Title Page

ABSTRACT

국문 초록

Contents

NOMENCLATURE 13

CHAPTER 1. Introduction 17

1.1. Tetrahydrofuran Derivatives 18

1.2. Direct Functionalization of THF Cores 20

1.3. Intramolecular Reaction for Synthesis of THF Derivatives 23

1.3.1. Cyclizations that Form C-C Bonds 24

1.3.2. Cyclizations that Form C-O Bonds 28

1.4. Intermolecular Reaction for Synthesis of THF Derivatives 35

1.4.1. [3+2] Cycloaddition 36

1.4.2. [4+1] Cycloaddition 45

1.4.3. [2+2+1] Cycloaddition 49

CHAPTER 2. The Synthesis of THF Derivatives via Pd-Catalyzed Oxidative Cycloaddition of Alkenes and Allyl Alcohols 51

2.1. Background and Motivation 52

2.2. Initial Hit and Identifying Diastereomers 57

2.3. Reaction Development 59

2.3.1. Optimization 59

2.3.2. Control Experiment 61

2.4. Alkene Scope 63

2.5. Proposed Mechanism 65

2.6. Gram-Scale Synthesis 67

2.7. Conclusion 68

2.8. Outlook 69

2.8.1. Reactivity of Alkenes 69

2.8.2. Reactivity of Allyl Alcohols 70

2.8.3. Asymmetric Synthesis 73

CHAPTER 3. Experimental Part 74

3.1. General Information 75

3.2. Synthesis of 4 76

3.3. Synthesis of THF derivatives 77

3.3. Detailed Optimized Table 86

REFERENCE 93

APPENDICES 107

Table 2.1. Optimized table 60

Table 2.2. Control experiment 62

Table 2.3. Alkene scope 64

Table 2.4. Screening of other alkenes 69

Table 2.5. Screening of allyl alcohols 71

Table 3.1. Substrate ratio 86

Table 3.2. DMSO loading 86

Table 3.3. Sulfoxide additive screening 87

Table 3.4. HFIP loading 87

Table 3.5. Catalyst screening 88

Table 3.6. Oxidant screening 89

Table 3.7. Additive screening 90

Table 3.8. Solvent screening 91

Table 3.9. Reaction temperature 92

Table 3.10. Reaction time 92

Figure 1.1. THF-containing natural products and pharmaceuticals 19

Figure 1.2. Possible disconnections of THFs by cleavage one bonds 23

Figure 1.3. Possible disconnections of THFs into 2 or 3 components 35

Figure 2.1. General mechanism of wacker oxidation 53

Figure 2.2. Proposed mechanism 66

Figure 3.1. Sulfoxide additives 87

Scheme 1.1. Challenge of direct generation of anionic cyclic ether 20

Scheme 1.2. Selective direct functionalization of THFs 22

Scheme 1.3. Selective olefin metathesis reaction 25

Scheme 1.4. Cycloisomerization for THF 27

Scheme 1.5. General C-O formation methods 28

Scheme 1.6. Selective nucleophilic substitution reaction 30

Scheme 1.7. Selective alkene functionalization reaction 32

Scheme 1.8. Dehydrogenative annulation 34

Scheme 1.9. [3+2] cycloaddition using O-C-C fragment 38

Scheme 1.10. A) General cycloaddition of carbonyl ylide and olefin. B) Restrosynthetic strategy of carbonyl ylide 39

Scheme 1.11. Selective [3+2] cycloaddition using carbonyl ylide 41

Scheme 1.12. Selective [3+2] cycloaddition with three-carbon partner with ketone 44

Scheme 1.13. Selective [4+1] cycloaddition using diazo compounds 46

Scheme 1.14. Selective THF synthesis by oxidation of 1,5-diene 48

Scheme 1.15. Fox's [2+2+1] cycloaddition 49

Scheme 2.1. General wacker oxidation 53

Scheme 2.2. Our aim 53

Scheme 2.3. A) General strategy of cycloaddition with vinyl ether and allyl alcohol. B, C) Selective reactions of alkene and propargyl alcohol or allyl alcohol. D) This work 56

Scheme 2.4. Initial hit 58

Scheme 2.5. Synthesis of 4 in specific condition 58

Scheme 2.6. Gram-scale synthesis 67

Scheme 2.7. Reaction with cinnamyl alcohol (2z) 72