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Highly Stereoselective Synthesis of Polycyclic Indoles through Rearrangement/[4+2] Cycloaddition under Sequential Catalysis.

ABSTRACT:

SUBMITTER: Zhang DH

PROVIDER: S-EPMC3922592 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

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Highly Stereoselective Synthesis of Polycyclic Indoles through Rearrangement/[4+2] Cycloaddition under Sequential Catalysis.

Zhang Di-Han DH Shi Min M

ChemistryOpen 20120911 5

PMID: 24551511

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Project description:Carbohydrate molecules with an α-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 α-glycosylated carboxylic acids in good yields with high diastereoselectivity. Although there is no apparent correlation between reaction conversion and pK a of carboxylic acids, we found that carboxylic acids with a pK a of 4-5 provide high selectivity while those of a pK a of 2.5 or lower do not. 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 α-face of the more reactive intermediate, resulting in the formation of α-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.

Dataset Information

Highly Stereoselective Synthesis of Polycyclic Indoles through Rearrangement/[4+2] Cycloaddition under Sequential Catalysis.

Publications

Highly Stereoselective Synthesis of Polycyclic Indoles through Rearrangement/[4+2] Cycloaddition under Sequential Catalysis.

Similar Datasets

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