Photoredox-Catalyzed Enantioselective α-Deuteration of Azaarenes with D2O

Abstract

Summary The site-specific incorporation of deuterium (D) into small molecules is frequently used to access isotopically labeled compounds with broad utility in many research areas, such as drug development, mechanistic studies, and NMR analyses. Nevertheless, the deuteration of a stereocenter in an enantioselective manner, which could slow the metabolism and improve the bioavailability of bioactive molecules, remains challenging owing to the lack of established catalytic methods. Here, we report an asymmetric α-deuteration strategy for azaarenes with inexpensive D 2 O as the deuterium source. A cooperative visible light-driven photoredox and chiral Brønsted acid–catalyzed system using a Hantzsch ester as the terminal reductant has been developed, which enables racemic α-chloro-azaarenes and prochiral azaarene-substituted ketones to experience a single-electron reduction–enantioselective deuteration process. The transition metal-free method provides important chiral α-deuterated azaarenes in satisfactory yields with good to excellent enantioselectivities (up to 99% ee) and substantial deuterium incorporation.

Chiral Spirocyclic Phosphoric Acids and Their Growing Applications

“…After that, Jiang demonstrated the asymmetric α‐deuteration strategy of azaarenes using cheap D 2 O as the deuterium source (Scheme 93). [ 97 ] A coordinated visible light‐driven photoreduction and chiral acid catalytic system was developed, which used Hanzester as a terminal reducing agent to make racemic α‐chloroazazepine and chiral azaarene substituted ketones could undergo single‐electron reduction‐enantioselective deuteration treatment with ( S )‐ SPA 39 . The transition metal‐free method provides important chiral α‐deuterated azaarenes in satisfactory yields, with good to excellent enantioselectivity (up to 99% ee).…”

Cooperative photoredox and chiral hydrogen-bonding catalysis

“…On the basis of these achievements in enantioselective reductive protonation 44,47 and enantioselective reductive dehalogenative protonation, 46 they subsequently developed an enantioselective reductive deuteration of azaarene-substituted ketones and an enantioselective reductive dehalogenative deuteration of racemic α-chloro-azaarenes with inexpensive D 2 O as the deuterium source. 48 Under cooperative photoredox and H-bonding catalysis (i.e., DPZ with SPINOL-CPA), a variety of chiral α-deuterated azaarenes were obtained in satisfactory yields with good to excellent enantioselectivities (up to 99% ee) and substantial deuterium incorporation. Indeed, the first example of the construction of chiral azaarene-based derivatives via enantioselective protonation was reported by the Jiang group in 2018, and they used a radical conjugate addition-enantioselective protonation of N-aryl glycine 32 to afford α-branched 2-vinylazaarenes 96 (Scheme 21).…”

Recent developments in enantioselective photocatalysis

“…It is notable that pyridyl ketones do not perform well in this reaction (1 example, 70:30 er). A further extension of this methodology includes the deuteration of 128 and alkyl halides 132 using D 2 O to afford 133 (18 examples, up to >99:1 er) and 134 (34 examples, up to 98:2 er), respectively ( Scheme 18 ) [ 65 ].…”