Enantioselective Chromatographic Separation and Lipase Catalyzed Asymmetric Resolution of Biologically Important Chiral Amines

Mohammed Farrag El-Behairy,Rasha M Hassan,Eirik Sundby

doi:10.3390/separations8100165

Mohammed Farrag El-Behairy, Rasha M Hassan + Show 1 more

Open Access

https://doi.org/10.3390/separations8100165

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Abstract

Cyanoacetamides are vital synthons in synthetic organic chemistry. However, methods to enantiopure cyanoacetamides have not yet been well explored. In this work, the preparation of cyanoacetamide synthons RS-(1a–4a) or methoxyacetamides RS-(1b–4b) in enantiopure/enriched form was investigated. Compounds S-1, S-2, R-1b, R-1a, andR-2b were prepared in enantiopure form (ee > 99%) while compounds S-4, R-2a, and R-4a were achieved in ee 9%, 80%, and 76%, respectively. Many baselines enantioselective HPLC separations of amines 1–4, their cyanoacetamides (1a–4a), and methoxyacetamides (1b–4b) were achieved by utilizing diverse mobile-phase compositions and two cellulose-based CSPs (ODH® and LUX-3® columns). Such enantioselective HPLC separations were used to monitor the lipase-catalyzed kinetic resolution of amines RS-(1–4).

Highlights

Chiral aromatic amines and their amides are found in around 40% of all active pharmaceutical ingredients [1,2] and are represented in many biologically important compounds, such as the natural products dysidenin, the antidiabetic repaglinide, the antidementia rivastigmine, the calcimimetic cinacalcet, and other drugs, as per Figure 1 [3]
Despite the wide applicability of chemical catalysis in asymmetric synthesis, biocatalysis has been introduced as a superior alternative to chemical catalysis and found plentiful applications in numerous fields to make chiral building blocks for the pharmaceutical industry [13,14]
chiral stationary phases (CSPs) has been demonstrated as a ubiquitous approach for enantiomeric resolution

Summary

Introduction

Chiral aromatic amines and their amides are found in around 40% of all active pharmaceutical ingredients [1,2] and are represented in many biologically important compounds, such as the natural products dysidenin, the antidiabetic repaglinide, the antidementia rivastigmine, the calcimimetic cinacalcet, and other drugs, as per Figure 1 [3]. The biological activity of β-adrenergic receptor and histamine H3-receptor agonists that are derivatized from chiral aromatic amines are strongly related to the stereo-configuration of these chiral amines [6,7] Based on their biological and synthetic impact, many asymmetric strategies have been adopted for the preparation of chiral amines in the enantiopure form [2,8]. Despite the wide applicability of chemical catalysis in asymmetric synthesis, biocatalysis has been introduced as a superior alternative to chemical catalysis and found plentiful applications in numerous fields to make chiral building blocks for the pharmaceutical industry [13,14] Of these building blocks, chiral amines were displayed as one of the most prominent examples where a plethora of biocatalysts have been implemented [1,15,16,17]

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