목차

1. 목차
   Introduction
   1. 퀴논 화합물 1
   2. 나프토퀴논 (Naphthoquinone)화합물 3
   3. 참고문헌 5
   Part 1 : An improved regioselective, one-step synthesis of β-lapachone from 2-hydroxy-1,4-naphthoquinone
   1. 서론 7
   1-1. β-lapachone 7
   1-2. 기존에 발표된 β-lapachone 합성법 9
   1-3. TiCl4 (Titanium tetrachloride) 12
   1-4. 연구 목적 13
   2. 결과 및 고찰 14
   2-1. βlapachone one-step 합성 최적화 연구 14
   2-2. βlapachone one-step 반응 메커니즘 연구 18
   2-3. 다른 기질을 이용한 β-lapachone 및 유도체 합성 21
   3. 결론 23
   4. 실험 24
   5. 참고문헌 29
   6. 스펙트럼 31
   Part 2 : Studies on the solvent-free synthesis of β-lapachone through the acid-mediated intramolecular cyclization of lapachol
   1. 서론 34
   1-1. Solvent-free 반응 및 녹색화학 개요 34
   1-2. 고체지지 시약 35
   1-3. 연구 목적 37
   2. 결과 및 고찰 38
   2-1. Solid-supported mineral acid를 이용한 lapachol의 분자 내 고리화 반응 연구 40
   2-2. Solid-supported Lewis acid를 이용한 lapachol의 분자 내 고리화 반응 연구 40
   2-3. Solid-supported reagent를 이용한 용매 반응 및 recyclization 연구 41
   3. 결론 44
   4. 실험 45
   5. 참고문헌 50
   6. 스펙트럼 51
   Part 3 : Synthesis of Isoxazolo-1,2-naphthoquinone derivatives and their biological evaluation
   1. 서론 53
   1-1. 연구 배경 53
   1-2. Isoxazole 화합물 55
   1-3. 연구 목적 56
   2. 결과 및 고찰 58
   2-1. Isoxazolo-1,2-naphthoquinone 유도체 전합성 58
   2-2. Isoxazolo-1,2-naphthoquinone 유도체 생리활성 실험 62
   2-2-1. NQO1 활성 측정 63
   2-2-1. 세포 내의 Lactate 변화 량 측정 64
   3. 결론 66
   4. 실험 67
   5. 참고문헌 92
   6. 스펙트럼 93
   Figure List
   Introduction
   [Figure 1] 다양한 퀴논 계열 화합물 1
   [Figure 2] 퀴논 화합물의 생리학적 반응 3
   [Figure 3] 다양한 naphthoquinone 유도체 4
   Part 1 : An improved regioselective, one-step synthesis of β-lapachone from 2-hydroxy-1,4-naphthoquinone
   [Figure 1] β-lapachone (β-Lap)이 관여하는 cell death의 메커니즘 8
   [Figure 2] 세포 내 NQO1에 의한 산화환원 반응 및 NAD+의 기능 8
   [Figure 3] 기존의 보고된 다양한 β-lapachone의 합성법 9
   [Figure 4] Mukaiyama aldol reaction 및 McMurry reaction 반응의 메커니즘에서 TiCl4의 역할 13
   [Figure 5] βlapachone 합성 조건에서 1H NMR Data 비교 19
   [Figure 6] βlapachone 합성 조건의 HPLC Data 20
   [Figure 7] D2SO4를 이용한 반응 중 황산의 역할 증명 20
   [Figure 8] 1H NMR of 2,2-Dimethyl-3,4-dihydro-2H-benzo[h]chromene-5,6-dione 31
   [Figure 9] 13C NMR of 2,2-Dimethyl-3,4-dihydro-2H-benzo[h]chromene5,6-dione 31
   [Figure 10] 1H NMR of 2-Methyl-3,4-dihydro-2H-benzo[h]chromene-5,6-dione 32
   [Figure 11] 13C NMR of 2-Methyl-3,4-dihydro-2H-benzo[h]chromene-5,6-dione 32
   Part 2 : Studies on the solvent-free synthesis ofβ-lapachone through the acid-mediated intramolecular cyclization of lapachol
   [Figure 1] 1H NMR of 2-Hydroxy-3-(3-methylbut-2-enyl)naphthalene-1,4-dione 51
   [Figure 2] 1H NMR of 2,2-dimethyl-3,4-dihydro-2H-benzo[g]chromene-5,10-dione -5,6-dione 51
   Part 3 : Synthesis of Isoxazolo-1,2-naphthoquinone
   derivatives and their biological evaluation
   [Figure 1] β-lapachone 및 tanshinone ⅡA (TSA) 구조 53
   [Figure 2] 기존에 합성된 βlapachone 유도체 54
   [Figure 3] Isoxazole 고리를 포함하는 류마티스염 관절염 치료제
   valdecoxib (Bextra) 및 정신분열증 치료제 Paliperidone (Invega)의 구조 56
   [Figure 4] molecule optimization을 위한 isoxazole 고리 도입 56
   [Figure 5] 목표 화합물 Isoxazolo-1,2-naphthoquinone 유도체 57
   [Figure 6] 3 4번 화합물 반응 메커니즘 (Fries-rearrangement) 59
   [Figure 7] 7 8번 화합물 반응 메커니즘 59
   [Figure 8] 1H NMR of 4-Methoxy-1-naphthol 93
   [Figure 9] 13C NMR of 4-Methoxy-1-naphthol 93
   [Figure 10] 1H NMR of 4-Methoxynaphthalen-1-yl acetate 94
   [Figure 11] 13C NMR of 4-Methoxynaphthalen-1-yl acetate 94
   [Figure 12] 1H NMR of 1-(1-Hydroxy-4-methoxynaphthalen-2-yl)ethanone 95
   [Figure 13] 13C NMR of 1-(1-Hydroxy-4-methoxynaphthalen-2-yl)ethanone 95
   [Figure 14] 1H NMR of 5-Methoxy-3-methylnaphtho[2,1-d]isoxazole 96
   [Figure 15] 13C NMR of 5-Methoxy-3-methylnaphtho[2,1-d]isoxazole 96
   [Figure 16] 1H NMR of 3-Methylnaphtho[2,1-d]isoxazol-5-ol 97
   [Figure 17] 13C NMR of 3-Methylnaphtho[2,1-d]isoxazol-5-ol 97
   [Figure 18] 1H NMR of 3-Methylnaphtho[2,1-d]isoxazole-4,5-dione 98
   [Figure 19] 13C NMR of 3-Methylnaphtho[2,1-d]isoxazole-4,5-dione 98
   [Figure 20] 1H NMR of 4-Methoxynaphthalen-1-yl isobutyrate 99
   [Figure 21] 13C NMR of 4-Methoxynaphthalen-1-yl isobutyrate 99
   [Figure 22] 1H NMR of 1-(1-Hydroxy-4-methoxynaphthalen-2-yl)-2-methylpropan-1-one 100
   [Figure 23] 13C NMR of 1-(1-Hydroxy-4-methoxynaphthalen-2-yl)-2-methylpropan-1-one 100
   [Figure 24] 1H NMR of 3-Isopropyl-5-methoxynaphtho[2,1-d]isoxazole 101
   [Figure 25] 13C NMR of 3-Isopropyl-5-methoxynaphtho[2,1-d]isoxazole 101
   [Figure 26] 1H NMR of 3-Isopropylnaphtho[2,1-d]isoxazol-5-ol 102
   [Figure 27] 13C NMR of 3-Isopropylnaphtho[2,1-d]isoxazol-5-ol 102
   [Figure 28] 1H NMR of 3-Isopropylnaphtho[2,1-d]isoxazole-4,5-dione 103
   [Figure 29] 13C NMR of 3-Isopropylnaphtho[2,1-d]isoxazole-4,5-dione 103
   [Figure 30] 1H NMR of 3-Isopropyl-7-nitronaphtho[2,1-d]isoxazole-4,5-dione 104
   [Figure 31] 13C NMR of 3-Isopropyl-7-nitronaphtho[2,1-d]isoxazole-4,5-dione 104
   [Figure 32] 1H NMR of 7-Amino-3-isopropylnaphtho[2,1-d]isoxazole-4,5-dione 105
   [Figure 33] 13C NMR of 7-Amino-3-isopropylnaphtho[2,1-d]isoxazole-4,5-dione 105
   [Figure 34] 1H NMR of 7-Chloro-3-isopropylnaphtho[2,1-d]isoxazole-4,5-dione 106
   [Figure 35] 13C NMR of 7-Chloro-3-isopropylnaphtho[2,1-d]isoxazole-4,5-dione 106
   [Figure 36] 1H NMR of 4-Methoxynaphthalen-1-yl benzoate 107
   [Figure 37] 13C NMR of 4-Methoxynaphthalen-1-yl benzoate 107
   [Figure 38] 1H NMR of (1-Hydroxy-4-methoxynaphthalen-2yl)(phenyl)methanone 108
   [Figure 39] 13C NMR of (1-Hydroxy-4-methoxynaphthalen-2yl)(phenyl)methanone 108
   [Figure 40] 1H NMR of 3-Phenyl-5-phenylnaphtho[2,1-d]isoxazole 109
   [Figure 41] 13C NMR of 3-Phenyl-5-phenylnaphtho[2,1-d]isoxazole 109
   [Figure 42] 1H NMR of 3-Isopropylnaphtho[2,1-d]isoxazol-5-ol 110
   [Figure 43] 13C NMR of 3-Isopropylnaphtho[2,1-d]isoxazol-5-ol 110
   [Figure 44] 1H NMR of 3-Phenylnaphtho[2,1-d]isoxazole-4,5-dione 111
   [Figure 45] 13C NMR of 3-Phenylnaphtho[2,1-d]isoxazole-4,5-dione 111
   [Figure 46] 1H NMR of 4-Methoxynaphthalen-1-yl pivalate 112
   [Figure 47] 13C NMR of 4-Methoxynaphthalen-1-yl pivalate 112
   [Figure 48] 1H NMR of 1-(1-Hydroxy-4-methoxynaphthalen-2-yl)-2,2-dimethylpropan-1-one 113
   [Figure 49] 13C NMR of 1-(1-Hydroxy-4-methoxynaphthalen-2-yl)-2,2-dimethylpropan-1-one 113
   [Figure 50] 1H NMR of 3-(tert-Butyl)-5-methoxynaphtho[2,1-d]isoxazole 114
   [Figure 51] 13C NMR of 3-(tert-Butyl)-5-methoxynaphtho[2,1-d]isoxazole 114
   [Figure 52] 1H NMR of 3-(tert-Butyl)naphtho[2,1-d]isoxazol-5-ol 115
   [Figure 53] 13C NMR of 3-(tert-Butyl)naphtho[2,1-d]isoxazol-5-ol 115
   [Figure 54] 1H NMR of 3-tert-Butylnaphtho[2,1-d]isoxazole-4,5-dione 116
   [Figure 55] 13C NMR of 3-tert-Butylnaphtho[2,1-d]isoxazole-4,5-dione 116
   Table List
   Part 1 : An improved regioselective, one-step synthesis of β-lapachone from 2-hydroxy-1,4-naphthoquinone
   [Table 1] Lawsone 으로부터 βlapachone one-step 합성에 대한 최적화 반응조건 연구 14
   [Table 2] βlapachone one-step 합성에 대한 TiCl4의 효과 15
   [Table 3] βlapachone one-step 합성에 대한 acid의 효과 16
   [Table 4] βlapachone one-step 합성에 대한 용매 효과 17
   [Table 5] 다양한 기질을 사용한 βlapachone 및 유도체 합성 22
   Part 2 : Studies on the solvent-free synthesis of β-lapachone through the acid-mediated intramolecular cyclization of lapachol
   [Table 1] SSA를 이용한 α- 및 β-lapachone의 무 용매 합성 실험 38
   [Table 2] 다양한 고체 지지 시약을 이용한 α- 및 β-lapachone 무 용매 합성 실험 40
   [Table 3] 다양한 solid-supported Lewis acid를 이용한 α- 및 β-lapachone 무 용매 합성 실험 41
   [Table 4] 용매 하에 다양한 solid-supported acid를 이용한 α- 및 β-lapachone 합성 실험 42
   Part 3 : Synthesis of Isoxazolo-1,2-naphthoquinone derivatives and their biological evaluation
   [Table 1] 생리활성 실험을 수행한 Isoxazolo-1,2-naphthoquinone 유도체 7종 list 62
   [Table 2] Isoxazolo-1,2-naphthoquinone 유도체 7종의 NQO1 활성도 63
   [Table 3] Isoxazolo-1,2-naphthoquinone 유도체 7종의 세포 내 Lactate 변화 량 65
   Scheme List
   Introduction
   [Scheme 1] Dihydroanthraquinone으로부터 과산화수소 합성 반응식 2
   Part 1 : An improved regioselective, one-step synthesis of β-lapachone from 2-hydroxy-1,4-naphthoquinone
   [Scheme 1] β-lapachone의 기존 합성 연구 (Route A) 10
   [Scheme 2] β-lapachone의 기존 합성 연구 (Route B) 10
   [Scheme 3] β-lapachone의 기존 합성 연구 (Route C) 11
   [Scheme 4] β-lapachone의 기존 합성 연구 (Route D) 11
   [Scheme 5] β-lapachone의 기존 합성 연구 (Route E) 12
   [Scheme 6] TiCl4을 이용한 1,4-benzoquinone의 위치 선택적 Arylation 반응 13
   [Scheme 7] 2-hydroxy-1,4-naphthoquinone으로부터 β-lapachone one-step 합성의 제안 메커니즘 18
   Part 2 : Studies on the solvent-free synthesis ofβ-lapachone through the acid-mediated intramolecular cyclization of lapachol
   [Scheme 1] silica-sulfuric acid (SSA) 합성 반응식 37
   [Scheme 2] 기존에 알려진 β-lapachone의 합성법 37
   [Scheme 3] TiCl4를 이용한 β-lapachone의 분자 내 recyclization 반응 43
   Part 3 : Synthesis of Isoxazolo-1,2-naphthoquinone derivatives and their biological evaluation
   [Scheme 1] methyl기를 가진 Isoxazolo-1,2-naphthoquinone 유도체 합성 59
   [Scheme 2] iso-propyl기를 가진 Isoxazolo-1,2-naphthoquinone 유도체 합성 61
   [Scheme 3] phenyl기를 가진 Isoxazolo-1,2-naphthoquinone 유도체 합성 62
   [Scheme 4] tert-butyl기를 가진 Isoxazolo-1,2-naphthoquinone 유도체 합성 62