TOTAL SYNTHESIS OF RAPAMYCIN

Details of the total synthesis of rapamycin (1) are reported. The synt hesis required the preparation of intermediates 4-9 in nonracemic form ; key coupling reactions included a chromium-mediated addition of viny l iodide 8 to aldehyde 7 and an Evans aldol reaction to couple fragmen ts 62 and 9. Intermediates 4 and 6 were joined through an amide bond f ormation to afford advanced intermediate 71. Swern oxidation of the di ol in 71 was followed by a selective removal of the TES groups and a s econd Swern oxidation. Finally, removal of the remaining silyl protect ing groups provided fully deprotected, penultimate intermediate 2 in w hich all carbons were in their proper oxidation state. Macrocyclizatio n was achieved through a tandem inter/intramolecular palladium-mediate d Stille coupling reaction between distannylethene 3 and bis(vinyl iod ide) 2. This latter process accomplished in one step the installation of the remaining two carbons of the natural product and the completion of its total synthesis.