Stereoselectivity

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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)

  These methods allow nowadays the syntheses of complex chiral organic structures that previously seemed unattainable to be synthesized in the laboratory. The synthetic efforts toward many drugs and natural prod- ucts have largely been driven by their intriguing chemical structures and interesting biological properties. 168 There are four types of selectivity that can be distin- guished in a chemical process: 1. Chemoselectivity—a selective reactivity of one func- tional group in the presence of another. For example, H 3 C O hydrogenation H 3 C OH H 3 C OH H 3 C O chemoselectivity hydroformylation CHO CHO regioselectivity hydrophosphonylation (R) O O O (R) O O (R) OH PO(OMe) 2 (R) O O (S) OH PO(OMe) 2 NH 2 Ph N H (S) Ph N H (R) Ph enantioselectivity intramolecular hydroamination diaStereoselectivity FIGURE 1.45. Selectivity of chemical conversions. THE MAIN STRATEGIES TO ACCESS OPTICALLYACTIVE PRODUCTS 37 if two chemically different functionalities are present in a molecule such as C  C and C  O (Figure 1.45) and both can be hydrogenated, the chemoselectivity refers to the extent to which both C  O or C  C bonds will be hydrogenated. 2. Regioselectivity—a property of a chemical process to produce selectively one isomer over the other theoret- ically possible structural isomers. Regioselective reactions are usually addition or elimination reactions. One such example is the hydroformylation reaction. As the formyl group can be attached to either the primary (terminal C-atom or the secondary (internal C-atom), two isomers (linear and the branched respectively) can be formed (Figure 1.45). 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.

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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)

  Part III General Characteristics of Stereoselective Reactions

  Selectivity is an all-important key feature of chemical reactions. Selectivity enables multistep reactions to take place economically. Moreover, without selectivity it would be impractical to analyze and purify the products of reactions. After defining stereospecificity and Stereoselectivity, this part provides the reader with a systematic analysis of the various types of selectivties with special emphasis on selectivities leading to single enantiomeric products.

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  Chapter 7 Types and Classification of Selectivities

  Selectivity in chemistry is interpreted in various ways. The terms chemoselectivity, regioselectivity, and Stereoselectivity (including dia- and enantioselectivity) are widely used. However, there is no general agreement on their precise meaning. Therefore, the following chapters are dedicated to this topic and attempt to provide a uniform interpretative framework.

  7.1 Main Types of Selectivity

  In chemistry, two main types of selectivities can be defined; one depends mainly on the properties of the substrate, while the other differs in the products of a reaction [1]. These two main types of selectivities are shown in the following figures.

  7.1.1 Substrate Selectivity

  A reagent or a catalyst is substrate selective (Figure 7.1 ) when it transforms different substrates (S1 , S2 , …) to products (P1 , P2 , …) under identical conditions at different rates (k1 ≠ k2 ).

  Figure 7.1

  Substrate-selective reactions.

  7.1.2 Product Selectivity

  A reagent or catalyst is product selective (Figure 7.2 ) when it permits the formation of more than one product at different rates (k1 ≠ k2 ) from a single substrate (S) whereby the products (P1 , P2 , …) are formed in a ratio differing from the one statistically expected.1

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  Molecular Orbitals and Organic Chemical Reactions

  • Ian Fleming(Author)
  • 2011(Publication Date)
  • Wiley

    (Publisher)

  5 Ionic Reactions—Stereochemistry

  To achieve control of stereochemistry, understanding is vital, and understanding requires a feeling for all the factors that influence the stereochemistry of organic reactions. We begin with two adjectives, stereoselective and stereospecific, which, with their derived adverbs, are much used and misused. They are defined following Zimmerman below, and used carefully in this book, because the distinction between them is useful.

  The more encompassing term stereoselective simply means that more of one stereoisomer is produced than of one or more others. Thus the reduction of camphor 5.1 takes place mainly with attack of the hydride reagent on the lesshindered face, avoiding the C-8 methyl group, to give more isoborneol 5.2 than borneol 5.3. The degree of Stereoselectivity is expressed as the diastereoisomer ratio of isoborneol to borneol. It is helpful to normalise the numbers as percentages (90:10 in this case), without implying that the yield is 100%.

  The less simple term stereospecific is used for those reactions where the configuration of the starting material and the configuration of the product are related in a mechanistically constrained way. Thus the diastereoisomeric bromides 5.4 and 5.6 give different alkenes 5.5 and 5.7 by anti elimination. Since each of these reactions produces more of one isomer than the other, they are also stereoselective. The characteristic feature of a stereospecific reaction is that one stereoisomer of the starting material gives one stereoisomer of the product, and a different stereoisomer of the starting material gives a different stereoisomer of the product.

  This particular reaction was studied when analytical methods were not available to measure the probably small degree to which each isomer gave some of the other alkene, either by a different mechanism or by incomplete stereospecificity in the E2 reaction itself. No matter how much stereochemical leakage there is, as long as the diastereoisomer ratio is greater than 50:50, the reaction is still stereospecific. It is not helpful to use the word stereospecific to mean 100% stereoselective, as many people thoughtlessly do—a useful distinction is lost, and understanding suffers.

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  Organic Chemistry

  • T. W. Graham Solomons, Craig B. Fryhle, Scott A. Snyder(Authors)
  • 2022(Publication Date)
  • Wiley

    (Publisher)

  • If a reaction produces preferentially one enantiomer over its mirror image, the reaction is said to be an enantioselective reaction. • If a reaction leads preferentially to one diastereomer over others that are possible, the reaction is said to be a diastereoselective reaction. For a reaction to be either enantioselective or diastereoselective, a chiral reagent, catalyst, or solvent must assert an influence on the course of the reaction. In nature, where most reactions are stereoselective, the chiral influences come from pro- tein molecules called enzymes. Enzymes are biological catalysts of extraordinary efficiency. Not only do they have the ability to cause reactions to take place much more rapidly than they would otherwise, they also have the ability to assert a dramatic chiral influence on a reaction. Enzymes do this because they, too, are chiral, and they possess an active site where the reac- tant molecules are momentarily bound while the reaction takes place. The active site is chiral (see Figure 5.7), and only one enantiomer of a chiral reactant fits it properly and is able to undergo the reaction. 5.11 Chiral Drugs 221 Many enzymes have found use in the organic chemistry laboratory, where organic chem- ists take advantage of their properties to bring about stereoselective reactions. One of these is an enzyme called lipase. Lipase catalyzes a reaction called hydrolysis, whereby an ester (Section 2.10B) reacts with a molecule of water to produce a carboxylic acid and an alcohol. O O hydrolysis R OH Carboxylic acid + R OR ′ Ester HO R′ Alcohol + HOH Water If the starting ester is chiral and present as a mixture of its enantiomers, the lipase enzyme reacts selectively with one enantiomer to release the corresponding chiral carboxylic acid and an alcohol, while the other ester enantiomer remains unchanged or reacts much more slowly.

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  Principles of Asymmetric Synthesis

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

    (Publisher)

  Science of Synthesis, Houben-Weyl Methods of Molecular Transformations , is being published in both paper and searchable electronic formats.

  It is our primary aim to provide a concise analysis of the stereochemical features of transition states in a variety of reaction types. These features are a manifestation of the intra- and intermolecular forces that govern transition state assemblies, which can sometimes be modeled by computers. The ultimate (attainable?) goal of stereoselective synthesis is clear: the production of any relative and absolute configuration of one or more stereogenic units through the use of chiral catalysts that do not require consideration of chirality elements extant in the substrate.

  1.3 Stereoselectivity, and What It Takes to Achieve It

  It is the primary goal of this book to analyze the factors that influence Stereoselectivity when one stereoisomer predominates over others. For illustrative purposes, consider the metal-mediated addition of a nucleophile to an aldehyde. The faces of aldehydes are heterotopic, either enantiotopic (if there are no stereogenic elements elsewhere in the molecule) or diastereotopic (if there are), as shown in Figure 1.1 . In order to achieve a predominance of one stereoisomer (enantiomer or diastereomer) over the other, the transition states resulting from addition of a fourth ligand to the heterotopic Re or Si faces must be diastereomeric. This will be the case if either the carbonyl compound, the reagent, or a metal catalyst (MLn ) are chiral. More than one stereogenic element, as in R* and ML* n gives rise to the possibility of matched or mismatched double asymmetric induction. In this chapter, we outline the physical principles that control selectivity, and provide precise definitions of stereochemical terms in the Glossary (Section 1.11

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  Stereochemistry

  Basic Concepts and Applications

  • M. Nógrádi(Author)
  • 2013(Publication Date)
  • Pergamon

    (Publisher)

  CHAPTER 3 Applied Stereochemistry 3.1 REACTIVITY AND MOLECULAR SYMMETRY 1 2 0 1 2 8 The formation and transformation of stereoisomers is discussed in this chapter, and as elsewhere the main emphasis will be on general principles accompanied by simple examples as illustrations. Stereochemical aspects of reaction mechanisms will not be covered in this book. 3.1.1 The formation of stereoisomers. Intramolecular Stereoselectivity The ability to predict the formation of stereoisomers is most important in organic chemistry, the stereochemical outcome of a reaction depending on the overall symmetry of the system comprising the substrate, the reagent, the medium, and not least of any catalyst used. Two possibilities present themsel-ves in this respect: (a) the symmetry of the substrate and of the reagent enable the formation of only one stereoisomer; (b) more than one stereo-isomer may be formed. The reverse of case (b) would be that of stereodestruc-tive reactions, being transformations which reduce the number of possible stereoisomers, i.e. convert two or more stereoisomers to the same product. Stereochemical changes associated with chemical reactions may involve either the transformation or replacement of ligands at centres, or alterna-tively a change in the coordination number of the atoms involved. For this reason, it is convenient therefore to analyze the formation of stereoisomers either in terms of the intramolecular symmetry of groups or of molecular faces (see below). 3.1.1.1 Transformations involving structurally identical groups Structurally identical groups are those which have the same constitution, configuration and equivalent positions. The intramolecular symmetry o f these groups has already been discussed above (p. 112); here the relationship 180

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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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  Chirality in Drug Design and Development

  • Indra K. Reddy, Reza Mehvar, Indra K. Reddy, Reza Mehvar(Authors)
  • 2004(Publication Date)
  • CRC Press

    (Publisher)

  5 Stereoselectivity in Drug Action and Disposition: An Overview Bhavesh K.Patel and Andrew J.Hutt King’s College London, London, England 1. INTRODUCTION In the foreword to the 1994 reprint of Edwin Abbott’s classic eighteenth-century science- fiction novel concerning a two-dimensional world, “Flatland,” Anjam Khursheed * comments, “Flatland will always be a profound inspiration to those who refuse to live in a world dominated by limited dimensionality.” Until relatively recently, pharmacology has been very much a limited-dimensionality science, the three-dimensional nature of drug molecules being largely neglected. Stereoselectivity in drug action has been known since the early years of the last century [1], but apart from a relatively few instances, it was overlooked in what was almost a golden age of drug discovery and development between the 1950s and the early 1970s. As a result of this neglect, by the late 1980s racemates accounted for 25% of the products available in a survey of 1675 drugs [2]. However, over the last 15 to 20 years there has been a change in philosophy with respect to chiral pharmaceuticals. This change has been brought about to a large extent by advances in methodology associated with the stereoselective synthesis and stereospecific analysis of chiral drug molecules, together with an increased appreciation of the potential significance of the differential biological properties of the * Khursheed, A. (1994). Foreword. In: E.A.Abbott, Flatland. Oxford: Oneworld Publications, pp. 1– 4. enantiomers of chiral drugs administered as racemates. The use of racemates is regarded by some as polypharmacy with the proportions of the drug dose being determined by chemical rather than therapeutic or pharmacological criteria, and by others as drugs containing 50% impurity.

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  Stereoselective Synthesis

  A Practical Approach

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

    (Publisher)

  1.4.2.3 Concept of Stereodifferentiation The above classification of stereoselective reactions according to the symmetry of products is useful inasmuch as it gives insight into the process but suffers from being not structured enough. Probably this prompted Izumi to suggest, in 1971, a new classification based on the symmetry of substrates [32, 331. Reactions giving unequal amounts of stereoisomers were called stereodifferentiating and prefixed according to the nature of the substrate as enantiomer- and diastereomer-, enantiotopos- and diastereotopos-, further enantioface- and diastereoface-differentiating reactions, ac- cording to whether stereoisomers, groups, or faces were differentiated. Note that the first two types cover substrate selective transformations, while the last four product selective ones. Izumi’s classification is rather appealing because the conditions of selectivity can be defined very simply: enantio-differentiation requires chiral means, whereas diastereo-differentiation does not. Also very enlightening is Izumi’s obser- vation that the key for enantio-differentiation is provided by the environment (reagent, solvent, catalyst), while that for diastereo-differentiation is within the molecule (steric hindrance by, or electronic and other effects of groups around the reaction center). 1.4.2.4 Methods for Inducing Stereoselectivity In the foregoing sections the fundamentals of stereoselective reactions have been discussed, but little information has been provided about the methodology of such reactions. For our topic, however, the various ways and means by which stereoselec- tivity can be generated is of primary importance. Enantioselectivity Selectivity in the transformation of enantiotopic groups and faces can only be achieved, as explained before, by chiral means. These may be characterized as fol- lows: (i) Photochemical transformations induced by “chiral’: i.e. circularly polarized, light. This is an impractical method giving only a few percent ee or less. ~~ * Note (i) that the process is totally diastereoselective giving only trans addition products and (ii) that oxidation

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  Drug Stereochemistry

  Analytical Methods and Pharmacology, Third Edition

  • Krzysztof Jozwiak, W. J. Lough, Irving W. Wainer, Krzysztof Jozwiak, W. J. Lough, Irving W. Wainer(Authors)
  • 2012(Publication Date)
  • CRC Press

    (Publisher)

  13 Regulatory perspective on the development of new stereoisomeric drugs Sarah K. Branch a and Andrew J. Hutt INTRODUCTION The regulation of chiral drugs is, in principle, no different from the regulation of any other drug substance. Satisfactory standards of quality, safety, and efficacy need to be demonstrated for medicines containing chiral active ingredients before they can receive an authorization to place them on the market. Of course, there are some special considerations or even challenges to take into account, particularly regarding the similar physicochemical properties of potential impurities in the traditional sense. Significant advances in synthetic, preparative, and analytical chemistry in the 1980s and 1990s allowed the development of synthetic, as opposed to the natural or semisynthetic, drug substances, which had dominated the area of stereochemically pure medicinal products up to then (e.g., Gal) (1). At the same time, there was increasing awareness of the different biological activities of stereoisomers and indeed the means to study these differences. It is now recognized that stereoisomers may differ in their pharmacody-namic activity at their biological target, for example, receptor, enzyme active site, etc., or in their pharmacokinetic properties (absorption, distribution, and clearance by metabolism and excretion). Regarding pharmacodynamic activity, differences between stereoisomers may be quantitative, in that the resulting action is the same but one isomer is more potent than the other. Alternatively, the difference may be qualitative in nature, the “unrequired” isomer may be biologically inert, that is, have no detectable biological activity, may act on a different biological target possibly giving an unwanted biological response, or may even have an opposing effect reducing the required pharmacodynamic activity if a racemate was to be administered.

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