Rapamycin (5) was isolated in 1975 from the soil bacteria Streptomyces hygroscopicus and its structure was determined from spectroscopic techniques and an x-ray crystallographic analysis. Although it was initially found to exhibit antibiotic activity, it was subsequently shown to possess potent immunosuppressive activity as well.
Three approaches to the synthesis of the tricarbonyl subunit (C1-C15) of 5 were investigated. The first plan for the synthesis of 127 envisioned a rearrangement of the a-acyloxy amide 135 to 136 followed by oxidation. The amide 135 was synthesized by coupling of the readily prepared chloroacetylpipecolate 131 with the carboxylic acid 134.
The second approach was based on a model study in which the acetylenic ester 144 was oxidized to the a,13-diketoester 146. However, synthesis of the requisite acetylenic amide precursor 150 was unsuccessful.
The third approach anticipated successful formation of 167 from the aldehyde 159 and bromoacetylpipecolate 166, followed by Dess-Martin oxidation to afford the tricarbonyl subunit of rapamycin. The aldehyde was successfully prepared in ten steps from (S)-3-hydroxy-2-methylpropionate (132)
