Introduction to Heterocyclic Chemistry (eBook)

Peter A. Jacobi (Autor)

eBook Download: EPUB

2018
John Wiley & Sons (Verlag)
978-1-119-41768-2 (ISBN)

Infos

A unique approach to a core topic in organic chemistry presented by an experienced teacher to students and professionals
Heterocyclic rings are present in the majority of known natural products, contributing to enormous structural diversity. In addition, they often possess significant biological activity. Medicinal chemists have embraced this last property in designing most of the small molecule drugs in use today. This book offers readers a fundamental understanding of the basics of heterocyclic chemistry and their occurrence in natural products such as amino acids, DNA, vitamins, and antibiotics. Based on class lectures that the author has developed over more than 40 years of teaching, it focuses on the chemistry of such heterocyclic substances and how they differ from carbocyclic systems.
Introductory Heterocyclic Chemistry offers in-depth chapters covering naturally occurring heterocycles; properties of aromatic heterocycles; ?-deficient heterocycles; ?-excessive heterocycles; and ring transformations of heterocycles. It then offers an overview of 1,3-dipolar cycloadditions before finishing up with a back-to-basics section on nitriles and amidines.

• Presents a conversational approach to a fundamental topic in organic chemistry teaching 
• Offers a unique look at this core organic chemistry topic via important naturally occurring and/or biologically active heterocycles 
• Based on the author's many years of class lectures for teaching at the undergraduate and graduate level as well as pharmaceutical-industry courses 
• Clear, concise, and accessible for advanced students of chemistry to gain a fundamental understanding of the basics of heterocyclic chemistry 

Introductory Heterocyclic Chemistry is an excellent text for undergraduate and graduate students as well as chemists in industrial environments in chemistry, pharmacy, medicinal chemistry, and biology.

PETER A. JACOBI, PHD, received his B.S. degree in Chemistry from the University of New Hampshire (1967), and his Ph.D. in Organic Chemistry from Princeton University (1973). After two years at Harvard as a postdoctoral fellow, he joined the faculty of Wesleyan University (1975). In the fall of 1997 he moved from Wesleyan to Dartmouth, where in 2004 he was appointed the New Hampshire Professor of Chemistry, a position he held until 2013. Dr. Jacobi is the recipient of numerous awards including the American Cyanamid Company Award for 'Advancement of the Art and Science of Synthesis' (1985); the Connecticut Valley ACS Award for 'Outstanding Contributions to Chemistry' (1988); and the Caleb T. Winchester Award for 'Excellence as a Scholar-Teacher' (1996). In 2010 he was elected as a Fellow of the American Chemical Society. He is the author of nearly 100 publications in the general area of heterocyclic chemistry, in particular as applied to natural product synthesis.

Inhalt

Preface ix

Acknowledgments xi

1 Some Biologically Important Heterocycles of Nature 1

1.1 Vitamins 3

1.2 Antibiotics and Tetrapyrroles 8

References 10

2 Orbitals and Aromaticity; Chemical Reactivity 11

References 15

3 A Prelude to Synthesis 17

References 21

4 pi-Deficient Heterocycles: Some Physical Properties 23

References 25

5 pi-Deficient Heterocycles: De Novo Syntheses 27

5.1 De Novo Syntheses, Pyrimidines 32

5.2 Fused-Ring Systems, Quinolines 33

5.2.1 Isoquinolines 34

References 37

6 pi-Deficient Heterocycles: Introduction of New Substituents: Nucleophilic Substitution 39

References 48

7 pi-Deficient Heterocycles: Introduction of New Substituents: Heterocyclic N-Oxides 49

7.1 Further Reactions of N-Oxides 61

References 73

8 pi-Deficient Heterocycles: Introduction of New Substituents: Quinolines and Isoquinolines 75

References 86

9 pi-Deficient Heterocycles: Manipulation of Existing Substituents 89

9.1 Summary 103

References 105

10 pi-Excessive Heterocycles: General Properties 107

References 114

11 pi-Excessive Heterocycles: De Novo Syntheses 115

11.1 Synthesis of 1,3-Azoles 127

11.2 Synthesis of 1,2-Azoles 131

11.3 Fischer Indole Synthesis 133

References 136

12 pi-Excessive Heterocycles: Introduction of New Substituents 139

References 153

13 Ring Transformations of pi-Excessive Heterocycles: Diels-Alder Reactions 157

References 175

14 Heterocycles as Synthons 177

References 205

15 1,3-Dipolar Cycloadditions--An Overview 207

References 234

16 Back to Basics 239

References 245

17 A Brief Synopsis 247

Index 251

Textauszug

1
Some Biologically Important Heterocycles of Nature

Heterocyclic rings come in many sizes and shapes, and they may be either aromatic or non‐aromatic, fused or non‐fused. This chapter provides a brief survey of some of the most biologically important heterocycles found in nature.

Let us begin our discussion with the three common amino acids tryptophan, proline, and histidine (Figure 1.1). Tryptophan contains an indole skeleton (blue), which is aromatic by virtue of having 10 π‐electrons in a cyclic conjugated array, two of which are donated by the ring nitrogen. Proline, on the other hand, is clearly non‐aromatic, since the pyrrolidine ring has only the free electron pair on nitrogen. But what about histidine, the distinguishing feature of which is an imidazole core with a total of eight electrons? Does this ring system satisfy Hückel's rule? The answer is yes, since one of the electron pairs resides in an orthogonal sp2‐orbital, leaving 6 π‐electrons to constitute the aromatic sextet. Lastly, while not an amino acid itself, we include in this introduction serotonin, a product of catabolism of tryptophan [1a]. The chief function of this indole alkaloid is as a neurotransmitter in the brain, and as such, it plays a key role in regulating mood. Drugs that alter the concentration of serotonin in the brain have found use in treating depression and anxiety disorders.

Figure 1.1 Some naturally occurring heterocycles.

As to their own biological role, amino acids are ubiquitous as the molecular building blocks of peptides, proteins, and enzymes. In addition to the three heterocyclic amino acids just described, 17 others make up the class of 20 naturally occurring amino acids, 9 of which are considered “essential” (i.e., they cannot be biosynthesized by humans, and must be provided by diet). In this context, one might wonder how nature functions at such a complex level with such a limited “tool chest.” Part of the answer is given by the simple equation N=20n, where N equals the number of possible peptides/proteins, 20 equals the number of monomer building blocks, and n equals the number of amino acids in the chain. The results can be staggering! For example, the number of structurally unique dipeptides would total 400; for n=5 this number jumps to 3,200,000; and for n=100, which is still quite a small protein, the possible combinations would be, well, astronomical (many orders of magnitude greater than the estimated number of atoms in the universe) [1b].

Proteins are one example of a class of compounds known as informational macromolecules, which control crucial life processes. We saw above how great complexity can be generated from a relatively small group of amino acid building blocks, even considering just the primary structure of the derived proteins. However, proteins are not unique in this capability, and it has been estimated that over 90% of all of the organic material found in living organisms, including many thousands of macromolecules, can be generated from about three dozen monomeric species [1a]. Of these, 20 constitute the naturally occurring amino acids. Another five are the DNA and RNA bases adenine (abbreviated A), thymine (T), guanine (G), and cytosine (C), all found in DNA, and uracil (U), which replaces thymine in RNA (Figure 1.2). A and G are examples of purine heterocycles, while T, C, and U are pyrimidines.

Figure 1.2 Naturally occurring heterocycles.

DNA is formally derived from A, T, G, and C by initial condensation of the NH groups shown in red with 2‐deoxyribose (an example of a furanose heterocycle, and another of nature's basic building blocks). The resultant deoxyribonucleosides then undergo phosphorylation at the primary hydroxyl group to afford the corresponding deoxyribonucleotides, which on polymerization lead to single stranded DNA. But this is not the end of the story. Most readers will be aware of the double helical nature of DNA, wherein base pairing through hydrogen bonding assures that identical concentrations of A and T will always be present. The same holds true for G and C. This observation was one of the keys to unraveling the structure of DNA, and it provided a molecular basis for the process of replication. RNA, produced from DNA by transcription, is a single stranded polynucleotide with uracil substituting for thymine, and ribose replacing deoxyribose. In the third step for processing genetic information, the message encoded in RNA is translated by ribosomes to that required for synthesizing specific proteins.

1.1 Vitamins

Who among us has not at some point been concerned with “getting enough vitamins?” Although generally required in only trace quantities, these micronutrients are one of five essential components of a healthy diet (the others being carbohydrates, fats, proteins, and certain mineral elements). Vitamins perform a myriad of biological functions, and they are generally classified as being either fat soluble or water soluble. All of the water‐soluble vitamins are heterocycles, a sampling of which are described below (Figure 1.3) [1].

Figure 1.3 Heterocyclic vitamins.

Pyridoxine is one of a group of three closely related pyridine heterocycles that constitute the vitamin B6 group of vitamins (Figure 1.3). These species are best known for their role in transamination reactions, wherein an amino group from one α‐amino acid is reversibly transferred to the α‐carbon of an α‐keto acid. This process is coupled with the interconversion of pyridoxal and pyridoxamine, according to the overall equation:

While the details for this enzyme catalyzed transformation are complex, we shall see later that each step finds precedent in common bond forming reactions employed in heterocycle synthesis.

Ascorbic acid (vitamin C) is best known as a preventive and curative agent for the debilitating disease scurvy, which is characterized by lethargy, brown spots on the skin and gums, open sores, and if left untreated, death from bleeding. Human beings are among the few vertebrates who cannot biosynthesize this substance from glucose. Up until the early 1800s scurvy was common among sailors and other adventurers lacking access to fresh citrus fruit, an excellent source of vitamin C. The British Navy is credited with making the observation that a daily ration of citrus juice, mixed of course with grog, prevented scurvy (hence the term “limey,” originally intended as derogatory slang for sailors in the Royal Navy). In this capacity, vitamin C serves as a co‐factor in the enzymatic hydroxylation of proline to afford 4‐hydroxyproline, a major component of connective tissue:

It is, of course, also well known for its antioxidant properties by virtue of its enediol functionality (shown in red in Figure 1.3).

As ascorbic acid is to scurvy, so vitamin B12 is to pernicious anemia, an autoimmune disorder in which the body fails to produce sufficient healthy red blood cells. A major breakthrough in treating this disease was made in 1926, when it was found that a diet rich in partially cooked liver effected a cure. It remained until the late 1940s for the anti‐pernicious anemia factor to be isolated in the crystalline state, in the form of cyanocobalamin (R=CN in Figure 1.3; in the physiologically active forms, R=5'‐deoxyadenosyl or CH3). Another 10 years were required to determine its very complex structure, containing a cobalt atom complexed in a corrin nucleus. In humans, vitamin B12 serves as a coenzyme in two important enzymatic processes. In the methylcobalamin form it functions as a methyltransferase, in which a methyl group transfers between two molecules. Alternatively, in the adenosylcobalamin form it functions as an isomerase, in which a hydrogen atom shifts from one carbon atom to an adjacent one, with concomitant exchange of a second group. See, for example, the conversion of glutamic acid to β‐methylaspartic acid below, where the group shown in red migrates from C3 to C4, exchanging with the hydrogen shown in blue [1a]:

Thiamin (vitamin B1) contains both a thiazole and a pyrimidine ring and it has played a rich role in the history of vitamin discovery. In fact, the name “vitamine” derives from early studies on this material, when it was recognized as a vital, amine containing dietary component in preventing beriberi (the “e” was later dropped when it was discovered that not all vitamins are amines). In animal tissues it is present mainly as a pyrophosphate derivative (TPP), in which form it serves as a coenzyme in several cellular processes. One of these involves decarboxylations of α‐keto acids, such as pyruvate, where TPP functions as a carrier of an intermediate aldehyde:

All such conversions exploit the unusually high acidity of the C‐2 hydrogen shown in red (pK a≈18 in the free state [2a]; thought to be considerably lower in the active site [2b]), and the nucleophilicity of the derived ylide (sometimes referred to as a heterocyclic carbene). Thus, the first step in pyruvate decarboxylation involves nucleophilic addition of TPP ylide across the ketone carbonyl group of pyruvate (Scheme 1.1). This is followed by decarboxylation to generate an enol, following a...

Produkt-Details

• Erscheint lt. Verlag: 8.8.2018
• Sprache: englisch
• Themenwelt: Naturwissenschaften ► Chemie ► Organische Chemie
• Schlagworte: Biochemie • Biochemie u. Chemische Biologie • biochemistry • Biochemistry (Chemical Biology) • biologically important heterocycles • Chemie • Chemistry • dipolar cycloadditions • heterocycles as synthons • Heterocyclic Chemistry • heterocyclic chemistry in amino acids • heterocyclic chemistry in DNA • heterocyclic chemistry in vitamins antibiotics • Heterocyclische Verbindungen • Introductory Heterocyclic Chemistry • Molecular Biology • nitriles and amidines • Organic Chemistry • organic synthesis • Organische Chemie • Pharmaceutical & Medicinal Chemistry • Pharmazeutische u. Medizinische Chemie • ring transformations of heterocycles • π-deficient heterocycles • π-excessive heterocycles
• ISBN-10: 1-119-41768-6 / 1119417686
• ISBN-13: 978-1-119-41768-2 / 9781119417682