Biocatalysis to amino acid-based chiral pharmaceuticals—examples and perspectives

doi:10.1016/S1381-1177(98)00009-5

Journal of Molecular Catalysis B: Enzymatic

Volume 5, Issues 1–4, 15 September 1998, Pages 1-11

https://doi.org/10.1016/S1381-1177(98)00009-5 Get rights and content

Abstract

The search for and development of new pharmaceutically active structures drives the need for new enantiomerically pure compounds (EPC). Many N-containing structures can be derived beneficially from either l- or d-amino acids [K. Drauz, Chimia 51 (1997) 310–314.]. The largest growth occurs in the area of unnatural amino acids. Two examples discussed from the Degussa portfolio concern (i) d-amino acids [A.S. Bommarius, M. Kottenhahn, H. Klenk, K. Drauz, NATO ASI Series C 381 (1992) 161–174.] as components of LHRH antagonists of which the Degussa's Cetrorelix is a prime example as well as (ii) l-tert-leucine, occurring in a fast-growing number of pharmaceutical compounds under development [A.S. Bommarius, M. Schwarm, K. Stingl, M. Kottenhahn, K. Huthmacher, K. Drauz, Tetrahedron Asymmetry 6 (1995) 2851–2888.]. For d-amino acids, results of the hydantoinase/carbamoylase route will be presented while redox catalysis by way of reductive amination is a suitable process to l-tert-leucine. The number of biocatalytic applications is growing and an updated list is discussed. The presentation will also cover comparisons of biocatalysis with potentially competitive technologies such as enantioselective crystallization, chemical asymmetric synthesis, or chromatographic separation of racemates. Future trends relevant to the perspective for biocatalysis include the need for ever more complex chiral molecules as well as shortened development times in the pharmaceutical industry.

Introduction

Ever more often, the motivation for the investigation of biocatalytic methods and processes is the synthesis of enantiomerically pure compounds (EPCs). The responsible factors are the following: (1) There is an increasing interest in EPCs in industries other than pharmaceutical, such as the food and agro industry. (2) Diseases are now tackled with novel approaches to treatment incorporating enzymological methodology; examples are AIDS (HIV-protease inhibitors) or cancer and rheumatic inflammation (MMPI (matrix metalloprotease inhibitors)). (3) Progress has been made in the development of structure-based selection and optimization of inhibitors which are derived from structures in Nature but do not occur there.

After discussing the frame in which biocatalysis research occurs, especially in industry, two examples of the synthesis of EPCs will be presented: (i) the route to d-amino acids according to the hydantoinase/carbamoylase process and (ii) the synthesis of unusual l-amino acids through reductive amination. Subsequently, competitive technologies to biocatalysis are discussed. In Section 7, some future trends of the pharmaceutical intermediates industry are presented.

Section snippets

Framework for biocatalysis

There are several trends that can be observed for both biochemical and chemical processes alike [1]: (1) Catalytic reactions instead of stoichiometric ones, (2) The goal of 100% selectivity at 100% conversion, (3) High concentration of substrates, (4) Neither detrimental solvents nor frequent solvent changes, (5) The increased use of either solid or volatile acids and bases such as zeolites, ammonia or carbon dioxide as well as pH-stat techniques.

When considering to run a large-scale reaction,

Hydantoinase/carbamoylase process

A promising route to enantiomerically pure amino acids, both l- and d-enantiomers, is based on conversion of hydantoins via hydantoinases and, additionally, carbamoylases to either d- or l-amino acids depending on the enzymes used (Fig. 1).

Hydantoinase systems to d-amino acids are more common. d-Amino acids are significant as components of antibiotics, pharmaceuticals, or pesticides that are often more active but also more stable that the l-containing analogs (Fig. 2).

In nature, d-hydantoinases

Reductive amination

Enantiomerically very pure l-amino acids can be obtained elegantly and efficiently by reductive amination of α-keto acids by amino acid dehydrogenases. Fig. 5 features the case of leucine dehydrogenase (LeuDH) which converts hydrophobic α-keto acids to the respective l-amino acids such as l-tert-leucine, l-neopentylglycine or analogs with the help of the cofactor NADH. The resulting form of the cofactor, NAD⁺, is regenerated to NADH by the well-known reaction employing FDH and ammonium formate.

List of scaled-up biocatalytical processes

By now, plenty of biotransformations have been developed to industrial scale; leading is the glucose–isomerase process (>10⁶ t/a) followed by production of cocoa butter and acrylamide and leading down to smaller productions in the lower ton range, most of them intermediates to pharmaceutically active compounds such as (R)-glycidyl butyrate, prepared with lipases, or to food and cosmetics compounds such as oligosaccharides, made with dextransucrase (Table 1).

Competitive technologies

Despite the upward trend for biocatalysis in the field of EPCs other competitive technologies in many cases often demonstrate similar performance:

(i) Enantioselective crystallization is the method of choice for the production of (S)-naproxen and (R)-phenylglycine (Scheme. 1).

(ii) Asymmetric synthesis can be successfully employed for large-scale processes in selected cases, especially in catalytic hydrogenation (Scheme. 2).

(iii) Chromatographic separation of racemates will be increasingly

Future trends in the markets for pharmaceutically active compounds

In the near future, three important trends can be discerned for the area of pharmaceuticals and the field of process development for pharmaceutical intermediates.

(1) The synthesis routes to pharmaceutically active molecules become more and more complicated. This raises the questions whether such molecules, usually featuring several chiral centers, can be synthesized at all within given process and cost constraints (Fig. 9).

(2) Owing to the high costs of development of novel pharmaceuticals, the

Acknowledgements

The authors gratefully acknowledge help from collaborators such as Maria-Regina Kula, Werner Hummel and Georg Krix, Institute of Enzyme Technology (University of Düsseldorf), Christian Wandrey (Research Center Juelich) as well as Christoph Syldatk (University of Stuttgart) and colleagues Kurt Günther (analytical dept., Degussa) and coworkers.

References (12)

R.A. Sheldon, CHEMTECH (1994)...
M. Pietzsch et al.
Ann. N.Y. Acad. Sci.
(1992)
A.S. Bommarius, K. Drauz, H. Klenk, K. Makryaleas, DE 4119029...
A.S. Bommarius, K. Drauz, H. Klenk, K. Makryaleas, US 5,554,518...
K. Makryaleas, K. Drauz, A.S. Bommarius, Method for the preparation of d-arginine and l-ornithine, US 5,591,613...
A.S. Bommarius et al.
Bioorg. Med. Chem.
(1994)

There are more references available in the full text version of this article.

Cited by (225)

Bacterial metabolites: An unexplored quarry
2021, Volatiles and Metabolites of Microbes
Bacteria are known sources of metabolites. These metabolites are promising in many fields. The main contributions of bacterial metabolites are in the areas of agriculture, therapeutics and also veterinary uses. These bacterial byproducts are proven effective in medical and health sectors, and also in the amplification of nutrition in food processing industries. Metabolites are broadly of two types, which are primary and secondary metabolites. The primary metabolites, such as amino acids, enzymes, vitamins, and organic acids, are well used in supply of nutrition and are also used as biotransformation agents. Whereas, the secondary metabolites are obtained after an extraction process are used in pharmaceutical industries for their promising capabilities in the disease management area. These bacterial metabolites, which comprise of alkaloids, peptides, and macrocyclic lactams, are also exploited in many fields of human use. These can also be used in flavor enhancement agents in buttermilk; the richness in high quality is due to the lactic acid in major amounts with acetic acid, diacetyl, and CO₂ in traces. The fermentation of citric acid results in formation of diacetyl, an important flavor compound in buttermilk. Bacteria can also produce antibiotics that use their primary metabolites. An outstanding example of such use is actinomycin, which comes from a primary metabolite tryptophan. Some bacterial metabolites are sugars like fructose and glucose which can also be used in their respective commercial production the secondary metabolites such as medicines, flavoring agents and recreational drugs, which can be used diversely for commercial and for laboratory purposes. Nevertheless, bacterial metabolites are promising for application in various fields, yet their dynamics are still unexplored and need research at laboratory scale.
Enzymes in Green Chemistry: The State of the Art in Chemical Transformations
2019, Advances in Enzyme Technology, First Edition
The global aspiration for more sustainable processes, and the development of products through biotechnological routes, has contributed to boost the use of enzymes in the industrial field. The concept of green chemistry is intrinsically linked to enzymatic catalysis, as enzymes can be obtained from renewable sources, and are capable of catalyzing various chemical reactions, being an alternative to the classical chemical catalysis. In this context, this chapter describes the importance of enzyme immobilization methods, particularly for large-scale applications. Particularly, the rise of “omics” technologies has also contributed to the fast growth of this field, and will certainly provide a means for development of new, useful proteins and enzymes in the near future. Despite that, this area still demands more detailed studies and investments, as enzymatic catalysis and production of bioproducts will surely assume crucial roles in respect to chemical transformations in the next few decades. For all these reasons, a current and concise review of enzymes as sustainable catalysts is presented in this chapter.
Enantioselective organocatalytic strategies to access noncanonical α-amino acids
2024, Chemical Science
Construction of metal–organic framework-based multienzyme system for l-tert-leucine production
2023, Bioprocess and Biosystems Engineering
Rational Design of Meso-Diaminopimelate Dehydrogenase with Enhanced Reductive Amination Activity for Efficient Production of D-p-Hydroxyphenylglycine
2023, Applied and Environmental Microbiology
Semi-Rational Design of Diaminopimelate Dehydrogenase from Symbiobacterium thermophilum Improved Its Activity toward Hydroxypyruvate for D-serine Synthesis
2023, Catalysts

View all citing articles on Scopus

View full text