Thioglycosides are useful analogs of carbohydrates in which the glycosidic oxygen between sugars is replaced with a sulfur atom. These sulfur-linked carbohydrates have useful applications as biological mimics, as they have similar biological properties to O-linked carbohydrates but also boast an increased resistance to hydrolysis by glycosidases. We are developing a synthesis of 4-nitrophenyl 4-thio-N-acetyl-β-D-muramic acid (4-S-MurNAc-pNP) to act as a glycosyl acceptor in the preparation of a thioglycosidic analog of GlcNAc-MurNAc, the peptidoglycan dimer. N-acetyl-D-glucosamine was converted to a 4,6-O-isopropylidene protected MurNAc derivative in 4 steps. A protecting group exchange was achieved using benzaldehyde dimethyl acetal in excess and p-toluenesulfonic acid, giving the 4,6-O-benzylidene acetal derivative in 83% yield. This benzylidene group was then opened regioselectively with boron trifluoride diethyl etherate and triethylsilane to afford the 6-benzyl ether derivative of MurNAc-pNP. We will proceed with the triflation and inversion of the C4 position followed by installation of the sulfur via an SN2 reaction. We are also exploring a potentially more expedient approach starting with N-acetyl-D-galactosamine. Commercially available N-acetyl-D-galactosamine was converted to the 4,6-O-isopropylidene ketal-protected GalNAc-pNP derivative over 4 steps with 9% yield. We are currently developing a strategy to alkylate this protected GalNAc-pNP to form the C4 epimer derivative of MurNAc-pNP which can then be converted to the desired 4-thio MurNAc derivative.

Progress towards the synthesis of (4-nitrophenyl) 4-thio-<i>N</i>-acetyl-β-D-muramic acid derivatives

ACS Spring 2022

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Progress towards the synthesis of (4-nitrophenyl) 4-thio-N-acetyl-β-D-muramic acid derivatives