Download PDF
Synthesis 2012(1): 63-68  
DOI: 10.1055/s-0031-1289616
PAPER
© Georg Thieme Verlag Stuttgart ˙ New York

Organozirconium Chemistry on Cyclosporin: A Novel Process for the Highly Stereoselective Synthesis of (E)-ISA247 (Voclosporin) and Close Analogues

Jun-Ho Maenga, Zhicai Yang*b, David D. Manninga, Liaqat Masiha, Yeyu Caob, Kevin G. Pattamanab, Frederic Boisb, Bruce F. Molinob
a Discovery R & D Chemistry Department, AMRI, 26 Corporate Circle, P.O. Box 15098, Albany, NY 12212-5098, USA
b Medicinal Chemistry Department, AMRI, 26 Corporate Circle, P.O. Box 15098, Albany, NY 12212-5098, USA
Fax: +1(518)5122079; e-Mail: zhicai.yang@amriglobal.com;
Further Information

Publication History

Received 3 October 2011
Publication Date:
22 November 2011 (online)

    Permissions and Reprints All articles of this category

Abstract

Application of organozirconium chemistry to cyclosporin has led to the development of a novel process for the highly stereoselective synthesis of the E-isomer of ISA247 (voclosporin), which is a potent immunosuppressive agent currently in late stage human clinical trials for treatment of psoriasis, prevention of kidney transplant rejection, and ophthalmic indications. Synthesis of deuterated analogues of ISA247 and a cyclosporin triene analogue using the same methodology is also described.

Key words

cyclosporin A - ISA247 - voclosporin - E-diene - organo­zirconium chemistry

    References

  • 1a Naicker S, Yatscoff R, Foster R, Abel M, Jayaraman S, Mair H.-J, Adam J.-M, and Lohri B. inventors; PCT Int. Pub. No. WO  2003/033526. 
  • 1b Naicker S, Yatscoff R, and Foster R. inventors; PCT Int. Pub. No. WO  2003/033527. 
  • 1c Adam J.-M, Abel M, and Jayaraman S. inventors; PCT Int. Pub. No. WO  2004/089960. 
  • 2a Aspeslet L. Freitag D. Trepanier D. Abel M. Naicker S. Kneteman N. Foster R. Yatscoff R. Transplant. Proc.  2001,  33:  1048 
    Google Scholar
  • 2b Abel M. D. Aspeslet L. J. Freitag D. G. Naicker S. Trepanier D. J. Kneteman N. M. Foster R. T. Yatscoff R. W. J. Heart Lung Transpl.  2001,  20:  161 
    Google Scholar
  • 2c Naicker S, Yatscoff RW, and Foster RT. inventors; US Patent No  6605593. 
  • 2d Naicker S, Yatscoff RW, and Foster RT. inventors; US Patent  6613739. 
  • 2e Dumont FJ. Curr. Opin. Invest. Drugs  2004,  5:  542 
    Google Scholar
  • 2f Bissonnette R. Papp K. Poulin Y. Lauzon G. Aspeslet L. Huizinga R. Mayo P. Foster RT. Yatscoff RW. Maksymowych WP. J. Am. Acad. Dermatol.  2006,  54:  472 
    Google Scholar
  • 2g

    Luveniq (oral voclosporin) completed in July 2008 a phase III LUMINATE clinical trial for treatment of uveitis. Details can be found at www.clinicaltrials.gov.

  • 3a Molino BF, Yang Z, Maeng J.-H, and Manning DD. inventors; US Patent  7799756. 
  • 3b Molino BF, and Yang Z. inventors; US Patent  7378391. 
  • 3c Molino BF, and Yang Z. inventors; US Patent  7361636. 
  • 4a Suzuki K. Hasegawa T. Imai T. Maeta H. Ohba S. Tetrahedron  1995,  51:  4483 
    Google Scholar
  • 4b Maeta H. Suzuki K. Tetrahedron Lett.  1992,  33:  5969 
    Google Scholar
  • 7a Naicker S, Yatscoff RW, and Foster RT. inventors; PCT Int. Pub. No. WO  1999/18120. 
  • 7b Lazarova T. Weng Z. Expert Opin. Ther. Pat.  2003,  13:  1327 
    Google Scholar
  • 8 Rajagopalan S. Zweifel G. Synthesis  1984,  111 
    Google Scholar
  • 10 Wu F. X. H, and Or Y. S. inventors; US Patent  2004/266669. For pharmaceutical utilities of similar cyclosporin triene analogues, see the recent US Patent:
  • Recent publications that reported the synthetic efforts on olefin metathesis of cyclosporin A:
  • 11a Lazarova T. Chen JS. Hamann B. Kang JM. Houth-Trombino D. Han F. Hoffmann E. McClure C. Eckstein J. Or YS. J. Med. Chem.  2003,  46:  674 
    Google Scholar
  • 11b Smulik J. Diver ST. Org. Lett.  2002,  4:  2051 
    Google Scholar
5

The coupling constant J ε , ζ of the corresponding Z-isomer is 11.0 Hz.

6

Preparation of 1a was conducted up to 10 g scale without reducing the E-selectivity.

9

The organozirconium chemistry also worked well in CH2Cl2. The desired product was the major portion of the crude product (typically 60-70%) by LC/MS or analytical HPLC analysis. However, the isolated yields were low in some cases after purification by semi-preparative HPLC. We usually got less than 70% recovery from semi-preparative HPLC purification.