Scalable, Telescoped Hydrogenolysis–Enzymatic Decarboxylation Process for the Asymmetric Synthesis of (R)-α-Heteroaryl Propionic Acids

Abstract

Enantiopure α-aryl propionic acids are useful building blocks for pharmaceutical research and can be accessed enzymatically using arylmalonate decarboxylases (AMDases) from the corresponding malonic acids. However, the intrinsic instability of malonic acids is a major drawback to this approach in which spontaneous decarboxylation can occur, subsequently eroding enantioselectivity and giving rise to racemic products. This was particularly evident for a panel of N-heterocyclic propionic acids that we wished to access using the approach. Herein, we describe a process to overcome the spontaneous decarboxylation problem in which hydrogenolysis of the corresponding dibenzyl malonates was performed in a biphasic toluene–basic aqueous buffer mixture and telescoped into the subsequent AMDase step. This procedure enabled compounds to be accessed in high enantioselectivities and was successfully demonstrated on 120 g with high yield (76%) and ee (98%).

Shortening Synthetic Routes to Small Molecule Active Pharmaceutical Ingredients Employing Biocatalytic Methods

“…514 A preparative scale synthesis of a series of (R)-2-heteroaryl propionic acids, mediated by a wild-type AMDase from Bordetella bronchiseptica, was reported recently. 515 The issue of spontaneous decarboxylation of the malonate substrates was resolved by hydrogenolysis of dibenzylmalonates in a biphasic system, followed by subsequent decarboxylation directly in the aqueous phase, without isolation of intermediates. The stability of the malonate intermediates in the aqueous phase was ensured by optimization of pH and temperature.…”

“…An additional route to enantiopure 2-arylpropionic acids has been made possible by arylmalonate decarboxylases (AMDases) catalyzing site-specific decarboxylation of a prochiral malonic acid derivative giving the optically enriched product with CO 2 as the only byproduct . A preparative scale synthesis of a series of ( R )-2-heteroaryl propionic acids, mediated by a wild-type AMDase from Bordetella bronchiseptica , was reported recently . The issue of spontaneous decarboxylation of the malonate substrates was resolved by hydrogenolysis of dibenzylmalonates in a biphasic system, followed by subsequent decarboxylation directly in the aqueous phase, without isolation of intermediates.…”

Arylmalonate Decarboxylase—A Versatile Biocatalyst for the Synthesis of Optically Pure Carboxylic Acids

“…The deprotection strategy was also successfully applied for the preparation of electron-deficient N-heteroaromatic malonic acids (Blakemore et al, 2020). The inherent instability of this compound class even surpasses the one of their common aromatic counterparts, thus fully preventing successful isolation without undesired spontaneous decarboxylation even under the typically mild hydrogenolysis conditions.…”

Synthesis of α-Heteroaryl Propionic Esters by Palladium-Catalyzed α-Heteroarylation of Silyl Ketene Acetals

“…Blakemore and co-workers recently reported a method of preparing enantiopure heteroaromatic propionic acids by employing a telescoped hydrogenolysis−AMDase process of malonates (Scheme 1d). 6 Following a three-step protocol from readily available heteroaromatic halides, this method was demonstrated on 120 g scale. The scope of the reaction was not extensively studied, and the enzymatic effectiveness was highly substratespecific.…”

“…It should be noted that heteroaryl halides are more accessible and attractive starting materials than the corresponding vinyl heteroaryls. Blakemore and co-workers recently reported a method of preparing enantiopure heteroaromatic propionic acids by employing a telescoped hydrogenolysis–AMDase process of malonates (Scheme d) . Following a three-step protocol from readily available heteroaromatic halides, this method was demonstrated on 120 g scale.…”