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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;
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Publikationsverlauf

Received 3 October 2011
Publikationsdatum:
22. November 2011 (online)

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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

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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.