Total Synthesis of Disciformycin A and B: Unusually Exigent Targets of Biological Significance

The first total synthesis of the potent antibiotic disciformycin B (2) is described, which is exceptionally isomerization‐prone and transforms into disciformycin A (1) even under notably mild conditions. To outweigh this bias, the approach to 2 hinged on the use of a silyl residue at C4 to lock the critical double bond in place and hence insure the integrity of the synthetic intermediates en route to 2. This tactic was instrumental for the preparation of the building blocks and formation of the macrocyclic ring via ring closing alkyne metathesis (RCAM). To make the end game successful, however, it proved necessary to cleave the C‐silyl protecting group off; it was at this stage that the exceptional sensitivity of the target became fully apparent. Capriccioso: Isomerization of the enone in disciformycin B is unusually facile but goes hand‐in‐hand with substantial loss of bioactivity of this antibiotic. While a strategically placed C‐silyl substituent allowed this chemical instability to be impeded until after the macrocycle had been closed, to succeed in gaining the target compounds, this stabilizing group had to be cleaved, even though this then meant handling exceptionally delicate intermediates.