Aim and Objective: The objective of our work was to synthesize and fully characterize Pamamycin-
621D, one of the less abundant members of a large family of macrodiolides with antimycobacterial properties,
which had never been synthesized before. Furthermore, we also wished to improve our general strategy by using
a new unsaturated precursor.
Materials and Method:
A new unsaturated ethylketone precursor was prepared using alkene cross metathesis,
and a convergent and flexible strategy based on a key diastereoselective aldol addition was implemented to afford
pamamycin-621D in 12 steps from that precursor.
Results:
Pamamycin-621D has been obtained and fully characterized for the first time. The structure of
pamamycin-621D was confirmed by HRMS and comparison of 1H-NMR spectra with the natural pamamycin-
621D. Both optical rotation and 13C-NMR had not been published previously due to lack of material, and the
latter are reported here for the first time. Given the scarce characterization available previously, our synthesis
also gives additional support to the initial structural assignment of pamamycin-621D. A significant improvement
of the key aldol addition via the use of a new unsaturated precursor is also reported.
Conclusion:
The work described above constitutes the first total synthesis of pamamycin-621D and has enabled
us to fully characterize this scarcely available natural product. More importantly, this work highlights the
fact that our synthetic approach provides ready access to various members of the pamamycin family, allowing
possible studies on structure-activity relationships and mode of action of even the least abundant of these natural
products. The synthesis of other pamamycin congeners and biological investigations will be published in
due course.
Total Synthesis and Structural Assignment of (‒)‐Fusaequisin A
