Medicinal Natural Products

1 About this book, and how to use it 1

The subject 1

The aim 1

The approach 2

The topics 2

The figures 2

Further reading 3

What to study 3

What to learn 3

Nomenclature 3

Conventions regarding acids, bases, and ions 4

Some common abbreviations 4

Further reading 5

2 Secondary metabolism: the building blocks and construction mechanisms 7

Primary and secondary metabolism 7

The building blocks 8

The construction mechanisms 11

Alkylation reactions: nucleophilic substitution 12

Alkylation reactions: electrophilic addition 12

Wagner-Meerwein rearrangements 15

Aldol and Claisen reactions 15

Imine formation and the Mannich reaction 18

Amino acids and transamination 20

Decarboxylation reactions 22

Oxidation and reduction reactions 24

Dehydrogenases 24

Oxidases 26

Monooxygenases 26

Dioxygenases 26

Amine oxidases 27

Baeyer-Villiger monooxygenases 27

Phenolic oxidative coupling 28

Halogenation reactions 28

Glycosylation reactions 31

Elucidating biosynthetic pathways 34

Further reading 38

3 The acetate pathway: fatty acids and polyketides 39

Fatty acid synthase: saturated fatty acids 39

Unsaturated fatty acids 44

Uncommon fatty acids 53

Prostaglandins 58

Thromboxanes 64

Leukotrienes 64

Polyketide synthases: generalities 66

Polyketide synthases: macrolides 68

Polyketide synthases: linear polyketides and polyethers 90

Diels-Alder cyclizations 96

Polyketide synthases: aromatics 96

Cyclizations 99

Post-polyketide synthase modifications 103

Starter groups 116

Further reading 131

4 The shikimate pathway: aromatic amino acids and phenylpropanoids 137

Aromatic amino acids and simple benzoic acids 137

Phenylpropanoids 148

Cinnamic acids and esters 148

Lignans and lignin 152

Phenylpropenes 156

Benzoic acids from C₆C₃ compounds 157

Coumarins 161

Aromatic polyketides 166

Styrylpyrones, diarylheptanoids 166

Flavonoids and stilbenes 167

Flavonolignans 173

Isoflavonoids 174

Terpenoid quinones 178

Further reading 184

5 The mevalonate and methylerythritol phosphate pathways: terpenoids and steroids 187

Mevalonic acid and methylerythritol phosphate 188

Hemiterpenes (C₅) 192

Monoterpenes (C₁₀) 193

Irregular monoterpenes 204

Iridoids (C₁₀) 206

Sesquiterpenes (C₁₅) 210

Diterpenes (C₂₀) 223

Sesterterpenes (C₂₅) 234

Triterpenes (C₃₀) 234

Triterpenoid saponins 242

Steroids 247

Stereochemistry and nomenclature 247

Cholesterol 248

Phytosterols 251

Vitamin D 256

Steroidal saponins 259

Cardioactive glycosides 265

Bile acids 275

Adrenocortical hormones/corticosteroids 277

Semi-synthesis of corticosteroids 277

Progestogens 287

Oestrogens 290

Androgens 296

Tetraterpenes (C₄₀) 298

Higher terpenoids 306

Further reading 306

6 Alkaloids 311

Alkaloids derived from ornithine 311

Polyamines 311

Pyrrolidine and tropane alkaloids 312

Pyrrolizidine alkaloids 324

Alkaloids derived from lysine 326

Piperidine alkaloids 326

Quinolizidine alkaloids 328

Indolizidine alkaloids 330

Alkaloids derived from nicotinic acid 331

Pyridine alkaloids 331

Alkaloids derived from tyrosine 336

Phenylethylamines and simple tetrahydroisoquinoline alkaloids 336

Modified benzyltetrahydroisoquinoline alkaloids 346

Phenethylisoquinoline alkaloids 359

Terpenoid tetrahydroisoquinoline alkaloids 363

Amaryllidaceae alkaloids 365

Alkaloids derived from tryptophan 366

Simple indole alkaloids 366

Simple ß-carboline alkaloids 369

Terpenoid indole alkaloids 369

Quinoline alkaloids 380

Pyrroloindole alkaloids 385

Ergot alkaloids 387

Alkaloids derived from anthranilic acid 395

Quinazoline alkaloids 395

Quinoline and acridine alkaloids 396

Alkaloids derived from histidine 398

Imidazole alkaloids 398

Alkaloids derived by amination reactions 400

Acetate-derived alkaloids 401

Phenylalanine-derived alkaloids 401

Terpenoid alkaloids 406

Steroidal alkaloids 406

Purine alkaloids 413

Caffeine 413

Saxitoxin and tetrodotoxin 416

Further reading 417

7 Peptides, proteins, and other amino acid derivatives 421

Peptides and proteins 421

Ribosomal peptide biosynthesis 422

Peptide hormones 426

Thyroid hormones 426

Hypothalamic hormones 427

Anterior pituitary hormones 429

Posterior pituitary hormones 430

Pancreatic hormones 432

Interferons 433

Opioid peptides 434

Ribosomal peptide toxins 434

Enzymes 438

Non-ribosomal peptide biosynthesis 438

Modified peptides: penicillins, cephalosporins, and other ß-lactams 458

Penicillins 458

Cephalosporins 465

Other ß-lactams 469

Cyanogenic glycosides 476

Glucosinolates 477

Cysteine sulfoxides 480

Further reading 481

8 Carbohydrates 485

Monosaccharides 485

Oligosaccharides 490

Polysaccharides 493

Aminosugars and aminoglycosides 498

Further reading 507

Index 509