A target oriented expeditious approach towards synthesis of certain bacterial rare sugar derivatives

Abstract

Bacterial rare amino deoxy sugars are found in the cell surface polysaccharides of multiple pathogenic bacterial strains, but are absent in the human metabolism. This helps in the differentiation between pathogens and host cells which can be exploited for target specific drug discovery and carbohydrate based vaccine development. The principal bacterial atypical sugar derivatives include 2-acetamido-4-amino-2,4,6-trideoxy-d-galactose (AAT), 2,4-diacetamido-2,4,6-trideoxy-d-galactose (DATDG) and N-acetylfucosamine (FucNAc). Herein, a highly streamlined protocol leading to the aforesaid derivatives is presented. The highlights of the method lie in radical mediated 6-deoxygenation along with a one-pot like protection profile manipulation on suitably derivatised d-glucosamine or d-mannose motifs to obtain a vital quinovosaminoside or rhamnoside from which rare sugar derivatives were synthesized in a diversity oriented manner.

Synthesis of the pentasaccharide repeating unit of the O-antigen from Enterobacter cloacae C4115 containing the rare α-d-FucNAc

“…2 ) required the development of the d -fucosamine equivalent and we have adopted the method reported by Ghosh et al 16 The synthesis began with di- tert -butylperoxide (DTBP) and tri-isopropylsilanethiol (TIPST) mediated deoxygenation 17 leading to the C -6 deoxygenated derivative 9. 16 Hereafter, we deviated from the aforesaid protocol as we found the methoxymethyl (MOM) protecting group as a suitable alternative for the tetrahydropyranyl (THP) protection used previously for O -3 protection. Accordingly, compound 9 was converted to 10 in 90% yield using dimethoxymethane in the presence of p -TsOH.…”

“…In their report, Ghosh et al 16 have used the THP group for orthogonal protection of the O -3 position of the glucosamine derivative. However, substantial acid lability of THP protection 22 limits its application in glycosylation reaction.…”

Deoxy sugars. General methods for carbohydrate deoxygenation and glycosidation

“…The β-scission in 67 is influenced by the angular torsion of the fused bicyclic structure. 163 As an example, Ghosh and co-workers based the synthesis of various bacterial rare sugars from d -glucose and d -mannose derivatives, 164 and the synthesis of the α- d -rhamnose trisaccharide related to the A-band polysaccharide of Pseudomonas aeruginosa 165 in this reaction.…”

Scalable Synthesis of Versatile Rare Deoxyamino Sugar Building Blocks from d-Glucosamine

“…Going beyond the original paths to 2-acetamido ,− and 2,4-diacetamido glycosides, − or post-glycosylation functionalization routes, − a large variety of advanced AAT intermediates featuring 2,4-orthogonal protecting groups were designed (Figure ). Most focus was on precursors to α-linked AAT for use in the synthesis of PS A1, − Sp1, ,,,− and Sp LTA. , Except for a precursor bearing a 2-imino group and stereotunable 2- N ,3- O -oxazolidinone donors, , intermediates set up for use as glycosylating agents basically feature a 2-azido moiety . Otherwise, interest in β-linked AAT led to donors equipped for anchimeric assistance at position 2 including N -phthaloyl, N -2,2,2-trichloroethoxycarbonyl, and N -trichloroacetyl ,− derivatives.…”

“…Otherwise, interest in β-linked AAT led to donors equipped for anchimeric assistance at position 2 including N -phthaloyl, N -2,2,2-trichloroethoxycarbonyl, and N -trichloroacetyl ,− derivatives. Besides routes based on an azidonitration step (Figure A) and original concepts such as a de novo path from l -threonine (Figure B) or a 4-amino group introduction by means of an intramolecular displacement , (Figure A,E), most syntheses start from d -glucosamine ,,,,,, (Figure E,F) or involve an elegant one-pot sequential inversion of 2,4-bistriflate d -thiorhamnoside intermediates (Figure C). ,,,, They comprise 10–15 steps in average with the orthogonal masking/unmasking of the amino/acetamido groups being common concerns owing to the harsh conditions employed for the C-6 deoxygenation step. Briefly, five interdependent key actions can be identified to build 2-amino-2,6-dideoxy-hexoses and 2,4-diamino-2,4,6-trideoxy-hexoses from d -glucosamine hydrochloride: 2-NH 2 masking, aglycon insertion, C-6 deoxygenation, 3-OH protection, and C-4 inversion, possibly complemented by protecting group exchange at positions 2 and/or 4 (Figure D).…”