{"id":5433,"date":"2024-09-05T08:00:00","date_gmt":"2024-09-05T02:30:00","guid":{"rendered":"https:\/\/chiralpedia.com\/blog\/?p=5433"},"modified":"2024-09-05T08:04:21","modified_gmt":"2024-09-05T02:34:21","slug":"asymmetric-synthesis-in-industry-from-lab-to-market","status":"publish","type":"post","link":"https:\/\/chiralpedia.com\/blog\/asymmetric-synthesis-in-industry-from-lab-to-market\/","title":{"rendered":"Asymmetric Synthesis in Industry: From Lab to Market"},"content":{"rendered":"\n

Introduction<\/strong><\/p>\n\n\n\n

Asymmetric synthesis<\/a> is a cornerstone of industrial chemistry, enabling the production of enantiomerically pure compounds that are essential in various sectors. Its importance lies in the ability to produce specific enantiomers that exhibit desired biological activities or material properties. Asymmetric synthesis is the process of turning a non-chiral starting material into a chiral product. This blog explores the industrial applications of chiral asymmetric synthesis, highlighting its critical role in pharmaceuticals, agrochemicals, fine chemicals, and materials science, as well as addressing the challenges and solutions related to its scalability and sustainability.<\/p>\n\n\n\n

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Source: https:\/\/doi.org\/10.3390\/ph16030339

Existence of chirality in the human body<\/mark>

Chirality is a fascinating and widespread phenomenon. In nature, chirality can be seen in both large and small objects. A molecule is considered chiral if it can exist in two forms, known as enantiomers, which are mirror images of each other but cannot be superimposed. Human body is classical chiral environment since it is filled with chiral discriminators (viz. amino acids, sugars, enzymes, receptors, and nucleic acids). Chiral enzymes, for example, will only bind to the enantiomer that perfectly fits their binding site. This means that each enantiomer has a unique role in the body and is metabolized differently. A notable example is thalidomide, which was initially sold as a mixture of enantiomers to treat morning sickness in pregnant women. Unfortunately, while the R-enantiomer had a positive therapeutic effect, the S-enantiomer caused severe birth defects, leading to the drug being withdrawn from the market.<\/em><\/figcaption><\/figure>\n\n\n\n

Pharmaceuticals<\/strong><\/p>\n\n\n\n

Enantioselective Drug Synthesis<\/strong><\/p>\n\n\n\n

Chiral drugs make up a significant portion of pharmaceuticals, as the efficacy and safety of many drugs depend on their chirality. Enantioselective synthesis is crucial in producing these drugs with the required stereochemical purity. Chiral catalysts and enzymes are often employed to achieve high enantioselectivity in drug synthesis, ensuring that only the therapeutically active enantiomer is produced. To highlight couple of case studies are presented below.<\/p>\n\n\n\n

Case Study 1:<\/strong> Esomeprazole (Nexium)<\/strong>:<\/p>\n\n\n\n

Esomeprazole<\/a> – the generic name of the (S)-enantiomer of omeprazole, a <\/mark>chiral switch<\/mark><\/a> – is currently under registration as Nexium\u2122, a new proton pump inhibitor. Used to treat gastroesophageal reflux disease (GERD), that offers better therapeutic outcomes. Consequently, we required an efficient synthesis of esomeprazole which could be used on a large scale.<\/mark> <\/p>\n\n\n\n

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Source: https:\/\/doi.org\/10.1016\/S0957-4166(00)00352-9<\/a>

Asymmetric synthesis of esomeprazole<\/strong><\/mark>

Reagents and conditions: (i) Ti(O\u0003iPr)4:(S,S)-DET:H2O (0.3:0.6:0.1), PhCH3 D; <\/em>
(ii) (iPr)2NEt:PhC(CH3)2OOH (0.3:1), 30\u00b0C; (iii) NaOH (0.7), MIBK; (iv) crystallisation from MIBK and MeCN<\/em>

.<\/mark> A highly efficient method for synthesizing esomeprazole has been developed, using a titanium-mediated asymmetric oxidation of the corresponding prochiral sulfide. This process is suitable for large-scale production. Interestingly, the study shows that having a benzimidazole or imidazole group next to the sulfur atom helps control the stereochemistry of the resulting sulfoxide. This finding further suggests that such functional groups could be used as directing agents when creating chiral sulfoxides for use in asymmetric synthesis.<\/em><\/figcaption><\/figure>\n\n\n\n

Case Study 2<\/strong>: L-DOPA<\/strong>:<\/p>\n\n\n\n

This drug is used in the treatment of Parkinson’s disease and must be synthesized enantioselectively to ensure the active L-enantiomer is obtained.<\/mark><\/p>\n\n\n\n

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Source: https:\/\/www.nobelprize.org\/prizes\/chemistry\/2001\/popular-information\/<\/a>

The first industrial catalytic asymmetric synthesis<\/mark>

Knowles and his colleagues utilized compound C as the initial substance in their industrial production of L-DOPA through synthesis. DiPAMP, one of the enantiomers, was utilized in the chiral hydrogenation process. Out of the product, the enantiomer D accounted for 97.5%. Subsequently, L-DOPA was obtained through the acid hydrolysis of D.<\/em> Knowles’ objective was to create a method for producing the amino acid L-DOPA on an industrial scale, as it had demonstrated its effectiveness in treating Parkinson’s disease. Through experimentation with different structural variations of phosphines, Knowles and his colleagues efficiently generated effective catalysts that exhibited a high level of enantiomeric excess, specifically favoring L-DOPA. The ligand subsequently employed in Monsanto’s industrial synthesis of L-DOPA was the diphosphine ligand DiPAMP. A rhodium complex, when combined with the ligand shown in the image above, produced both enantiomers of DOPA in a 100% yield. The product consisted of 97.5% L-DOPA. Knowles quickly and successfully utilized his own fundamental research and the research of others to develop an industrial process for synthesizing a drug.<\/em><\/figcaption><\/figure>\n\n\n\n

Case Study 3:<\/strong> Clopidogrel (Plavix)<\/strong>: <\/p>\n\n\n\n

An antiplatelet drug, clopidogrel is marketed as a single enantiomer, which is critical for its efficacy in preventing blood clots<\/mark>. (S)-Clopidogrel, known by its brand names Plavix and Iscover, is one of the world\u2019s best-selling drugs and is listed as an essential medicine by the World Health Organization. This medication is a powerful antithrombotic and antiplatelet agent, used to prevent serious conditions like heart attacks and strokes. Interestingly, only the S-enantiomer of the drug is effective in preventing blood clots, which means that creating an asymmetric synthesis or resolving the racemic mixture through diastereoisomeric salts is necessary.<\/p>\n\n\n\n

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Source: EurJOC 2023, https:\/\/doi.org\/10.1002\/ejoc.202300744<\/a>

Asymmetric Synthesis of Chiral Drug (S)\u2010Clopidogrel
<\/mark>
A groundbreaking one-pot method has been developed for the catalytic preparation of the widely-used antiplatelet drug (S)-clopidogrel, also known as Plavix. This innovative synthesis uses readily available chemicals like ortho-chlorobenzaldehyde, 1-naphthylsulfonyl acetonitrile, tert-butyl hydroperoxide (TBHP), 4,5,6,7-tetrahydrothieno[3,2-c]pyridine, and 20 mol% of a quinidine-derived organocatalyst, all in a single solvent. The process involves a sequence of reactions – Knoevenagel condensation, asymmetric epoxidation, and domino ring-opening esterification (DROE) – to produce (S)-clopidogrel with a 61% overall yield and 62% enantiomeric excess (ee). Careful optimization of the reaction conditions was essential to achieve a selective and efficient synthesis<\/em><\/figcaption><\/figure>\n\n\n\n

Case Study 4:<\/strong> S-Naproxen<\/strong>:<\/p>\n\n\n\n

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Source: https:\/\/www.nobelprize.org\/uploads\/2018\/06\/advanced-chemistryprize2001.pdf<\/a>

(S)-naproxen, anti-inflammatory agent, synthesized in high yield and ee (enantiomeric excess)
employing Noyori\u2019s catalyst.<\/mark>

This is an illustration of a stereoselective reduction of a ketone, in which the ester group remains unchanged. Noyori’s catalysts have been extensively utilized in the synthesis of fine chemicals, pharmaceutical products, and novel advanced materials. Noyori recognized the necessity for more versatile catalysts that could be applied to a wider range of situations. The substitution of rhodium, Rh(I), with ruthenium, Ru(II), was found to be successful. The ruthenium(II)-BINAP complex is capable of catalyzing the hydrogenation of various molecules that contain different functional groups. These reactions exhibit a significant enantiomeric excess and high yields, making them suitable for industrial-scale production.<\/em><\/figcaption><\/figure>\n\n\n\n

Chirality in FDA Approved Drugs<\/strong><\/p>\n\n\n\n

Since the FDA\u2019s policy change in 1992, there\u2019s been a growing focus on synthesizing single enantiomers rather than racemic drugs. Today, about 56% of the pharmaceuticals on the market are chiral, and of those, 88% are administered as racemates. However, since 2001, racemic drugs can no longer be registered. Because drugs often share structural similarities with biological targets, understanding new chemical entities and how to construct them is believed to enhance drug discovery. To minimize the toxicity and side effects of inactive enantiomers, synthesizing enantiomerically pure compounds is crucial. This makes chirality a significant challenge in drug synthesis.<\/p>\n\n\n\n

In recent years, the number of approved chiral drugs has been on the rise. For example, in 2020, 20 out of the 35 pharmaceuticals approved by the FDA were chiral. Chiral drugs can be synthesized from commercially available substrates with stereocenters or from naturally occurring substrates (the chiral pool). Other methods include using a chiral auxiliary, a chiral reagent, or resolving the racemic precursor. The recent increase in chiral drugs underscores the importance of asymmetric synthesis in making biologically active compounds, especially in pharmaceuticals.<\/p>\n\n\n\n

Classification of drugs based on their chiral induction mode<\/mark> used during the synthesis.<\/p>\n\n\n\n

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Source: https:\/\/doi.org\/10.3390\/ph16030339<\/a>


The methods used for synthesizing FDA-approved chiral drugs during 2016 -2020 were examined, with a special focus on asymmetric synthesis <\/mark><\/em>

This study examined the synthetic routes for 89 new molecular entities approved by the FDA within the period of 2016\u20132020. These drugs were categorized based on the method by which chirality was induced during the manufacturing process, Here are the main methods:
Chiral Pool Approach<\/strong>: Synthesizing drugs from naturally occurring or already chiral substances.
Chiral Resolution<\/strong>: Involves separates the racemic mixture at any point during the synthesis.
Asymmetric Synthesis<\/strong>: Employs a chiral auxiliary, catalyst, or reagent to achieve chirality.<\/em><\/figcaption><\/figure>\n\n\n\n

FDA-Approved Chiral Drugs<\/strong> – 2020<\/p>\n\n\n\n

As an illustration FDA-approved chiral drugs in 2020 is presented below. This further highlights the importance of asymmetric synthesis.<\/p>\n\n\n\n

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Source: https:\/\/doi.org\/10.3390\/ph16030339<\/a>

Structure of chiral drugs approved in 2020<\/mark><\/figcaption><\/figure>\n\n\n\n

Agrochemicals<\/strong><\/p>\n\n\n\n

Synthesis of Chiral Pesticides and Herbicides<\/strong><\/p>\n\n\n\n

The agrochemical industry also relies on chiral compounds for the development of effective pesticides and herbicides. Asymmetric synthesis enables the production of these compounds with high enantioselectivity, ensuring their biological activity and reducing the required doses.<\/p>\n\n\n\n

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Source: https:\/\/doi.org\/10.1021\/acs.jafc.4c02343<\/a><\/figcaption><\/figure>\n\n\n\n

Environmental Benefits<\/strong><\/p>\n\n\n\n

The use of enantiomerically pure agrochemicals offers significant environmental benefits. By targeting specific pests or weeds more effectively, these chemicals minimize collateral damage to non-target species and reduce environmental contamination. Moreover, the production of pure enantiomers can lower the overall chemical load, contributing to more sustainable agricultural practices.<\/p>\n\n\n\n

Fine Chemicals and Materials<\/strong><\/p>\n\n\n\n

Production of Chiral Intermediates<\/strong><\/p>\n\n\n\n

Chiral intermediates are essential building blocks in the synthesis of various fine chemicals. Asymmetric synthesis allows for the efficient production of these intermediates with high purity, which is critical for their subsequent use in the production of pharmaceuticals, agrochemicals, and other fine chemicals.<\/p>\n\n\n\n

Material Science<\/strong><\/p>\n\n\n\n

Chirality is also important in material science, where chiral compounds are used to create materials with unique optical, electronic, and mechanical properties. For example, chiral liquid crystals are used in display technologies, and chiral polymers are explored for their potential in creating new types of sensors and catalysts.<\/p>\n\n\n\n

Challenges and Solutions<\/strong><\/p>\n\n\n\n

Scalability of Asymmetric Reactions<\/strong><\/p>\n\n\n\n

One of the main challenges in industrial asymmetric synthesis is scaling up reactions from the laboratory to the production level. Factors such as reaction efficiency, cost of chiral catalysts, and the need for high enantioselectivity must be carefully managed. Process optimization and the development of robust catalytic systems are essential for overcoming these challenges.<\/p>\n\n\n\n

Catalyst Recovery and Recycling<\/strong><\/p>\n\n\n\n

The recovery and recycling of chiral catalysts are crucial for making asymmetric synthesis economically viable and environmentally friendly. Advances in catalyst design, such as the development of immobilized and recyclable catalysts, have addressed some of these issues, enabling the repeated use of catalysts without significant loss of activity or selectivity.<\/p>\n\n\n\n

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Source: https:\/\/doi.org\/10.1016\/j.ccr.2017.08.011<\/a>

\u201cGreen\u201d has become a buzzword in recent decades for sustainability. <\/mark>

Sustainable chemistry is incredibly important as it drives the creation of cleaner processes and technologies. This includes reducing waste, minimizing the use of materials and energy, focusing on renewability, and using environmentally friendly reagents and efficient methods. Recycling, particularly the reuse of catalysts, is crucial given the limited and dwindling supply of expensive noble metals. For industrial applications, it\u2019s highly desirable for catalysts to have a long lifespan and be easy to recycle. Both environmental and economic factors push for the development of processes that allow for the separation, recovery, and reuse of catalysts. Ideally, any catalyst should be highly active, selective, and stable for long-term use, while also having a low environmental impact<\/em><\/figcaption><\/figure>\n\n\n\n

Conclusion<\/strong><\/p>\n\n\n\n

Chiral asymmetric synthesis has a profound impact on various industrial sectors, driving the production of enantiomerically pure compounds essential for pharmaceuticals, agrochemicals, and fine chemicals. Despite the challenges related to scalability and catalyst recovery, ongoing innovations in catalyst design and process optimization continue to enhance the efficiency and sustainability of asymmetric synthesis.<\/p>\n\n\n\n

As research and development in this field progress, future trends may include the integration of green chemistry principles, the use of renewable feedstocks, and the application of artificial intelligence to optimize catalytic processes. The continued interdisciplinary collaboration between chemists, chemical engineers, and industry professionals will be key to unlocking new possibilities and ensuring that chiral asymmetric synthesis remains at the forefront of industrial innovation.<\/p>\n\n\n\n

By bridging the gap between laboratory research and market applications, chiral asymmetric synthesis not only advances scientific knowledge but also contributes to the development of safer, more effective, and environmentally friendly products.<\/p>\n\n\n\n

Further Readings<\/strong><\/p>\n\n\n\n

Vincenzo Battaglia et al<\/em>., One\u2010Pot Catalytic Synthesis of Optically Active Drug (S<\/em>)\u2010Clopidogrel, European Journal of Organic Chemistry, 2023<\/strong>. https:\/\/doi.org\/10.1002\/ejoc.202300744<\/a><\/p>\n\n\n\n

Hanna Cotton et al<\/em>., Asymmetric synthesis of esomeprazole, Tetrahedron: Asymmetry, 2000<\/strong>, 11, (18), 22, 3819-3825. https:\/\/doi.org\/10.1016\/S0957-4166(00)00352-9<\/a>.<\/p>\n\n\n\n

https:\/\/www.nobelprize.org\/prizes\/chemistry\/2001\/popular-information\/<\/a><\/p>\n\n\n\n

Tamatam, R.; Shin, D. Asymmetric Synthesis of US-FDA Approved Drugs over Five Years (2016\u20132020): A Recapitulation of Chirality. Pharmaceuticals<\/em> 2023<\/strong>, 16<\/em>, 339. https:\/\/doi.org\/10.3390\/ph16030339<\/a><\/p>\n\n\n\n

Williams, A. The role of chirality in the agrochemical industry. Phytoparasitica, 2000<\/strong>, 28(4), 293\u2013296.<\/em> doi:10.1007\/bf02981823<\/a><\/p>\n\n\n\n

Jeschke, P. Current status of chirality in agrochemicals. Pest Management Science. <\/em>2018<\/strong>.<\/em> doi:10.1002\/ps.5052<\/a> <\/p>\n\n\n\n

Xiaoqun Yang, et al<\/em>., J. Agric. Food Chem. 2024<\/strong>, https:\/\/doi.org\/10.1021\/acs.jafc.4c02343<\/a><\/p>\n\n\n\n

GuiPing Han, et al.<\/em>, Application of chiral recyclable catalysts in asymmetric catalysis, RSC Adv.<\/a><\/em>, 2024<\/strong>, 14, 16520-16545. doi:10.1039\/D4RA01050G<\/a><\/p>\n\n\n\n

Moln\u00e1r, \u00c1., & Papp, A. Catalyst recycling – A survey of recent progress and current status. Coordination Chemistry Reviews, 2017<\/strong>, 349, 1\u201365.<\/em> doi:10.1016\/j.ccr.2017.08.01 https:\/\/doi.org\/10.1016\/j.ccr.2017.08.011<\/a><\/p>\n\n\n\n

Hughes, D. L. (2012). 9.1 Introduction to Industrial Applications of Asymmetric Synthesis. Comprehensive Chirality, 1\u201326. doi:10.1016\/b978-0-08-095167-6.00901-0<\/a><\/p>\n","protected":false},"excerpt":{"rendered":"

Introduction Asymmetric synthesis is a cornerstone of industrial chemistry, enabling the production of enantiomerically pure compounds that are essential in various sectors. Its importance lies in the ability to produce specific enantiomers that exhibit desired biological activities or material properties. Asymmetric synthesis is the process of turning a non-chiral starting material into a chiral product. This blog explores the industrial applications of chiral asymmetric synthesis, highlighting its critical role in pharmaceuticals, agrochemicals, fine chemicals, and …<\/p>\n

Asymmetric Synthesis in Industry: From Lab to Market<\/span> Read More »<\/a><\/p>\n","protected":false},"author":1,"featured_media":5932,"comment_status":"open","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"_monsterinsights_skip_tracking":false,"_monsterinsights_sitenote_active":false,"_monsterinsights_sitenote_note":"","_monsterinsights_sitenote_category":0,"site-sidebar-layout":"","site-content-layout":"","ast-main-header-display":"","ast-hfb-above-header-display":"","ast-hfb-below-header-display":"","ast-hfb-mobile-header-display":"","site-post-title":"","ast-breadcrumbs-content":"","ast-featured-img":"","footer-sml-layout":"","theme-transparent-header-meta":"","adv-header-id-meta":"","stick-header-meta":"","header-above-stick-meta":"","header-main-stick-meta":"","header-below-stick-meta":"","footnotes":"[]"},"categories":[96],"tags":[97,22,67],"ppma_author":[93,95],"class_list":["post-5433","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-asymmetric-synthesis","tag-asymmetric_synthesis","tag-chirality","tag-chiralpedia"],"authors":[{"term_id":93,"user_id":1,"is_guest":0,"slug":"chiralusrblg","display_name":"Valliappan Kannappan","avatar_url":{"url":"https:\/\/chiralpedia.com\/blog\/wp-content\/uploads\/2024\/09\/vk.jpg","url2x":"https:\/\/chiralpedia.com\/blog\/wp-content\/uploads\/2024\/09\/vk.jpg"},"first_name":"","last_name":"","user_url":"https:\/\/chiralpedia.com\/blog\/","job_title":"Founder, chiralpedia.com","description":""},{"term_id":95,"user_id":2,"is_guest":0,"slug":"chandramouli-r","display_name":"Chandramouli R","avatar_url":"https:\/\/secure.gravatar.com\/avatar\/dafe0b6a18e9248eb688088e3e993360328363d8d087bbd01648f0bddae05eb5?s=96&d=mm&r=g","first_name":"","last_name":"","user_url":"","job_title":"","description":""}],"_links":{"self":[{"href":"https:\/\/chiralpedia.com\/blog\/wp-json\/wp\/v2\/posts\/5433","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/chiralpedia.com\/blog\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/chiralpedia.com\/blog\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/chiralpedia.com\/blog\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/chiralpedia.com\/blog\/wp-json\/wp\/v2\/comments?post=5433"}],"version-history":[{"count":60,"href":"https:\/\/chiralpedia.com\/blog\/wp-json\/wp\/v2\/posts\/5433\/revisions"}],"predecessor-version":[{"id":6235,"href":"https:\/\/chiralpedia.com\/blog\/wp-json\/wp\/v2\/posts\/5433\/revisions\/6235"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/chiralpedia.com\/blog\/wp-json\/wp\/v2\/media\/5932"}],"wp:attachment":[{"href":"https:\/\/chiralpedia.com\/blog\/wp-json\/wp\/v2\/media?parent=5433"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/chiralpedia.com\/blog\/wp-json\/wp\/v2\/categories?post=5433"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/chiralpedia.com\/blog\/wp-json\/wp\/v2\/tags?post=5433"},{"taxonomy":"author","embeddable":true,"href":"https:\/\/chiralpedia.com\/blog\/wp-json\/wp\/v2\/ppma_author?post=5433"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}