Synthesis Of Pharmaceuticals Research Articles

Engineered enzymes for the synthesis of pharmaceuticals and other high-value products

Engineered enzymes for the synthesis of pharmaceuticals and other high-value products

Application of synthetic biology strategies to promote biosynthesis of fatty acids and their derivatives.

Fatty acids and their derivatives are indispensable biomolecules in all organisms, and can be used as intermediates in the synthesis of pharmaceuticals, biofuels and pesticides, and thus their demand has increased dramatically in recent years. In addition to serving as structural components of cell membranes and metabolic energy, fatty acids and their derivatives can also be used as signal transduction and regulatory bioactive molecules to regulate cell functions. Biosynthesis of fatty acids and their derivatives through microbial catalysis provides green and alternative options to meet the goal. However, the low biosynthetic titer of fatty acids and their derivatives limits their industrial production and application. In this review, we first summarize the metabolic pathways and related enzymes of fatty acids and their derivatives biosynthesis. Then, the strategies and research progress of biosynthesis of fatty acids and derivatives through metabolic and enzyme engineering were reviewed. The biosynthesis of saturated fatty acids (medium chain fatty acids and long chain fatty acids), bioactive fatty acids (PUFAs, oxylipins, ether lipids), and their derivatives with microbial and enzymatic catalysis were respectively summarized. Finally, synthetic biology strategies to improve fatty acids and their derivatives production through enzyme rational design, carbon metabolism flux, cofactors balance, and metabolic pathways design were discussed. The review provides references and prospects for fatty acids and their derivatives biosynthesis and industrial production.

Mesoporous metal-organic framework NH2-MIL-101(Cr) as an efficient photocatalyst for the epoxidation of styrene.

Oxidation of styrene is a key reaction in the synthesis of pharmaceuticals and fine chemicals, and therefore oxidizing styrene with selective, efficient, and recyclable heterogeneous catalysts is significant from an environmental and economic standpoint. In this study, we report the transition Cr-based metal-organic framework [NH2-MIL-101(Cr)] as a heterogeneous photocatalyst, which efficiently promotes styrene epoxidation using H2O2 as a green oxidant, achieving high conversion efficiency (98%) and excellent selectivity (82%) under ambient conditions. Radical detection and quenching experiments reveal that the superoxide radical anion (O2˙-) acts as an active oxygen species, selectively promoting the oxidation of styrene to its oxidized form. This work provides insight into the development of a sustainable and cost-effective method for producing styrene oxide.

Challenges and opportunities on sustainable electrochemical transformations: application towards the synthesis of pharmaceuticals and precursors of drug-like molecules

This article highlighted the recent demand for sustainable and resource efficient drug synthesis using electrochemical strategies.

Exploring the reductive CO2 fixation with amines and hydrosilanes using readily available Cu(II) NHC-phenolate catalyst precursors.

N-Methylation of amines is of great interest in the synthesis of pharmaceuticals and valuable compounds, and the possibility to perform this reaction with an inexpensive and non-toxic substrate like CO2 and its derivatives is quite appealing. Herein, the synthesis of four novel homoleptic Cu(II) complexes with hybrid NHC-phenolate (NHC = N-Heterocyclic Carbene) ligands is reported, and their use in the catalytic N-methylation of amines with CO2 in the presence of hydrosilanes is explored. Both bidentate or tetradentate ligands can be used in the preparation of the complexes provided that the structural requirement that the two NHC and the two phenolate donors in the metal coordination sphere are mutually in trans is fulfilled. A new reaction protocol to perform the N-methylation of secondary aromatic amines and dibenzylamine in high yield under mild reaction conditions is developed, using the ionic liquid [BMMIM][NTf2] (1-butyl-2,3-dimethylimidazolium bis(trifluoromethylsulfonyl)imide) as solvent and the catalyst precursor [Cu(L2)2]. Reactivity studies indicate that the reaction follows two different pathways with different hydrosilanes, and that the starting Cu(II) complexes are reduced under the catalytic conditions.

Metal-catalyzed asymmetric reactions enabled by organic peroxides.

As a class of multifunctional reagents, organic peroxides play vital roles in the chemical industry, pharmaceutical synthesis and polymerization reactions. Metal-catalyzed asymmetric catalysis has emerged as one of the most straightforward and efficient strategies to construct enantioenriched molecules, and an increasing number of metal-catalyzed asymmetric reactions enabled by organic peroxides have been disclosed by researchers in recent years. Despite remarkable progress, the types of asymmetric reactions facilitated by organic peroxides remain limited and the catalysis systems need to be further broadened. To the best of our knowledge, there is still no review devoted to summarizing the reactions from this perspective. In this review, we will endeavor to highlight the advances in metal-catalyzed asymmetric reactions enabled by organic peroxides. We hope that this survey will summarize the functions of organic peroxides in catalytic reactions, improve the understanding of these compounds and inspire future developments in this area.

Combined Experimental and Molecular Dynamics Approach Towards a Rational Design of the YfeX Biocatalyst for Enhanced Carbene Transferase Reactivity

Pharmaceutical synthesis has been a driving force behind advancements in the field of biocatalysis. In this paper, we report the further optimization of the heme protein YfeX for regio- and...

New Progress of Fully Continuous Flow Reaction Technologies in Pharmaceutical Synthesis (2019~2022)

New Progress of Fully Continuous Flow Reaction Technologies in Pharmaceutical Synthesis (2019~2022)

Electrochemical chlorination of least hindered tertiary and benzylic C(sp3)–H bonds

Functionalization of C(sp3)–H bonds should greatly benefit the synthesis of natural products and pharmaceuticals.

Iron-catalysed intramolecular C(sp3)-H amination of alkyl azides.

Iron-catalysed intramolecular C(sp3)-H amination of alkyl azides (N3R, R = alkyl) via the iron-alkylnitrene/alkylimido (Fe(NR)) intermediate, is an appealing synthetic approach for the synthesis of various N-heterocycles. This approach provides a direct atom-economy strategy for constructing C(sp3)-N bonds, with nitrogen gas as the only by-product and iron is a biocompatible, cheap, and earth-abundant metal. However, C(sp3)-H amination with alkyl azides is challenging because alkyl nitrenes readily undergo 1,2-hydride migration to imines. This article summarizes recent major advances in this field in terms of catalyst design, substrate scope expansion, stereoselectivity control, understanding of key reaction intermediates, and applications in the synthesis of complex natural products and pharmaceuticals.

Organic photosensitized aziridination of alkenes.

We report a new TADF-catalyzed aziridination of alkenes under visible light. In this protocol, a free triplet nitrene is in situ generated from the commercially available tosyl azide by energy transfer of the excited photocatalyst 4DPAIPN. Our finding enables the smooth installation of the strained aziridine ring into a remarkably wide scope of alkenes and pharmaceutical-derived olefins and natural products, as well as the synthesis of sitagliptin. This metal-free method provides a new opportunity for the late-stage modification of complex molecules or synthesis of nitrogen-containing pharmaceuticals.

Enantioselective Lewis base catalysed allylation of picoline- and quinaldine-based latent pronucleophiles.

Picolines and quinaldines are valuable building blocks and intermediates in the synthesis of natural products and pharmaceuticals. Functionalization of the methyl group in picolines and quinaldines under mild conditions is challenging. We report that the concept of latent pronucleophiles enables Lewis base catalysed allylation of picolines and quinaldines with allylic fluorides starting from silylated picolines and quinaldines. Reactions afford enantioenriched allylation products when chiral Lewis base catalysts are used. The allylation products can be rapidly transformed to quinolizine-4-ones.

Levoglucosenone as a starting material for cascade continuous-flow synthesis of (R)-γ-carboxy-γ-butyrolactone.

The global imperative to shift towards renewable and sustainable resources has spurred significant interest in exploring and utilizing platform chemicals derived from renewable feedstocks. Among these, levoglucosenone (LGO) and Cyrene™ have emerged as promising candidates. LGO, derived from the pyrolysis of cellulose and hemicellulose, exhibits structural versatility, making it an attractive starting material for various valuable products. Its chemical transformations can yield a diverse array of derivatives, including levulinic acid, furan derivatives, and intermediates for pharmaceutical and agrochemical synthesis, as well as bio-based materials such as bioplastics and resins. Cyrene™, produced through the hydrogenation of LGO, serves as a renewable, biodegradable, and non-toxic dipolar aprotic solvent, offering sustainability advantages for green chemistry applications. Herein we report our results on the continuous-flow cascade transformation of LGO into Cyrene™ and then (R)-γ-carboxy-γ-butyrolactone in good yields with an additional mechanistic investigation for the Baeyer-Villiger oxidation of Cyrene™.

Brønsted acid-catalyzed regioselective ring opening of 2H-azirines by 2-mercaptopyridines and related heterocycles; one pot access to imidazo[1,2-a]pyridines and imidazo[2,1-b]thiazoles.

A catalytic and versatile synthetic method for the synthesis of imidazo[1,2-a]pyridines has been developed. Brønsted acid-catalysis plays a major role in the regioselective ring opening of 2H-azirines. Nucleophilic attack via the N-centre of mercaptopyridines and their analogues, followed by cyclisation by cleaving the C-S bond, allowed a library of imidazo[1,2-a]pyridines and related heterocycles to be built. The reaction protocol has been applied to various 2H-azirines, 2-mercaptopyridines, and thiazole-2-thiols, illustrating the generality of reaction conditions. The practical applications include the synthesis of pharmaceuticals, such as anti-tumor agents. This study introduces a novel approach to the synthesis of functional molecules with extensive potential.

Development of a green, concise synthesis of nicotinamide derivatives catalysed by Novozym® 435 from Candida antarctica in sustainable continuous-flow microreactors.

An increasing number of studies have shown that many nicotinamide derivatives exhibited extensive biological activities, such as anti-inflammatory and antitumor activity. In this paper, a green, concise synthesis of nicotinamide derivatives in sustainable continuous-flow microreactors catalysed by Novozym® 435 from Candida antarctica has been developed. Application of an easily obtainable and reusable lipase in the synthesis of nicotinamide derivatives from methyl nicotinate and amines/benzylamines reacted for 35 min at 50 °C led to high product yields (81.6-88.5%). Environmentally friendly tert-amyl alcohol was applied as a reaction medium. Substantially shorter reaction times as well as a significant increase in the product yield were obtained as compared to the batch process. This innovative approach provides a promising green, efficient and rapid synthesis strategy for pharmaceutical synthesis and further activity research of novel nicotinamide derivatives.

Metal- and photosensitizer-free cross-dehydrogenative coupling through photoinduced energy transfer

This study introduces a novel, eco-friendly method for Minisci alkylation without harmful catalysts, advancing sustainable pharmaceutical synthesis through energy transfer from heteroarenes to peroxide, offering significant environmental benefits.

Pd(II)/LA-catalyzed acetanilide olefination with dioxygen.

Transition-metal-catalyzed aromatic olefination through direct C-H activation represents an atom and step-economic route for versatile pharmaceutical syntheses, and in many cases, different stoichiometric oxidants are frequently employed for achieving a reasonable catalytic efficiency of the transition metal ions. Herein, we report a Lewis acid promoted Pd(II)-catalyzed acetanilide olefination reaction with atmospheric dioxygen as the oxidant source. The linkage of the Lewis acid to the Pd(II) species through a diacetate bridge significantly improved its catalytic efficiency, and independent kinetic studies on the olefination step revealed that adding the Lewis acid significantly accelerated the olefination rate as well as the C-H activation step. A strong basicity of the internal base in the Pd(II) salt also benefited the olefination reaction plausibly through base-assisted β-hydride elimination.

Rational Engineering of Mesorhizobium Imine Reductase for Improved Synthesis of N-Benzyl Cyclo-tertiary Amines

The effective synthesis of N-benzyl cyclo-tertiary amines using imine reductase, key components in natural products and pharmaceutical synthesis, is a green approach. Traditional methods faced challenges with enzyme activity and selectivity. This study focused on enhancing Mesorhizobium imine reductase (MesIRED) for better N-benzyl cyclo-tertiary amine production. Through alanine scanning and consensus mutation, 12 single-site MesIRED mutants were identified from 23 candidates, showing improved conversion of N-benzylpyrrolidine and N-benzylpiperidine. Notably, mutants from I177, V212, I213, and A241 significantly boosted conversions. The best-performing mutant for N-benzylpyrrolidine, MesIREDV212A/I213V (M1), increased conversion from 23.7% to 74.3%. For N-benzylpiperidine, MesIREDV212A/I177A/A241I (M2) enhanced conversion from 22.8% to 66.8%. Tunnel analysis revealed M1 and M2 have more efficient tunnels for larger product movement compared to wild-type MesIRED. Using recombinant E. coli coexpressing MesIRED and glucose dehydrogenase (GDH), high conversions were achieved: 75.1% for N-benzylpyrrolidine (M1) and 88.8% for N-benzylpiperidine (M2). A preparative experiment resulted in 86.2% conversion and 60.2% yield for N-benzylpiperidine. This research offers an efficient method for engineering IRED, significantly improving conversion and selectivity for N-benzyl cyclo-tertiary amines, aiding drug synthesis and providing insights into rational design of other enzymes.

Development and Applications of Water-Compatible Reactions: A Journey to Be Continued.

ConspectusThe pursuit of novel and eco-friendly methods in organic synthesis is gaining prominence, with a strong emphasis on green transformations using renewable and sustainable resources. Among these environmentally conscious approaches, water-compatible reactions stand out for their many advantages. Water, as a solvent, offers unmatched abundance, cost-efficiency, and environmental compatibility compared to organic solvents. Its use eliminates the need for complex protection and deprotection steps for reactive functional groups in multistep synthesis and enables the use of water-soluble substrates like proteins and carbohydrates. Water-compatible reactions also provide opportunities to combine with enzymes, resulting in chemoenzymatic transformations that can increase efficiency. Additionally, these reactions facilitate site-specific modification and the bioconjugation of biomolecules, leading to bioconjugate therapeutics.Over nearly three decades, our research group has been dedicated to developing innovative water-compatible methodologies and concepts. This Account provides a comprehensive overview of our contributions since 1994. Our central strategy revolves around integrating green chemistry principles into our methods, focusing on (i) developing reactions that can operate under mild conditions, including room temperature, atmospheric pressure, and physiological pH; (ii) designing atom-economical reactions that minimize waste production; (iii) replacing toxic and flammable organic solvents with eco-friendly alternatives like water and ethanol; and (iv) reducing reliance on metals or halogenated compounds in specific reactions.In this Account, we detail our achievements in developing efficient methodologies in aqueous media, highlighting their scope, limitations, asymmetric control, and applications for synthesizing complex molecules and functionalizing peptides and proteins. Mechanistic investigations underlying these developments are also discussed when applicable. Furthermore, we offer insights into the reasoning behind our work and address future opportunities and challenges in this area of research. We hope that this Account will inspire continued interest and foster new breakthroughs. By exploring innovative and broadly applicable strategies that expand the water-compatible synthetic toolbox, we aim to pave the way for the truly green and sustainable synthesis of complex molecules and pharmaceuticals.

Metabolic Engineering of Escherichia coli for De Novo Production of 1,2-Butanediol.

1,2-Butanediol (1,2-BDO) is an important platform chemical widely utilized in the synthesis of polyester polyols, plasticizers, cosmetics, and pharmaceuticals. However, no natural metabolic pathway for its biosynthesis has been identified, and biological production of 1,2-BDO from renewable bioresources has not been reported so far. In this study, we designed and experimentally verified a feasible non-natural synthesis pathway for the de novo production of 1,2-BDO from renewable carbohydrates for the first time. This pathway extends the l-threonine synthesis pathway by introducing two artificial metabolic modules to sequentially convert l-threonine into 2-hydroxybutyric acid and 1,2-BDO. Following key enzyme screening and enhancement of l-threonine synthesis module in the chassis microorganism, the best engineered Escherichia coli strain was able to produce 0.15 g/L 1,2-BDO using glucose as the sole carbon source. This work lays the foundation for the bioproduction of 1,2-BDO from renewable resources.