New chemical flowers bloomed by old reagents: dimethyl sulfate and diisopropyl sulfate as practical and versatile reagents in O-sulfation

Dimethyl sulfate and diisopropyl sulfate, once alkylation agents, now serve as versatile tools in O-sulfation, resembling new chemical flowers.
Published in Chemistry
 New chemical flowers bloomed by old reagents: dimethyl sulfate and diisopropyl sulfate as practical and versatile reagents in O-sulfation

O-Sulfation is a vital post-translational modification, which occurs in a diverse range of biomolecules, including polysaccharides, peptides, proteins, natural products and drug metabolites. It has significant implications in developmental biology, immunology, and neurobiology, as well as disease processes. Introducing sulfate group into the biomolecules could change their specific and non-specific recognition via electrostatic or hydrogen bonding interactios. Therefore, appropriately designed non-natural sulfated scaffolds expand their structural diversity and provide valuable insights into a wide range of biological functions. However, chemical synthesis of sulfated molecules remains challenging due to their lability to acid and temperature, insolubility in nearly all organic solvents, and limited maneuverability following introduction. Traditionally, H2SO4 has been successfully applied to straightforward alkenes and alcohols, but it is unsuitable for compounds containing delicate functional groups due to the strong acidity. Sulfur trioxide-nitrogen base complexes are the most commonly used reagents for sulfating various molecular motifs, but abrasive and severe conditions could constrain their synthetic adaptability. Therefore, it is of great significance to develop a general and robust approach to realize the O-sulfation.

Sulfate diesters, such as dimethyl sulfate (DMS) and diisopropyl sulfate (DPS), consist of a sulfate group with two alkyl groups attached to it. They are commonly used as alkylation agents in alkaine conditions, resulting in the formation of sulfate byproducts. We investigated the possibility of developing a different activation method that leverages the sulfate group rather than the alkyl group for sulfation. Bu4NHSO4 was identified as the optimal activation agent when paired with DMS as the sulfate source. The Bu4NHSO4 protonates the sulfate group of DMS, enhancing the electrophilicity of the sulfur atom and facilitating the departure of the methyl group.

In this manuscript, we discovered a different activation method for dimethyl sulfate and diisopropyl sulfate that enables the versatile synthesis of organic sulfates. This represents a notable advancement in the utilization of traditional reagents for significant chemical transformations. The versatility of this O-sulfation protocol is interrogated with a diverse range of alcohols, phenols and N-OH compounds, including carbohydrates, amino acids and natural products. We expect that the general applicability of this O-sulfation method and the ready availability of the reactants will expand the utility of organic sulfates in the study of biological functions and the discovery of new drugs. 

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Organic Chemistry
Physical Sciences > Chemistry > Organic Chemistry

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