Synthesis of β‐Substituted γ‐Aminobutyric Acid Derivatives through Enantioselective Photoredox Catalysis

Abstract

β-Substituted chiral γ-aminobutyric acids feature important biological activities and are valuable intermediates for the synthesis of pharmaceuticals. Herein, an efficient catalytic enantioselective approach for the synthesis of β-substituted γ-aminobutyric acid derivatives through visible-light-induced photocatalyst-free asymmetric radical conjugate additions is reported. Various β-substituted γ-aminobutyric acid analogues, including previously inaccessible derivatives containing fluorinated quaternary stereocenters, were obtained in good yields (42-89 %) and with excellent enantioselectivity (90-97 % ee). Synthetically valuable applications were demonstrated by providing straightforward synthetic access to the pharmaceuticals or related bioactive compounds (S)-pregabalin, (R)-baclofen, (R)-rolipram, and (S)-nebracetam.

Catalytic radical generation of π-allylpalladium complexes

“…This could be the possible reason for higher selectivity when BINAP was employed in this system. Again, cyclic (19, 21, 23), heterocyclic (18,19) and acyclic (24)(25)(26)(27)(28)(29), difluorinated (20), indane (22) moieties smoothly participated in the cross-coupling reaction. A broad range of functional groups such as trifluoromethyl (5), amides (12, 16, 18), ethers (13,17) and esters (6,15) were found to be compatible.…”

“…5c), the possible palladium(II) complex (71 or 71' or 71'') has been generated. Finally, it is proposed that the phthalimide unit (generated in the first step and usually treated as a waste byproduct [23][24][25][26][27][28][29][30][31][32][33][34][35] ) attacks the proposed -allylpalladium complex IX to selectively afford the product 3 and regenerate the Pd(0) catalyst. Additionally, a similar π-allylpalladium complex 58 has been pre-formed and subjected to our reaction condition, the corresponding allylic amine was obtained in 69% isolated yield which supports our proposed allylic amination step and is consistent to the previous work reported by Liu 59 and White 60 .…”

“…1b). Inspired by the numerous elegant reports of radical decarboxylation using N-hydroxyphthalimide (NHP) esters derived from inexpensive and abundant aliphatic carboxylic acids, [23][24][25][26][27][28][29][30][31][32] especially, Shang & Fu 33,34 and Glorius 35 have reported excellent examples of palladium-catalyzed decarboxylative Heck reaction 33,35 and desaturation 34 mediated by visible light, we hypothesized that -allylpalladium complexes could be generated by merging abundant NHP esters and feedstock dienes under palladium catalysis. However, it was uncertain at the outset of our studies whether NHP esters could be used as bifunctional reagents (both radical precursor and nucleophile) in this approach, 36,37 or if the stereo-and regioselectivity of the diene difunctionalization could be controlled in such a radical process.…”

Alkyl Carbon–Carbon Bond Formation by Nickel/Photoredox Cross‐Coupling

“…Owing to the sheer volume of recent literature on transition metal/photoredox dual catalysis and the existence of several relevant reviews, [9,15] we have chosen to focus the scope of this Minireview on photoredox reactions that use C(sp 3 )r adicals to forge carbon-carbon bonds through aN icatalyzed cross-coupling cycle.P hotoredox reactions that accomplish carbon-heteroatom coupling or that employ other metals are therefore excluded. Processes that form carbon-carbon bonds through non-metal catalyzed photoredox mechanisms such as the Giese addition, [16] protoncoupled electron transfer (PCET), [17] radical/polar crossover processes, [18] the Minisci reaction, [19] or cycloadditions, [20] although useful in their own right, are also not discussed.…”

Alkyl‐C‐C‐Bindungsbildung durch Nickel/Photoredox‐Kreuzkupplung

“…Photoredoxreaktionen, in denen eine Kohlenstoff-Heteroatom-Kupplung erfolgt oder andere Metalle eingesetzt werden, bleiben daher hier unberücksichtigt. Prozesse,i n denen Kohlenstoff-Kohlenstoff-Bindungen durch nichtmetallkatalysierte Photoredoxmechanismen gebildet werden, wie die Giese-Addition, [16] der protonengekoppelte Elektronentransfer (PCET), [17] radikalisch-polare Crossover-Prozesse, [18] die Minisci-Reaktion [19] oder Cycloadditionen, [20] werden trotz ihres großen Nutzens ebenfalls nicht diskutiert.…”