Total Synthesis of Thiostrepton. Retrosynthetic Analysis and Construction of Key Building Blocks

The first phase of the total synthesis of thiostrepton (1), a highly complex thiopeptide antibiotic,
is described. After a brief introduction to the target molecule and its structural motifs, it is shown that
retrosynthetic analysis of thiostrepton reveals compounds 23, 24, 26, 28, and 29 as potential key building
blocks for the projected total synthesis. Concise and stereoselective constructions of all these intermediates
are then described. The synthesis of the dehydropiperidine core 28 was based on a biosynthetically inspired
aza-Diels−Alder dimerization of an appropriate azadiene system, an approach that was initially plagued
with several problems which were, however, resolved satisfactorily by systematic investigations. The
quinaldic acid fragment 24 and the thiazoline−thiazole segment 26 were synthesized by a series of reactions
that included asymmetric and other stereoselective processes. The dehydroalanine tail precursor 23 and
the alanine equivalent 29 were also prepared from the appropriate amino acids. Finally, a method was
developed for the direct coupling of the labile dehydropiperidine key building block 28 to the more advanced
and stable peptide intermediate 27 through capture with the highly reactive alanine equivalent 67 under
conditions that avoided the initially encountered destructive ring contraction process.