Total synthesis of rapamycin.

For over 30 years, rapamycin has generated a sustained and intense interest from the scientific community as a result of its exceptional pharmacological properties and challenging structural features. In addition to its well known therapeutic value as a potent immunosuppressive agent, rapamycin and its derivatives have recently gained prominence for the treatment of a wide variety of other human malignancies. Herein we disclose full details of our extensive investigation into the synthesis of rapamycin that culminated in a new and convergent preparation featuring a macro-etherification/catechol-templating strategy for construction of the macrocyclic core of this natural product.

Total synthesis studies on macrocyclic pipecolic acid natural products: FK506, the antascomicins and rapamycin.

This chapter derives its inspiration from the challenges presented to total synthesis chemists, by a particular group of macrocyclic pipecolic acid natural products. Although there is considerable emphasis on the completed syntheses of the main characters (FK506 (1), the antascomycins (4 and 5) and rapamycin (7)), the overall complexity of the molecular problem has stimulated a wealth of new knowledge, including the development of novel strategies and the invention of new synthetic methods. The ingenious and innovative approaches to these targets have enabled new generations of analogues, and provided material to further probe the biology of these fascinating molecules.

Synthesis, structure and reactivity of 5-pyranosyl-1,3,4-oxathiazol-2-ones.

5-(1,2,3,4-tetra-O-acetyl-alpha-D-xylopyranos-5S-C-yl)-1,3,4-oxathiazol-2-one (8) has been prepared from glucuronamide in two steps and 73% overall yield by conversion to the tetra-O-acetyl derivative 7 followed by reaction with chlorocarbonylsulfenyl chloride. 5-(2,3,4-Tri-O-acetyl-beta-D-xylopyranosyl)-1,3,4-oxathiazol-2-one (12) was synthesised from D-xylose by a four-step sequence involving conversion to the xylopyranosylnitromethane derivative 9, reaction with PCl3 to afford nitrile 10, hydrolysis to amide 11, and finally treatment with ClCOSCl. D-glucose-derived analogue 13 was prepared similarly.