SYNTHETIC STUDIES TOWARD RAPAMYCIN - A SOLUTION TO A PROBLEM IN CHIRALITY MERGER THROUGH USE OF THE IRELAND REACTION

A program directed toward a total synthesis of rapamycin is described. This paper reports the synthesis of enoate 36, a fragment that would correspond to carbons 28-49 of rapamycin. The two building blocks required to reach 36 were allylic alcohol 5 and acid 6. The former was obtained in a straightforward way from D-(+)-glucose. The route passed through a 5,6-methylene derivative (see structure 12) that underwent Ferrier transformation to the hydroxycyclohexanone derivative 13. The acid 6 was built from aldehyde 15. An addition reaction of allyltrimethylsilane to 15 and a subsequent addition of crotylboronate 18 to aldehyde 17 were the key steps in the chain extension leading to the acid. The central issue of the synthesis was the merging of two chiral sectors (see A and B) to produce an ensemble in which the achiral spacer element consists of a single methylene carbon, C39. This problem was solved by establishing an ester bond between 5 and 6. The strategic C40-C39 carbon-carbon bond was generated by application of the Ireland ester enolate rearrangement. The extraneous carboxyl group (see structure 28) was removed by photolysis of the N-hydroxyphthalimide ester (see transformation 30 --> 31).