Asymmetric catalysis, or enantioselective catalysis, is a chemical reaction that produces a chiral compound from achiral starting materials. In this type of catalysis, the catalyst is itself chiral, and it selectively induces the formation of a specific stereoisomer over its mirror image.
Asymmetric catalysis, typically involving transition metal organometallic catalysts such as rhodium, offers a highly efficient and selective approach. Researchers are now focusing on utilizing more abundant metals like copper to reduce costs and improve accessibility. This shift also enables reactions under milder conditions, minimizing the use of hazardous reagents and solvents, thereby advancing sustainable chemistry. Additionally, non-metal enantioselective organocatalysts, such as proline derivatives, alongside biocatalysts employing enzymes, have gained prominence for their effectiveness in producing specific enantiomers.
Alternative methods to generate specific enantiomers include stoichiometric synthesis directly from chiral substrates, conversion of racemic mixtures into diastereomers that are not mirror images, and crystallization and chromatographic resolution. These traditional methods can be costly and time-consuming, often generating significant waste while delivering suboptimal yields and enantiomeric purity.
This white paper presents examples from recent peer-reviewed research that show how the in-depth information and precise control provided by METTLER TOLEDO technologies aid in supporting green and sustainable chemistry across four thematic topics:
Asymmetric catalysis is a valuable tool for synthesizing high-quality products in an efficient and environmentally friendly manner. It has several advantages over traditional synthetic methods:
Chirality, or "handedness," can be introduced into an asymmetric catalysis reaction to produce large quantities of a single stereoisomer via several different mechanisms. The specific mechanism will depend on the particular reaction conditions and the type of catalyst used. The most commonly used mechanisms include:
Asymmetric synthesis is the process of synthesizing a molecule with a specific stereochemistry in high yield. It is a key area of chemical synthesis research, as the properties and biological activities of a molecule are often dependent on its stereochemistry.
While asymmetric catalysis is a crucial tool in asymmetric synthesis, molecules with specific stereochemistry can also be produced via chiral catalysis, biocatalysis, or organocatalysis.
Chiral catalysis is a subfield of asymmetric catalysis that involves the use of chiral catalysts to facilitate chemical reactions in a stereoselective manner. A chiral catalyst is a molecule that has a specific spatial arrangement of its atoms, giving it a handedness or chirality. When used in a chemical reaction, the chiral catalyst can interact with the substrate to produce a single stereoisomer in high yield.
The importance of chiral catalysis lies in the fact that many chemical reactions produce a mixture of stereoisomers, which can have different properties and biological activities. By using chiral catalysts, a single stereoisomer can be selectively produced. This stereoisomer can have improved properties and greater usefulness.
For example, in the pharmaceutical industry, the efficacy and safety of a drug often depends on its stereochemistry. Chiral catalysis can produce a single stereoisomer of a drug. This method achieves a high yield. It improves the therapeutic potential of the drug. It also reduces the likelihood of side effects. The ability to selectively produce single stereoisomers of these compounds can improve properties. It can also increase efficiency and reduce waste.
Biocatalysis, or enzymatic catalysis, is the use of biologically active components to catalyze chemical transformations. Biocatalysis facilitates a spectrum of primarily carbon-centric reactions that occur in environments ranging from cell-free, fully in vitro to fermentation-mediated processes in living cell culture.
Biocatalysis represents a useful alternative to traditional chemical catalysis for several reasons. Enzymatic biocatalyst reactions:
1. Are highly chemo-, regio- and enantiospecific
2. Often have rapid kinetics
3. Operate under milder conditions than chemical catalysts
4. Eliminate the issue of waste, toxicity, and cost of metal catalysts
5. Reduce energy requirements associated with chemical reactions
Organocatalysis uses specific organic molecules that can accelerate chemical reactions via catalytic activation. Due to their efficiency and selectivity, organocatalysts are attractive in efforts toward sustainable chemistry, enabling several primary tenets of green chemistry, resulting in less hazardous syntheses, more energy efficiency, and atom economy.
Asymmetric organocatalysis is beneficial in achieving the desired enantiomeric and/or diastereomeric forms of compounds, which is important in pharmaceutical syntheses. Reactions using organocatalysts typically proceed via four distinct mechanisms based on whether the catalyst acts as a Lewis acid, Lewis base, Brønsted acid, or Brønsted base. Thus, the scope of organocatalysis is broad, influencing many different classes of reactions.
A thorough understanding of reaction kinetics, mechanism, catalytic cycles, and the impact of variables is essential to optimizing enantiomeric ratios and product yield, as well as reducing costs and waste.
To obtain accurate data, precise control of fundamental reaction parameters such as temperature, pressure, reactant dosage rate, and stirring rate is critical. Automated laboratory reactors are widely used in academic and industrial settings to achieve this control. The recent expansion of EasyMax™ lab reactor capabilities to include precise temperature control as low as -78 °C expands the design space for catalytic processes.
Superior reactor control enhances the accuracy of reaction measurements, including the analysis of reagents, reactants, catalyst species, transient intermediates, and by-product impurities. Real-time tracking of reaction species enables the collection of data-rich experiments that can inform the development of kinetic parameters and support proposed reaction mechanisms, including catalytic cycles.
In-situ, real-time FTIR and Raman spectroscopy are established techniques for gaining a deeper understanding of catalytic reactions. ReactIR™ and ReactRaman™ spectrometers were designed for chemical reaction analysis, offering a range of insertion probes and flow cells that can handle the wide range of temperatures and pressures often required for catalytic reaction investigations.
Automated sampling of chemical reactions enables increased productivity by addressing challenges on two scales:
EasySampler™ is an automated reactor sampling system designed for inline acquisition, quenching, and dilution of reaction samples. It allows samples to be retrieved under reaction conditions and eliminates manual sampling process challenges.
DirectInject-LC™ delivers in-situ, real-time analysis of chemical reactions using chromatographic measurements. The automated system addresses the inherent difficult issues associated with chromatography, such as reaction sampling, quenching, dilution, and interfacing with the chromatograph. DirectInject-LC differentiates and measures key species as the reaction proceeds, yielding an in-depth understanding of reaction kinetics, mechanism, and the effect of variables on reaction outcome. DirectInject-LC interfaces with HPLC-MS, UHPLC, and chiral HPLC systems for advanced separation and analysis capability.
When scaling up catalytic reactions, recent advances in chemical reaction modeling provide the information necessary for safer, higher-yield reactions with fewer impurities. Dynamic modeling of experimental data also offers deeper insights into reaction kinetics and the effect of reaction variables.
Chen, W., Cheng, Y., Zhang, T., Mu, Y., Jia, W., & Liu, G. (2021). NI/ANTPHOS-Catalyzed stereoselective asymmetric intramolecular reductive coupling of N-1,6-Alkynones. The Journal of Organic Chemistry, 86(7), 5166–5182. https://doi.org/10.1021/acs.joc.1c00079
The authors report the synthesis of a range of pyrrolidines containing chiral tertiary allylic alcohols (with >99:1 E/Z stereoselectivity and >99:1 er), from the asymmetric nickel-catalyzed reductive coupling of N-1,6-alkynones. They accomplished this using bis(cyclooctadiene)nickel(0) with a P-chiral mono-phosphine ligand [(R)-AntPhos] and triethylsilane as the reducing agent. Next, they investigated the mechanism of the reaction, focusing on how the (R)-AntPhos affects the stereoselectivity and enantioselectivity of the tertiary allylic alcohol moiety. They proposed a monomeric metallocyclic model for the catalytic cycle of the asymmetric reductive coupling of N-1,6-alkynones with (R)-AntPhos and performed an in-situ FTIR experiment to investigate the catalytic cycle.
Stoichiometic amounts of Ni(cod)2 and (R)-AntPhos ligand were mixed and an IR band at 1392-1 was tracked, indicative of the Ni(0) (R)-AntPhos compound in the first stage of the catalytic cycle. With the addition of the N-1,6-alkynone, a strong ketone band appeared at 1708 cm-1 which gradually diminished as the alkynone reacted to form the Ni(II) metallocycle in the third stage of the proposed catalytic cycle. With the addition of the HSiEt3 reducing agent, a band at 2092 cm-1 was observed that diminished over time as the cyclized tertiary allylic alcohol formed. In-depth mechanistic examination and ReactIR data allowed the authors to determine that the cycloaddition stage Ni(II) metallacycle determines the enantioselectivity, and the (R)-AntPhos ligand is key by providing a bulky π-conjugated system that affects the stereochemistry.
Sharma, H. A., Essman, J. Z., & Jacobsen, E. N. (2021). Enantioselective catalytic 1,2-boronate rearrangements. Science, 374(6568), 752–757. https://doi.org/10.1126/science.abm0386
The authors commented that a catalytically accessed common chiral intermediate could be valuable for the synthesis of a wide range of molecules featuring trisubstituted stereocenters. They postulated that an enantioselective rearrangement of pinacol-substituted dichloromethyl boronates via a catalyst could result in the trisubstituted stereocenters. As a model reaction, the rearrangement of a lithium boronate substrate was investigated. Using an arylpyrrolidine-tert-leucine–derived thiourea, an α-chloro boronic ester product was synthesized with a 48% ee. They found that when the thiourea was present during the initial synthesis of the lithium boronate (from dichloromethyl boronic acid pinacol ester and n-butyllithium), the resultant α-chloro boronic ester product exhibited a 92% ee.
Following this work, a stable isothiourea-boronate precatalyst was developed and when this compound was lithiated with LiHMDS, in-situ FTIR (ReactIR) measurements showed significant shifts in both the isothiourea N–C–N band and the amide C–O band. These shifts were reversible when HCl was added. The authors postulated that the N–H bond in the precatalyst was deprotonated by the LiHMDS via a chelation process. DFT measurements were performed and supported the observed experimental IR shifts. With this information, the authors went on to examine the scope of the novel lithium-thiourea-boronate catalyst system for the synthesis of a wide range of molecules containing C–C, C–N, and C–O bonds and having excellent ee and yields.
Zhang, Z., Bae, H. Y., Guin, J., Rabalakos, C., Van Gemmeren, M., Leutzsch, M., Klußmann, M., & List, B. (2016). Asymmetric counteranion-directed Lewis acid organocatalysis for the scalable cyanosilylation of aldehydes. Nature Communications, 7(1). https://doi.org/10.1038/ncomms12478
The authors report developing an asymmetric Lewis acid catalysis method for cyanosilylation of aldehydes using trimethylsilyl cyanide and a chiral disulfonimide pre-catalyst. As a result of the high activity, catalyst loadings of 0.05%-0.005% were effective in producing the desired cyanohydrin product. The authors report that an inactive period of the catalyst is observed that can be reversibly induced by water. To further understand this development, in-situ FTIR was used and provided significant insight into the pre-catalytic cycle.
To monitor the concentration of the aldehyde reactant, the 1703 cm-1 carbonyl band was tracked vs. time. Interestingly, no reaction was observed for a period of time, after which the transformation proceeded rapidly. The authors thought that the reason for the dormant period might be related to water in the reaction mixture. Through an experimental protocol of adding controlled amounts of water to the reaction mixture, it was proved that water was indeed responsible for the lack of activity via hydrolysis of the catalytically active species. In earlier work in which a silyl ketene acetal was reacted with an aldehyde in the presence of a disulfonimide catalyst, no dormant period was observed. They thought this might be due to the high reactivity of the silyl ketene acetal with the pre-catalyst, instantly regenerating the active Lewis acid catalyst. To test this hypothesis in the current work, they used a catalytic amount of silyl ketene acetal as an activator and found that the dormant period was avoided. Based on further experiments, they proposed a pre-catalytic cycle that reflects the dormant period.
Asymmetric catalysis is a widely applied method of synthesizing specific enantiomers of chiral molecules. Typically, asymmetric catalysis involves organometallic compounds containing one or more chiral ligands. Since the process is catalytic, insignificant amounts of the chiral catalyst act on the prochiral substrate producing significant amounts of the desired enantiomer. Thus, it is an efficient means to produce the enormous quantities of specific enantiomeric compounds required by the pharmaceuticals, food, agrochemical, and cosmetic industries.
Asymmetric catalysis plays a significant role in the production of important chemicals such as pharmaceuticals, agrochemicals, and materials, as well as in the synthesis of natural products. It enables the efficient production of enantiopure compounds, which are essential for drug development and for many other applications in the chemical industry. Asymmetric catalysis can be achieved by a variety of mechanisms, including Lewis acid-base interactions, hydrogen bonding, and metal-ligand coordination. Examples of chiral catalysts that are commonly used in asymmetric catalysis include chiral ligands, chiral auxiliaries, and chiral Lewis acids. The development of new and more efficient asymmetric catalytic processes is an active area of research in chemistry, with the aim of improving the efficiency and selectivity of chiral synthesis.
There are many examples of chiral catalysts used in asymmetric catalysis. The most common are:
The stereochemistry of a product in asymmetric catalysis is controlled by the chiral catalyst. The catalyst induces a chiral environment around the reacting molecules, which selectively favors the formation of one enantiomer over the other. The exact mechanism by which the chiral catalyst controls the stereochemistry of the reaction depends on the type of catalyst and the reaction being catalyzed.