Studies directed towards the synthesis of FK-506

Smith, Kevin John (1993) Studies directed towards the synthesis of FK-506. University of Southampton, Doctoral Thesis.

Abstract

Two routes towards the synthesis of the powerful immunosuppressant FK-506 are described.

The first of these routes began with the synthesis of two small fragments followed by an investigation of a sulphone - epoxide coupling to accomplish their linkage and form the C23-C24 bond of FK-506. The reaction was only found to be successful when carried out in the presence of boron trifluoride etherate. Several methods for removal of the sulphone moiety, both oxidatively and reductively, were then examined. The application of an Evans' alkylation reaction then led to a stage where coupling to the pyran unit could be investigated. A synthesis of the pyran unit is briefly described. Several methods for the formation of the C15-C16 bond of FK-506 were examined using model systems. When the results were applied to the real system, the best yield was obtained when coupling a sulphone with an aldehyde in the presence of magnesium bromide etherate but even then the yield was poor.

The second method is the continuation of a route started by co-workers. A brief summary of the work carried out previously towards the syntheses of two fragments of FK-506 is first described. The syntheses of these fragments was completed and the boron trifluoride etherate mediated sulphone - epoxide coupling reaction devised earlier applied to form the C23-C24 bond of FK-506. Removal of the sulphone moiety led to the stage where coupling to the pyran unit of FK-506 could be attempted when a suitable method is found.

A review of the biological activity and the two total syntheses of FK-506 is included along with a discussion of studies towards the synthesis of FK-506 between September 1990 and September 1993.

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