Axially chiral biaryl skeletons widely exist in natural products, pharmaceutical molecules, chiral ligands, and catalysts. Asymmetric catalytic aryl-aryl cross-coupling represents a straightforward and convenient approach to these chiral structures. For this purpose, the P-chiral monophosphorus ligand, BaryPhos has been developed.
BaryPhos has several unique structural and physical features (Figure 1): 1) The upper benzooxophosphole moiety allows BaryPhos to adopt an unambiguous conformation during the catalytic process; 2) The existence of a tertiary alcohol moiety facilitates the formation of non-covalent interactions between ligand and substrates, exerting efficient enantiocontrol; 3) The presence of two cyclopentyl groupsenables sufficient steric effect for substrate orientation and induces enantioselective cross-coupling; 4) The ligand is air-stable and easy to handle for industrial applications.
Figure 1. The new catalytic mode for asymmetric aryl-aryl cross-coupling.
BaryPhos is a prominent ligand for the synthesis of axially chiral biaryl compounds through aryl-aryl cross-couplings, especially the Suzuki-Miyaura coupling. A wide range of axially chiral tetra-ortho-substituted biaryls with significant structural diversity were synthesized in high yields and excellent enantio-/diastereoselectivities (Figure 2). Several functional groups, such as halogen atoms, amides, alcohols, aldehydes, nitro and alkoxyl groups, as well as heterocycles including pyridine and quinoline rings, were well tolerated during the cross-coupling.
Figure 2. BaryPhos facilitated asymmetric aryl-aryl cross-coupling.
The efficient enantioselective synthesis of (-)-gossypol has proven BaryPhos to be a reliable and practical ligand in the synthesis of axially chiral biaryl natural products and drugs (Figure 3).
Figure 3. BaryPhos enabled enantioselective synthesis of gossypol.
It is expected that BaryPhos should be applicable and valuable to industrial production. More efficient and powerful asymmetric catalytic reactions will be developed with BaryPhos in the near future.
References:
1. J. Am. Chem. Soc. 2020, 142, 8036-8043.
2. Chin. J. Org. Chem. 2020, 40, 1409-1422.
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