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Biocatalysis has emerged as a powerful and useful strategy for the synthesis of active pharmaceutical ingredients (APIs). The outstanding developments in molecular biology techniques allow nowadays the screening, large-scale production, and designing of biocatalysts, adapting them to desired reactions. Many enzymes can perform reactions both in aqueous and non-aqueous media, broadening even further the opportunities to integrate them in complex pharmaceutical multi-step syntheses.This paper showcases several examples of biocatalysis in the pharmaceutical industry, covering examples of different enzymes, such as lipases, oxidoreductases, and transaminases, to deliver active drugs through complex synthetic routes. Examples are critically discussed in terms of reaction conditions, motivation for using an enzyme, and how biocatalysts can be integrated in multi-step syntheses. When possible, biocatalytic routes are benchmarked with chemical reactions.The reported enzymatic examples are performed with high substrate loadings (100 g L

In their Editorial for the Special Issue on Biocatalysis as Key to Sustainable Industrial Chemistry, Guest Editors Andrés Alcántara, Pablo Domínguez de María, Jennifer Littlechild, and Roland Wohlgemuth and their co-workers on the European Society of Applied Biocatalysis' (ESAB) Working Group on Sustainable Chemistry Martin Schürmann and Roger Sheldon discuss the Special Issue and the importance of biocatalysis in carrying out cutting-edge industrial chemistry in a sustainable way, as well as the future prospects for the field.

The role and power of biocatalysis in sustainable chemistry has been continuously brought forward step by step to its present outstanding position. The problem-solving capabilities of biocatalysis have been realized by numerous substantial achievements in biology, chemistry and engineering. Advances and breakthroughs in the life sciences and interdisciplinary cooperation with chemistry have clearly accelerated the implementation of biocatalytic synthesis in modern chemistry. Resource-efficient biocatalytic manufacturing processes have already provided numerous benefits to sustainable chemistry as well as customer-centric value creation in the pharmaceutical, food, flavor, fragrance, vitamin, agrochemical, polymer, specialty, and fine chemical industries. Biocatalysis can make significant contributions not only to manufacturing processes, but also to the design of completely new value-creation chains. Biocatalysis can now be considered as a key enabling technology to implement sustainable chemistry.

Apart from being one of the most important intermediates in chemical synthesis, broadly used in the formation of C–C bonds among other processes, the β-dicarbonyl structure is present in a huge number of biologically and pharmaceutically active compounds. In fact, mainly derived from the well-known antioxidant capability associated with the corresponding enol tautomer, β-diketones are valuable compounds in the treatment of many pathological disorders, such as cardiovascular and liver diseases, hypertension, obesity, diabetes, neurological disorders, inflammation, skin diseases, fibrosis, or arthritis; therefore, the synthesis of these structures is an area of overwhelming interest for organic chemists. This paper is devoted to the advances achieved in the last ten years for the preparation of 1,3-diketones, using different chemical (Claisen, hydration of alkynones, decarboxylative coupling) or catalytic (biocatalysis, organocatalytic, metal-based catalysis) methodologies: Additionally, the preparation of branched β-dicarbonyl compounds by means of α-functionalization of non-substituted 1,3-diketones are also discussed.

Chitosan has garnered much interest due to its properties and possible applications. Every year the number of publications and patents based on this polymer increase. Chitosan exhibits poor solubility in neutral and basic media, limiting its use in such conditions. Another serious obstacle is directly related to its natural origin. Chitosan is not a single polymer with a defined structure but a family of molecules with differences in their composition, size, and monomer distribution. These properties have a fundamental effect on the biological and technological performance of the polymer. Moreover, some of the biological properties claimed are discrete. In this review, we discuss how chitosan chemistry can solve the problems related to its poor solubility and can boost the polymer properties. We focus on some of the main biological properties of chitosan and the relationship with the physicochemical properties of the polymer. Then, we review two polymer applications related to green processes: the use of chitosan in the green synthesis of metallic nanoparticles and its use as support for biocatalysts. Finally, we briefly describe how making use of the technological properties of chitosan makes it possible to develop a variety of systems for drug delivery.

Chitosan arouses large interest due to its properties and possible applications. Every year the number of publications and patents based on this polymer increases. Chitosan exhibits poor solubility in neutral and basic media limiting its use in such conditions. Another serious obstacle is directly related to its natural origin. Chitosan is not a single polymer with a defined structure but a family of molecules with differences in their composition, size, and monomer distribution. These properties have a fundamental effect on the biological and technological performance of the polymer. Moreover, some of the biological properties claimed are discrete. In this review, we discuss how chitosan chemistry can solve the problems related to its poor solubility and can boost the polymer properties. We focus on some of the main biological properties of chitosan and the relationship with the physicochemical properties of the polymer. Then, we visit two polymer applications related to green processes: the use of chitosan in the green synthesis of metallic na-noparticles and its use as support in biocatalyst. Finally, we briefly describe how making use of the technological properties of chitosan it is possible to develop a variety of systems for drug delivery

Introduction: Alzheimer's disease (AD), the most common type of dementia among older adults, is a chronic neurodegenerative pathology that causes a progressive loss of cognitive functioning with a decline of rational skills. It is well known that AD is multifactorial, so there are many different pharmacological targets that can be pursued. Areas covered: The authors highlight the strategic value of privileged scaffolds in a multi-target lead compound generation against AD, exploring the concept of multi-target design, with a special emphasis on hybrid compounds. Hence, the most promising building blocks for designing and synthesizing hybrid anti-AD drugs are shown, while also presenting the more advanced hybrid compounds. Expert opinion: The available therapeutic arsenal for AD, designed under the traditional paradigm of 'one-drug/one target/one-disease', is based on the inhibition of brain acetylcholinesterase (AChE) to increase acetylcholine (ACh) levels. However, this classical approach has not been sufficiently effective when used to treat any multifactor-depending pathology (cancer, diabetes or AD). The multi-target drug concept has been quickly adopted by medicinal chemists. The basic research developments reported in recent years are a solid foundation that will pave the way for the construction of future AD therapeutics.

The quest for sustainable solvents is currently a matter of intense research and development, as solvents significantly contribute heavily to the waste generated by chemical industries. Cyclopentyl methyl ether (CPME) is a promising eco-friendly solvent with valuable properties such as low peroxide formation rate, stability under basic and acidic conditions, and relatively high boiling point. This Review discusses the potential use of CPME for applications in biotechnology (e.g., biotransformations, as solvent or cosolvent), biorefineries, and bioeconomy (e.g., for furan synthesis or as an extractive agent in liquid-liquid separations), as well as for other purposes, such as chromatography or peptide synthesis. Although CPME is currently produced by petrochemical means with a remarkably high atom economy, its biogenic production can be envisaged from substrates such as cyclopentanol or cyclopentanone, which can be derived from furfural or from (bio-based) adipic acid, respectively. The combination of the promising properties of CPME as a (co)solvent with a future (economic) biogenic origin would be advantageous for setting strategies aligned with the sustainable chemistry principles.

The intrinsic degradative α-elimination of Li carbenoids somehow complicates their use in synthesis as C1-synthons. Nevertheless, we herein report how boosting such an α-elimination is a straightforward strategy for accomplishing controlled ring-opening of epoxides to furnish the corresponding β-halohydrins. Crucial for the development of the method is the use of the eco-friendly solvent 2-MeTHF, which forces the degradation of the incipient monohalolithium, due to the very limited stabilizing effect of this solvent on the chemical integrity of the carbenoid. With this approach, high yields of the targeted compounds are consistently obtained under very high regiocontrol and, despite the basic nature of the reagents, no racemization of enantiopure materials is observed.

The use of magnetic biocatalysts is highly beneficial in bioprocesses technology, as it allows their easy recovering and enhances biocatalyst lifetime. Thus, it simplifies operational processing and increases efficiency, leading to more cost-effective processes. The use of small-size matrices as carriers for enzyme immobilization enables to maximize surface area and catalysts loading, also reducing diffusion limitations. As highly expensive nanoparticles (nm size) usually aggregate, their application at large scale is not recommended. In contrast, the use of magnetic micro-macro (µm-mm size) matrices leads to more homogeneous biocatalysts with null or very low aggregation, which facilitates an easy handling and recovery. The present review aims to highlight recent trends in the application of medium-to-high size magnetic biocatalysts in different areas (biodiesel production, food and pharma industries, protein purification or removal of environmental contaminants). The advantages and disadvantages of these above-mentioned magnetic biocatalysts in bioprocess technology will be also discussed. Santander Foundation (XSAN001906) 11.889 Q1 JCR 2021 2.354 Q1 SJR 2021 No data IDR 2021 UEM

The intrinsic degradative α-elimination of Li carbenoids somehow complicates their use in synthesis as C1-synthons. Nevertheless, we herein report how boosting such an α-elimination is a straightforward strategy for accomplishing controlled ring-opening of epoxides to furnish the corresponding β-halohydrins. Crucial for the development of the method is the use of the eco-friendly solvent 2-MeTHF, which forces the degradation of the incipient monohalolithium, due to the very limited stabilizing effect of this solvent on the chemical integrity of the carbenoid. With this approach, high yields of the targeted compounds are consistently obtained under very high regiocontrol and, despite the basic nature of the reagents, no racemization of enantiopure materials is observed.

Benzil reductases are dehydrogenases preferentially active on aromatic 1,2-diketones, but the reasons for this peculiar substrate recognition have not yet been clarified. The benzil reductase (KRED1-Pglu) from the non-conventional yeast Pichia glucozyma showed excellent activity and stereoselectivity in the monoreduction of space-demanding aromatic 1,2-dicarbonyls, making this enzyme attractive as biocatalyst in organic chemistry. Structural insights into the stereoselective monoreduction of 1,2-diketones catalyzed by KRED1-Pglu were investigated starting from its 1.77 A resolution crystal structure, followed by QM and classical calculations; this study allowed for the identification and characterization of the KRED1-Pglu reactive site. Once identified the recognition elements involved in the stereoselective desymmetrization of bulky 1,2-dicarbonyls mediated by KRED1-Pglu, a mechanism was proposed together with an in silico prediction of substrates reactivity.

This review intends to present some of the latest studies on the lipase A from Candida antarctica (CALA). This lipase is among the most stable ones and has some capability to attack the sn-2 position of triglycerides. This makes it a very interesting lipase, especially considering that it is commercially available. The cloning and production of the enzyme together with some structural facts and applications will be discussed in this review. Special focus will be put on the immobilization of the enzyme. The use of the commercially available crosslinked enzyme aggregates of this enzyme will be explained, together with the use of the enzyme in some new trends in enzyme immobilization, such as bio-imprinting of the open form of CALA by detergents and the fixation of the open structure, the design of heterofunctional supports able to take full advantage of the immobilization via interfacial activation but preventing enzyme release, or the design of strategies for the preparation of multiple layers of lipase enzymes (using just CALA or combining CALA with other lipases). ABM (RTI2018-095291-B-I00, MINECO/FEDER) and RFL (project number CTQ2017-86170-R). Thank MICINN for financial support, ABM also thanks Generalitat Valenciana (PROMETEOII/2018/076). JJVO thanks to CONACYT (Mexico) for the financial support to the basic science project number, CB-2016-01, 286,992. JCSS thanks to Brazilian Agencies for Scientific and Technological Development, Fundação Cearense de Apoio ao Desenvolvimento Científico e Tecnológico (FUNCAP), project number BP3-0139-00005.01.00/18 and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Project number 422942/2016-2. The continous support supply of lipases from R. Martinez (Novozym Spain) is gratefully recognized.

This review mainly focuses on the use of glucose oxidase in the production of D-gluconic acid, which is a reactant of undoubtable interest in different industrial areas. The enzyme has been used in numerous instances as a model reaction to study the problems of oxygen supply in bioreactors. One of the main topics in this review is the problem of the generated side product, hydrogen peroxide, as it is an enzyme-inactivating reagent. Different ways to remove hydrogen peroxide have been used, such as metal catalysts and use of whole cells; however, the preferred method is the coupling glucose oxidase with catalase. The different possibilities of combining these enzymes have been discussed (use of free enzymes, independently immobilized enzymes or co-immobilized enzymes). Curiously, some studies propose the addition of hydrogen peroxide to this co-immobilized enzyme system to produce oxygen in situ. Other cascade reactions directed toward the production of gluconic acid from polymeric substrates will be presented; these will mainly involve the transformation of polysaccharides (amylases, cellulases, etc.) but will not be limited to those (e.g., gluconolactonase). In fact, glucose oxidase is perhaps one of most successful enzymes, and it is involved in a wide range of cascade reactions. Finally, other applications of the enzyme have been reviewed, always based on the production of D-gluconic acid, which produces a decrease in the pH, a decrease in the oxygen availability or the production of hydrogen peroxide; in many instances, cascade reactions are also utilized. Thus, this review presents many different cascade reactions and discusses the advantages/drawbacks of the use of co-immobilized enzymes. We gratefully recognize the financial support from Ministerio de Ciencia e Innovación-Spanish Government and FEDER funds (project number CTQ2017-86170-R, RTI2018-095291-BI00, MAT2017-87579-R) and Generalitat Valenciana (PROMETEO/2018/076). DC thank to Ministerio de Ciencia e Innovacion-Spanish Government by a FPI. PWT thanks to the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – Brasil (CAPES) – Finance Code 001.

To date, to simulate biodiesel production, kinetic models from different authors have been provided, each one usually applied to the use of a specific vegetable oil and experimental conditions. Models, which may include esterification, besides transesterification simulation, were validated with their own experimental conditions and raw material. Moreover, information about the intermediate reaction steps, besides catalyst concentration variation, is either rare or nonexistent. Here, in this work, a universal mathematical model comprising the chemical kinetics of a two-step (esterification and transesterification) vegetable oil-based biodiesel reaction is proposed. The proposed model is universal, as it may simulate any vegetable oil biodiesel reaction from the literature. For this purpose, a mathematical model using the software MATLAB has been designed. Using the mathematical model, the estimation of mass variation with time, of both reactants and products, as well as glyceride conversion and homogeneous catalyst concentration variation (instead of only alcohol/catalyst solution) are allowed. Moreover, analysis of the influence of some important variables affecting the reaction kinetics of biodiesel production (e.g., catalyst concentration), along with comparison and model validation with data from different authors may be carried out. In addition, Supplementary material with a collection of 290 rate constants, derived from 55 different experiments using different vegetable oils and conditions is provided.

The increasing relevance of cascade reactions in biocatalysis has sparked a great interest for enzyme co-immobilization. Enzyme co-immobilization allows access to some kinetic advantages that in some instances are necessary to get the desired product, avoiding side-reactions. However, the kinetic effect is very relevant mainly at the initial reaction rates, while it may be less relevant in the whole reaction course, depending on the kinetic parameters of the involved enzymes. This review not only critically discusses the advantages but also the drawbacks of enzymes co-immobilization: immobilization on the same support and surface, under similar conditions, discarding the whole biocatalyst when one of the co-immobilized enzymes is inactivated. We will discuss when co-immobilization is almost compulsory, when the advantages of co-immobilization may not be enough to compensate their problems and when it should be fully discarded. The co-immobilization of cofactors and enzymes bears special interest, as this can open up the opportunity to the building of artificial cells and extremely complex one-pot transformations. Finally, some recent strategies to overcome some the co-immobilization problems will be presented. We gratefully recognize the financial support from Ministerio de Ciencia e Innovación-Spanish Government (project number CTQ2017-86170-R) and Generalitat Valenciana (PROMETEO/2018/076). RMS thank to Ministerio de Educacion -Spanish Government for a FPU fellowship, DC thank to Ministerio de Ciencia e Innovacion-Spanish Government by a FPI.

© 2020 by the authors., Lipases are among the most utilized enzymes in biocatalysis. In many instances, the main reason for their use is their high specificity or selectivity. However, when full modification of a multifunctional and heterogeneous substrate is pursued, enzyme selectivity and specificity become a problem. This is the case of hydrolysis of oils and fats to produce free fatty acids or their alcoholysis to produce biodiesel, which can be considered cascade reactions. In these cases, to the original heterogeneity of the substrate, the presence of intermediate products, such as diglycerides or monoglycerides, can be an additional drawback. Using these heterogeneous substrates, enzyme specificity can promote that some substrates (initial substrates or intermediate products) may not be recognized as such (in the worst case scenario they may be acting as inhibitors) by the enzyme, causing yields and reaction rates to drop. To solve this situation, a mixture of lipases with different specificity, selectivity and differently affected by the reaction conditions can offer much better results than the use of a single lipase exhibiting a very high initial activity or even the best global reaction course. This mixture of lipases from different sources has been called “combilipases” and is becoming increasingly popular. They include the use of liquid lipase formulations or immobilized lipases. In some instances, the lipases have been coimmobilized. Some discussion is offered regarding the problems that this coimmobilization may give rise to, and some strategies to solve some of these problems are proposed. The use of combilipases in the future may be extended to other processes and enzymes., This research was funded by Ministerio de Ciencia e Innovación-Spanish Government (project number CTQ2017-86170-R) and Generalitat Valenciana (PROMETEO/2018/076).

Genipin is a reagent isolated from the Gardenia jasminoides fruit extract, and whose low toxicity and good crosslinking properties have converted it into a reactive whose popularity is increasing by the day. These properties have made it widely used in many medical applications, mainly in the production of chitosan materials (crosslinked by this reactive), biological scaffolds for tissue engineering, and nanoparticles of chitosan and nanogels of proteins for controlled drug delivery, the genipin crosslinking being a key point to strengthen the stability of these materials. This review is focused on the mechanism of reaction of this reagent and its use in the design of biocatalysts, where genipin plays a double role, as a support activating agent and as inter- or intramolecular crosslinker. Its low toxicity makes this compound an ideal alterative to glutaraldehyde in these processes. Moreover, in some cases the features of the biocatalysts prepared using genipin surpassed those of the biocatalysts prepared using other standard crosslinkers, even disregarding toxicity. In this way, genipin is a very promising reagent in the design of biocatalysts. A.B.-M. thanks MICIU (RTI2018-095291-B-I00, MINECO/FEDER) and the Generalitat Valenciana (PROMETEOII/2018/076) for financial support, and R.F.-L. gratefully recognizes the support from MICIU from Spanish Government (project number CTQ2017-86170-R). J.J.V.-O. thanks to CONACYT (Mexico) for the financial support to the basic science project number, CB-2016-01, 286992.

The pancreatic hormone amylin is co-synthesized and co-released with insulin from pancreatic beta-cells, although it is also expressed in the central nervous system, in particular in parts involved in metabolic control, such as the lateral hypo-thalamus. The thioester rac-4 was resolved with Pseudomonas cepacia lipase in the presence of a tert-amine base, trioctylamine. Incretins are gut hormones that potentiate insulin secretion after meal ingestion in a glucose-dependent manner. The G protein-coupled receptor 119, responsive to natural ligands oleoylethanolamide and monooleoylglycerol, is a potential target for the development of oral antidiabetic drugs. Inhibition of enzymes involved in metabolic pathways is undoubtedly one of the most active areas inside Medicinal Chemistry. An increased abnormal concentration of glucocorticoids may lead to its precipitation, with the concomitant aggravation of truncal obesity, insulin resistance, hepatic triacylglycerol accumulation, hyperglycemia, hypertension and dyslipidemia.

An effective stereocontrolled synthesis of the HIV protease inhibitor Nelfinavir is reported. Two transformations were identified crucial for achieving success: the formation of a densely functionalized α-chloroketone via the homologation of a Weinreb amide with chloromethyllithium (LiCH2Cl), followed by its erythro selective reduction into the corresponding chiral chlorohydrin. A commercially available enzyme P2-C02 was particularly well suited for this purpose, affording the key alcohol (in an excellent 99% de), which was then smoothly converted into the active biologically active agent.

This is the presentation of the Special Issue “Biocatalysis in Spain”, covering the work of several Spanish groups in the field of Biocatalysis and Biotransformations. Thus, both research articles and reviews allow one to draw an accurate view of the state-of-the-art development in Spain.

The biocatalyzed production of building blocks for synthesizing drugs is a very attractive research field, because of the sustainability introduced in a synthetic schedule when chemical steps are substituted by biocatalyzed protocols. In this article, we will show how different antidiabetic drugs, for treating diabetes mellitus Type 1 and Type 2, can be more efficiently and effectively synthetized with the help of different types of biocatalysts. The huge overall drug market for these drugs, as well as the great number of people suffering from diabetes (the prevalence of all types of diabetes is growing), makes this topic attractive enough to focus on more efficient synthetic protocols for preparing antidiabetic drugs. Examples covering biocatalyzed synthesis of insulin analogues, sensitizers (PPAR agonists), secretagogues (GLP-1 analogues, GPR119 agonists) and enzyme inhibitors (α-glucosidase inhibitors, DPP4-inhibitors, SGLT-2 inhibitors and 11β-HSD1 inhibitors) will be presented.