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

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-D-glucosamine and D-galactosamine analogs. The key intermediates were the corresponding multiply fluorinated glucosazide and galactosazide thiodonors prepared from deoxyfluorinated 1,6-anhydro-2-azido-β-D-hexopyranose precursors by ring-opening reaction with phenyltrimethylsilyl 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 b-configured thioglycosides (Scheme 128). 429 This process, originally described with a 2-O-benzoylated b-configured methyl galactoside, 145 had been expanded by the Lin group (with bthiophenolates), 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 a-898 arising from clean deoxyfluorination of the a-anomer of 897, whilst b-898, a-899, and b-899 arose from the b-anomer of 897.…”

“…429 This process, originally described with a 2-O-benzoylated b-configured methyl galactoside, 145 had been expanded by the Lin group (with bthiophenolates), 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 a-898 arising from clean deoxyfluorination of the a-anomer of 897, whilst b-898, a-899, and b-899 arose from the b-anomer of 897. The major product was the migration product a-899.…”

“…Formation of 1,3-difluorinated 2-azidohexopyranoses based on a DAST-induced 1®6 migration process. 429,430 The Voznyi group reported a synthesis of a 1,4-difluorinated glucosamine derivative 905 from levoglucosan (Scheme 129A). 294 After a 3-step conversion of levoglucosan to 305, as shown in Scheme 41B, treatment with ammonia initiated 2,3-anhydro formation and subsequent opening with ammonia at the usual 2-position.…”

“…Scheme 128) reported by the Karban group, now starting from 4-fluorinated b-configured thioglycoside 906d (Scheme 129B). 429…”

“…Synthesis of 1,4-difluorinated gluco-and galactosamine derivatives. 294,429 8.1.4 Fluorination at positions 1 and 5…”