Bode Kinetic Resolution

Introduction

Despite the widespread use of chiral amines and amides in modern pharmaceutical and agrochemical compounds, synthetic access to such building blocks, particularly in an enantioenriched form, has traditionally been very challenging. In many cases, especially for secondary amines, the state of the art remains chromatography on chiral supports or classical resolution by diastereomer formation.

The Bode research group has developed a method for the kinetic resolution of cyclic amines (saturated N-heterocycles) via enantioselective amidation (Scheme 1). In this process, an N-heterocyclic carbene (NHC) catalyst 3 reacts with the α-hydroxyenone 2 to generate an acyl azolium species, which then reacts with a chiral hydroxamic acid co-catalyst 4 to generate a traditional activated carboxylate that readily couples with amines 1, resulting in the recovery of both of the readily separable enantioenriched amine 5 and amide 6. The presence of the co-catalyst is crucial, as amines do not react directly with the NHC-derived acyl azolium species, and amidation does not occur in the absence of the co-catalyst.

Scheme 1. Kinetic resolution of amines.
 

Advantages

This kinetic resolution methodology utilizes readily available catalysts, co-catalysts, and an α-hydroxyenone, all of which are commercially available. It tolerates a broad spectrum of functional groups and is effective in the resolution of a wide range of amines (Figure 1). Good selectivities can be achieved using either catalytic or stoichiometric amounts of the chiral hydroxamic acid with the reaction proceeding at room temperature. The recovered, enantiopure amine can usually be isolated by aqueous extraction. Unlike chiral chromatography, the general procedure shown below requires no special equipment or skill sets and thus offers a robust alternative. This simple laboratory process can also be operated in parallel and provides rapid access to enantioenriched chiral amine building blocks.

Figure 1. Recovered amines following kinetic resolution of N-heterocycles.
 

General procedure

The hydroxamic acid co-catalyst 4 (804568 or 804584; 7.1 mg, 25 µmol, 0.05 equiv), triazolium salt 3 (688487, 16.4 mg, 50 µmol, 0.10 equiv), α-hydroxyenone 2 (804576; 81.4 mg, 0.35 mmol, 0.70 equiv), K2CO3 (13.8 mg, 0.1 mmol, 0.20 equiv) and the respective amine (0.50 mmol, 1.00 equiv) were dissolved in iPrOAc (2.5 mL, 0.20 M) and the reaction mixture stirred at 23 °C for 24 hours. EtOAc (25 mL) was added, and the mixture was filtered through Celite and concentrated in vacuo. Purification by column chromatography affords the readily separable enantioenriched amine and amide.

Special thanks to Paula Nichols and Jeff Bode for contributing this Technology Spotlight!
 

Materials

     
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