Rh-Catalyzed Asymmetric Hydroaminomethylation of α-Substituted Acrylamides: Application in the Synthesis of RWAY

Abstract

The successful rhodium-catalyzed asymmetric hydroformylation and hydroaminomethylation of α-substituted acrylamides is described using 1,3-phosphite-phosphoramidite ligands based on a sugar backbone. A broad scope of chiral aldehydes and amines were afforded in high yields and excellent enantioselectivities (up to 99%). Furthermore, the synthetic potential of this method is demonstrated by the single-step synthesis of the brain imaging molecule RWAY.

Comprehensive Chirality

“…Only two existing publications reporting the AHF of α-substituted acrylamides appeared in 2020. 120,123 Godard et al reported the first use of 1,3-phosphite-phosphoramidite ligands based on a sugar backbone derived from D-xylose in AHF of α-substituted acrylamides (L13, Scheme 42). The best catalytic performance was obtained with ligands bearing a bulky group on nitrogen atom (R= Cy and R= (S)-CHMePh) and a (S ax ,S ax )-biaryl moiety (Scheme 42).…”

Modular Synthesis of Phosphite and Phosphoramidite Ligands for Rh‐Catalyzed Hydroformylation

“…The hemiacetal reaction via PCC/ Et 3 N one-pot method afforded bridged [2,2,1]bicyclic lactones in high yield (up to 95 %) and excellent enantioselectivity (Scheme 22f). [59] Sugar backbone ligands were also applied to phosphoramidite ligands, Godard [60] et al synthesized a sugar-backbone phosphoramidite ligand L18 for the rhodium-catalyzed asymmetric hydroformylation and hydroaminomethylation of αsubstituted acrylamides. The ee value of the chiral aldehyde product was as high as 99 %, and the ee value of the chiral amine product was up to 86 %.…”

“…Sugar backbone ligands were also applied to phosphoramidite ligands, Godard [60] et al. synthesized a sugar‐backbone phosphoramidite ligand L18 for the rhodium‐catalyzed asymmetric hydroformylation and hydroaminomethylation of α‐substituted acrylamides.…”

Evolution in the metal-catalyzed asymmetric hydroformylation of 1,1′-disubstituted alkenes

“…Indeed, only a few examples were reported in the asymmetric hydroformylation of nonsubstituted acrylamides with moderate yields and enantioselectivities (18). The only two existing publications reporting the AHF of α-substituted acrylamides appeared in 2020 (15,19). In one of them, only three substrates were studied.…”

“…Their modularity was key to achieve the best catalytic performance, being ligands with a bulky N-group and an (S ax , S ax )-biaryl moiety the ones that provided the best results (R ¼ Cy and R ¼ (S)-CHMePh) (Scheme 9). With the optimal ligands, it was possible to hydroformylate for the first time a broad range of acrylamides with different substituents at the α-position and on the amide group with high-to-excellent enantioselectivities (74-99% ee) and good-to-high yields (50-87%) (19). Furthermore, hydroformylation reactions could be performed at 60 °C.…”