Photocatalytic Synthesis of Difluorinated Glycoamino Acids and Neoglycopeptides via Hydrodifluoroacetamidation of Vinyl-C-glycosides

Abstract

A photocatalytic approach for the synthesis of difluorinated glycoamino acids and neoglycopeptides from bromodifluoroacetamides and sugar-derived olefins is presented. This method stands out because of its simplicity, atomic economy, and mild reaction conditions, allowing compatibility with both natural and unnatural amino acids and peptides. Additionally, it demonstrates efficacy across a variety of carbohydrates, including furanoses, pyranoses, pentose, hexoses, and disaccharides, accommodating an extensive range of protecting groups, even in their deprotected forms.

Scheme 1. (A and B) Photocatalytic Strategies for Perfluoroalkylation of Sugar Olefins and (C) sLe^x and Its Mimetics

Scheme 2. Scope of Bromides Derived from Amino Acids and Peptides

Reaction performed at a 1.5 mmol scale using one Kessil blue lamp (456 nm, 40 W) at 22–25 °C for 20 h. Reaction conditions: 1a (0.1 mmol), 2a (0.15 mmol), 4CzIPN (1 mol %), DMF (0.05 M, 2 mL), LED lamps (450–456 nm 3 W), 20 °C, 10 h.

Scheme 3. Scope of Sugar Olefins

Bromide 2f was used instead of 2a. Reaction conditions: 1a (0.1 mmol), 2a (0.15 mmol), 4CzIPN (1 mol %), DMF (0.05 M, 2 mL), LED lamps (450–456 nm 3 W), 20 °C, 10 h.

Scheme 4. Scope of Fluorinated Sugars Using Different Bromides

Irradiated with blue light for 20 h. Irradiated with blue light for 38 h. Reaction conditions: 1a (0.1 mmol), 2 (0.15 mmol), 4CzIPN (1 mol %), DMF (0.05 M, 2 mL), LED lamps (450–456 nm 3 W), 20 °C, 10 h.

Scheme 5. Mechanistic Studies

(A) Deuteration experiment. (B) Radical trapping. (C) Evaluation of the XAT process. Standard conditions for reactions A–C: 1a (0.1 mmol), 2a or 9 (0.15 mmol), 4CzIPN (1 mol %), DMF-d₇ or DMF (0.05 M, 2 mL), LED lamps (450–456 nm, 3 W), 20 °C, 10 h. (D) Light on/off experiment, in which standard conditions were employed. Aliquots were collected every 30 min to monitor the reaction. PhCF₃ was used as the internal ¹⁹F NMR standard for quantification. Standard conditions: 1a (0.1 mmol), 2a (0.15 mmol), 4CzIPN (1 mol %), PhCF₃ (1 equiv), DMF (0.05 M, 2 mL), LED lamps (450–456 nm, 3 W), 20 °C.

Figure 1

Proposed reaction mechanism.