利用含硼醛類合成胜肽異腈硼酯(I)
根據文獻報導，近年來已知上百種含有異腈官能基 (Isocyanide) 之天然物。而這些特殊的天然物在抗菌或抗腫瘤上具有顯著的特效。所以，異腈化合物之合成實為一值得探討的研究主題。本研究成功藉由Ugi多組成反應合成出含硼之甲醯胺，接著成功地將之脫水轉換為含硼之異腈化合物。
含硼胜肽四唑衍生物之合成(II)
根據文獻指出，含四唑結構之化合物，具有相當顯著的生物活性。在藥物化學上，此結構可以取代羰基結構，在提供與羰基相同的化學鍵結作用力之外，此官能基之代謝穩定度亦遠優於羰基。因此，四唑化合物的合成值得深入探討。本研究成功藉由含硼異腈化合物進行合環，生成含硼之四唑化合物。
依照Ugi-Passerini反應順序合成含硼衍生物(III)
根據文獻記載，許多天然物皆含有depsipeptide結構。因此本研究將合成包含此官能基之含硼化合物作為目標。首先，我先利用Ugi-3CR合成出具有甲醯胺官能基之含硼雙胜肽化合物，接著進行脫水反應，轉化為相對應之含硼異腈化合物。最後在使用Passerini-3CR合成出具備含硼之depsipeptide化合物。

1. Synthesis of Peptidyl Isocyano Boronate Ester using Boron-containing Aldehydes :
Isocyanide (or isonitrile) is a unique class of functional groups that appears in many biological active natural products. Many of these isocyanide-based natural products can be used as antitumor agents or antibiotics. Thus, incorporation of this functional group could potentially generate a biological interesting compound. 
In the first part of my research, I have successfully synthesized 2 boron-containing formamides by microwave assisted Ugi-3CR in good yields (92%-97%). At the same time, I have successfully converted these 2 boron-containing formamides to the corresponding boron-containing isocyanides. 
2. Synthesis of Peptidyl Boron-containing Tetrazole Analogs :
Tetrazole derivatives are often recognized for their impressive biological activities. The tetrazole ring is considered as a bioisostere of carboxylic acid, which possess a much-improved metabolic stability. 
In the second part of my research, I have successfully synthesized 2 boron-containing tetrazoles by microwave.
3. Synthesis of Boron-containing Analogs using Sequential Ugi 4CR/Passerini-3CR Reactions :
Depsipeptide is a class of functional groups that frequently appears in variety of natural products. It composes of one ester group with at least one peptide bond(s). Therefore, inclusion of this functional group to the boron-containing compounds might generate interesting biologically active compounds.
In the third part of my research, I have utilized Ugi-3CR to synthesize boron-containing formamides via microwave irradiation. These formamides were subjected to dehydration process where the corresponding isocyanides were obtained. The desired boron-containing isocyanides were then utilized as one of the building blocks in the Passerini-3CR to generate boron-containing depsipeptide analogs.

謝誌	I
主目錄	VII
圖表目錄	XI
光譜目錄	XVI
Chapter 1緒論	1
1.1研究動機	1
1.2硼化學簡介	3
1.2.1硼酸化合物 (boronic acid)	3
1.2.2硼酯化合物 (boronate ester)	4
1.2.3三氟硼酸化合物 (trifluoroborates)	5
1.3含硼化合物之合成應用	6
1.3.1 Metal-catalyzed cross-couplings	7
1.3.2 Petasis reaction	7
1.4含硼化合物之藥物應用	8
1.5目前在臨床實驗中之含硼藥物	9
1.5.1第一期臨床試驗 (PhaseⅠ)	9
1.5.2第二期臨床試驗 (PhaseⅡ)	10
1.5.3第三期臨床試驗 (PhaseⅢ)	10
1.5.4第四期臨床試驗 (PhaseⅣ)	11
Chapter 2利用含硼醛類合成胜肽異腈硼酯	13
2.1異腈化合物之簡介	13
2.2異腈化合物之化性探討	14
2.2.1 α-addition	15
2.2.2 Free radicals	15
2.2.3 α-acidity	17
2.3異腈化合物之應用	19
2.4異腈化合物之合成	20
2.4.1 Bienaymé團隊	22
2.4.2 Bossio團隊	23
2.4.3 Armstrong團隊	23
2.5含硼異腈化合物之介紹	24
2.6結果與討論	25
2.6.1含硼異腈化合物合成策略	25
2.6.2合成含硼甲醯胺	26
2.6.3合成含硼異腈化合物	27
2.7 結論	28
Chapter 3含硼胜肽四唑衍生物之合成	29
3.1四唑化合物於藥物上之簡介	29
3.2 四唑化合物之合成	34
3.2.1合成1-substituted tetrazoles	36
3.2.2合成2-substituted tetrazole	38
3.2.3合成5-substituted tetrazole	39
3.3 含硼四唑化合物之介紹	43
3.4 結果與討論	44
3.4.1含硼四唑化合物合成策略	44
3.4.2合成四唑化合物	44
3.4.3合成含硼四唑化合物	46
3.5 結論	49
Chapter 4依照Ugi-Passerini反應順序合成含硼衍生物	50
4.1 Depsipeptide與相關藥物介紹	50
4.2多組成反應	52
4.2.1 Strecker amino acid synthesis	54
4.2.2 Hantzsch reaction	54
4.2.3 Passerini reaction	55
4.2.4 Ugi reaction	56
4.2.5 其他重要的多組成反應	57
4.3結果與討論	58
4.3.1含硼Ugi-Passerini化合物合成策略	58
4.3.2合成含硼Ugi-Passerini化合物	59
4.4結論	63
Chapter 5實驗藥品與實驗儀器	64
5.1使用藥品	64
5.2實驗儀器與測試方法	66
Chapter 6實驗步驟	67
6.1含硼異腈化合物之合成	67
6.1.1硼酯起始物之合成(通用合成步驟A )	67
6.1.2合成含硼酯之甲醯胺起始物(通用合成步驟F)	69
6.1.3合成含硼酯之異腈(通用合成步驟S)	72
6.2含硼四唑化合物之合成(通用合成步驟T)	75
附錄一 光譜資料	78
附錄二 參考資料	92
 
圖表目錄
Fig. 1.1治療癌症的藥物	2
Fig. 1.2市售含硼藥物的結構	3
Fig. 1.3進入FDA臨床測試階段的含硼化合物	3
Fig. 1.4常見硼酸型態：(a) boronic acid；(b) boronic acid, X hydrate；(c) boroxine	4
Fig. 1.5常見硼酯型態：(a) ethylene glycol ester；(b) pinacol ester；(c) neopentylglycol ester；(d) catechol ester	5
Fig. 1.6具旋光性硼酯：(a) Pinanediol ester；(b) DICHED ester	5
Fig. 1.7常見硼酸鹽類型態：(a) tirfluoroborate；(b) trihydroxyborate	6

Fig. 2.1含異腈之天然化合物	14
Fig. 2.2不同取代基之異腈	17
Fig. 2.3異腈聚合反應生成polyiminomethylenes	18
Fig. 2.4 Bienaymé以多組成反應合成結構多元化的異腈	23

Fig 3.1雜環藥物結構	29
Fig 3.2含四唑雜環藥物結構	30
Fig 3.3具有抗發炎以及抗細菌之生物活性之含四唑雜環化合物	30
Fig 3.4具有抗真菌以及抗細菌之生物活性之含四唑雜環化合物	31
Fig 3.5治療癌症之藥物結構	32
Fig 3.6四唑的三種異構體	34
Fig 3.7本實驗室先前所合成出之含硼四唑化合物與其X-ray圖譜	43
Fig 3.8化合物T01其X-ray圖譜	48

Fig 4.1 depsipeptide analogs之結構示意圖	50
Fig 4.2 Etamycin之結構示意圖	51
Fig 4.3 Sansalvamide之結構示意圖	51
Fig 4.4 (a) Linear approach；(b) Convergent Approach；(c) Multicomponent Approach	52
Fig 4.5理想的合成條件	53
Fig 4.6粗產物P01之1H NMR光譜圖	60
Fig 4.7粗產物P02之1H NMR光譜圖	61
Fig 4.8經純化後P01之1H NMR光譜圖	62
Fig 4.9經純化後P02之1H NMR光譜圖	63

Scheme 1.1硼酸化合物於cross-coupling之反應	7
Scheme 1.2硼酸化合物於Petasis reaction之反應	8

Scheme 2.1兩種不同構型的異腈	13
Scheme 2.2異腈之水解過程	14
Scheme 2.3可作為親核基或是親電子基之化合物	15
Scheme 2.4抑制劑K252a合成途徑	16
Scheme 2.5 Curran使異腈用環化合成天然物Camptothecin	16
Scheme 2.6與路易氏鹼反應生成α-metalated isocyanides途徑	17
Scheme 2.7與路易士鹼形成α-metalated isocyanides之應用	18
Scheme 2.8 van Leusen團隊合成雜環之反應機構	19
Scheme 2.9 Jieping Zhu團隊合成之oxazole反應式	19
Scheme 2.10異腈合成以及水解過程	20
Scheme 2.11 Bienayme以多組成反應合成異腈之路徑	23
Scheme 2.12 Bossio團隊所設計出異腈合成反應	23
Scheme 2.13 Armstrong將異腈直接應用於多組成反應	24
Scheme 2.14含硼之異腈化合物合成過程	25
Scheme 2.15合成含硼之異腈化合物之設計路徑	26

Scheme 3.1 Bladin所預測之反應結構式	34
Scheme 3.2由Bamberger和De Gruyter以及Widman修正後的反應結構式	35
Scheme 3.3 Hantzsch的tetrazole合成法	35
Scheme 3.4 Stollé修改後的tetrazole合成法	35
Scheme 3.5 Dimroth跟Fester的tetrazole合成法	36
Scheme 3.6先前最常見的1-substituted tetrazole合成法	37
Scheme 3.7 Tienan Jin改良的1-substituted tetrazole合成法	37
Scheme 3.8利用胺類當起始物的1-substituted tetrazole合成法	38
Scheme 3.9利用alkylation之2-substituted tetrazole合成法	38
Scheme 3.10利用alkylation所得到之產物dibromopropane	39
Scheme 3.11利用arylation之2-substituted tetrazole合成法	39
Scheme 3.12常見之5-substituted tetrazole合成法	40
Scheme 3.13 Sharpless團隊研發出之5-substituted tetrazole合成法	41
Scheme 3.14利用Sharpless團隊的方法合成5-substituted tetrazole	41
Scheme 3.15 Amantini使用TMS-N3合成5-substituted tetrazole	42
Scheme 3.16 Alterman等人利用微波加熱合成5-substituted tetrazole	42
Scheme 3.17合成含硼四唑化合物之設計路徑	44
Scheme 3.18合成含硼四唑化合物所遇到的困難	46

Scheme 4.1 Strecker多組成反應	54
Scheme 4.2 Hantzsch多組成反應	54
Scheme 4.3 Passerini多組成反應	55
Scheme 4.4 Ugi多組成反應	56
Scheme 4.5 Ugi多組成反應之反應機構	56
Scheme 4.6合成含硼depsipeptide化合物之設計路徑	58
Scheme 4.7 Passerini之反應機構	59

Table 1.1各含硼藥物在FDA之試驗階段	12

Table 2.1其他重要的異腈反應方式	21
Table 2.2含硼甲醯胺之合成	26
Table 2.3合成含硼異腈之條件優化	27
Table 2.4含硼異腈之合成	28

Table 3.1改變官能基並測試抑制效果	33
Table 3.2合成1-tert-butyl tetrazole之條件優化	45
Table 3.3合成含硼四唑化合物之條件優化	47
Table 3.4含硼四唑之合成	48

Table 4.1其他重要多組成反應	57
Table 4.2含硼Ugi-Passerini之反應條件	59
 
光譜目錄
附圖1化合物F01之1H-NMR (600 MHZ, CDCl3-d1)	79
附圖2化合物F01之13C-NMR (150 MHZ, CDCl3-d1)	79
附圖3化合物F01之11B-NMR (192.5 MHZ, CDCl3-d1)	80
附圖4化合物F01之HRMS (ESI, positive ion) [M + H]+	80
附圖5化合物F02之1H-NMR (600 MHZ, CDCl3-d1)	81
附圖6化合物F02之13C-NMR (150 MHZ, CDCl3-d1)	81
附圖7化合物F02之11B-NMR (192.5 MHZ, CDCl3-d1)	82
附圖8化合物F02之HRMS (ESI, positive ion) [M + H]+	82
附圖9化合物S01之1H-NMR (600 MHZ, CDCl3-d1)	83
附圖10化合物S01之13C-NMR (150 MHZ, CDCl3-d1)	83
附圖11化合物S01之11B-NMR (192.5 MHZ, CDCl3-d1)	84
附圖12化合物S01之HRMS (ESI, positive ion) [M + H]+	84
附圖13化合物S01之IR	85
附圖14化合物S02之1H-NMR (300 MHZ, CDCl3-d1)	85
附圖15化合物S02之13C-NMR (150 MHZ, CDCl3-d1)	86
附圖16化合物S02之11B-NMR (192.5 MHZ, CDCl3-d1)	86
附圖17化合物S02之HRMS (ESI, positive ion) [M + H]+	87
附圖18化合物T01之1H-NMR (600 MHZ, CDCl3-d1)	87
附圖19化合物T01之13C-NMR (150 MHZ, CDCl3-d1)	88
附圖20化合物T01之11B-NMR (192.5 MHZ, CDCl3-d1)	88
附圖21化合物T01之X-ray	89
附圖22化合物T02之1H-NMR (600 MHZ, CDCl3-d1)	89
附圖23化合物T02之13C-NMR (150 MHZ, CDCl3-d1)	90
附圖24化合物T02之11B-NMR (192.5 MHZ, CDCl3-d1)	90
附圖25化合物T02之HRMS (ESI, positive ion) [M + H]+	91

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