Synthesis Of Chiral Drugs Research Articles

Development Trends in Chiral Drug Synthesis Techniques

Development Trends in Chiral Drug Synthesis Techniques

Improvement of the enantioselectivity of lipase catalyzed reactions with deoxycholic acid‐based molecular tweezers

AbstractBACKGROUNDLipase as a hydrolase has important applications in the synthesis of chiral drugs. Based on the special interfacial activity of lipase, bile salt as a biosurfactant can effectively improve the catalytic activity of lipase.RESULTSIn this work, the strong selective recognition of the molecular tweezers and guest molecules helps improve the guest molecule concentration near the lipase catalytic center. However, this strong recognition will also make it difficult for the guest molecules to break away from the molecular tweezers. Therefore, there is an optimal value for this recognition that can effectively improve the chiral resolution effect of lipase.CONCLUSIONSThe two hydroxyl groups on deoxycholic acid were modified to prepare deoxycholic acid‐based molecular tweezers with two ‘arms’ and one ‘crack.’ The recognition performance between the molecular tweezers and amino acid methyl ester was determined by UV spectrophotometry. According to the binding constant, Ka, and free energy, −ΔG0, a complex formed between the deoxycholic acid‐based molecular tweezers (host) and amino acid methyl ester (guest) due to chiral recognition. Molecular tweezers were subsequently mixed with porcine pancreatic lipase (PPL) and candida rugosa lipase (CRL), respectively, to catalyze the transesterification of racemic tryptophan methyl ester. © 2023 Society of Chemical Industry.

Chemical Synthesis of Chiral Drugs

Chirality exists in most drugs and has a non-negligible impact on the pharmacological activity, metabolic process, and toxicity of drugs in the human body. Drug molecules can only bind to specific receptor molecules in the human body, and the difference in chirality will lead to different structures of drug molecules, which will lead to the inability of drug molecules to bind to receptor molecules, resulting in a decrease in the efficacy of the drug and even adverse effects on the human body. Therefore, the synthesis of correct chiral drugs has always been an area worth exploring. At present, there are two main approaches for the asymmetric synthesis of chiral drugs: chemical synthesis and biosynthesis. This paper explores the application of chemical synthesis to chiral drugs by combining asymmetric organocatalysis with chemical synthesis. In addition, this paper finds that asymmetric organocatalysis is a very worthwhile way to synthesize chiral drugs and has great potential in the development of new drugs.

Synthesis of Chiral Diaryl Methanols via RuPHOX‐Ru Catalyzed Asymmetric Hydrogenation

AbstractThe RuPHOX‐Ru catalyzed asymmetric hydrogenation of diaryl ketones has been established, providing the corresponding chiral diaryl methanols in up to 99% yield and 99% ee. The protocol could be performed on a gram‐scale with a relatively low catalyst loading (2000 S/C) and the resulting products allow for several useful transformations, in particular for the synthesis of chiral drugs, such as, (S)‐Orphenadrine and (S)‐Neobenodine. Deuterium labeling and control experiments revealed that the RuPHOX‐Ru‐catalyzed asymmetric hydrogenation is fully subject to hydrogenation with H2 as the sole hydrogen source.magnified image

Rapid discrimination of enantiomers by ion mobility mass spectrometry and chemical theoretical calculation: Chiral mandelic acid and its derivatives

Because R/S-mandelic acids (MA) and their derivatives are critical starting materials or intermediates in the synthesis of chiral drugs, their chirality discrimination is important. In this study, R/S-MA and its derivatives, including R/S-2-phenylpropionic acid (2-PPA), R/S-methoxyphenylaceticacid (MPA), and R/S-2-hydroxy-4-phenylbutyric acid (HPBA), were accurate simultaneous mobility-discriminated by forming diastereomer complexes for the first time, which were obtained by simply mixing with cyclodextrins (α, β, γ-CD) and transition-metal ions (Mn2+, Fe2+, Co2+, Ni2+, Cu2+, and Zn2+). The mass spectra revealed non-covalent diastereomer complexes formed by CD, enantiomers, and metal ions, and ion-mobility spectrometry (IMS) was performed for 109 pairs of complexes. Significant chiral discrimination was observed in the formed diastereomeric complexes, and their separation peak-to-peak resolution (Rp−p) for the enantiomers depended on the transition metal ion type. In most cases, the Rp−p value gradually increases with CD size, with quaternary complexes having the largest Rp−p value. The greatest chiral distinctions of 2-PPA, MA, MPA, and HPBA were obtained by the diastereomeric complex ions of [(2-PPA)(α)2+Zn2+-H]+, [(MA)(α)2+Zn2+-H]+, [(MPA)2(β)+Co2+-H]+, and [(HPBA)(α)2+Fe2+-H]+, with Rp−p values of 1.35, 1.57, 1.70, and 0.71, respectively. Furthermore, the favorable conformation and collisional cross section (CCS) value of the different [CD + R/S-MA + Cu–H]+ complexes were measured using chemical theoretical calculations to detail their intermolecular interaction, revealing that [α-CD + R/S-MA + Cu–H]+ has two favored gas complexes, and the CCS calculated were consistent with the TIMS observed. In addition, R2 > 0.99 was obtained for the relative quantification of the chiral enantiomers. Overall, the proposed method provides a promising strategy for distinguishing the enantiomers of MA and their derivatives, with the advantages of simplicity, speed, and accuracy, without the need for complex chemical derivatization or chromatographic separation.

Nonlinear Effects in Asymmetric Catalysis by Design: Concept, Synthesis, and Applications.

Asymmetric synthesis constitutes a key technology for the preparation of enantiomerically pure compounds as well as for the selective control of individual stereocenters in the synthesis of complex compounds. It is thus of extraordinary importance for the synthesis of chiral drugs, dietary supplements, flavors, and fragrances, as well as novel materials with tunable and reconfigurable chiroptical properties or the assembly of complex natural products. Typically, enantiomerically pure catalysts are used for this purpose. To prepare enantiomerically pure ligands or organocatalysts, one can make use of the natural chiral pool. Ligands and organocatalysts with an atropisomeric biphenyl and binaphthyl system have become popular, as they are configurationally stable and contain a C2-symmetric skeleton, which has been found to be particularly privileged. For catalysts with opposite configurations, both product enantiomers can be obtained. Configurationally flexible biphenyl systems initially appeared to be unsuitable for this purpose, as they racemize after successful enantiomer separation and thus are neither storable nor afford a reproducible enantioselectivity. However, there are strategies that exploit the dynamics of such ligands to stereoconvergently enrich one of the catalyst enantiomers. This can be achieved, for example, by coordinating an enantiomerically pure additive to a ligand-metal complex, which results in deracemization of the configurationally flexible biphenyl system, thereby enriching the thermodynamically preferred diastereomer. In this Account, we present our strategy to design stereochemically flexible catalysts that combine the properties of supramolecular recognition, stereoconvergent alignment, and catalysis. Such systems are capable to recognize the chirality of the target product, leading to an increase in enantioselectivity during asymmetric catalysis. We have systematically developed and investigated these smart catalyst systems and have found ways to specifically design and synthesize them for various applications. In addition to (i) reaction product-induced chiral amplification, we have developed systems with (ii) intermolecular and (iii) intramolecular recognition, and successfully applied them in asymmetric catalysis. Our results pave the way for new applications such as temperature-controlled enantioselectivity, controlled inversion of enantioselectivity with the same chirality of the recognition unit, generation of positive nonlinear effects, and targeted design of autocatalytic systems through dynamic formation of transient catalysts. Understanding such systems is of enormous importance for catalytic processes leading to symmetry breaking and amplification of small imbalances of enantiomers and offer a possible explanation of homochirality of biological systems. In addition, we are learning how to target supramolecular interactions to enhance enantioselectivities in asymmetric catalysis through secondary double stereocontrol. Configurationally flexible catalysts will enable future resource-efficient development of asymmetric syntheses, as enantioselectivities can be fully switched by stereoselective alignment of the stereochemically flexible ligand core on demand.

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

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.

Iridium-catalyzed enantioselective synthesis of chiral γ-amino alcohols and intermediates of (S)-duloxetine, (R)-fluoxetine, and (R)-atomoxetine

Chiral γ-amino alcohols are the prevalent structural motifs and building blocks in pharmaceuticals and bioactive molecules. Enantioselective hydrogenation of β-amino ketones provides a straightforward and powerful tool for the synthesis of chiral γ-amino alcohols, but the asymmetric transformation is synthetically challenging. Here, a series of tridentate ferrocene-based phosphine ligands bearing modular and tunable unsymmetrical vicinal diamine scaffolds were designed, synthesized, and evaluated in the iridium-catalyzed asymmetric hydrogenation of β-amino ketones. The system was greatly effective to substrates with flexible structure and functionality, and diverse β-tertiary-amino ketones and β-secondary-amino ketones were hydrogenated smoothly. The excellent reactivities and enantioselectivities were achieved in the asymmetric delivery of various chiral γ-amino alcohols with up to 99% yields, >99% ee values, and turnover number (TON) of 48,500. The gram-scale reactions with low catalyst loading showed the potential application in industrial synthesis of chiral drugs, such as (S)-duloxetine, (R)-fluoxetine, and (R)-atomoxetine.

Fourier Transform Infrared (FTIR) Spectroscopic Analysis of Amino Acid Serine for its Chiral Identification

Synthesis of chiral drugs required chiral starting materials organic compounds. DL serine is an amino acid that is used as a key starting material in the synthesis of many drug substances. D or L isomer of Serine will lead to the chiral drug substances whereas DL mixture will lead to racemic drug substances. FTIR can be used as the primary analytical tool for the identification of Serine isomers and its racemic mixture. Many absorption bands in FTIR spectra identify whether a molecule is a specific isomer or racemic mixture. A systematic comparison of FTIR spectroscopic data is carried out revealing that the compound is the specific isomer and the racemic mixture shows different spectra with different bands.

Mechanoenzymology in the Kinetic Resolution of β-Blockers: Propranolol as a Case Study.

Recent advances in biotechnology, protein engineering, and enzymatic immobilization have made it possible to carry out biocatalytic transformations through alternative non-conventional activation strategies. In particular, mechanoenzymology (i.e., the use of the mechanical force produced by milling or grinding to activate a biotransformation) has become a new area in so-called "green chemistry", reshaping key fundaments of biocatalysis and leading to the exploration of enzymatic transformations under more sustainable conditions. Significantly, numerous chiral active pharmaceutical ingredients have been synthesized via mechanoenzymatic methods, boosting the use of biocatalysis in the synthesis of chiral drugs. In this regard and aiming to widen the scope of the young field of mechanoenzymology, a dual kinetic resolution of propranolol precursors was explored. The biocatalytic methodology mediated by Candida antarctica Lipase B (CALB) and activated by mechanical force allowed the isolation of both enantiomeric precursors of propranolol with high enantiomeric excess (up to 99% ee), complete conversion (c = 50%), and excellent enantiodifferentiation (E > 300). Moreover, the enantiomerically pure products were used to synthesize both enantiomers of the β-blocker propranolol with high enantiopurity.

Structure-guided protein engineering of ammonia lyase for efficient synthesis of sterically bulky unnatural amino acids

Enzymatic asymmetric amination addition is seen as a promising approach for synthesizing amine derivatives, especially unnatural amino acids, which are valuable precursors to fine chemicals and drugs. Despite the broad substrate spectrum of methylaspartate lyase (MAL), some bulky substrates, such as caffeic acid, cannot be effectively accepted. Herein, we report a group of variants structurally derived from Escherichia coli O157:H7 MAL (EcMAL). A combined mutagenesis strategy was used to simultaneously redesign the key residues of the entrance tunnel and binding pocket to explore the possibility of accepting bulky substrates with potential application to chiral drug synthesis. Libraries of residues capable of lining the active center of EcMAL were then constructed and screened by an effective activity solid-phase color screening method using tyrosinase as a cascade catalyst system. Activity assays and molecular dynamics studies of the resultant variants showed that the substrate specificity of EcMAL was modified by adjusting the polarity of the binding pocket and the degree of flexibility of the entrance tunnel. Compared to M3, the optimal variant M8 was obtained with a 15-fold increase in catalytic activity. This structure-based protein engineering of EcMAL can be used to open new application directions or to develop practical multi-enzymatic processes for the production of various useful compounds.

Recent Advances in Catalytic Asymmetric Aza‐Michael Addition Triggered Cascade Reactions

AbstractAs an important branch of the Michael addition reaction, the aza‐Michael addition cascade reaction has been developed rapidly in recent years. This is because the reaction serves as an important method for effectively constructing functionalized C−N bonds, which can be widely used in the synthesis of chiral drugs and their intermediates and natural products. Given the importance of this topic, this review highlights the recent developments of aza‐Michael addition triggered cascade reactions in asymmetric synthesis, including aza‐Michael/Michael, aza‐Michael/Aldol, aza‐Michael/Henry, aza‐Michael/hemiacetal, aza‐Michael/Mannich, aza‐Michael/alkylation, aza‐Michael/cyclization, aza‐Michael/ring‐opening, aza‐Michael‐IED/HAD, aza‐Michael/INCR, and aza‐Michael/1,6‐conjugate addition reactions. In this paper, the reaction mechanism and derivatization experiments of different reactions are timely introduced to provide a more comprehensive theoretical basis for subsequent studies.magnified image

High-pressure asymmetric hydrogenation in a customized flow reactor and its application in multi-step flow synthesis of chiral drugs

Asymmetric homogeneous hydrogenation under high pressure in continuous flow was achieved with a slug flow reactor. High hydrogen pressure enabled iridium-catalyzed asymmetric hydrogenation of acetophenone with a turn-over-frequency (TOF) of up to 274,000 h−1. An operando infrared tool was used to provide in-situ monitoring of the reaction. The effect of gas-liquid ratio and speed of slug flow in the microchannel were studied. The multi-step flow synthesis of active pharmaceutical ingredients, in which asymmetric hydrogenation is a key step, was successfully demonstrated, with subsequent reactions carried out under longer residence times within a cascade of CSTRs.

Research progress of molecularly imprinted polymers in separation of chiral drugs by capillary electrochromatography

Chiral drugs exert pharmacological effects through strict matching with chiral biological macromolecules and chiral recognition. Each enantiomer has different pharmacological activities, metabolic processes and rates, as well as toxicity pharmacokinetic characteristics owing to the difference in its interactions with the chiral environment. Therefore, method development for the resolution of chiral drugs is of great significance for the synthesis of chiral drugs and for quality control during the production process. Molecularly imprinted polymers (MIPs) are prepared by using a target molecule as the template. MIPs demonstrate highly specific recognition properties toward the target molecule since they have specific spatial molecular structures and functional groups. Hence, MIPs are particularly suitable for the separation and purification of chiral drugs. Capillary electrochromatography (CEC) offers the advantages of high separation efficiency and high selectivity owing to the dual separation mechanisms including capillary electrophoresis and liquid chromatography. By using MIPs as the stationary phases for CEC, the advantages of the two technologies can be combined to achieve efficient separation of chiral drugs. MIPs were first applied to CEC for chiral resolution in 1994, and since then, there have been notable advances in this field. The four main chiral separation modes in CEC involve the use of MIPs as the stationary phases of open tubular, packed, and monolithic columns, and as the pseudostationary phase in the separation medium. This review summarizes the research progress of these four methods and reveals the potential of MIPs in chiral resolution by CEC. The advantages and disadvantages of these methods are commented. MIPs as the stationary phases of packed columns can allow for chiral separation. However, the preparation of packed columns in narrow capillaries is difficult. In addition, frits must be prepared at the ends of the capillaries to seal the MIPs. The frits lead to the formation of bubbles during the CEC analysis, thus resulting in poor repeatability and stability. These problems can be overcome by using MIP-based open tubular columns. Furthermore, conditioning of open tubular columns is easy and less time-consuming. However, open tubular columns have limited capacity. MIP-based monolithic columns have greater capacity than do open tubular columns, and frits are not required in this case. However, in situ preparation of MIPs monolith in narrow capillaries is still challenging. The application of MIPs to chiral CEC can also be realized by using them as pseudostationary phases (additives) in the separation medium, and this allows for ease of operation. Moreover, the amount of MIPs introduced into the capillary can be accurately controlled. Thus, the batch-to-batch reproducibility can be improved, but this has the disadvantage of increased MIP consumption. In order to further expand the potential of MIPs in chiral CEC, the following aspects must be considered. First, improvement of the preparation method. In most reported MIP-based-chiral CEC techniques, the peaks of the imprinted molecules show severe tailing, and this problem must be resolved. Improving the mass transfer rate of the prepared MIPs may be a suitable solution in this regard. Second, development of new functional monomers. A functional monomer is an indispensable component in the preparation of MIPs. New functional monomers can be prepared according to the "three-point interaction" rule. Third, selection of template molecules. A single enantiomer of chiral drugs is used as the template molecule to prepare chiral MIPs. The method is not suitable for the preparation of MIPs of chiral drugs for which a single enantiomer is difficult to obtain. Therefore, appropriate choice of the template molecules for these drugs is imperative. Fourth, discussion of chiral separation mechanism. The mechanism of interaction between the template molecules and MIPs needs to be explored further, in order to obtain theoretical guidance for the design and preparation of chiral MIPs.

Neutrophil-Membrane-Directed Bioorthogonal Synthesis of Inflammation-Targeting Chiral Drugs

Summary Targeted bioorthogonal catalysis holds great potential for localized prodrug activation. Although enantiomerically pure drugs are of vital importance in the clinic, chiral drug synthesis by bioorthogonal reactions in living systems is scarcely reported. Toward this goal, we constructed chirally modified Pd catalysts for the asymmetric transfer hydrogenation (ATH) reaction by using sodium formate as the biocompatible reductant. By combining the ATH reaction and chemotaxis of neutrophil membrane, we achieved inflammation site-selective chiral drug synthesis in living cells. As a proof of concept, we synthesized the chiral model drug ibuprofen in situ by a targeted ATH reaction to alleviate inflammation in the mouse paw as an in vivo model. Compared with controls, the neutrophil-membrane-coated chiral Pd catalysts exhibited inflammation-targeted capability and enantioselectivity simultaneously in the anti-inflammatory action. This study could offer a novel perspective for bioorthogonal catalysis in targeted prodrug activation.

Efficient Synthesis of Chiral Drugs Facilated by P-Chiral Phosphorus Ligands

Efficient Synthesis of Chiral Drugs Facilated by <i>P</i>-Chiral Phosphorus Ligands

Increased Selectivity of Novozym 435 in the Asymmetric Hydrolysis of a Substrate with High Hydrophobicity Through the Use of Deep Eutectic Solvents and High Substrate Concentrations.

The effects of the reaction medium and substrate concentration were studied on the selectivity of Novozym 435 using the asymmetric hydrolysis of dimethyl-3-phenylglutarate as a model reaction. Results show that the use of choline chloride ChCl:urea/phosphate buffer 50% (v/v) as a reaction medium increased the selectivity of Novozym 435 by 16% (e.e = 88%) with respect to the one in 100% phosphate buffer (e.e = 76%). Best results were obtained when high substrate concentrations (well above the solubility limit, 27-fold) and ChCl:urea/phosphate buffer 50% (v/v) as reaction medium at pH 7 and 30 °C were used. Under such conditions, the R-monoester was produced with an enantiomeric purity of 99%. Novozym 435 was more stable in ChCl:urea/phosphate buffer 50% (v/v) than in phosphate buffer, retaining a 50% of its initial activity after 27 h of incubation at pH 7 and 40 °C. Results suggest that the use of deep eutectic solvents (ChCl:urea/phosphate buffer) in an heterogeneous reaction system (high substrate concentration) is a viable and promising strategy for the synthesis of chiral drugs from highly hydrophobic substrates.

A chiroptical nanoprobe for highly selective recognition of histidine enantiomers in aqueous media

Histidine is one of the essential amino acids in the human body, and the variation of its concentration in vivo has shown it to align with some liver and kidney diseases. In this work, a series of novel poly(2-oxazoline) derivatives bearing chiral pyrrolidine–triazole moieties in the side chain were designed and synthesized to serve as chemical sensors for histidine. The results demonstrated that the homopolymer HPOx2 is capable of selectively binding optically active histidine through nitrogen/Cu2+ coordination to form complexes exhibiting induced circular dichroism (ICD) signals with signs related to the absolute configuration of the guest compound. Interestingly, the micelle-type nanoparticles assembled from the corresponding amphiphilic copolymer (CPOx2) gave a much stronger CD response, with an intensity five times that of its small molecule- or homopolymer counterparts. The proposed method, based on the chiroptical probe, allows for enantioselective detection of histidine in aqueous media, showing potential application in the field of biomedical assay and chiral drug synthesis.

Properties, biosynthesis, and catalytic mechanisms of hydroxy-amino-acids

The hydroxy amino acids have its unique effects in the biotechnology and molecular biology, and all sorts of synthetic hydroxy amino acids have also been developed. The hydroxy amino acids have been proved to be valuable for antifungal, antibacterial, antiviral and anticancer properties and known as a constituent of pharmaceutical intermediates. In addition to these fundamental researches, the hydroxy amino acids are applied widely to the synthesis of chiral drugs, such as (2S, 3R, 4S)-4-hydroxyisoleucine (4-HIL) is proved to be worthy in medical treatment, cis-4-hydroxy-L-proline (C4LHyp) and trans-4-hydroxy-L-proline (T4LHyp) are applied to build the chiral intermediates in pharmaceutical synthesis. Through comparisons chemical synthesis with biological catalysis to form hydroxy amino acids, enantioselective biocatalysts will undoubtedly be used in the synthesis of chiral pharmaceuticals. Mononuclear non-heme Fe(II)/α-ketoglutarate-dependent dioxygenases (Fe/αKGDs) that use an Fe(IV) complex intermediate to active diverse oxidative transformations with key biological roles. Studies identifying the important intermediates in catalysis and the proposed mechanisms are explained. In summary, we describe the physiological properties and synthesis regarding hydroxy amino acids, particularly 4-HIL and hydroxyproline. And the proposed catalysis mechanisms of Fe/αKGDs are also explained, while we also discussed the applications of hydroxy amino acids in fundamental research and industrial.

Dynamic kinetic resolution of amines by using palladium nanoparticles confined inside the cages of amine-modified MIL-101 and lipase

Dynamic kinetic resolution (DKR) of amines is an important strategy for the synthesis of chiral drugs and their building blocks; however, improving the matchability of metal-catalyzed racemization and enzymatic resolution is still a task. In this paper, Pd nanoparticles (NPs) were encapsulated inside the cages of ethylenediamine-grafted MIL-101 (ED-MIL-101), giving highly efficient catalysts (Pd/ED-MIL-101) for the racemization of primary amines. The racemization can be combined with lipase-catalyzed resolution in a one-pot DKR of rac-1-phenylethylamine leading to optically pure product (>99% ee value) with an excellent conversion and selectivity up to 99% and 93%, respectively, superior to other catalysts, such as Pd/MIL-101, Pd/MCM-41 and commercially available Pd/C. Furthermore, the heterogeneous chemoenzymatic catalyst combination can be recovered and recycled 8 times without significant loss of efficiency. The enhance catalytic performances were found to depend on the amine modification of MIL-101 that not only endows the surface of its cages with basic property, but also enables efficiently confining Pd NPs in the cages. In addition, the matchability of such chemoenzymatic catalyst combination can be further enhanced by conducting the DKR process under microwave irradiation.