合成路线1

A total synthesis of rapamycin has been described: The condensation of the iodo-compound (I) with dithiane (II) by means of tert-butyllithium in THF followed by elimination of the acetal group with trichloroacetic acid gives the aldehyde (III), which is condensed with the dithiane (IV) by means of tert-butyllithium in THF, and the resulting compound methylated with NaH and methyl iodide to afford the acetal (V) as a diastereomeric mixture (in the newly formed methoxy group) that was resolved by flash chromatography. The sequential reaction of (V) first with p-toluenesulfonic acid to hydrolyze the acetal group, and then with CBr4 in THF/HMPT and finally with butyllithium in THF gives the terminal acetylene derivative (VI). Elimination of the dithiane and PMB groups, and reaction with tributyl tin hydride affords the trans-vinylene alcohol (VII), which is esterified with piperidine carboxylic acid (VIII) by means of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (EDC) and DMAP in dichloromethane yielding the condensation ester (IX). Finally, this compound is submitted to an intramolecular Stille cyclization with the tris(2-furyl)phosphine palladium dichloride complex in DMF/THF, which after desilylation with tetrabutylammonium fluoride (TBAF) and HF.pyridine afforded rapamycin.