We have found that activating either 2,3-bis(2,3,4-trimethoxyphenyl)cyclopropenone or 2,3-bis(2,3,4-trimethoxyphenyl)cyclopropene-1-thione with oxalyl bromide results in the formation of a species that promotes the glycosylation between 2,6-dideoxy-sugar hemiacetals and glycosyl acceptors in good yield and high α-selectivity. Both reactions are mild and tolerate a number of sensitive functional groups including highly acid-labile 2,3,6-trideoxy-sugar linkages.
A mixture of 3,3‐dibromocyclopropene and TBAI promotes highly α‐selective glycosylation reactions (up to >20:1) by using deoxy sugar hemiacetal donors. The reaction provides a convenient method for generating highly reactive glycosyl donors in situ from shelf‐stable starting materials. Both armed and disarmed sugars undergo the reaction, and selectivity is independent of the configuration of the donor sugar.
Dehydrative glycosylation reactions using 2-deoxy- and 2,6-dideoxy-sugar donors promoted by a combination of 3,3-dichloro-1,2-diphenylcyclopropene and tetrabutylammonium iodide (TBAI) are described. The reactions are α-selective and proceed under mild conditions at room temperature without the need for special dehydrating agents. The reaction is shown to be effective with a number of glycosyl acceptors, including those possessing acid and base sensitive functionality.
The introduction of solid-phase peptide synthesis in the 1960s improved the chemical synthesis of both the A- and B-chains of insulin and insulin analogs. However, the subsequent elaboration of the synthetic peptides to generate active hormones continues to be difficult and complex due in part to the hydrophobicity of the A-chain. Over the past decade, several groups have developed different methods to enhance A-chain solubility. Two of the most popular methods are use of isoacyl dipeptides, and the attachment of an A-chain C-terminal pentalysine tag with a base-labile 4-hydroxymethylbenzoic acid linker. These methods have proven effective but can be limited in scope depending on the peptide sequence of a specific insulin. Herein we describe an auxiliary approach to enhance the solubility of insulin-based peptides by incorporating a tri-lysine tag attached to a cleavable Fmoc-Ddae-OH linker. Incorporation of this linker, or "helping hand", on the N-terminus greatly improved the solubility of chicken insulin A-chain, which is analogous to human insulin, and allowed for coupling of the insulin A- and B-chain via directed disulfide bond formation. After formation of the insulin heterodimer, the linker and tag could be easily removed using a hydrazine buffer (pH 7.5) to obtain an overall 12.6% yield based on A-chain. This strategy offers an efficient method to enhance the solubility of hydrophobic insulin-based peptides as well as other traditionally difficult peptides.
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