Protecting Groups

9 Key excerpts on "Protecting Groups"

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  Greene's Protective Groups in Organic Synthesis

  • Peter G. M. Wuts(Author)
  • 2014(Publication Date)
  • Wiley

    (Publisher)

  Without her understanding and encouragement, the volume probably would never have been completed. PETER G. M. WUTS Kalamazoo, Michigan May 1990 xviii PREFACE TO THE SECOND EDITION PREFACE TO THE FIRST EDITION The selection of a protective group is an important step in synthetic methodology, and reports of new protective groups appear regularly. This book presents information on the synthetically useful protective groups (∼500) for five major functional groups: -OH, -NH, -SH, -COOH, and >CO. References through 1979, the best method(s) of formation and cleavage, and some information on the scope and limitations of each protective group are given. The protective groups that are used most frequently and that should be considered first are listed in Reactivity Charts, which give an indication of the reactivity of a protected functionality to 108 prototype reagents. The first chapter discusses some aspects of protective group chemistry: the properties of a protective group, the development of new protective groups, how to select a protective group from those described in this book, and an illustrative example of the use of protective groups in a synthesis of brefeldin. The book is organized by functional group to be protected. At the beginning of each chapter are listed the possible protective groups. Within each chapter protective groups are arranged in order of increasing complexity of structure (e.g., methyl, ethyl, t-butyl, . . . , benzyl). The most efficient methods of formation or cleavage are described first. Emphasis has been placed on providing recent references, since the original method may have been improved. Consequently, the original reference may not be cited; my apologies to those whose contributions are not acknowledged. Chapter 8 explains the relationship between reactivities, reagents, and the Reactivity Charts that have been prepared for each class of protective groups. This work has been carried out in association with Professor Elias J.

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  Green Sustainable Process for Chemical and Environmental Engineering and Science

  Sonochemical Organic Synthesis

  • Rajender Boddula, Abdullah M. Asiri, Inamuddin, Dr. Inamuddin(Authors)
  • 2020(Publication Date)
  • Elsevier

    (Publisher)

  In that respect, the reactive sites of a compound having multiple functional groups are in general temporarily blocked to carry out the reaction at one particular reaction center, and it can be brought off by appropriate protection and deprotection of functionality to survive in the chemical environments. Keeping in mind, the orthogonal protection protocols are selected mildly so that expected demasking could be focused by alternative cleavage mechanisms rather than the rate of reactions. A simple example is displayed below to provide the answer to the question: why protecting and deprotecting of the functional group is important and how it is carried out? When 1° and 2° alcohol groups are present simultaneously in the molecule, oxidation of the 2° alcohol group could be accomplished with the assistance of oxidizing agents like PCC or DCC, but the primary alcohol is more sensitive (reactive) to oxidation (Scheme 1) than the others. Scheme 1 Oxidation of alcohol group and selectivity. Thus, to solve the problem, two additional steps are required; firstly, the protecting group could be introduced to protect primary alcohol and makes it inert toward oxidation and facilitating the secondary hydroxyl group oxidation easily to get the intermediate keto derivative. After successful oxidation, the cleavage of the protecting group also could be performed straightforwardly regenerating the primary alcohol easily, as shown in Scheme 2. Scheme 2 Oxidation of the hydroxy group and selectivity using Protecting Groups. This context indicates that the functional groups which are required to be preserved, protected by proper functionality and then the required reactions are implemented on the desired functional group, keeping the other functionalities intact during the reaction period/workup and in purification steps. After completion of the reaction, the parent functional group could be restored by cleaving protecting group, which is presented graphically in Fig. 1

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  Handbook for Chemical Process Research and Development, Second Edition

  • Wenyi Zhao(Author)
  • 2023(Publication Date)
  • CRC Press

    (Publisher)

  13 Protecting Groups

  DOI: 10.1201/9781003288411-13

  Protection and deprotection of functional groups have been playing a great role in organic synthesis. Protections fall predominately into three categories: protection of amino groups, protection of carboxylic acids as esters, and protection of hydroxyl groups. The most common protecting group

  1

  for the amino group is tert-butyloxycarbonyl (Boc), followed by benzyl and carbobenzyloxy (Cbz) groups (these two groups can be removed by catalytic hydrogenolysis). Frequently, carboxylic acids are protected as their corresponding alkyl esters, such as methyl ester or ethyl ester. A wide variety of Protecting Groups are used for the protection of the hydroxyl group. The most common Protecting Groups are benzyl, silicon-containing groups, and acetyl and benzoyl groups. In general, the benzyl-protecting group works well and tolerates acidic or basic conditions. There are concerns, however, regarding product contamination over the use of palladium-catalyzed deprotection of Protecting Groups, especially at the late stage in the synthesis. Both acetyl and benzoyl groups proved to be labile under basic conditions and extensive protecting group migration was observed.

  13.1 PROTECTION OF HYDROXYL GROUP

  13.1.1 Prevention of Side Reactions

  13.1.1.1 Friedel–Crafts Alkylation

  Selection of the right protecting group is critical for the success of a reaction. For example, attempts to make indeno-β-lactam 2a under Friedel–Crafts alkylation conditions by treatment of benzyl-protected phenol 1a with TfOH failed, giving, instead of 2a, chroman 3 in 44% yield (Equation 13.1).

  2

  (13.1)

  To circumvent the undesired cyclization, a bulky triisopropylsilyl (TIPS) group was used to reduce the nucleophilicity of the oxygen atom. The reaction was conducted in dichloromethane in the presence of Sc(OTf)3 and 2,6-di-tert-butylpyridine (DTBP) affording the desired indeno-β-lactam 2b

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  Green Chemistry and Applications

  • Aide Sáenz-Galindo, Adali Facio, Raul Rodriguez-Herrera, Aide Sáenz-Galindo, Adali Facio, Raul Rodriguez-Herrera, Aide Sáenz-Galindo, Adali Oliva Castañeda Facio, Raul Rodriguez-Herrera(Authors)
  • 2020(Publication Date)
  • CRC Press

    (Publisher)

  The synthesis starts by assembling the molecular skeleton (not shown), with carbon-carbon double and triple bonds as profunctionality (Hu and Brown, 2005). This is followed by the generation tetrahydrofuran rings and alcohol functions through a series of functionalization reactions. The final stage of the synthesis involves a series of transition-metal-catalyzed processes, for the completion of the molecular skeleton, resulting in an overall avoidance of the protecting group. This undoubtfully suggests the fact that the variation in the order of introduction of functional groups can drastically minimize or even completely avoid the use of Protecting Groups in an organic synthesis. Thus this concept of designing the order of introduction of a functional group by first assembling the molecular skeleton in a reaction will indeed open up the realization of protecting group free synthesis (Fraunhoffer et al., 2005; Yoshimitsu et al., 1997; McFadden and Stoltz, 2006; Ding et al., 2006).

  Conclusion

  The percentage atom utilization in a chemical reaction is a critical factor that characterizes the greenness of the reaction. Minimizing the use of derivatives in a chemical synthesis can be achieved by avoiding the use of Protecting Groups which will result in an increase of atom economy on the reaction. Avoiding the use of Protecting Groups increases the atom economy of the synthesis. Enzyme catalysis, sequential introduction of functional groups and biomimicking approaches can help achieve this goal to a great extent. But one may have to be resigned to the fact that complete removal of Protecting Groups from a synthetic scheme, though ideal may not be feasible in all cases. Alternate approaches like non-covalent and photolabile protection/deprotection groups can be relied on to improve the greenness of a synthetic process. Functionalization to improve selectivity can be used to avoid additional deprotection steps and can further increase the eco-friendliness of a synthetic route. Careful choice of starting materials and well-designed sequential introduction of functional groups can significantly reduce dependency of a synthetic scheme on Protecting Groups. It may be worth noting that other aspects of a modification or derivatization step might determine the overall effectiveness of the synthetic route and indirectly contribute to a greener process.

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  Carbohydrates: The Essential Molecules of Life

  • Robert V. Stick, Spencer Williams(Authors)
  • 2010(Publication Date)
  • Elsevier Science

    (Publisher)

  1–6 ]

  Much of today’s chemistry is concerned with synthesis, and carbohydrate chemistry is no exception. The large pharmaceutical companies (‘Big Pharma’) once employed small armies of chemists to synthesize a myriad of compounds that were necessary for lead development of a potential ‘block buster’ drug. Nowadays, however, the same companies ‘outsource’ much of their synthetic work to smaller, private companies, but there is still a (growing) need for synthetic chemists to do the work. If you want to do synthesis, you need to know about Protecting Groups.

  The Protecting Groups used in carbohydrates are generally the same as those of mainstream organic chemistry; the difference, however, is that even a monosaccharide presents a myriad of hydroxyl groups that need protection, in either an individual (regioselective) or a unique (orthogonal) manner. Also, the introduced Protecting Groups may affect the reactivity of the resulting molecule or even participate in some of its reactions.

  Synthesis with carbohydrates would be a less complicated matter if it were confined to the natural and abundant aldoses, ketoses and oligosaccharides. However, there often arises the need for modified monosaccharides or, perhaps, an unusual or rare oligosaccharide. For example, how would one approach the synthesis of a molecule such as ‘3-deoxy-d-glucose’

  [a ]

  starting from d-glucose?

  a As ‘3-deoxy-d-allose’ is just as good, an unambiguous name should be used: 3-deoxy-d-ribo-hexose. The molecule is depicted as an α/β mixture of pyranose forms.

  The problems are twofold: first, the need for a chemical reaction that will replace a hydroxyl group by a hydrogen atom; second, the need to carry out this replacement only

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  Carbohydrates

  • Helen Osborn(Author)
  • 2003(Publication Date)
  • Academic Press

    (Publisher)

  2 Selective Hydroxyl Protection and Deprotection Jeremy Robertson, Petra M. Stafford Dyson Perrins Laboratory, South Parks Road, Oxford OX1 3QY, UK 2.1 INTRODUCTION In an ideal world it would be possible to effect any desired glycosylation between two free sugars with total control of regio- and stereochemistry to produce a single oligosaccharide. Although enzymes can be sufficiently selective to catalyse such transformations, a general chemical solution to this problem is yet to be found. Aside from the problem of controlling the stereochemistry at the newly formed glycosidic linkage, it is simply not possible to select unambiguously, and at will, which hydroxyl group participates in glycosylation and complex mixtures often result. As in other areas of organic synthesis, ensuring that a particular functional group undergoes reaction without interference from others can be achieved by blocking those others with Protecting Groups. The general principles of protecting group chemistry and the multitude of methods for their introduction and removal have been summarised in a number of excellent books [ 1 ] and review articles [ 2 ] but carbohydrates present particular problems as they possess a number of nucleophilic and mildly acidic hydroxyl groups arranged on relatively short carbon chains, and the density of functionality is accordingly high [ 3 ]. In general, the various hydroxyl groups cannot be considered in isolation; their reactivity influences, and is influenced by, neighbouring functionality and any modifications made to one of them often leads to changes in the relative reactivity of the others. Because of these subtleties, carbohydrate chemistry may appear to have a large associated ‘lore’ which can seem unnecessarily arcane to the uninitiated; this has led, in the past, to a separation of carbohydrate chemistry from what was regarded as mainstream organic synthesis

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  Protecting Groups: Strategies and Applications in Carbohydrate Chemistry

  • Sebastien Vidal(Author)
  • 2018(Publication Date)
  • Wiley-VCH

    (Publisher)

  1 Protecting Group Strategies in Carbohydrate Chemistry Anne G. Volbeda Gijs A. van der Marel and Jeroen D. C. Codée Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2333 CC, Leiden, The Netherlands Carbohydrates are the most densely functionalized class of biopolymers in nature. Every monosaccharide features multiple contiguous stereocenters and bears multiple hydroxyl functionalities. These can, in turn, be decorated with sulfate groups, acyl esters, lactic acid esters and ethers, or phosphate moieties. Amine and carboxylate functions can also be present. Most often, the amine groups are acetylated, but different amide functions are also found, as well as N‐sulfates and alkylated amines. The discrimination of the functional groups on a carbohydrate ring has been and continues to be one of the great challenges in synthetic carbohydrate chemistry [ 1 – 3 ]. This chapter describes the differences in the reactivity of the various functional groups on a carbohydrate ring and how to exploit these in the design of effective protecting group strategies. The Protecting Groups on a carbohydrate dictate the reactivity of the (mono)saccharide, and this chapter will describe how protecting group effects can be used to control stereoselective transformations (most importantly, glycosylation reactions) and reactivity‐controlled one‐pot synthesis strategies. Applications and strategies in automated synthesis are also highlighted. 1.1 Discriminating Different Functionalities on a Carbohydrate Ring The main challenge in the functionalization of a carbohydrate (mono)saccharide is the discrimination of the different hydroxyl functionalities. The – often subtle – differences in reactivity can be capitalized upon to formulate effective protecting group strategies (see Scheme 1.1 A). The primary alcohol functionality is generally the most reactive of the hydroxyl groups because of steric reasons (see Chapter 2)

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  Enzymatic Peptide Synthesis

  • W. Kullman(Author)
  • 2018(Publication Date)
  • CRC Press

    (Publisher)

  Chapter 12

  Proteases as Catalysts in Protecting Group Chemistry

  I. Introduction

  The use of proteases in synthetic peptide chemistry is not confined solely to the basic step of peptide bond formation. In addition, proteases have also been described as useful and efficient agents for the introduction and removal of Protecting Groups. This area of synthetic methodology is by no means marginal in interest; indeed as noted previously (cf. Chapter 6 , Section I.B and Chapter 8 , Section II ), a judicious protecting group strategy is indispensable for a successful peptide synthesis. Consequently, a major part of peptide synthetic chemistry has been concerned with the development of suitable Protecting Groups,1 , 2 which are commonly subdivided into two categories: semipermanent and temporary blocking groups. To recap briefly, the so-called semipermanent protector groups have to survive the multiple reaction steps occurring during the progress of synthesis and their final removal usually represents the last step of the synthetic pathway, i.e., the release of the free target peptides. In contrast, temporary protector groups must be removed prior to each elongation step of the growing peptide chain. Criteria for appropriate semipermanent blocking groups are readily categorized as follows: convenient introduction, inertness to the conditions prevailing during synthetic manipulations, and reversibility without affecting the integrity of the final product. Satisfactory temporary Protecting Groups must be selectively removable under mild conditions without injuring semipermanent blocking groups or, as a matter of course, the peptidic backbone. The traditional procedure of unidirectional, stepwise incorporation of single amino acid derivatives involves the removal of the Nα -protecting group prior to each elongation cycle. In cases where the synthetic strategy involves fragment coupling as well, the α-carboxyl protection has also to be a selectively removable in the presence of semipermanent and temporary Nα

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  Amino Acids, Peptides and Proteins in Organic Chemistry, Protection Reactions, Medicinal Chemistry, Combinatorial Synthesis

  • Andrew B. Hughes(Author)
  • 2011(Publication Date)
  • Wiley-VCH

    (Publisher)

  The solution to carry out peptide synthesis in a chemoselective way is to mask the reactivity of the groups on amino acids that will not be the components of the peptide bond prior to peptide coupling step. This is done by converting the intervening functional group into an unreactive (or less reactive) form by attaching to it a new segment, referred to as a protecting group (or protection or protective function). The chemical reactions used for this purpose are known as protection reactions. The Protecting Groups are solely of synthetic interest and are removed whenever the functional group has to be regenerated. In other words, the protection is reversible. In the light of the concept of protection, the steps involved in the synthesis of the above dipeptide A–B are depicted in Figure 1.1. Figure 1.1 Illustration of synthesis of a dipeptide using α-amino and carboxy protections. Protections are employed for α-amino, carboxy, and side-chain functional groups (Figure 1.2). Since peptide synthesis is a multistep and repetitive process, the longevity of different Protecting Groups on the peptide under synthesis varies. In the present and widely followed approach of assembling peptides, wherein the peptide chain extension is from the carboxy- to amino-terminus (C → N direction), the α-amino protection is removed after each peptide coupling step to obtain a free amino group for subsequent acylation and, hence, this protection is temporary. The carboxy and side-chain protections are generally retained until the entire sequence is assembled, and are removed simultaneously in a single step at the end of the synthesis. Hence, they can be regarded as semipermanent groups. The transient α-amino protection should be removed using reagents/conditions that do not affect the stability of semipermanent groups and, importantly, the newly assembled peptide bond(s)

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