Facile and robust methods for the regioselective acylation of N-acetylneuraminic acid

Abstract

The stereoselective synthesis of sialic acid glycoconjugates is still a challenge in the field. Surprisingly, little is known on the regioselective O-substitution of sialic acids. Consequently, the effect of O-protecting groups and/or regioselectively protected building blocks in sialylations, remains practically unexplored. O-Picoloyl protecting groups have emerged as novel substituents that have a profound effect on sialylations. Recently, high stereoselectivities were obtained by introducing picoloyl groups at the C-4 and C-7/C-8 positions. However, to understand the relationship between the position of the picoloyl group and its exact effect in sialylations, a convenient access to a wider range of regioselectively picoloylated building blocks is needed. Reported herein is a new method that provides an accessible route to a wide array of regioselectively acylated building blocks. The regioselective introduction of picoloyl groups at various O-positions was achieved either by controlled direct picoloylation or by applying a modified ReSET methodology.

Comparative Study on the Effects of Picoloyl Groups in Sialylations Based on Their Substitution Pattern

“…Our initial attempt for the synthesis of sialyl donor 3 was to conduct a regioselective 8-O-picoloylation of 7,8-di- O -trimethylsilyl precursor 24 , easily accessible from polyol 25 (Scheme A). However, standard picoloylation of precursor 24 resulted in a mixture of partially deprotected compounds 26 and 27 . On the other hand, regioselective picoloylation of diol 26 (obtained from polyol 25 ) was more successful, and yielded 8-O-picoloylated thiosialoside 28 , albeit in a modest yield of 31%.…”

“…One pot: sialoside 26 (250 mg, 0.50 mmol) was dissolved in pyridine (2.5 mL). The solution was cooled to 0 °C in an ice bath.…”

“…A solution of 4 (19.5 mg, 0.030 mmol), 7 (4.0 mg, 0.015 mmol), and 3 Å molecular sieves (70.0 mg) in dichloromethane (0.62 mL) was stirred overnight at −40 °C under an argon atmosphere. The next day, N -iodosuccinimide (14.0 mg, 0.062 mmol) was added followed by triflic acid (3.3 mg, 0.022 mmol, 1.9 μL) and stirred for 16 h. Workup: reaction was brought to room temperature for 30 min, diluted with dichloromethane, filtered through Celite, and washed with 20% sodium thiosulfate (5 mL) and brine (5 mL × 2).…”

“…For the latter, we noticed an unusual dependence of yields and stereoselectivities on an excess of triflic acid being used as a co-promoter in reactions in the presence of NIS. In order to gain a better understanding of the effects of picoloyl groups based on their position and number, we developed a new methodology for streamlining the synthesis of sialyl donors monopicoloylated at C-4, 7, or 9 positions as well as 4,9- and 7,8-di-O-picoloylated derivatives ( 2 , 4–6 ) . Herein, we report the investigation of these novel derivatives as sialyl donors in reactions with primary glycosyl acceptors 7–9 in application to the synthesis of α(2–6)-linked disaccharides ( 10–13 , 17–23 ).…”

“…In order to gain a better understanding of the effects of picoloyl groups based on their position and number, we developed a new methodology for streamlining the synthesis of sialyl donors monopicoloylated at C-4, 7, or 9 positions as well as 4,9-and 7,8-di-O-picoloylated derivatives (2, 4−6). 7 Herein, we report the investigation of these novel derivatives as sialyl donors in reactions with primary glycosyl acceptors 7−9 in application to the synthesis of α(2−6)-linked disaccharides (10−13, 17−23). In addition, we report a novel synthesis of an 8-O-picoloylated sialyl donor 3, and its evaluation in sialylation reactions for the synthesis of disaccharides 14−16.…”