Biocatalysis: A smart and green tool for the preparation of chiral drugs

Abstract

Over the last decades, biocatalysis has achieved growing interest thanks to its potential to enable high efficiency, high yield, and eco-friendly processes aimed at the production of pharmacologically relevant compounds. Particularly, biocatalysis proved an effective and potent tool in the preparation of chiral molecules, and the recent innovations of biotechnologies and nanotechnologies open up a new era of further developments in this field. Different strategies are now available for the synthesis of chiral drugs and their intermediates. Enzymes are green tools that offer several advantages, associated both to catalysis and environmentally friendly reactants. Specifically, the use of enzymes isolated from biological sources or of whole-cell represents a valuable approach to obtain pharmaceutical products. The sustainability, the higher efficiency, and cost-effectiveness of biocatalytic reactions result in improved performance and properties that can be translated from academia to industry. In this review, we focus on biocatalytic approaches for synthesizing chiral drugs or their intermediates. Aiming to unveil the potentialities of biocatalysis systems, we discuss different examples of innovative biocatalytic approaches and their applications in the pharmaceutical industry.

Keywords: biocatalysis; chiral resolution; enantioselective synthesis; green chemistry; homochiral drugs.

FIGURE 1

Number of documents per year on biocatalysis applications for the preparation of chiral drugs. The number of publications on scientific journals is reported as a yellow dotted line; the number of patents is reported as blue bars (source: Scopus and Espacenet by using as query: biocatalysis, chiral and pharmaceutical or drug ‐ last update May 20, 2022)

FIGURE 2

Enzyme immobilization methods, pros, and cons

FIGURE 3

Nanomaterials for biocatalytic processes

FIGURE 4

(A) Schematic representation of COF synthesis, functionalization, and enzyme immobilization; (B) Example of a strategy for enzyme immobilization on CNF. COF, covalent organic framework; CNF, carbon nanofiber

FIGURE 5

Chemical structures of commercially available prazole‐family PPIs, chiral form (racemic/enantiopure), and approval year thereof by European or USA regulatory agencies. PPIs, proton pump inhibitors

SCHEME 1

Comparison between chemo‐ and biocatalytic approaches for the synthesis of (R)‐lansoprazole (dexlansoprazole) from the sulfide precursor

SCHEME 2

Comparison between first generation and green syntheses of pregabalin

SCHEME 3

Synthesis of paroxetine. Comparison between the early development route and the more recent green synthesis

SCHEME 4

Enantioselective reduction of ketones catalyzed by KRED, with NAD(P)H recycling system (top); examples of the use of KRED in the synthesis of APIs (bottom). The carbonyl that is selectively reduced is colored in red in the precursors, whereas the stereocenter that is thus introduced in the final product is marked with a red asterisk.

SCHEME 5

(A) Kinetic resolution of racemic intermediates of two β‐blocker drugs; (B) enantioselective reduction of a prochiral ketone for the synthesis of crizotinib.

SCHEME 6

In vitro biocatalytic cascade synthesis of islatravir

SCHEME 7

Examples of the application of whole‐cell biocatalysts in the synthesis of pharmaceuticals