Total Synthesis of (+)‐Disorazole Z1

We wish to report the first total synthesis of (+)-disorazole Z1, a biologically extremely potent natural product (picomolar cytotoxicity) with complex molecular architecture featuring a 26-membered macrodiolide with lateral chains including a quaternary chiral carbon center. The complex acyclic lateral chains containing a stereochemical triad with the quaternary center surrounded by two hindered secondary alcohols were synthesized in a straightforward way by the use of two consecutive and highly diastereoselective aldol reactions with a lactone intermediate and further transformations to yield the desired (Z)-vinyl iodide. Successful esterification with a functionalized diene-stannane yielded the fully elaborated carbon skeleton. Making use of the C2 symmetry of the natural product, a double Stille coupling gave the protected natural product. Final deprotection provided (+)-disorazole Z1, which was fully identical to a natural sample.