Tongshuang Li has extensive experience in synthetic organic chemistry and medicinal chemistry, with over 22 years in the pharmaceutical industry and 12 years in academia. Currently, he is working as a chemistry consultant for both biotech companies and academics. Dr. Li's work primarily focuses on the synthesis of target compounds for drug discovery, with two new drugs recently approved in China.

Preface xv

Abbreviations xix

1 Opinions and Suggestions 1

1.1 Be a "Doctor," Not Just a "Drug Fetcher" 1

1.2 Synthetic Organic Chemistry: Still as Much an Art as a Science 1

1.3 Synthetic Organic Chemistry Is an Experimental Science under the Guidance of Theory 2

1.4 Reduce Mistakes in Your Synthetic Work 2

1.5 Your Knowledge, Experience, and Skills Can Never Be Too Much 3

1.6 What Is a Mistake? 4

1.7 Beyond Experience: Combining Literature and Insight for Optimal Synthetic Design 6

1.8 Improve Your Decision-Making Ability 6

1.9 Know the Mechanism of the Reactions You Perform 7

1.10 Always Learn Something from the Reaction You Performed 8

1.11 Knowing Reaction Mechanisms Alone Doesn't Make an Excellent Chemist-But It's Essential 8

1.12 Patents Do Not Tell You the Full Story of Chemistry 8

1.13 Summarize Your Work After Completing a Synthesis 9

1.14 Two Examples 9

References 12

2 General Terms and Concepts in Synthetic Organic Chemistry 13

2.1 Reaction Mechanism 13

2.2 Approaches to Draw Reaction Mechanism 13

2.2.1 Linear Way: Catalytic and Noncatalytic Reactions 14

2.2.2 Cyclic Way: Catalytic Reactions 14

2.3 Desired Product 14

2.4 Unexpected Product 14

2.5 Side Reaction 15

2.6 Side Product and By-product 15

2.7 Impurity 15

2.8 Theoretical Yield, Percentage Yield (Yield), Net Yield, and Overall Yield 16

2.9 Intermediate 16

2.10 Transition State 17

2.11 Species 17

2.12 Free Radical 17

2.13 Stoichiometric Reaction 17

2.14 Catalytic Reaction 17

2.15 Material Balance 17

2.16 Electron Balance 18

2.17 Nucleophile 18

2.18 Electrophile 18

2.19 Acid 18

2.20 Base 18

2.21 Acidity and pK a 19

2.22 Acid-Base Reaction 19

2.23 Reaction Selectivity 20

2.24 Chemoselectivity 20

2.25 Regioselectivity 21

2.26 Stereoselectivity 21

2.27 Iteroselectivity 23

2.28 One-pot Synthesis/Telescoping Process 25

2.29 Cascade Reaction 27

2.30 Multicomponent Reaction 29

2.31 Flow Chemistry 29

2.32 Atom Economy 30

2.33 Green Chemistry 31

2.34 Partial Synthesis, Total Synthesis, and Formal Synthesis 32

2.35 Linear Synthesis and Convergent Synthesis 34

2.36 Divergent Synthesis 36

2.37 Click Chemistry 36

2.38 Parallel Synthesis 37

2.39 Solid-phase Synthesis 38

2.40 Combinatorial Chemistry 38

2.41 Process Chemist versus Medicinal Chemist 39

References 40

3 General Terms and Concepts in Medicinal Chemistry 43

3.1 What Is a Drug? 43

3.2 Drug Discovery 43

3.3 Medicinal Chemistry 44

3.4 Drug Target 45

3.5 Enzyme 45

3.6 Receptor 46

3.7 Inhibitor 47

3.8 Activator 48

3.9 Drug Design 48

3.10 Ligand-based Drug Design 49

3.11 Structure-based Drug Design 50

3.12 Lipinski's Rule of Five 50

3.13 Lead Compound 51

3.14 Hit-to-Lead 52

3.15 High-Throughput Screening 52

3.16 Pharmacophore 52

3.17 Affinity, Efficacy, and Potency 53

3.18 Structure-Activity Relationship 54

3.19 Partition Coefficient and Log P/Clog P 54

3.20 Drug Candidate 55

3.21 Preclinical Studies 55

3.22 Toxicity 56

3.23 Pharmacokinetics and Pharmacodynamics 56

3.24 Absorption, Distribution, Metabolism, and Excretion 56

3.25 Bioavailability 57

3.26 Pharmacology 58

3.27 Formulation 58

3.28 Active Pharmaceutical Ingredient 59

3.29 Drug Stability 59

3.30 Prodrugs 60

3.31 Deuterium-containing Drug 61

3.32 Antibody Drug Conjugates 62

3.33 Good Laboratory Practice 62

3.34 Good Manufacturing Practice 63

3.35 Chemistry, Manufacturing, and Controls 64

3.36 Contract Research Organization 65

3.37 Investigational New Drug Application 65

3.38 Clinical Trials 65

3.39 New Drug Application 66

References 67

4 Mechanism Problems from Reactions Give Expected Products 71

4.1 Formation of Noncyclic Compounds 71

Problem 1: t-BuOK Promoted Isomerization of Terminal Alkyne to Internal Alkyne 71

Problem 2: Dimerization of Terminal Aziridines to (E)-but-2-ene-1,4-diamines 72

Problem 3: Thiourea-Mediated Conversion of Alcohols to Alkylhalides 74

Problem 4: Oxidative Decarboxylation of N-Aroylglycines with Lead(IV) Acetate 76

Problem 5: Preparation of Aromatic Amines Promoted by DDQ and Ph 3 P 78

Problem 6: Conversion of Alkyl Aryl Ketones to ¿-Arylalkanoic Acids Using DPPA 80

Problem 7: Synthesis of ¿ß¿-Aryl-¿-Keto Acid from Benzaldehyde and Hydantoin 82

Problem 8: ¿-Amination of Amides 83

Problem 9: ¿-Oxidation of Amides 85

Problem 10: Tsunoda Reagent for Mitsunobu Reaction 87

Problem 11: Preparation of Arylacetonitriles from Arylbromides 89

Problem 12: Transformation of Aromatic Bromides into Aromatic Nitriles 90

Problem 13: Preparation of Nitriles from Carboxylic Acid by Smiles Rearrangement 91

Problem 14: Synthesis of Disubstituted Malononitriles 92

Problem 15: Preparation of 2-Arylacetonitriles from Aromatic Ketones 95

Problem 16: Synthesis of Aminophosphonate by Birum-Oleksyszyn Reaction 97

Problem 17: Synthesis of Primary Sulfonamide by using N-Sulfinyl-O- (tert-butyl)hydroxylamine 98

4.2 Formation of Hydrazine Derivatives 101

Problem 18: Preparation of Hydrazines from Amines by Using Oxaziridines 101

Problem 19: Preparation of Hydrazines from Alcohols 102

Problem 20: Synthesis of Arylacetohydrazonoyl Cyanide 103

4.3 Formation of Cyclic Alkane and Derivatives 105

4.3.1 Cyclopropane 105

Problem 21: Preparation of Methyl (1S,5R)-2-oxo-3- oxabicyclo[3.1.0]hexane-1-carboxylate 105

Problem 22: Synthesis of Cyclopropylamines 107

Problem 23: Formation of Cyclopropane by Dialkylation of Active Methylene 109

Problem 24: A Tandem Cyclopropanation Ring-Expansion Reaction 111

4.3.2 Cyclobutane 115

Problem 25: Synthesis of 3-Ethylbicyclo[3.2.0]hept-3-en-6-one 115

4.3.3 Cyclopentane 117

Problem 26: Preparation of cis-2-(Methoxycarbonyl)cyclopentane-1- carboxylic Acid 117

Problem 27: Rearrangement of Furfuryl Alcohol to 4-Hydroxy-2-cyclopen-tenone 119

4.3.4 Cycloheptane 120

Problem 28: Preparation of Homobenzylic Ketones by 1,2-shift in 1,1¿-disubstituted Olefins 120

4.4 Formation of Aromatic Compounds 122

Problem 29: Formation of Hexasubstituted Benzene Ring by Cyclization 122

Problem 30: Vicarious Nucleophilic Substitution of Hydrogen in Aromatic Nitro Compounds 124

Problem 31: Synthesis of Tetralone from 1-Naphthol and

1,2-Dichlorobenzene 125

4.5 Formation of Nonaromatic Heterocycles 126

4.5.1 Lactone 126

Problem 32: Preparation of Thiolactone from Lactone 126

Problem 33: Preparation of D-Erythronolactone from Erythorbic Acid 129

Problem 34: Synthesis of L-lyxonolactone-2,3-O-isopropylidene 129

Problem 35: Thermal Rearrangement of Ozonides 131

4.5.2 Hydrofuran 133

Problem 36: Preparation of 2,2-Dimethyl-5-phenylfuran-3(2H)-one by a Rearrangement 133

Problem 37: Decarboxylative Elimination of ¿ß¿-Hydroxycarboxylic Acid 134

4.5.3 Tetrahydropyran 137

Problem 38: Construction of Fosdenopterin Core by Viscontini Reaction 137

4.5.4 Pyrrolidine 138

Problem 39: Formation of 2,5-Dibenzyltetrahydropyrrolo[3,4-c] pyrrole-1,3-dione 138

Problem 40: Synthesis of trans-3-substituted Proline Derivatives 139

Problem 41: Preparation of 5,5-Dimethyl-3-methylene-1-(prop-1-en-2-yl) pyrrolidin-2-one 141

Problem 42: Synthesis of Heteroaromatic-Fused Pyrrolidines via Cyclopropane Ring-Opening Reaction 144

Problem 43: Synthesis of Spiro[3H-indole-3,2¿-pyrrolidin]-2(1H)-one 146

4.5.5 Piperidine 148

Problem 44: Synthesis of (2S,4R)-4-Hydroxypipecolic Acid from Homoallyl Alcohol 148

Problem 45: Preparation of a Spiropiperidine 151

Problem 46: Dealkylation of Tertiary Amine with DEAD 153

Problem 47: A Novel Synthesis of ¿¿¿-Keto -¿-amino Acids 155

Problem 48: Construction of Morphine Core by Acid Promoted Cyclization 157

Problem 49: Preparation of 8a-Phenyloctahydroquinolin-4a(2H)-ol 159

Problem 50: Preparation of an Octahydroquinolizine 160

Problem 51: Preparation of a Chromeno[3,2-i]quinolizine 162

4.5.6 Imidazoline 163

Problem 52: Preparation of Phenytoins from Benzils 163

4.5.7 Oxazolidine 164

Problem 53: Preparation of a Chiral (R)-5-(Hydroxymethyl)-3-aryloxazolidin-2-one 164

4.5.8 Tetrahydropyrimidine 166

Problem 54: Synthesis of Tetrahydropyrimidinol 166

4.5.9 Diazepine 167

Problem 55: Synthesis of 2,3,4,5-Tetrahydro-1Hbenzo[e][1,4]diazepine 167

4.5.10 Trioxane 170

Problem 56: Formation of 1,2,4-Trioxanes from Cyclic Peroxides and Carbonyl Compounds 170

Problem 57: Synthesis of 1,2,4-Trioxanes from 4-Alkylphenols and Aldehydes 172

Problem 58: A Key Step for Industrial-Scale Synthesis of Artemisinin (Qinghaosu) 173

4.6 Formation of Monocyclic Aromatic Heterocycles 175

4.6.1 Oxathiolane 175

Problem 59: Synthesis of Substituted 1,3-Oxathiolane 175

4.6.2 Pyrrole 177

Problem 60: Preparation of Pyrrole-2-Aldehyde from Pyrrole-2-t-butyl ester 177

Problem 61: Synthesis of 2¿Formylpyrroles from Pyridinium Iodide Salts 179

Problem 62: Preparation of 2-Aminopyrroles 180

Problem 63: Synthesis of...