Enantio- and Diastereoselective De Novo Synthesis of 3-Substituted Proline Derivatives via Cooperative Photoredox/Brønsted Acid Catalysis and Epimerization

Abstract

Herein, a novel strategy for the catalytic asymmetric synthesis of enantioenriched 3-cis- and 3-trans-substituted prolines has been successfully established via an unprecedented cascade radical addition/cyclization enabled by synergistic photoredox/Brønsted acid catalysis and subsequent base-assisted epimerization. The current protocol provides a unique de novo access to all four stereoisomers of 3-substituted prolines which are not readily achieved via currently established methods. This methodology could be further extended to the asymmetric synthesis of the full complement of stereoisomers of 3-substituted pipecolinic acids.

Asymmetric Catalytic Synthesis by Synergistic Chiral Phosphoric Acid Photoredox Catalyzed Reactions

“…(Scheme 5) [13] In 2020 Wang's group achieved a visible lightmediated synthesis of enantiomeric non-natural amino acid derivatives (20) using Brønsted acid/photoredox synergistic catalysis. In this work, an unprecedented radical cross-coupling reaction between glycine esters (18) and racemic α-bromo ketones (19) was achieved under the co-catalysis of CPA-5 and [Ir(dF-(CF 3 )ppy) 2 (dtbbpy)](PF 6 ) (PC-2), providing an efficient way to synthesize high-value enantiomerically enriched non-natural amino acid derivatives, which can play an important role in drugs and biomaterials by enhancing the functionality of peptides. This dual catalysis provides a powerful ability to control the reaction radical intermediates and imine ions, thus achieving enantiomerically normalized bond formation in a highly stereochemical manner.…”

“…This approach can be further extended to the asymmetric synthesis of all stereoisomers of 3-substituted pyrrolidine acids. (Scheme 10) [18] Scheme 7. tandem Photoredox-CPA-6 catalyzed radical À radical cross-coupling for enantioselective synthesis of 3-Hydroxyoxindoles. Scheme 8. radical conjugate addition/enantioselective additions between N-aryl glycines and alkenyl oxazolines.…”

Asymmetric [3 + 2] Photocycloaddition of β-Keto Esters and Vinyl Azides by Dual Photoredox/Nickel Catalysis

“…Chiral amine and Brønsted acid could also induce high enantioselectivity through interaction with the carbonyl- or pyridyl-containing alkene substrates. Very recently, the Wang group realized a cascade radical addition/polar cyclization between γ-chloro ketones and N -aryl glycine esters by synergistic photoredox/Brønsted acid catalysis and base-promoted epimerization, providing de novo access to chiral 3- cis - and 3- trans -substituted proline derivatives . Despite these impressive advances, however, broadly applicable visible-light-induced asymmetric [3 + 2] cycloadditions that enable the construction of medicinally significant chiral five-membered nitrogen heterocycles remain largely unexplored.…”

“…Very recently, the Wang group realized a cascade radical addition/polar cyclization between γ-chloro ketones and N-aryl glycine esters by synergistic photoredox/Brønsted acid catalysis and basepromoted epimerization, providing de novo access to chiral 3cis-and 3-trans-substituted proline derivatives. 12 Despite these impressive advances, however, broadly applicable visible-lightinduced asymmetric [3 + 2] cycloadditions that enable the construction of medicinally significant chiral five-membered nitrogen heterocycles remain largely unexplored. Vinyl azides have recently been well explored as radical acceptors for synthesis of nitrogen-containing and other functionalized compounds because of the unique chemical reactivities.…”

Copper-Catalyzed Enantioselective Aerobic Alkene Aminooxygenation and Dioxygenation: Access to 2-Formyl Saturated Heterocycles and Unnatural Proline Derivatives

“…The backbone substitution pattern of unnatural prolines has inspired different synthetic approaches. , The multistep synthesis of enantioenriched unnatural 4-substituted proline analogs typically is achieved starting from the chiral pool, e.g., 4-hydroxyproline or glutamic acid, , and in some instances, only the racemic route has been reported . Enantioselective deprotonation with a stoichiometric amount of a chiral base followed by carboxylation with CO 2 has also been reported .…”