Synthetic methods for the preparation of basic - and -pseudo-sugars. Synthesis of carbocyclic analogues of -acetyl-muramyl--alanyl--isoglutamine (MDP)

Optimized and Scalable Synthesis of Carba‐α‐d‐Glucosamine

“…Unfortunately, a more detailed analysis of this unique mode of action as well as further development is severely hampered by supply issues. [ 9,13,14,15 ] There are several synthetic strategies towards carbapyranosides reported in the literature, using both carbohydrates as starting material [ 16–20 ] and non‐carbohydrate approaches. [ 19,21–25 ] However, most of these previous synthetic research does not treat carba analogs of amino sugars like GlcN (α‐ 4 ).…”

“…As shown in Figure 2, the carbocyclic core 5 of target carbasugar 3 was envisioned to arise from a Ferrier rearrangement of a suitably functionalized pyranoside α/β‐ 6 , in analogy to the described route. [ 9,13,15 ] However, in contrast to this report, a more bulky substrate bearing a benzyl residue at the anomeric oxygen was chosen. This would allow for a more convenient and uniform protective group strategy.…”

“…As shown in Scheme 1, the implementation of this synthetic design was initiated by Cbz‐protection of α/β‐ 4 , which efficiently proceeded in aqueous solution with benzyl chloroformate (80 %). [ 27 ] Derived α/β‐ 7 was then elaborated as benzylidene acetal using benzaldehyde and zinc chloride to access α/β‐ 8 , [ 13 ] likewise in high yield (93 %). Importantly, both steps were readily scalable (25 g), without the need for chromatographic purification.…”

“…The remaining free secondary hydroxyl group was then protected with benzyl bromide under strong basic conditions (NaH), which also led to the elimination of HI to obtain vinyl ether α/β‐ 6 , in agreement with an earlier observation for a related substrate. [ 13 ] Again, all four steps proceeded with improved yields. [ 13 ] Furthermore, we could explicitly show, that either anomer reacts with essentially identical yield and selectivity, which opens up the valuable option of carrying out the sequence with epimeric mixtures, as these converge into the desired epimer at a later step of the route (see below).…”

“…[ 13 ] Again, all four steps proceeded with improved yields. [ 13 ] Furthermore, we could explicitly show, that either anomer reacts with essentially identical yield and selectivity, which opens up the valuable option of carrying out the sequence with epimeric mixtures, as these converge into the desired epimer at a later step of the route (see below).…”