Synthesis of multiply fluorinated N-acetyl-D-glucosamine and D-galactosamine analogs via the corresponding deoxyfluorinated glucosazide and galactosazide phenyl thioglycosides

Abstract

Multiple fluorination of glycostructures has emerged as an attractive way of modulating their protein affinity, metabolic stability, and lipophilicity. Here we described the synthesis of a series of mono-, di- and trifluorinated N-acetyl-ᴅ-glucosamine and ᴅ-galactosamine analogs. The key intermediates are the corresponding multiply fluorinated glucosazide and galactosazide thioglycosides prepared from deoxyfluorinated 1,6-anhydro-2-azido-β-ᴅ-hexopyranose precursors by ring-opening reaction with phenyl trimethylsilyl sulfide. Nucleophilic deoxyfluorination at C4 and C6 by reaction with DAST, thioglycoside hydrolysis and azide/acetamide transformation completed the synthesis.

The Synthesis and Glycoside Formation of Polyfluorinated Carbohydrates

“…There are no dedicated syntheses of 1,3-difluorinated aminosugars, but it is worth mentioning observations by the Karban group regarding a 1 → 6 migration process when deoxyfluorinating the 6-position of β-configured thioglycosides (Scheme 128). 429 This process, originally described with a 2-O-benzoylated β-configured methyl galactoside, 145 had been expanded by the Lin group (with β-thiophenolates), where they showed that high yields of migration can be achieved, for example in the conversion of 895 to 896 (Scheme 128A). 430 Upon treatment of a mixture of anomers 897 (Scheme 128B, see below Scheme 139 for their synthesis), the Karban group isolated four products, 429 with α-898 arising from clean deoxyfluorination of the α-anomer of 897, while β-898, α-899, and β-899 arose from the β-anomer of 897.…”

“…429 This process, originally described with a 2-O-benzoylated β-configured methyl galactoside, 145 had been expanded by the Lin group (with β-thiophenolates), where they showed that high yields of migration can be achieved, for example in the conversion of 895 to 896 (Scheme 128A). 430 Upon treatment of a mixture of anomers 897 (Scheme 128B, see below Scheme 139 for their synthesis), the Karban group isolated four products, 429 with α-898 arising from clean deoxyfluorination of the α-anomer of 897, while β-898, α-899, and β-899 arose from the β-anomer of 897. The major product was the migration product α-899.…”

“…Scheme 128) reported by the Karban group, now starting from 4-fluorinated β-configured thioglycoside 906d (Scheme 129B). 429 Hence, reaction of β-906d (see below, Scheme 143 for its synthesis) with DAST under microwave irradiation delivers the 1,4-difluorinated GalNAc derivative 907 in 57% yield, alongside 34% of the direct deoxyfluorination product 908.…”

“…Unlike the corresponding gluco-configured analogue 977 (see Scheme 136), treatment of 990 with PhSTMS/ZnI 2 was reported to lead to decomposition. 429 Hence, 989 was subjected to PhSTMS/ZnI 2 instead, leading to 993. This was then converted to the 6-O-benzyl ether 994 to allow deoxyfluorination at C-4, which proceeded smoothly with the expected inversion of configuration to give 995.…”

“…The Picq/ Anker group used the aziridinium-mediated fluorination Scheme 136. Synthesis of 3,4-Difluorinated GlcNAc Derivatives 429,451 Scheme 137. Synthesis of 3,4-Difluorinated GalNAc derivatives 429,451 461 The Karban group reported an approach to 3,6-dideoxy-3,6difluorinated GlcNAc derivatives using 1,6-anhydro intermediates (Scheme 139).…”