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Carbohydrate molecules with an alpha-glycosylated carboxylic acid motif provide access to biologically relevant chemical space but are difficult to synthesize with high selectivity. To address this challenge, we report a mild and operationally simple protocol to synthesize a wide range of functionally and structurally diverse alpha-glycosylated carboxylic acids in good yields with high diastereoselectivity. While there is no apparent correlation between reaction conversion and the pKa of carboxylic acids, there is a notable trend in selectivity. Carboxylic acids with a pKa ranging from 4 to 5 exhibit high selectivity, whereas those with a pKa of 2.5 or lower do not display the same level of selectivity. Our strategy utilizes readily available 2,9-dibutyl-1,10-phenanthroline as an effective nucleophilic catalyst to displace a bromide leaving group from an activated sugar electrophile in a nucleophilic substitution reaction, forming phenanthrolinium intermediates. The attack of the carboxylic acid takes place from the alpha-face of the more reactive intermediate, resulting in the formation of alpha-glycosylated carboxylic acid. Previous calculations suggested that the hydroxyl group participates in the hydrogen bond interaction with the basic C2-oxygen of a sugar moiety and serves as a nucleophile to attack the C1-anomeric center. In contrast, our computational studies reveal that the carbonyl oxygen of the carboxylic acid serves as a nucleophile, with the carboxylic acid-OH forming a hydrogen bond with the basic C2-oxygen of the sugar moiety. This strong hydrogen bond (1.65 Å) interaction increases the nucleophilicity of the carbonyl oxygen of carboxylic acid and plays a critical role in the selectivity-determining step. In contrast, when alcohol acts as a nucleophile, this scenario is not possible since the -OH group of the alcohol interacts with the C2-oxygen and attacks the C1-anomeric carbon of the sugar moiety. This is also reflected in alcohol-OH's weak hydrogen bond (1.95 Å) interaction with the C2-oxygen. The O(C2)-HO (carboxylic acid) angle was measured to be 171° while the O(C2)-HO (alcohol) angle at 122° deviates from linearity, resulting in weak hydrogen bonding.
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Revisiting the role of acids and hydrogen bond acceptors in enamine formation
A systematic investigation into the effects of acids and hydrogen bond acceptors on the reaction rates and equilibria of enamine formation is reported. Acids can accelerate the reaction but do not change the reaction equilibria. In comparison, hydrogen bond acceptors facilitate the enamine formation via their strong hydrogen bonding interaction with the water generated in the reaction.
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- Award ID(s):
- 1855972
- PAR ID:
- 10197642
- Date Published:
- Journal Name:
- Organic & Biomolecular Chemistry
- Volume:
- 18
- Issue:
- 35
- ISSN:
- 1477-0520
- Page Range / eLocation ID:
- 6849 to 6852
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1039/d0ob01579b
