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

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.

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

References

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

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

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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.

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