The term ‘steroid’ has become virtually synonymous with androgenic–anabolic compounds (mainly analogues of testosterone) to the majority of the public. The sport sections of many newspapers carry almost daily exposses of the usage of these drugs by athletes seeking to enhance their performance. The androgens in question, however, comprise only a single, relatively small, class of biologically active steroids. What may be called the athletic androgens are in reality overshadowed by a large universe of compounds that share the same tetracyclic nucleus. The term ‘androgen’ in fact represents only one-tenth of the hits when Googling the term ‘steroid’. The very sizeable number of steroids that are approved by regulatory agencies as therapeutic drugs eclipses the group of legal androgenic–anabolic drugs.
By the 1940s, about a decade after their structure had been firmly established, it became evident that steroids might well comprise a structural lead for drug design. Preliminary results from pharmacological studies, carried out at that time, suggested that selected steroids could potentially lead to drugs aimed at targets as diverse as oral contraceptives on the one hand and inflammation on the other. The potential markets for such drugs spurred major chemical efforts in industrial and to some extent in academic laboratories. Research that led to steroid-based therapeutic agents was carried out largely in the laboratories of ‘Big Pharma’ over the two decades following the end ofWorldWar 2. This resulted in the accretion of a large body of organic chemistry often denoted ‘Steroid Chemistry’, and also a sizable number of new therapeutic agents. The assignment of a USAN designation, more familiarly known as a generic name, to a potential drug indicates that the sponsor intends to take the initial steps to assess the clinical activity of the compound. Close to 130 steroids have been assigned official USAN non-proprietary names.
Reports of side-effects that accumulated as the drugs became more widely used led chemists to go back to modify the structures of the offending agent in the hope of producing better tolerated entities. It would be nai¨ve to dismiss the aim of obtaining a place in the market by means of one’s own proprietary and patented entity as additional motivation for that task. It became evident by the mid-1970s that many of the undesired properties, that is, side-effects, were often simply another aspect of the desired hormonal activity. Research aimed at novel steroid-based drugs consequently decreased markedly. The preceding chemical research in the area had by the accumulated a significant body of specialized reactions.
All steroids, be they derived from natural sources or produced by total synthesis, share the same rigid, fixed, three dimensional framework. Many of the chemical properties of steroids, such as the dependence of the reactivity of functional groups on their specific location, are determined by steric properties of the steroid nucleus. That nucleus incorporates over half a dozen chiral centers not counting the side chain. Cholesterol, for example, can in theory consist of no fewer than 512 stereoisomers. This compound actually occurs as a single chiral species, as do virtually all other steroid-based products. The chemistry of these compounds thus provides a rich source for the study of the effects of stereochemistry on chemical reactivity. The reactivity of a pair of ketones in the same molecule, for example, will often differ markedly due to differences in their steric milieu. Structural features of steroids generally determine biological activity. Steroids with an aromatic A ring will, for example, act as estrogens. Differing structural features found in each of those groups has a marked influence on the reactions and reaction sequences used in preparing potential drugs. A text on steroid chemistry could in theory be organized either on the basis of reactions or alternatively by structural class. Grouping compounds by reaction-based sections it is felt would lead to somewhat jumbled presentations. Many of the organic reaction schemes in used steroid chemistry are characteristic of one or another of the broad structural classes. This volume is accordingly divided into the traditional broad structural chapters. The circumstance that biological activity follows the same organization merely illustrates the concordance of structure and activity.
Rules of nomenclature appear early on in many beginning organic chemistry texts. In somewhat the same vein, the Introduction to this book starts with the conventions for naming steroids. This is followed by a concise account of the molecular mechanism of action by which many steroids exert their biological effects. More detailed descriptions of the activity of these compounds will be found in the opening paragraphs of the individual structural classes. Chapter 1 describes the history of steroids with particular attention to the research aimed defining the chemical structure of what were at the time fairly complex molecules. The reader may find it convenient to skim over this section at first reading and to then return after acquiring more familiarity with steroid chemistry.
Chapter 2 opens with a description of the biosynthesis of naturally occurring steroids. The conversion of two very different phytochemicals to steroids that can be elaborated to potential drugs follows. The narrative focuses on a discussion of the chemistry whereby these steroidal natural products are modified into steroid starting materials. Specifically, this describes first the chemistry used to convert diosgenin from Mexican yam roots to dehydropregnenolone and then a discussion of the preparation of pregnenolone from stigmasterol obtained from soybeans. Chemical manipulations of aromatic A-ring steroids, the estranes, are described in Chapter 3. The relative simplicity of the structure of estranes has led to the development of close to half a dozen syntheses that differ in approach, starting from laboratory chemicals. One of these total syntheses, in contrast to those found in subsequent chapters, is used in actual practice to prepare intermediates for the gonanes discussed in Chapter 4. There follows a description of the process long used to prepare aromatic A-ring steroids from phytochemical-derived sources. Chemical reactions of estranes close this chapter.
The chemistry of gonanes, more familiarly known as 19-nor steroids, constitutes the subject matter of Chapter 4. This chapter opens with a discussion the general methods used to prepare the gonane nucleus. Those methods include two syntheses starting from laboratory chemicals that differ markedly in their approach. The description of the chemistry of the gonanes is divided according the disparate biological activity structural variants. These comprise a section on compounds that act as androgenic–anabolic agents and another that includes progestational agents. This last section includes most of the oral contraceptives. A discussion of the newer 11-arylgonane progesterone antagonist concludes Chapter 4.
The androstanes, often called C-19 steroids in that they include methyl groups at each of the angular carbons at C10 and C13, are described in Chapter 6. This section, like the preceding one, also starts with a description of the chemistry used to provide starting material. It also includes a discussion of a total synthesis based on an electrocyclic reaction. The bulk of the chapter comprises of a ring-by-ring description of the chemistry that has been used to prepare modified C-19 androstanes. The bulk of the compounds in this first part of the chapter exhibit androgenic-anabolic activity. Incorporation of a spirobutyrolactone at C17 of the C-19 androstanes leads to compounds that act as diuretics as a result of their aldosterone blocking activity. A brief section on those compounds completes Chapter 5.
Pregnanes in essence comprise androstanes that in addition feature a two-carbon side chain, almost exclusively acetyl, at C17. This carbon skeleton is common to both progestins and corticosteroids. Chapter 6 is devoted to a discussion of the chemistry used to prepare derivatives of the simpler of the two, progesterone. Sources of starting materials for modified progestins from both diosgenin and stigmasterol are discussed at the beginning of the chapter. This is followed by a total synthesis that includes a cascade electrocyclization reaction that somewhat resembles the biosynthetic process by which squalane goes to lanosterol. There follows a ring-by-ring examination of the chemistry used to modify the basic pregnane nucleus.
Structurally more complex corticosteroids, commonly called corticoids, are grouped in Chapter 7, the second section on pregnanes. The biological activity of this class of pregnanes depends on the presence of an oxygen atom, either as a ketone or as an alcohol, at C11 in ring C. The rarity of this structural feature in Nature placed high priority on developing methods for adding that feature to more abundant steroids from Nature. Chapter 7, as in the preceding chapter, opens with a discussion of the methods that have been developed for preparing the starting 11-oxypreganes required for both
clinical supplies and research on analogues. Methods for preparing analogues that include single modifications are considered first. Corticoids comprise one of the rare classes of compounds in which the potentiating effects of structural changes are additive. The closing sections of Chapter 7 discuss the chemistry for preparing compounds with multiple modification.
Groups of steroids that are too small for a full chapter are to be found in the seemingly inevitable chapter termed Miscellaneous. The first section considers steroids in which one of the ring carbon atoms is replaced by a heteroatom, more specifically oxygen or nitrogen. Two compounds in this class, both androstanes, are approved for use in humans. Cardenolides, the steroid-based compounds obtained on removal of the sugars from the so-called cardiac glycosides, are considered in the next section. The chapter closes with a brief discussion of the chemistry involved in modifying the unsaturated cholestanes related to vitamin D.
Contents
1 Steroids: a Brief History 10
1.1 Structure Determination 10
1.1.1 Cholesterol and Cholic Acid 10
1.1.2 The Sex Steroids 13
1.1.3 Corticosteroids 16
2 Sources of Steroids 20
2.1 Biosynthesis 20
2.2 Commercial Steroid Starting Materials 22
2.2.1 Diosgenin 23
2.2.2 Soybean Sterols 25
3 Estranes: Steroids in Which Ring A is Aromatic 28
3.1 Biological Activity 28
3.2 Sources of Estranes 28
3.2.1 From Androstanes 28
3.2.2 Estrogens by Total Synthesis 32
3.3 Chemical Reactions of Estranes 37
3.3.1 Aromatic A-ring Reactions 37
3.3.2 Modifications on Ring B 40
3.3.3 Modifications on Ring C 41
3.3.4 Modifications on Ring D 42
3.4. Some Drugs Based on Estranes 45
4 Gonanes or 19-nor-Steroids 48
4.1 Preparation of Gonane Starting Materials 48
4.1.1 Birch Reduction 48
4.1.2 Synthesis by Sequential Annulation Reactions 49
4.2 Anabolic–Androgenic Gonanes 50
4.2.1 Biological Activity 50
4.2.2 Synthesis of 19-Norandrogens 51
4.3 Progestational Gonanes 55
4.3.1 Biological Activity 55
4.3.2 Preparation of 19-Norprogestins 55
4.4 Some Drugs Based on Gonanes 67
4.4.1 Androgenic–Anabolic Agents 67
4.4.2 Progestins 67
4.4.3 Progestin Antagonists 67
5 Androstanes, C19 Steroids and Their Derivatives 68
5.1 Biological Activity 68
5.2 Sources of Androstanes 68
5.2.1 From Pregnenolone 68
5.2.2 Fermentations 69
5.2.3 Total Synthesis 69
5.3 Modified Anabolic–Androgenic Androstanes 69
5.3.1 17-Desalkyl Compounds 69
5.3.2 17-Alkyl Compounds 73
5.3.3 Modifications on Ring B 77
5.3.4 Modifications on Ring C 79
5.3.5 Modifications on Ring D 80
5.4 17-Spirobutyrolactone Aldosterone Antagonists 83
5.5 Some Drugs Based on Androstanes 85
5.5.1 Androgens 85
5.5.2 Spirobutyrolactones 85
6 Pregnanes, Part 1: Progestins 86
6.1 Biological Activity 86
6.2 Sources of Progesterone 86
6.2.1 From Phytochemicals 86
6.2.2 By Total Synthesis 87
6.2.3 From Dehydroepiandrosterone (DHEA) Acetate 88
6.3 Modified Pregnanes 88
6.3.1 17-Hydroxy and Acyloxy Derivatives 88
6.3.2 Modifications on Ring A 89
6.3.3 Modifications on Ring B 90
6.3.4 General Methods for Modifications on Ring D 94
6.3.5 More Progesterone Analogues 96
6.4 Some Drugs Based on Progestins 100
6.4.1 Medroxyprogesterone Acetate (10-2) 100
6.4.2 Megestrol Acetate (10-3) 101
6.4.3 Melengestrol Acetate (26-7) 101
7 Pregnanes, Part 2: Corticosteroids 102
7.1 Biological Activity 102
7.2 Sources of Corticoids 102
7.2.1. Introduction of Oxygen at C11 102
7.2.2 Construction of the Dihydroxyacetone Side Chain 103
7.3 Modified Corticoids 105
7.3.1 Unsaturation 105
7.3.2 Additional Alkyl Groups 106
7.3.3 Halogenated Corticoids 109
7.3.4 Hydroxylation: 16,17-Diols 111
7.3.5 Corticoids with Multiple Modifications 112
7.3.6 Miscellaneous Corticoids 117
7.4 Some Drugs Based on Corticoids 119
8 Miscellaneous Steroids 122
8.1 Heterocyclic Steroids 122
8.1.1 Introduction 122
8.1.2 Steroids with a Heteroatom in Ring A 122
8.1.3 Steroids with a Heteroatom in Ring B 124
8.1.4 Steroids with a Heteroatom in Ring C 126
8.1.5 Steroids with a Heteroatom in Ring D 128
8.2 Cardenolides 129
8.2.1 Actodigin Aglycone 130
8.2.2 Synthesis from a Bile Acid 130
8.3 Compounds Related to Cholesterol 132
Subject Index 135
Reactions Index 141
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By the 1940s, about a decade after their structure had been firmly established, it became evident that steroids might well comprise a structural lead for drug design. Preliminary results from pharmacological studies, carried out at that time, suggested that selected steroids could potentially lead to drugs aimed at targets as diverse as oral contraceptives on the one hand and inflammation on the other. The potential markets for such drugs spurred major chemical efforts in industrial and to some extent in academic laboratories. Research that led to steroid-based therapeutic agents was carried out largely in the laboratories of ‘Big Pharma’ over the two decades following the end ofWorldWar 2. This resulted in the accretion of a large body of organic chemistry often denoted ‘Steroid Chemistry’, and also a sizable number of new therapeutic agents. The assignment of a USAN designation, more familiarly known as a generic name, to a potential drug indicates that the sponsor intends to take the initial steps to assess the clinical activity of the compound. Close to 130 steroids have been assigned official USAN non-proprietary names.
Reports of side-effects that accumulated as the drugs became more widely used led chemists to go back to modify the structures of the offending agent in the hope of producing better tolerated entities. It would be nai¨ve to dismiss the aim of obtaining a place in the market by means of one’s own proprietary and patented entity as additional motivation for that task. It became evident by the mid-1970s that many of the undesired properties, that is, side-effects, were often simply another aspect of the desired hormonal activity. Research aimed at novel steroid-based drugs consequently decreased markedly. The preceding chemical research in the area had by the accumulated a significant body of specialized reactions.
All steroids, be they derived from natural sources or produced by total synthesis, share the same rigid, fixed, three dimensional framework. Many of the chemical properties of steroids, such as the dependence of the reactivity of functional groups on their specific location, are determined by steric properties of the steroid nucleus. That nucleus incorporates over half a dozen chiral centers not counting the side chain. Cholesterol, for example, can in theory consist of no fewer than 512 stereoisomers. This compound actually occurs as a single chiral species, as do virtually all other steroid-based products. The chemistry of these compounds thus provides a rich source for the study of the effects of stereochemistry on chemical reactivity. The reactivity of a pair of ketones in the same molecule, for example, will often differ markedly due to differences in their steric milieu. Structural features of steroids generally determine biological activity. Steroids with an aromatic A ring will, for example, act as estrogens. Differing structural features found in each of those groups has a marked influence on the reactions and reaction sequences used in preparing potential drugs. A text on steroid chemistry could in theory be organized either on the basis of reactions or alternatively by structural class. Grouping compounds by reaction-based sections it is felt would lead to somewhat jumbled presentations. Many of the organic reaction schemes in used steroid chemistry are characteristic of one or another of the broad structural classes. This volume is accordingly divided into the traditional broad structural chapters. The circumstance that biological activity follows the same organization merely illustrates the concordance of structure and activity.
Rules of nomenclature appear early on in many beginning organic chemistry texts. In somewhat the same vein, the Introduction to this book starts with the conventions for naming steroids. This is followed by a concise account of the molecular mechanism of action by which many steroids exert their biological effects. More detailed descriptions of the activity of these compounds will be found in the opening paragraphs of the individual structural classes. Chapter 1 describes the history of steroids with particular attention to the research aimed defining the chemical structure of what were at the time fairly complex molecules. The reader may find it convenient to skim over this section at first reading and to then return after acquiring more familiarity with steroid chemistry.
Chapter 2 opens with a description of the biosynthesis of naturally occurring steroids. The conversion of two very different phytochemicals to steroids that can be elaborated to potential drugs follows. The narrative focuses on a discussion of the chemistry whereby these steroidal natural products are modified into steroid starting materials. Specifically, this describes first the chemistry used to convert diosgenin from Mexican yam roots to dehydropregnenolone and then a discussion of the preparation of pregnenolone from stigmasterol obtained from soybeans. Chemical manipulations of aromatic A-ring steroids, the estranes, are described in Chapter 3. The relative simplicity of the structure of estranes has led to the development of close to half a dozen syntheses that differ in approach, starting from laboratory chemicals. One of these total syntheses, in contrast to those found in subsequent chapters, is used in actual practice to prepare intermediates for the gonanes discussed in Chapter 4. There follows a description of the process long used to prepare aromatic A-ring steroids from phytochemical-derived sources. Chemical reactions of estranes close this chapter.
The chemistry of gonanes, more familiarly known as 19-nor steroids, constitutes the subject matter of Chapter 4. This chapter opens with a discussion the general methods used to prepare the gonane nucleus. Those methods include two syntheses starting from laboratory chemicals that differ markedly in their approach. The description of the chemistry of the gonanes is divided according the disparate biological activity structural variants. These comprise a section on compounds that act as androgenic–anabolic agents and another that includes progestational agents. This last section includes most of the oral contraceptives. A discussion of the newer 11-arylgonane progesterone antagonist concludes Chapter 4.
The androstanes, often called C-19 steroids in that they include methyl groups at each of the angular carbons at C10 and C13, are described in Chapter 6. This section, like the preceding one, also starts with a description of the chemistry used to provide starting material. It also includes a discussion of a total synthesis based on an electrocyclic reaction. The bulk of the chapter comprises of a ring-by-ring description of the chemistry that has been used to prepare modified C-19 androstanes. The bulk of the compounds in this first part of the chapter exhibit androgenic-anabolic activity. Incorporation of a spirobutyrolactone at C17 of the C-19 androstanes leads to compounds that act as diuretics as a result of their aldosterone blocking activity. A brief section on those compounds completes Chapter 5.
Pregnanes in essence comprise androstanes that in addition feature a two-carbon side chain, almost exclusively acetyl, at C17. This carbon skeleton is common to both progestins and corticosteroids. Chapter 6 is devoted to a discussion of the chemistry used to prepare derivatives of the simpler of the two, progesterone. Sources of starting materials for modified progestins from both diosgenin and stigmasterol are discussed at the beginning of the chapter. This is followed by a total synthesis that includes a cascade electrocyclization reaction that somewhat resembles the biosynthetic process by which squalane goes to lanosterol. There follows a ring-by-ring examination of the chemistry used to modify the basic pregnane nucleus.
Structurally more complex corticosteroids, commonly called corticoids, are grouped in Chapter 7, the second section on pregnanes. The biological activity of this class of pregnanes depends on the presence of an oxygen atom, either as a ketone or as an alcohol, at C11 in ring C. The rarity of this structural feature in Nature placed high priority on developing methods for adding that feature to more abundant steroids from Nature. Chapter 7, as in the preceding chapter, opens with a discussion of the methods that have been developed for preparing the starting 11-oxypreganes required for both
clinical supplies and research on analogues. Methods for preparing analogues that include single modifications are considered first. Corticoids comprise one of the rare classes of compounds in which the potentiating effects of structural changes are additive. The closing sections of Chapter 7 discuss the chemistry for preparing compounds with multiple modification.
Groups of steroids that are too small for a full chapter are to be found in the seemingly inevitable chapter termed Miscellaneous. The first section considers steroids in which one of the ring carbon atoms is replaced by a heteroatom, more specifically oxygen or nitrogen. Two compounds in this class, both androstanes, are approved for use in humans. Cardenolides, the steroid-based compounds obtained on removal of the sugars from the so-called cardiac glycosides, are considered in the next section. The chapter closes with a brief discussion of the chemistry involved in modifying the unsaturated cholestanes related to vitamin D.
Contents
1 Steroids: a Brief History 10
1.1 Structure Determination 10
1.1.1 Cholesterol and Cholic Acid 10
1.1.2 The Sex Steroids 13
1.1.3 Corticosteroids 16
2 Sources of Steroids 20
2.1 Biosynthesis 20
2.2 Commercial Steroid Starting Materials 22
2.2.1 Diosgenin 23
2.2.2 Soybean Sterols 25
3 Estranes: Steroids in Which Ring A is Aromatic 28
3.1 Biological Activity 28
3.2 Sources of Estranes 28
3.2.1 From Androstanes 28
3.2.2 Estrogens by Total Synthesis 32
3.3 Chemical Reactions of Estranes 37
3.3.1 Aromatic A-ring Reactions 37
3.3.2 Modifications on Ring B 40
3.3.3 Modifications on Ring C 41
3.3.4 Modifications on Ring D 42
3.4. Some Drugs Based on Estranes 45
4 Gonanes or 19-nor-Steroids 48
4.1 Preparation of Gonane Starting Materials 48
4.1.1 Birch Reduction 48
4.1.2 Synthesis by Sequential Annulation Reactions 49
4.2 Anabolic–Androgenic Gonanes 50
4.2.1 Biological Activity 50
4.2.2 Synthesis of 19-Norandrogens 51
4.3 Progestational Gonanes 55
4.3.1 Biological Activity 55
4.3.2 Preparation of 19-Norprogestins 55
4.4 Some Drugs Based on Gonanes 67
4.4.1 Androgenic–Anabolic Agents 67
4.4.2 Progestins 67
4.4.3 Progestin Antagonists 67
5 Androstanes, C19 Steroids and Their Derivatives 68
5.1 Biological Activity 68
5.2 Sources of Androstanes 68
5.2.1 From Pregnenolone 68
5.2.2 Fermentations 69
5.2.3 Total Synthesis 69
5.3 Modified Anabolic–Androgenic Androstanes 69
5.3.1 17-Desalkyl Compounds 69
5.3.2 17-Alkyl Compounds 73
5.3.3 Modifications on Ring B 77
5.3.4 Modifications on Ring C 79
5.3.5 Modifications on Ring D 80
5.4 17-Spirobutyrolactone Aldosterone Antagonists 83
5.5 Some Drugs Based on Androstanes 85
5.5.1 Androgens 85
5.5.2 Spirobutyrolactones 85
6 Pregnanes, Part 1: Progestins 86
6.1 Biological Activity 86
6.2 Sources of Progesterone 86
6.2.1 From Phytochemicals 86
6.2.2 By Total Synthesis 87
6.2.3 From Dehydroepiandrosterone (DHEA) Acetate 88
6.3 Modified Pregnanes 88
6.3.1 17-Hydroxy and Acyloxy Derivatives 88
6.3.2 Modifications on Ring A 89
6.3.3 Modifications on Ring B 90
6.3.4 General Methods for Modifications on Ring D 94
6.3.5 More Progesterone Analogues 96
6.4 Some Drugs Based on Progestins 100
6.4.1 Medroxyprogesterone Acetate (10-2) 100
6.4.2 Megestrol Acetate (10-3) 101
6.4.3 Melengestrol Acetate (26-7) 101
7 Pregnanes, Part 2: Corticosteroids 102
7.1 Biological Activity 102
7.2 Sources of Corticoids 102
7.2.1. Introduction of Oxygen at C11 102
7.2.2 Construction of the Dihydroxyacetone Side Chain 103
7.3 Modified Corticoids 105
7.3.1 Unsaturation 105
7.3.2 Additional Alkyl Groups 106
7.3.3 Halogenated Corticoids 109
7.3.4 Hydroxylation: 16,17-Diols 111
7.3.5 Corticoids with Multiple Modifications 112
7.3.6 Miscellaneous Corticoids 117
7.4 Some Drugs Based on Corticoids 119
8 Miscellaneous Steroids 122
8.1 Heterocyclic Steroids 122
8.1.1 Introduction 122
8.1.2 Steroids with a Heteroatom in Ring A 122
8.1.3 Steroids with a Heteroatom in Ring B 124
8.1.4 Steroids with a Heteroatom in Ring C 126
8.1.5 Steroids with a Heteroatom in Ring D 128
8.2 Cardenolides 129
8.2.1 Actodigin Aglycone 130
8.2.2 Synthesis from a Bile Acid 130
8.3 Compounds Related to Cholesterol 132
Subject Index 135
Reactions Index 141
Book Details
- Paperback: 152 pages
- Publisher: Wiley (December 28, 2010)
- Language: English
- ISBN-10: 0470660848
- ISBN-13: 978-0470660843
- Product Dimensions: 11.6 x 8.1 x 0.5 inches
List Price: $49.95