Enantioselective Synthesis

11 Key excerpts on "Enantioselective Synthesis"

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  Process Chemistry in the Pharmaceutical Industry

  • Kumar Gadamasetti(Author)
  • 1999(Publication Date)
  • CRC Press

    (Publisher)

  ASYMMETRIC SYNTHESIS AND ENANTIOSELECTIVITY Enantioselective Synthesis: The Optimum Process John J. Partridge and Brian L. Bray Chemical Development Department, Glaxo Wellcome Inc, Research Triangle Park, North Carolina 27709 I. Introduction In the field of synthetic organic chemistry, chiral chemical entities are being launched as breakthrough pharmaceutical specialties ( 1 ), agrochemicals ( 2 ) and flavor and fragrance ingredients (3). A review of the 1997 edition of the Physician’s Desk Reference (4) reveals that well over half of the drugs used in clinical medicine are chiral compounds. Yet the majority of these chiral compounds are still prescribed as racemates. As the next century and millennium approach, the emphasis on single chiral compounds will increase. In the United States, the Food and Drug Administration (FDA) has enunciated a specific policy on stereoisomers since 1992. This policy continues to evolve with periodic Internet updates (5). Authorities and health providers are now questioning the need for racemic drugs when one enantiomer does not contribute to efficacy, but may contribute to toxicity. As a result of this shift in thinking, a significant niche in the chemical industry has been created for chiral substances. Reactions of high enantioselectivity are defined here as having enantiomeric ratios of greater than 95:5 (i.e. >90% enantiomeric excess or >90% ee). Such reactions were sparse in the 60’s and 70’s, much more abundant in the 80’s and commonplace in the 90’s. In parallel fashion, the number of scientific papers on asymmetric synthesis or Enantioselective Synthesis has spiraled upward in the last 40 years. In addition to teaching several generations of chemists about chirality and stereochemistry (6 ), Eliel set out some guidelines for good Enantioselective Synthesis in 1974 (7). To these three guidelines is added a fourth, that the process be economically viable (Scheme 1).

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  Stereoselective Synthesis of Drugs and Natural Products

  • Vasyl Andrushko, Natalia Andrushko, Vasyl Andrushko, Natalia Andrushko(Authors)
  • 2013(Publication Date)
  • Wiley

    (Publisher)

  3. Enantioselectivity—a degree to which one of the possible enantiomers of a chiral product can be pref- erentially formed during a chemical process. Although a substrate is achiral, the enantiopure or enantio-enriched catalyst may give rise to the forma- tion of one specific product-enantiomer. 4. Diastereoselectivity—a preference during the chemi- cal process for the formation of one diastereomer over the other diastereomers. When a substrate contains already a stereogenic center, this (possibly also together with a chiral catalyst) will direct a chemical reaction in a certain direction to produce two diastere- omers in unequal amounts. Diastereoselectivity is provided usually as a ratio of diastereomers formed during a chemical process. A more general term that combines both enantioselec- tivity and diastereoselectivity is stereoselectivity, and it is used to denote a selective formation of one of the possible stereoisomers over another. Substitutions at a stereogenic center can proceed with either retention or inversion of configuration. If during the chemical process the configuration at a chiral center is retained, i.e., the spatial arrangement of substituents during the reaction course is not changed, such a reaction is said to occur with retention of configuration. One of the most commonly encountered examples is a substitution of the HO-group in chiral tertiary alcohols in the presence of SOCl 2 (Figure 1.46). Inversion of configuration occurs if a spatial arrange- ment of substituents during the reaction course is inverted; i.e., the configuration changes from one enantiomeric form to the other (mirror image change). Excellent examples of the reactions that go with inversion of configuration are S N 2 reactions. They exhibit second-order kinetic behavior and are stereospecific.

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  Chirality in Drug Research

  • Eric Francotte, Wolfgang Lindner, Eric Francotte, Wolfgang Lindner, Raimund Mannhold, Hugo Kubinyi, Gerd Folkers(Authors)
  • 2007(Publication Date)
  • Wiley-VCH

    (Publisher)

  (Data taken from [20]). forts in academic and industrial settings led to significant progress in the areas of asymmetric synthesis [22] and enantioselective biotransformation [23–26] provid- ing an economic basis for large-scale production of enantiomerically pure drug can- didates. Simultaneously, major advances have been achieved in the field of analyti- cal chromatographic enantiomer separation methodologies [27–29] establishing a rich repertoire of analytical tools for determination of enantiomer purity. Enantioselective analytical assays play a key role in the development of chiral drug candidates throughout the entire development cycle. During lead discovery and optimization of active chiral substances enantioselective analytical methods are required to monitor the outcome of asymmetric reactions in which the crucial chiral center(s) are created, and to ensure that the stereochemical integrity is maintained throughout subsequent synthesis steps. In cases where the starting materials already contain the desired chiral centers, initial stereochemical purity must be established by employing validated enantioselective assays [30, 31]. Simi- lar requirements apply to cases in which resolution strategies are deployed to iso- late the desired stereoisomer(s) of the active compound(s) [32]. Resolution steps are considered an integral part of the manufacturing process, and the stereoche- mical purity of the starting materials and intermediates must be assessed for each enrichment cycle. Sensitive enantioselective analytical procedures must also be available to aid the specification of single enantiomer drug candidates. When a chiral drug is presented as a single enantiomer, the unwanted enantiomer is con- sidered an impurity, demanding identification and accurate quantification.

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  Enantioselective Chemical Synthesis

  Methods, Logic, and Practice

  • Elias J. Corey, Laszlo Kurti(Authors)
  • 2013(Publication Date)
  • Academic Press

    (Publisher)

  However, there is another and less appreciated aspect of the dramatic advances in enantiocontrolled synthetic chemistry which has to do with a greatly increased understanding of the way in which enantioselective chemical processes take place. This section examines that new knowledge first from a historical perspective and then in terms of future implications. Our present ability to construct complex chemical structures by multistep sequences would not have been possible without a certain amount of serendipity, and also the revolutionary advances in our understanding of: (a) structure-reactivity relationships; (b) reaction mechanisms and pathways; (c) electronic and steric effects on chemical reactions; (d) fundamental bases of catalysis; (e) energetic of molecular conformations and conformational dynamics and (f) three-dimensional (stereochemical) aspects of molecular structure and transformations. Pre-Transition State Assemblies By the mid 1960s the theory of many of the basic stereocontrolled reactions (e.g., nucleophilic displacement at sp 3 -carbon, addition to C=C or elimination to form C=C) was sufficiently understood to allow their application in complex situations with confidence. In addition, extensive information was available on the various reactive intermediates that intervene in chemical reactions, and it became possible even to generate and utilize such intermediates for synthetic purposes. The integration of the chemistry of the various elements, including transition metals, into synthetic practice allowed a further explosion in the variety of available reagents and reaction methodology. All of these developments helped to set the stage for the current era of chemical synthesis. The existence of this book was compelled by the enormous range of the recent developments in enantioselective synthetic chemistry, and especially by the discovery or development of reactions that are very enantioselective (>95% ee ).

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  Stereochemistry and Stereoselective Synthesis

  An Introduction

  • Mihály Nógrádi, László Poppe, József Nagy, Gábor Hornyánszky, Zoltán Boros(Authors)
  • 2016(Publication Date)
  • Wiley-VCH

    (Publisher)

  Similarly, it is to be avoided to call a reaction stereospecific if in the reaction the formation of a single stereoisomer is observed because this is a rather relative statement and depends on the analytical method applied. A sample declared to be a pure enantiomer based on its optical rotation might prove to be a 99.8:0.2 mixture of enantiomers when examined with chiral GC techniques. In addition, this manner of interpretation disregards real differences based on reaction mechanisms.

  Consequently, in our opinion, the concept of stereospecificity should be strictly confined to cases when it follows from the mechanism of the reaction that only a single one of the conceivable stereoisomers is formed. In all other cases, the concept stereoselectivity should be applied.

  8.3 Selective Syntheses of Enantiomers

  In the earlier and also in the more recent literature, the term “asymmetric synthesis” is used to cover syntheses involving both enantio- and diastereoselective reactions. In addition, manipulations with pure enantiomers originating from the “chiral pool”1 are also often denoted as asymmetric syntheses. Since in our opinion the term “asymmetric synthesis” is both restrictive and inaccurate, we recommend to use the term enantiomer or enantiotope selective, whichever applies for the transformation in question. Chemoselectivity and regioselectivity as well as diastereomer selectivity discussed in the preceding chapters are “simple” cases of selectivity since constitutional isomers and diastereomers are chemically distinct entities differing in all of their scalar properties. They can be therefore separated rather easily and differ in their achiral interactions too. With enantiomers, the situation is quite different. Since all the scalar characteristics of enantiomers are identical, their separation is a complex task, and to realize enantiomer selectivities, chiral interactions are required.

  If one wishes to prepare a pure enantiomer of a chiral compound, multiple means are at our disposal as summarized in Figure 8.2 .

  Figure 8.2

  Methods available for the preparation of pure enantiomers of a chiral compound.

  Utilization of a chiral pool

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  Stereoselective Synthesis

  A Practical Approach

  • Mihály Nógrádi(Author)
  • 2008(Publication Date)
  • Wiley-VCH

    (Publisher)

  The products are of course racemic. Fig. 1-23. Stereoselective synthesis by intramolecular transfer of chirality. 1.4.3 Stereoselective Synthetic Strategies 1.4.3.1 Enantioconvergent Synthesis The synthesis of optically active compounds containing several chiral centers from an achiral starting material poses serious problems of economy, even at a laboratory scale. Apart from less than quantitative chemical yields, at least half of the material is lost when generating the first chiral center, while losses in the creation of the other chiral centers are rather unpredictable owing to the diastereoselective character of the 1.4.3 Stereoselective Synthetic Strategies 37 a t b a f b -C * a t b C* c* X D2 R*= y:02Me Ho D O H I R*COCI FDW 2) OH' (1R,2R)-(25) Fig. 1-24. Enantioconvergent synthesis according to the Fischli scheme. 38 1.4 Selectivity in Chemistry transformations. At least one highly enantioselective step or resolution of enan- tiomers at some stage is unavoidable, and, since the more material involved the higher the costs due to labor, chemicals and energy, this operation has to be carried out at an as early stage as possible. Enantioselective Synthesis, even if it produces some of the unwanted enantiomer, is certainly the more efficient approach, since the aSOn Me OH iBu I MeC(OEt)i, i A ?Et Me iBu 1 I A I JI QH ! Li/liq.NH, ?H iBu -M e I Fig. 1-25. Enantioconvergent synthesis according to the scheme of Cohen and Saucy. 1.4.3 Stereoselective Synthetic Strategies 39 maximum yield of resolution cannot be higher than 50%. If the chiral compound obtained either by resolution or enantioselection contains a single element of chirali- ty it may be possible to racemize the unwanted isomer, whereas the racemization of diastereomers is only very rarely possible. In 1975 Fischli et al. [65] proposed an ingeniously simple scheme by which a start- ing material with enantiotopic groups can be converted completely to a predetermin- ed enantiomer.

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  Heterocycles

  Synthesis, Catalysis, Sustainability, and Characterization

  • Teresa M. V. D. Pinho e Melo, Marta Pineiro, Teresa M. V. D. Pinho e Melo, Marta Pineiro(Authors)
  • 2022(Publication Date)
  • Wiley-VCH

    (Publisher)

  The photon is considered as a traceless reagent [ 6, 7 ]. For these reasons, these reactions are now highly appreciated in chemical and pharmaceutical industry [ 8 – 10 ]. Stereoselectivity also plays a central role in organic synthesis. Biological activity and material properties strongly depend on the stereochemistry of chemical compounds. Sooner or later, almost all synthesis methods will face this problem. In the past, photochemical reactions have been considered as being inherently stereo-unselective. It was thought that the high energy uptake by light absorption induces uncontrolled relaxation processes that lead to unselective reactions with large amounts of degradation either of the substrates or the photoproducts [11]. In this regard, it must however be pointed out that stereoselective and stereospecific photochemical reactions have been known from the very beginning of this research area [ 12, 13 ]. The controlled dissipation of the high electronic excitation energy in photochemical reactions is the reason for the high stereoselectivity in such reactions [11]. In particular, photochemical reactions can be conducted enantioselectively in chiral supramolecular structures [ 14, 15 ]. Enantiopure compounds are obtained in different ways: they can be prepared directly from other chiral precursors such as natural products (“chiral pool”) or by optical resolution using different types of chromatography or crystallization techniques. Asymmetric syntheses using chiral auxiliaries, which are removed after the stereoselective reaction, also provide enantiopure compounds. Asymmetric catalysis and enzymatic catalysis directly yield enantioenriched compounds. A chiral enantiopure environment in a supramolecular structure or in a crystal may be the inductor of chirality in asymmetric reactions

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  Principles of Asymmetric Synthesis

  • Robert E. Gawley, Jeffrey Aube(Authors)
  • 2012(Publication Date)
  • Elsevier

    (Publisher)

  Chapter 1

  Introduction, General Principles, and Glossary of Stereochemical Terms

  1.1 Why We Do Asymmetric Syntheses

  L’univers est dissymétrique Louis Pasteur (1874)

  In modern terminology, Pasteur would say “The universe is chiral.”1 We are constantly learning more about the implications of chirality, from weak bosons in nuclear physics to the origins of life on earth and the double helix of DNA [1 –5] . Most organic compounds are chiral. Chemists working with perfumes, cosmetics, nutrients, flavors, pesticides, vitamins, and pharmaceuticals, to name a few examples [6 –11] , require access to enantiomerically pure compounds. Single enantiomer formulations now account for most of the chiral drugs on the market. One estimate suggests that approximately half of the worldwide revenues from chiral products were the result of traditional synthesis from the chiral pool or resolution, whereas less than half result from chemical catalysis [12] .

  As our ability to produce enantiomerically pure compounds grows, so does our awareness of the differences in pharmacological properties that a chiral compound may have when compared with its enantiomer or racemate [13 –19] . We easily recognize that all biological receptors are chiral, and as such can distinguish between the two enantiomers of a ligand or a substrate. Enantiomeric compounds often have different odors or tastes [20 –22] .2 Thus, it is obvious that two enantiomers should be considered different compounds when screened for pharmacological activity [10 ,13 ,23] . The demand for enantiomerically pure compounds as drug candidates is not likely to let up in the foreseeable future.

  How might we obtain enantiomerically pure compounds? Historically, the best answer to that question has been to isolate them from natural sources. Derivatization of natural products or their use as synthetic starting materials has long been a useful tool in the hands of the synthetic chemist, but it has now been raised to an art form by some practitioners, wherein complex molecules are dissected into chiral fragments that may be obtained from natural products [24 –34]

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  Asymmetric Synthesis of Drugs and Natural Products

  • Ahindra Nag(Author)
  • 2018(Publication Date)
  • CRC Press

    (Publisher)

  6 Use of Specific New Artificial or Semisynthetic Biocatalysts for Synthesis of Regio- and Enantioselective Compounds Marco Filice, Oscar Romero, and Jose M. Palomo

  CONTENTS 6.1Introduction 6.2Regioselective Preparation of Monodeprotected Esters 6.2.1Regioselective Monodeprotection of Peracetylated Carbohydrates 6.2.2Regioselective Preparation of Monodeprotected Nucleosides 6.3Regio- and Enantioselective Preparation of Chiral Alcohols and Amines 6.4Regioselective Artificial Hydrolase-Catalyzed C–C Bond Formation References

  6.1Introduction

  Enzymes are versatile biocatalysts and find increasing application in many areas, including organic synthesis. The major advantages of using enzymes in biotransformations are their chemo-, regio-, and stereoselectivity as well as the very mild reaction conditions that can be used, where the generation of the side products is minimized.1 , 2 , 3 Their stereoselectivity (the ability to selectively act on a single enantiomer) their regioselectivity (the possibility to recognize one position in a molecule), and, finally, their selectivity toward defined functional group among others quite similar in reactivity allowed distinguishing them precisely. Each type of selectivity shows advantages that can accrue to chemical processes because of the special properties of the enzymes.

  Indeed, regioselective and enantiomerically pure molecules are key compounds for many industrially relevant processes. The application of biocatalysts ranges from the synthesis of regio- and chiral intermediates (usually building blocks in drug chemistry), via

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  Organocatalysis

  Stereoselective Reactions and Applications in Organic Synthesis

  • Maurizio Benaglia(Author)
  • 2021(Publication Date)
  • De Gruyter

    (Publisher)

  11  Enantioselective organocatalytic approaches to active pharmaceutical ingredients – selected industrial examples

  Armando Carlone

  Department of Physical and Chemical Sciences , Università degli Studi dell’Aquila , Coppito, via Vetoio , L’Aquila , 67100 , Italy

  Luca Bernardi

  Department of Industrial Chemistry “Toso Montanari” & INSTM RU Bologna , Alma Mater Studiorum - University of Bologna , V. Risorgimento 4 , Bologna , 40136 , Italy

  This article has previously been published in the journal Physical Sciences Reviews. Please cite as: Carlone, A., Bernardi, L. Enantioselective organocatalytic approaches to active pharmaceutical ingredients – selected industrial examples Physical Sciences Reviews [Online] 2019, 8. DOI: 10.1515/psr-2018-0097

  Abstract

  Catalysis is, often, the preferred approach to access chiral molecules in enantioenriched form both in academia and in industry; nowadays, organocatalysis is recognised as the third pillar in asymmetric catalysis, along with bio- and metal-catalysis. Despite enormous advancements in academic research, there is a common belief that organocatalysis is not developed enough to be applicable in industry. In this review, we describe a selection of industrial routes and their R&D process for the manufacture of active pharmaceutical ingredients, highlighting how asymmetric organocatalysis brings added value to an industrial process. The thorough study of the steps, driven by economic stimuli, developed and improved chemistry that was, otherwise, believed to not be applicable in an industrial setting. The knowledge discussed in the reviewed papers will be an invaluable resource for the whole research community.

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  Chirality in Drug Design and Synthesis

  • C. Brown(Author)
  • 2013(Publication Date)
  • Academic Press

    (Publisher)

  Traditionally, pharmacologists and physicians have assumed that the administration of a ‘drug’ would act as a ‘single agent’ and would produce a ‘single action’. When pure enantiomers are administered, this may be the outcome. But this is frequently not the case when racemic mixtures are given since several different pharmacological outcomes are possible depending on the pharmacological action of each enantiomer and on the disposition of the enantiomers in the body.

  Enantioselectivity in pharmacology following administration of a racemic xenobiotic has been recognized since the early part of this century. These differences were anticipated because of the diastereomeric relationship between asymmetrical molecules and asymmetrical receptors (enzymes plasma proteins and activity receptors) (Simonyi, 1984 ; Testa, 1989 ). It has only been within the past 10–20 years, however, that advances in analytical and preparative technology have allowed researchers to separate and study individual enantiomers. This has allowed us to begin to understand the differences in activity of enantiomers and identify factors that alter the expected pharmacodynamic response under therapeutic conditions. With these new tools in hand, investigators have been able to carefully describe the differences in pharmacological activity in drug enantiomers and been able to relate these differences to clinical and toxicological findings.

  Pharmacological assessment of chiral compounds in an early research phase can lead to the selection of a single isomer for development. This selection process can maximize the potential for specific activity and minimize the potential for side-effects. For various reasons, however, many racemates have been developed and for these compounds the pharmacological picture is considerably more complex than the single enantiomer activity picture.

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