikawa reagent - microbial deprotection

References

• 1 Information update: Drugs Future  2000,  25:  516 
• 2a Rabasseda X. Silvestre J. Castañer J. Drugs Future  1999,  24:  488 
• 2b Ng JS, Wang PT, Baez JA, Liu C, Anderson DK, Lawson JP, Erb D, Wieczorek J, Mucciariello G, Vanzanella F, Kunda SA, Letendre LJ, Pozzo MJ, and Sing Y.-L. inventors; WO  9721720. 
• 3 McMahon EG. Curr. Opin. Pharmacol.  2001,  1:  190 
• 4 White MJ, Wuts PGM, and Beck D. inventors; US 0034215  A1. 
• 5 Fu X. Tann C.-H. Thiruvengadam TK. Lee J. Colon C. Tetrahedron Lett.  2001,  42:  2639 
• 7a Maeda K. Farrington EJ. Galardon E. John BD. Brown JM. Adv. Synth. Catal.  2002,  344:  104 
• 7b Takas JM. Lawson EC. Clement F. J. Am. Chem. Soc.  1997,  119:  5956 
• 7c Andersson PG. Schab S. Organometallics  1995,  14:  1 
• 8 Wuts PGM. Ritter AR. J. Org. Chem.  1989,  54:  5180 
• 9 Wuts PGM. Ashford SW. Anderson AM. Atkins JR. Org. Lett.  2003,  5:  1483 
• 10 Takahashi Y. Tsukiyama K. Sakai S. Ishii Y. Tetrahedron Lett.  1970,  1913 
• 11 Murahashi S.-I. Imada Y. Taniguchi Y. Higashiura S. J. Org. Chem.  1993,  58:  1538 
• 12 Microbial Transformations of Steroids: A Hand-book,Charney W., Herzog H. L.   Academic Press; New York: 1967. 
• 13 Kieslich K, and Kapp JF. inventors; German Patent DE  2656575. 
• 14 Kieslich K. inventors; German Patent DE  2746298. 
• 15 Boeren S. Laane C. Biotech. Bioeng  1987,  29:  305 
• 16 White MJ, Beck DM, Wuts PGM, and Gilbert IG. inventors; US  265948. 

6

Mackey, S. S.; Matison, M. E.; Wu, H. unpublished results.