Enantioselective Synthesis of 2′- and 3′-Substituted Natural Flavans by Domino Asymmetric Transfer Hydrogenation/Deoxygenation

Abstract

A concise and highly enantioselective synthesis of the natural flavans kazinol U and (2S)-7,3'-dihydroxy-4'-methoxyflavan is reported for the first time. The key transformation is a single-step conversion of a racemic flavanone to a flavan by means of an asymmetric transfer hydrogenation/deoxygenation cascade with kinetic resolution.

Enantioselective Total Synthesis of Natural Isoflavans: Asymmetric Transfer Hydrogenation/Deoxygenation of Isoflavanones with Dynamic Kinetic Resolution

“…Despite its interesting bioactivity and structural simplicity, catalytic protocols for the asymmetric synthesis of equol ( 1 ) are scarce . Spurred by our recent success in the enantioselective synthesis of flavanones, flavans, and isoflavanones by means of asymmetric transfer hydrogenation (ATH), we envisioned establishing an efficient protocol for the catalytic asymmetric synthesis of isoflavans. We anticipated that a dynamic kinetic resolution (DKR) of racemic isoflavanones by means of an ATH/deoxygenation cascade might yield enantiopure isoflavans in a single step.…”

“…First, the natural products 1 – 4 can be traced back to the respective phenols 5a – c . We envisioned that enantiopure isoflavans 5a – c might be obtainable from the racemic isoflavanones 6a – c in a single step through a domino ATH/deoxygenation process involving an o -quinone methide ( I ) as the crucial intermediate . In contrast to the previously reported transformation of flavanones, the isoflavanones 6a – c might readily racemize under the reaction conditions and, thus, allow for a dynamic kinetic resolution .…”

“…We envisioned that enantiopure isoflavans 5a – c might be obtainable from the racemic isoflavanones 6a – c in a single step through a domino ATH/deoxygenation process involving an o -quinone methide ( I ) as the crucial intermediate . In contrast to the previously reported transformation of flavanones, the isoflavanones 6a – c might readily racemize under the reaction conditions and, thus, allow for a dynamic kinetic resolution . Finally, the isoflavanones rac - 6a – c should be attainable from chromone 7 by means of protecting group interchange, Suzuki coupling, and conjugate reduction.…”

Enantioselective Organocatalytic Intramolecular Aza‐Diels–Alder Reaction

“…For example, the phenol close to the secondary amine was protected in a highly regioselective manner with 1,1‐carbonyldiimidazole (CDI), thus allowing differentiation between the C4 and C11 hydroxy groups of 6 a to give 8 in excellent yield . Pleasingly, the remaining C4 phenol was triflated with N ‐phenylbistriflimide in the presence of triethylamine and 4‐dimethylaminopyridine (DMAP) in quantitative yield and then underwent palladium‐catalyzed reduction to yield 9 without erosion of enantioselectivity . Furthermore, the deoxygenation of both phenol groups of 6 a by a triflation/palladium‐catalyzed reduction sequence afforded enantiomerically enriched 10 in 79 % yield over two steps.…”

Asymmetric hydrogenation and transfer hydrogenation in the enantioselective synthesis of flavonoids

“…In the same year, the authors reported in another work 79 the total synthesis of 2′- and 3′-substituted natural flavans through this Rh-catalysed ATH/deoxygenation cascade reaction strategy. The total synthesis of both the natural flavans (2 S )-7,3′-dihydroxy-4′-methoxyflavan ( S )- 78 and kazinol U ( S )- 79 employed the racemic flavanone hesperetin ( rac )- 80 as a starting material (Scheme 22).…”