Cobalt-assisted Medium Ring Cyclization for Solanoeclepin A and Taxoid Synthesis

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研究生：	林雅婷 Lin, Ya-Ting
論文名稱：	Cobalt-assisted Medium Ring Cyclization for Solanoeclepin A and Taxoid Synthesis
指導教授：	磯部稔 Minoru, Isobe 汪炳鈞 Uang, Biing-Jiun
口試委員:	廖俊臣 Liao, Chun-Chen 洪上程 Hung, Shang-Cheng 葉明倉 Yeh, Ming-Chang
學位類別：	博士 Doctor
系所名稱：	理學院 - 化學系 Department of Chemistry
論文出版年：	2015
畢業學年度：	103
語文別：	英文
論文頁數：	262
中文關鍵詞：	紫杉醇、八羰基二鈷、尼古拉斯反應、細見-櫻井反應、普林斯羰基-烯反應
外文關鍵詞：	Taxol, dicobalt hexacarbonyl, Nicholas reaction, Hosomi-Sakurai reaction, Prins-Carbonyl-ene reaction
相關次數：	點閱：4 下載：0
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紫杉醇 Taxol 1和天然物 Solanoeclepin A 148的多碳骨架建構方法在最近十幾年受到有機化學加的關注. 紫杉醇 Taxol 1 及其衍生物 2, 3與4唯有潛力的抗腫瘤藥物; 而天然物Solanoeclepin A 148 具有刺激馬鈴薯中囊腫線蟲提早孵化的功能, 可用於農業病蟲害防治.
本論文將著重于雙環四烯 25 的十二圓環與四環雙烯 231 的七圓環骨架之建構. 經由八羰基二鈷 Co2 (CO)8 與炔進行錯合反應後得到的前驅物 23 與217 不止彎曲成易於反應的角度與方向, 在路易士酸的催化下更可利用尼古拉斯反應, 分子內細見-櫻井反應及普林斯羰基-烯反應進行還化反應得到產物四烯25與雙烯231, 最後脫去鈷試劑即官能基轉換可得十二圓環25與七圓環149.

The synthesis of Taxol 1 and Solanoeclepin A 148 has been attracted chemist’s attention in recent three decades, due to the challenge to construct those poly-carbocyclic sub-structures. Taxol 1 and its derivatives 2, 3, and 4 are known as the potent agents against a wide range of tumor cells. Solanoeclepin A 148, on the other hand, shows a significant hatch-stimulating activity towards the potato cyst nematodes.
In this thesis, we have focused on the construction of twelve-membered carbocyclic substructure and seven-membered carbocyclic substructure of bicylic tetraene 25 and tetracyclic diene 231, respectively. The complexation of dicobalthexacarbonyl group played important roles not only in bending the molecule to suitable orientation to bring the moieties closer, but also using Nicholas effect and further Hosomi-Sakurai reaction and Prins-ene/halo reaction induced by Lewis acid to complete the synthesis of tetraene 25 and diene 231 frameworks.

Contents
中文摘要.....................................................................................................I Abstract.............................................................................II Acknowledgment.................................................................III Contents............................................................................IV Abbreviations...................................................................VIII
Part I
Toward Macrocarbocyclic Taxoid Synthesis using Acetylene-Cobalt Method
Chapter 1 Introduction and Research Motif..........................................2 1.1 General Introduction...........................................................2 1.2 Review of Synthetic Literature...............................................4
1.2.1 Nicolaou’s group –enantioselective synthesis of Taxol................4 1.2.2 Kuwajima’s group –enantioselective total synthesis of (-)-Taxol.5 1.2.3 Nakada’s group –studies on the Taxane skeleton....................6
1.3 Isobe’s group –synthesis of a diterpene taxoid skeleton..................7
1.4 Introduction of Nicholas effect...............................................8
1.5 Hosomi-Sakurai reaction......................................................9
Chapter 2 Results and Discussion....................................................10
IV
2.1 Twelve-Membered Ring cyclization following Shibuya’s Route......10 2.1.1 Synthesis of three building blocks....................................10 2.1.2 Intermolecular reaction among three building blocks..............12 2.1.3 Intramolecular Nicholas reaction induced by Lewis acid..........13 2.1.4 Removal of dicobalt hexacarbonyl group...........................16
2.2 Study on Different Position of Methyl Group ..............................18 2.2.1 Retrosynthesis .............................................................................18 2.2.2 Synthesis of three building blocks....................................19 2.2.3 Toward synthesis of precursor 50.....................................20
2.2.4 Twelve-membered ring cyclization ..................................22 2.2.5 Removal of dicobalt hexacarbonyl group............................22 2.3 Study on Cyclization with Multifunctional Groups......................24 2.3.1 Retrosynthesis .............................................................................24 2.3.2 Synthesis of cyclohexenone 82........................................25 2.3.3 Synthesis of cyclohexenone 95........................................27 2.3.4 Twelve-membered ring cyclization under basic condition.........32 2.3.5 Twelve-membered ring cyclization under acidic condition .......35 2.4 Study on Cyclization with Grubbs Metathesis..............................39 2.4.1 Retrosynthesis .............................................................................39 2.4.2 Synthesis of side chain 125.............................................40 2.4.3 Toward synthesis of precursor 122 for Grubbs metathesis.........41
V
2.5 Conclusion...................................................................46
Part II
Novel Synthesis of the ABC Rings of Solanoeclepin A
Chapter 3 Introduction and Research Motif......................................51 3.1 General Introduction...........................................................51 3.2 Review of Synthetic Literature..............................................52
3.2.1 Synthesis of solanoeclepin A left segment. by Hiemstra......52
3.2.2 Total synthesis of solanoeclepin A by Tanino’s group........54 3.3 Toward synthesis of Solanoeclepin A by Isobe’s group.............55 3.3.1 Synthesis of solanoeclepin A right segment by Tsao.................55 3.3.2 Synthesis of solanoeclepin A right segment by Chuang......57 3.3.3 Toward synthesis of Solanoeclepin A left segment............58 3.4 Lewis-Acid-Catalyzed Prins-Ene and Prins-Halo Reactions.............61 3.4.1 Carbonyl-ene reaction via Nicholas stabilization...................62 Chapter 4 Results and Discussion....................................................64 4.1 Synthesis of ABC rings of Solanoeclepin A.................................64 4.1.1 Retrosynthesis .............................................................................64
4.1.2 Yield improvement with FYL’s route................................ .65 4.1.3 Seven-membered ring cyclization via Lewis acid catalysis .......66 4.1.4 Removal of dicobalthexacarbonyl moiety .........................69
4.1.5 Completion of ABC rings of Solanoeclepin A ......................72
VI
4.1.6 Functional group transformation and double bond migration......77 4.1.7 Hydrosilylation route ....................................................78 4.1.8 Dihydroxylation...........................................................79 4.1.9 Oxygen-phosphine exchange ............................................80
4.2 Model Study with Gem-dimethylcyclohexnone ............................81 4.2.1 Retrosynthesis............................................................81 4.2.2 Synthesis of ketone 260 and vinyl iodide 265.......................81
4.2.3 Synthesis of seven-membered ring cyclization precursor 259.....84 4.3 Conclusion.........................................................................91
Chapter 5 Experiments and References..............................................93 5.1 General.........................................................................93 5.2 Experiment Procedure.....................................................95 5.3 References and Notes...................................................160
Appendix....................................................................................169
                                

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