Acid and Base Stable Esters: New Linkers for Solid-Phase Organic Synthesis
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US Utility Patent: US 7858825
At A Glance
Researchers at Colorado State University have developed compounds and methods that are useful as linkers in solid phase synthesis and as protecting groups for use in organic synthesis.
The linkage displays excellent stability under a variety of common reaction conditions (e.g., unaffected by most Brønsted and Lewis acids, Brønsted bases, nucleophiles, or UV light) and may be selectively cleaved with a mild 20% TFA solution in less than one hour. Furthermore, the linker is easily regenerated, allowing for multiple uses.
This new linker provides unprecedented advantages for polymer-supported synthesis. The exceptional stability of the new linkage allows for a diverse set of reactions to be performed on the bound target molecules, making it amenable to complex, multi-step syntheses. This trait is particularly advantageous for the synthesis of complex, biologically relevant target molecules as these compounds frequently require diverse, multi-step procedures and conditions which would interfere with other types of linkers. A second key advantage is that the linkage can be cleaved under mild conditions which will not degrade the products. These characteristics enhance the advantages already present with solid-phase synthesis (e.g., delivery of complex target molecules in high yield and purity, development of drug-screening libraries, protection of reactive functional groups).
These new linkers should be a valuable asset for both polymer-supported organic synthesis and the creation of drug-screening libraries. In fact, the utility of the new linker has been demonstrated in the creation of libraries based on uridine B-hydroxyamino acid, useful for screening potential MraY inhibitors (important agents in antibacterial drug development, such as those used to fight tuberculosis).
Carboxylic acid functional groups are present in a wide variety of compounds including amino acids, pharmaceutically active compounds, polymers, etc. Carboxylic acids are also used in many solid-phase synthesis to form esters, amides, and other carbonyl linkages. In addition, carboxylic acid functional groups are used to form a wide variety of different functional groups. However, in many instances when a carboxylic acid functional group is present in the molecule, it can interfere with other desired reactions. In these instances, the carboxylic acid group is protected to avoid undesired side reactions.
While there are a variety of protecting groups available for carboxylic acids, each has different reactivity and use. In many instances, it is desirable to be able to remove the carboxylic acid protecting group selectively or simultaneously in the presence of other functional group protecting groups. This is especially true in syntheses of target molecules that require multiple different protecting groups. If one can remove several protecting groups in a single reaction, it would reduce the time and cost of synthesis of target compound.
The widely utilized protecting groups for alcohol (e.g., diol) compounds are cleavable ether or silyl ethers or esters via acidic or basic conditions. Acetal is a typical protecting group for carbonyl molecules. Carboxylic acids are generally protected as their esters or orthoesters. There are many instances in organic synthesis where simultaneous or “one-pot” removal of protecting groups is needed or desired. Unfortunately, there are limitations of available carboxylic acid protecting groups and/or deprotection conditions that allow such one-pot removal of carboxylic acid protecting group with other protecting groups for alcohols or amines or carbonyls.
Therefore, there is a need for novel protecting groups which can be used in a variety of applications, including carboxylic acid protecting groups, linkers for solid-phase organic synthesis, etc., that can react with carboxylic acid functional group and allow for removal under relatively mild conditions.
- Binds target molecules with carboxylic acid, amine, alcohol, or phenol functional groups to polymer support.
- Stable under a diverse set of reaction conditions, but can be cleaved under mild conditions that do not degrade the products.
- Useful for complex syntheses, generation of drug-screening libraries, as a protecting group.
- Versatile and reusable.
- Use as linkers for solid phase synthesis producing peptides and small proteins
- New protecting groups for protecting carboxylic acids (which will be utilized by synthetic chemists)
- Synthesis of stable polymers (e.g. polyester)
Kurosu, Michio, et al. “Polymer-Supported (2,6-Dichloro- 4-Alkoxyphenyl)(2,4-Dichlorophenyl)Methanol: A New Linker for Solid-Phase Organic Synthesis.” ACS Publications, Feb. 2007, pubs.acs.org/doi/10.1021/ol070150f.
Last updated: December 2020