Unlocking the Potential of Copper for Creating Chiral Amines
A team of researchers, led by Feng Zhou, Xin Wang, and Jian Zhou, have developed a groundbreaking new method for creating complex molecules known as chiral α-tertiary amines (ATA) using copper-catalysed asymmetric amination (ACPA) (1). This new method, reported in Nature Chemistry, allows for the creation of these important structural motifs in high enantiopurities, or high levels of purity in terms of their three-dimensional structure.
Chiral amines are a crucial class of molecules found in many natural products and pharmaceuticals, and the ability to create them in high levels of purity is a significant challenge in the field of synthetic chemistry. The new ACPA method uses sterically confined ligands to create ATAs with high levels of enantioselectivity, or the ability to create only one of the two possible mirror-image forms of the molecule.
The new ACPA method is a significant improvement over previous methods for creating ATAs, which often required the use of specific electrophile classes or the formation of a C-N bond by stereoselective substitution at a tertiary carbon-center. These methods can be complicated by the fact that ketimines, which are intermediate compounds in the formation of ATAs, can exist as E- or Z-stereoisomers, and separation of these isomers is not always straightforward.
The new ACPA method, on the other hand, uses a dynamic kinetic asymmetric transformation for the deracemization of easily prepared tert-butylcarbonyloxy-activated propargylic alcohols to propargyl ATAs. This means that the method can create the desired ATA molecules in high levels of purity, even when starting with a mixture of E- and Z-stereoisomers.
Furthermore, the alkyne functional group present in the propargyl ATAs created using the new ACPA method represents a powerful synthetic archetype that can be reacted in many different chemical processes. The researchers demonstrate this by converting the ACPA products to 5- and 6-membered heterocyclic ATAs, including the synthesis of a BACE-1 inhibitor target, and enabling several diversity-oriented synthesis applications to complex heterocycles and diamines.
Overall, the new ACPA method represents a significant advance in the field of synthetic chemistry and the creation of complex molecules. Its ability to create chiral amines in high levels of purity using sterically confined ligands is a major step forward in the field, and its potential for creating a wide variety of other complex molecules is vast.
Source:
Zhang, Z. et al. Copper catalysed asymmetric amination. Nat. Chem. (2024). <https://doi.org/10.1038/s41557-024-01487-z>
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