Chiral Pharmaceuticals: Synthesis and Chiral Switching

INTRODUCTION

The concept of chirality is a subgroup of isomerism, one of the most critical yet challenging concepts in organic chemistry, which describes the handedness of organic molecules. To understand chirality, one must have an appreciation of the fact that molecules occupy a three-dimensional space, where atoms have a spatial arrangement. The phenomenon arises when four distinct types of groups/atoms bonded to a sp¹ hybridized carbon center. Chirality is also observed for other heteroatoms like sulfur, silicon, and nitrogen when they have four diverse types of groups attached regardless of the hybridization. It is now widely known that the fundamental processes relevant for the action of the drug, like binding to receptors, transportation across membranes, and inhibition of enzymes, are dependent on the stereochemistry of the drug (Sanganyado, 2019). This is because biological systems are sensitive to the stereochemistry of molecules. After all, active sites have three-dimensional arrangements.

Since the efficacy of many drugs depends on the chirality of the molecules, single enantiomers should be produced where possible. Ever since the thalidomide saga of the 1960s, pharmaceutical companies have invested millions in ensuring that drugs are synthesized as single enantiomers (Kim and Scialli, 2011; Reist et al„ 1998). The drug thalidomide (Figure 14.1) was administered as a racemic mixture, with adverse effects of the racemate reported in the UK, where it was approved. Other countries like the United States were spared because the FDA wanted more studies performed before approving thalidomide, although they were not aware of the problems associated with the racemate at that stage.

The drug was widely prescribed to pregnant women for the treatment of morning sickness, with devastating consequences. Because human bodies are sensitive to the chirality of molecules, these two enantiomers solicited different biological responses in pregnant women. The /^-enantiomer was responsible for the observed therapeutic properties, while the 5-enantiomer resulted in teratogenicity (Smith, 2009). After its banning, regulatory bodies ensured that pharmaceutical companies began to pay more attention to chiral drug synthesis and performed extensive biological tests for any drugs that were offered as racemates (Mori et al., 2018). Likewise, researchers are continuously

FIGURE 14.1 Structure of thalidomide.

developing novel and stereo divergent synthetic methods, ensuring that the thalidomide saga is never repeated. Despite the tremendous strides taken to avoid such tragedies, there are still several drugs being offered as racemates on the market. This creates the need for continuous development of stereoselective methods for the synthesis of drugs.

CHIRAL SYNTHETIC METHODS

The diverse nature of chiral drugs implies that there are a plethora of methods currently available to furnish these compounds. In synthesis, the desire is always to reveal the desired compound as pure as possible, employing the shortest possible route. Due to the environmental impact of chemical processes, chemists and companies alike are now more than ever incorporating the famous Sheldon’s E-factor and modifications thereof in the design of their processes (Tieves et ah, 2019). Syntheses of chiral drugs can be achieved by chemoenzymatic or chemical means. Each of these approaches has its own set of advantages and disadvantages; therefore, scientists try to use the best approach for each target molecule. The proceeding examples highlight some of the employed approaches to make the reader aware of the complexity and diversity of the available methods.

Chemoenzymatic Methods

In biological systems, many enzymes contribute to the rapid assembly of chiral products, and nature has evolved to produce only one enantiomer in most cases (Hollmann et ah, 2020). This is because enzymes have an inherent ability to discriminate between enantiomers of racemic substances. The application of enzymatic processes for the synthesis of enantiopure drugs grew since the 1980s due to the high selectivity of enzymes (Margolin, 1993). In some cases, the selectivity of enzymes often significantly exceeds that of analogous chemical-synthetic methodology. The major drawbacks associated with enzyme use for syntheses include substrate specificity, stereoselectivity, stability, and reaction stability. In addition, because enzymes mostly react faster with one enantiomer, it means the maximum theoretical yield of enzymatic resolution is 50%. As a solution to this problem, dynamic kinetic resolution methods have been developed for some reactions. Dynamic kinetic resolution methods work by racemizing the unreactive enantiomer resulting in a theoretical increase in yield of 100% (Martfn-Matute and Backvall, 2007; Nakano and Kitamura, 2014).

Despite these disadvantages, enzyme-catalyzed reactions are often highly regio- and stereoselective when optimized. Temperature and pressure conditions are optimized to avoid extreme conditions that cause isomerization, epimerization, racemization, and product rearrangements commonly observed with chemical processes (Margolin, 1993; Patel, 2001a). Immobilized enzymes can also be used for many cycles, which significantly reduce the E-factor of the processes. Recent technology has also allowed producing tailor-made enzymes (by random and site-directed mutagenesis) with modified activity and novel stereoselective applications.

As an example, Patel published a mini-review article showcasing an alternative enzymatic synthesis of the chiral intermediates for omapatrilat, an antihypertensive drug (Patel, 2001b). The same author went on to publish a review article on the use of enzymes in the synthesis of key drug intermediates (Patel, 2001a). Scheme 14.1 shows the enantioselective enzymatic reduction of ketone 1,

SCHEME 14.1 Enantioselective reduction of 4-benzyloxy-3-methanesulfonylamino-2'-bromoacetophe- none 1 to Л-alcohol 2.

which unveiled Л-alcohol 2. a crucial intermediate in the synthesis of рЗ-receptor agonist. Excellent yields of >85% were recovered, and enantiomeric excess (ее) values of >98% were obtained. In this example, the reduction of the ketone group was achieved selectively, and the recovered yields were high because the starting ketone was achiral.

Formoterol (Figure 14.2), a very potent p₂-agonist prescribed as a bronchodilator for patients who have asthma and chronic bronchitis, was initially synthesized by a convergent enantio- and diastereoselective method (Campos et al., 2000; Hett et ah, 1998). The drug was generally offered as a racemate, but earlier studies had already revealed that the Л,Л-isomer was 1000 times more active than the 5,5-isomer, although the activity of the Л,Л-isomer was not affected by the presence of the 5,5-isomer (Trofast et ah, 1991).

After several reports of enantiopure Л,Л-formoterol, Campos et ah (2000) reported the incorporation of a key enzymatic resolution step for two of the intermediates in the synthesis protocol (Scheme 14.2). Amano PS-lipase successfully resolved racemic alcohol 3 in the presence of vinyl acetate as the acetylating reagent furnishing the bromoacetate 4 and the alcohol 5 in 48% yield and 96% enantiomeric excess. An overall yield of 11% and enantiomeric excess of 94% was reported for the amidation of racemic amine 6. yielding the desired amide 7 and amine 8. Because both the starting materials w'ere racemic, the maximum theoretical yields of the desired product were 50%, and the reactions produced an undesired side product. From these results, it is evident that enzymatic resolution reactions, although they are more environmentally friendly, they have a high E-factor because of a possible 50% waste from the unwanted enantiomer if a dynamic kinetic resolution is not employed.

FIGURE 14.2 Structure of Л,Л-formoterol.

SCHEME 14.2 Enzymatic enantioselective synthesis of Л.Л-formoterol.