The synthesis of the hexasaccharide fragment of landomycin A is reported. Using ptoluenesulfonyl chloride mediated dehydrative glycosylation, we constructed the deoxy-sugar linkages in a stereoselective fashion without the need for temporary prosthetic groups to control selectivity. Through this approach, the hexasaccharide was obtained in 28 steps and 8.9% overall yield, which is an order of magnitude higher than that of previously reported approaches.

An automated continuous flow system capable of producing protected deoxy‐sugar donors from commercial material is described. Four 2,6‐dideoxy and two 3‐amino‐2,3,6‐trideoxy sugars with orthogonal protecting groups were synthesized in 11–32 % overall yields in 74–131.5 minutes of total reaction time. Several of the reactions were able to be concatenated into a continuous process, avoiding the need for chromatographic purification of intermediates. The modular nature of the experimental setup allowed for reaction streams to be split into different lines for the parallel synthesis of multiple donors. Further, the continuous flow processes were fully automated and described through the design of an open‐source Python‐controlled automation platform.

A flexible de novo route capable of producing libraries of 2,6-dideoxy sugars is described. We have found that Au(JackiePhos)SbF 6 MeCN promotes the conversion of homopropargyl orthoesters into functionalized 2,3-dihydro-4H-pyran-4-ones in good to excellent yields (71−90%). These latter compounds can be easily converted into a number of otherwise difficult to access 2,6-dideoxy sugars.

The use of a continuous flow platform for the rapid and highly efficient construction of differentially protected glycals from commercial sources is described.

Landomycin A (LaA) is the largest member of the landomycin group of angucyclic polyketides. Its unusual structure and strong anticancer properties have attracted great interest from chemists and biologists alike. This, in particular, has led to a detailed picture of LaA biosynthesis in Streptomyces cyanogenus S136, the only known LaA producer. LanK is a TetR family repressor protein that limits the export of landomycins from S136 cells until significant amounts of the final product, LaA, have accumulated. Landomycins carrying three or more carbohydrate units in their glycosidic chain are effector molecules for LanK. Yet, the exact mechanism that LanK uses to distinguish the final product, LaA, from intermediate landomycins and sense accumulation of LaA was not known. Here, we report crystal structures of LanK, alone and in complex with LaA, and bioassays of LanK's interaction with synthetic carbohydrate chains of LaA (hexasaccharide) and LaE (trisaccharide). Our data collectively suggest that the carbohydrate moieties are the sole determinants of the interaction of the landomycins with LanK, triggering the latter's dissociation from the lanK-lanJ intergenic region via structure conversion of the helices in the C-terminal ligand-binding domain. Analysis of the available literature suggests that LanK represents an unprecedented type of TetR family repressor that recognises the carbohydrate portion of a natural product, and not an aglycon, as it is the case, for example, with the SimR repressor involved in simocyclinone biosynthesis.