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研究生:徐俊浩
研究生(外文):Jun-Hao Hsu
論文名稱:他汀類藥物3,5-二羥基羧酸部分之合成研究
論文名稱(外文):Studies Toward Synthesis of 3,5-Dihydroxy Carboxylic Acid Moiety of Statins
指導教授:林正坤林正坤引用關係
指導教授(外文):Cheng-Kun Lin
口試委員:何文岳李東昇
口試委員(外文):Wen-Yueh HoDong-Sheng Lee
口試日期:2022-07-29
學位類別:碩士
校院名稱:國立中興大學
系所名稱:化學系所
學門:自然科學學門
學類:化學學類
論文種類:學術論文
論文出版年:2022
畢業學年度:110
語文別:中文
論文頁數:256
中文關鍵詞:他汀類藥物DBDMH分子內溴合環反應腈基Grignard反應Baeyer-Villiger氧化反應
外文關鍵詞:statinsDBDMHintramolecular bromocyclizationnitrile Grignard reactionBaeyer-Villiger oxidation
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他汀類藥物為一種HMG-CoA還原酶抑制劑,主要治療血脂異常和預防心血管疾病的藥物,其中以syn-1,3-二醇為主要結構,而tert-butyl 2-((4R,6R)-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate為合成atorvastatin (Lipitor®)中非常重要的中間體。在本文中我們探討了使用DBDMH對不同保護基之起始物進行分子內溴合環反應建立出syn-1,3-二醇,並比較出各個保護基之差異性。並將其產物應用於合成他汀類藥物之中間體。
在本研究中,關鍵步驟為a) 利用DBDMH進行分子內溴合環反應; b) 將溴基置換為腈基,並利用苯基Grignard試劑建立出苯基酮化合物; c) 使用過氧酸化合物進行Baeyer-Villiger氧化反應。我們使用產物6e作為合成他汀類藥物中間體之起始物,經由8步合成,總產率5%,合成出產物25。
Statins are HMG-CoA reductase inhibitors, mainly used to treat dyslipidemia and prevent cardiovascular diseases. tert-Butyl 2-((4R,6R)-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate is a very important intermediate in the synthesis of atorvastatin (Lipitor®). In this paper, we explores the formation of syn-1,3-diol by intramolecular bromination of starting materials with different protecting groups using DBDMH and compare the differences of each protecting group. And its products are used in the synthesis of intermediates of statins.
In this study, the key steps are a) Intramolecular bromocyclization with DBDMH; b) The bromine group was replaced with a nitrile group, and the phenyl ketone compound was established using the phenyl Grignard reagent; c) the Baeyer-Villiger oxidation was performed using peroxyacid compounds. We used the product 6e as the starting material for the synthesis of statin intermediates. After 8 steps of synthesis, the product 25 was synthesized in a total yield of 5%.
中文摘要 i
Abstract ii
縮寫表 iii
目次 vi
表目次 vii
圖目次 viii
路徑目次 ix
壹、前言 1
(一) 他汀類藥物 (Statin)的介紹 1
(二) 海洋巨環內酯類化合物(Marine Macrolides)的介紹 3
(三) 不對稱還原反應建立掌性與syn-1,3-diol骨架 5
(四) 利用酵素催化建立掌性與建立syn-1,3-diol骨架 7
(五) 不對稱烯丙基化反應建立掌性與syn-1,3-diol骨架 10
(六) oxa-Michael addition建立syn-1,3-diol骨架 12
(七) 不對稱羥醛反應建立掌性與syn-1,3-diol骨架 13
(八) 不對稱合環反應建立syn-1,3-diol骨架 15
(九) 利用掌性磷酸催化劑對外消旋1,3-二氧六環 (1,3-dioxane) 進行平行動力學拆分建立具有掌性之syn-1,3-diol 16
(十) Kaneka alcohol的全合成 18
(十一) Pitavastatin calcium之全合成 20
(十二) 研究動機 23
貳、結果與討論 25
(一) 建立syn-1,3-diol骨架 25
(二) Krische丙烯基反應進行不對稱合成 35
(三) 他汀類藥物中間體之合成 38
參、 結論 58
肆、未來展望 59
伍、實驗步驟 61
陸、參考文獻 108
柒、化合物之1H與13C核磁共振光譜 114
捌、X-ray晶體數據 248
1.台灣衛生福利部統計處https://dep.mohw.gov.tw/DOS/mp-113.html.
2.Huang, G.; Liu, M.; Xiong, F.; Meng, G.; Tao, Y.; Wu, Y.; Peng, H.; Chen, F. Chiral Syn-1,3-diol Derivatives via a One-Pot Diastereoselective Carboxylation/ Bromocyclization of Homoallylic Alcohols. iScience 2018, 9, 513–520.
3.Wu, Y.; Xiong, F.-J.; Chen, F.-E. Stereoselective synthesis of 3-hydroxy-3-methylglutaryl–coenzyme A reductase inhibitors. Tetrahedron 2015, 71, 8487–8510.
4.Wess, G.; Kesseler, K.; Baader, E.; Bartmann, W.; Beck, G.; Bergmann, A.; Jendralla, H.; Bock, K.; Holzstein, O.; Kleine, H.; Schnierer, M. Stereoselective synthesis of HR 780 a new highly potent HMG-CoA reductase inhibitor. Tetrahedron Lett. 1990, 31, 2545–2548.
5.Yeung, K.-S.; Paterson, I. Advances in the Total Synthesis of Biologically Important Marine Macrolides. Chem. Rev. 2005, 105, 4237–4313.
6.Pettit, G. R.; Cichacz, Z. A.; Herald, C. L.; Gao, F.; Boyd, M. R.; Schmidt, J. M.; Hamel, E.; Bai, R. Antineoplastic agents 300. Isolation and structure of the rare human cancer inhibitory macrocyclic lactones spongistatins 8 and 9. J. Chem. Soc. Chem. Commun. 1994, 1605–1606.
7.Kobayashi, M.; Aoki, S.; Kitagawa, I. Absolute stereostructures of altohyrtin A and its congeners, potent cytotoxic macrolides from the Okinawan marine sponge hyrtios altum. Tetrahedron Lett. 1994, 35, 1243–1246.
8.Pettit, G. R.; Chicacz, Z. A.; Gao, F.; Herald, C. L.; Boyd, M. R.; Schmidt, J. M.; Hooper, J. N. A. Antineoplastic agents. 257. Isolation and structure of spongistatin 1. J. Org. Chem. 1993, 58, 1302–1304.
9.Pettit, G. R.; Cichacz, Z. A.; Gao, F.; Herald, C. L.; Boyd, M. R. Isolation and structure of the remarkable human cancer cell growth inhibitors spongistatins 2 and 3 from an eastern indian ocean Spongia sp. J. Chem. Soc. Chem. Commun. 1993, 1166–1168.
10.Bai, R.; Cichacz, Z. A.; Herald, C. L.; Pettit, G. R.; Hamel, E. Spongistatin 1, a highly cytotoxic, sponge-derived, marine natural product that inhibits mitosis, microtubule assembly, and the binding of vinblastine to tubulin. Mol. Pharmacol. 1993, 44, 757–766.
11.Bai, R.; Taylor, G. F.; Cichacz, Z. A.; Herald, C. L.; Kepler, J. A.; Pettit, G. R.; Hamel, E. The Spongistatins, Potently Cytotoxic Inhibitors of Tubulin Polymerization, Bind in a Distinct Region of the Vinca Domain. Biochemistry 1995, 34, 9714–9721.
12.Evans, D. A.; Coleman, P. J.; Dias, L. C. Enantioselective Synthesis of Altohyrtin C (Spongistatin 2): Synthesis of the AB- and CD-Spiroketal Subunits. Angew. Chem. Int. Ed. Engl. 1997, 36, 2738–2741.
13.Xiong, X. J. X. J. J.; He, N. B.: CN102391243A, 2011.
14.Claffey, M. M.; Hayes, C. J.; Heathcock, C. H. Synthesis of the C1−C28 Portion of Spongistatin 1 (Altohyrtin A). J. Org. Chem. 1999, 64, 8267–8274.
15.Fan, W.; Li, W.; Ma, X.; Tao, X.; Li, X.; Yao, Y.; Xie, X.; Zhang, Z. Ru-Catalyzed Asymmetric Hydrogenation of γ-Heteroatom Substituted β-Keto Esters. J. Org. Chem. 2011, 76, 9444–9451.
16.Yasohara, Y.; Kizaki, N.; Hasegawa, J.; Wada, M.; Kataoka, M.; Shimizu, S. Stereoselective reduction of alkyl 3-oxobutanoate by carbonyl reductase from Candida magnoliae. Tetrahedron: Asymmetry 2001, 12, 1713–1718.
17.Patel, R. N.; Banerjee, A.; McNamee, C. G.; Brzozowski, D.; Hanson, R. L.; Szarka, L. J. Enantioselective microbial reduction of 3,5-dioxo-6-(benzyloxy) hexanoic acid, ethyl ester. Enzyme Microb. Technol. 1993, 15, 1014–1021.
18.Öhrlein, R.; Baisch, G. Chemo-Enzymatic Approach to Statin Side-Chain Building Blocks. Adv. Synth. Catal. 2003, 345, 713–715.
19.DeSantis, G.; Wong, K.; Farwell, B.; Chatman, K.; Zhu, Z.; Tomlinson, G.; Huang, H.; Tan, X.; Bibbs, L.; Chen, P.; Kretz, K.; Burk, M. J. Creation of a Productive, Highly Enantioselective Nitrilase through Gene Site Saturation Mutagenesis (GSSM). J. Am. Chem. Soc. 2003, 125, 11476–11477.
20.David, S. C. G. J. H.; Gray, D. R: Gruber, J. M.; Huisman, G. W.; Ma, S. K.; Newman, L. M.; Sheldon, R.; Wang, L. A.; WO 2004/015132 A2, 2004.
21.Gijsen, H. J. M.; Wong, C.-H. Unprecedented Asymmetric Aldol Reactions with Three Aldehyde Substrates Catalyzed by 2-Deoxyribose-5-phosphate Aldolase. J. Am. Chem. Soc. 1994, 116, 8422–8423.
22.Liu, J.; Hsu, C.-C.; Wong, C.-H. Sequential aldol condensation catalyzed by DERA mutant Ser238Asp and a formal total synthesis of atorvastatin. Tetrahedron Lett. 2004, 45, 2439–2441.
23.Sawant, P.; Maier, M. E. A novel strategy towards the atorvastatin lactone. Tetrahedron 2010, 66, 9738–9744.
24.Murata, K.; Minami, R.; Fuwa, H. Asymmetric Synthesis of (−)-Atorvastatin Calcium by Tandem Catalysis. Bull. Chem. Soc. Jpn. 2021, 94, 2028–2035.
25.Evans, D. A.; Gauchet-Prunet, J. A. Diastereoselective synthesis of protected syn 1,3-diols by base-catalyzed intramolecular conjugate addition of hemiacetal-derived alkoxide nucleophiles. J. Org. Chem. 1993, 58, 2446–2453.
26.Kawato , Y.; Chaudhary, S.; Kumagai, N.; Shibasaki , M. Streamlined Catalytic Asymmetric Synthesis of Atorvastatin. Chem. Eur. J. 2013, 19, 3802–3806.
27.Braun, M.; Devant, R. (R)- and (S)-2-acetoxy-1,1,2-triphenylethanol-effective synthetic equivalents of a chiral acetate enolate. Tetrahedron Lett. 1984, 25, 5031–5034.
28.Roth, B. D.; Blankley, C. J.; Chucholowski, A. W.; Ferguson, E.; Hoefle, M. L.; Ortwine, D. F.; Newton, R. S.; Sekerke, C. S.; Sliskovic, D. R.; Wilson, M. Inhibitors of cholesterol biosynthesis. 3. Tetrahydro-4-hydroxy-6-[2-(1H-pyrrol-1-yl)ethyl]-2H-pyran 2-one inhibitors of HMG-CoA reductase. 2. Effects of introducing substituents at positions three and four of the pyrrole nucleus. J. Med. Chem. 1991, 34, 357–366.
29.Paterson, I.; Oballa, R. M.; Norcross, R. D. Studies in marine macrolide synthesis: Stereocontrolled synthesis of the AB-spiroacetal subunit of spongistatin 1 (altohyrtin A). Tetrahedron Lett. 1996, 37, 8581–8584.
30.Evans, D. A.; Trotter, B. W.; Cǒté, B.; Coleman, P. J. Enantioselective Synthesis of Altohyrtin C (Spongistatin 2): Synthesis of the EF-Bis(pyran) Subunit. Angew. Chem. Int. Ed. Engl. 1997, 36, 2741–2744.
31.Smith, A. B.; Lin, Q.; Nakayama, K.; Boldi, A. M.; Brook, C. S.; McBriar, M. D.; Moser, W. H.; Sobukawa, M.; Zhuang, L. Spongistatin synthetic studies. 3. Construction of the C(1–17) spiroketal. Tetrahedron Lett. 1997, 38, 8675–8678.
32.Bartlett, P. A.; Meadows, J. D.; Brown, E. G.; Morimoto, A.; Jernstedt, K. K. Carbonate extension. A versatile procedure for functionalization of acyclic homoallylic alcohols with moderate stereocontrol. J. Org. Chem. 1982, 47, 4013–4018.
33.Guo, J.; Duffy, K. J.; Stevens, K. L.; Dalko, P. I.; Roth, R. M.; Hayward, M. M.; Kishi, Y. Total Synthesis of Altohyrtin A (Spongistatin 1): Part 1. Angew. Chem. Int. Ed. 1998, 37, 187–190.
34.Yang, H.; Zheng, W.-H. Parallel Kinetic Resolution of Unsymmetrical Acyclic Aliphatic syn-1,3-Diols. Org. Lett. 2019, 21, 5197–5200.
35.Hu, C.; Liu, M.; Yue, X.; Huang, Z.; Chen, F. Development of a Practical, Biocatalytic Synthesis of tert-Butyl (R)-3-Hydroxyl-5-hexenoate: A Key Intermediate to the Statin Side Chain. Org. Process Res. Dev. 2020, 24, 1700–1706.
36.Chen, W.; Xiong, F.; Liu, Q.; Xu, L.; Wu, Y.; Chen, F. Substrate stereocontrol in bromine-induced intermolecular cyclization: asymmetric synthesis of pitavastatin calcium. Tetrahedron 2015, 71, 4730–4737.
37.He, C.; Chu, H.; Stratton, T. P.; Kossler, D.; Eberle, K. J.; Flood, D. T.; Baran, P. S. Total Synthesis of Tagetitoxin. J. Am. Chem. Soc. 2020, 142, 13683–13688.
38.Alam, A.; Takaguchi, Y.; Tsuboi, S. Simple, Extremely Fast, and High‐Yielding Oxidation of Thiols to Disulfides. Synthetic Commun. 2005, 35, 1329–1333.
39.Smith, A. B.; Razler, T. M.; Ciavarri, J. P.; Hirose, T.; Ishikawa, T. (+)-Phorboxazole A Synthetic Studies. A Highly Convergent, Second Generation Total Synthesis of (+)-Phorboxazole A. Org. Lett. 2005, 7, 4399–4402.
40.Reddy, K. M.; Yamini, V.; Singarapu, K. K.; Ghosh, S. Synthesis of Proposed Aglycone of Mandelalide A. Org. Lett. 2014, 16, 2658–2660.
41.Cooper, M. S. H. H.; Newbold, A. J.; Sanderson, W. R. Oxidation Reaction Using Urea-Hydrogen Peroxide ; A Safe Alternative to Anhydrous Hydrogen Peroxide. Synlett 1990, 533–535.
42.Guo, H.; Madhushaw, R. J.; Shen, F.-M.; Liu, R.-S. Synthesis of chiral oxacyclic dienes via ruthenium-catalyzed enyne metathesis: useful building blocks for chiral tricyclic oxygen derivatives. Tetrahedron 2002, 58, 5627–5637.
43.Terada, M.; Machioka, K.; Sorimachi, K. High Substrate/Catalyst Organocatalysis by a Chiral Brønsted Acid for an Enantioselective Aza-Ene-Type Reaction. Angew. Chem. Int. Ed. 2006, 45, 2254–2257.
44.Xiao, Q.; Liu, Y.; Qiu, Y.; Zhou, G.; Mao, C.; Li, Z.; Yao, Z.-J.; Jiang, S. Potent Antitumor Mimetics of Annonaceous Acetogenins Embedded with an Aromatic Moiety in the Left Hydrocarbon Chain Part. J. Med. Chem. 2011, 54, 525–533.
45.White, J. D.; Hansen, J. D. Asymmetric Synthesis of Epicylindrospermopsin via Intramolecular Nitrone Cycloaddition. Assignment of Absolute Configuration. J. Am. Chem. Soc. 2002, 124, 4950–4951.
46.Brun, E.; Bellosta, V.; Cossy, J. Total Synthesis of (+)-Cryptocaryol A Using a Prins Cyclization/Reductive Cleavage Sequence. J. Org. Chem. 2015, 80, 8668–8676.
47.Jiang, S.-S.; Xu, Q.-C.; Zhu, M.-Y.; Yu, X.; Deng, W.-P. Kinetic Resolution of α-Methylene-β-hydroxy Esters Catalyzed by Acyl Transfer Catalyst An-PIQ. J. Org. Chem. 2015, 80, 3159–3169.
48.Xue, F.; Lu, H.; He, L.; Li, W.; Zhang, D.; Liu, X.-Y.; Qin, Y. Formal Total Syntheses of (−)- and (+)-Actinophyllic Acid. J. Org. Chem. 2018, 83, 754–764.
49.Mear, S. J.; Nguyen, L. V.; Rochford, A. J.; Jamison, T. F. Synthesis of (±)-Emtricitabine and (±)-Lamivudine by Chlorotrimethylsilane–Sodium Iodide-Promoted Vorbrüggen Glycosylation. J. Org. Chem. 2022, 87, 2887–2897.
50.Commandeur, M.; Commandeur, C.; Cossy, J. Synthesis of a Platform To Access Bistramides and Their Analogues. Org. Lett. 2011, 13, 6018–6021.
51.Padma, R.; Srinivas, B.; Yadav, J. S.; Mohapatra, D. K. General Asymmetric Synthetic Strategy for the α-Alkylated 2,5,6-Trisubstituted Pyran of Indanomycin and Related Natural Products. Eur. J. Org. Chem. 2020, 1947–1955.
52.Bézier, D.; Park, S.; Brookhart, M. Selective Reduction of Carboxylic Acids to Aldehydes Catalyzed by B(C6F5)3. Org. Lett. 2013, 15, 496–499.
53.Mitchell, T. A.; Zhao, C.; Romo, D. Diastereoselective, Three-Component Cascade Synthesis of Tetrahydrofurans and Tetrahydropyrans Employing the Tandem Mukaiyama Aldol-Lactonization Process. J. Org. Chem. 2008, 73, 9544–9551.
54.Carneiro, V. M. T.; Avila, C. M.; Balunas, M. J.; Gerwick, W. H.; Pilli, R. A. Coibacins A and B: Total Synthesis and Stereochemical Revision. J. Org. Chem. 2014, 79, 630–642.
55.Kumar, D. N.; Reddy, C. R.; Das, B. Stereoselective Synthesis of Cytotoxic Marine Metabolite Harzialactone A by Three Different Routes. Synthesis 2011, 2011, 3190–3194.
56.Keck, G. E.; Tarbet, K. H.; Geraci, L. S. Catalytic asymmetric allylation of aldehydes. J. Am. Chem. Soc. 1993, 115, 8467–8468.
57.Wu, Y.; Liu, M.-J.; Huang, H.-Q.; Huang, G.-X.; Xiong, F.-J.; Chen, F.-E. Asymmetric Synthesis of Atorvastatin Calcium through Intramolecular Oxidative Oxygen-Nucleophilic Bromocyclization. Eur. J. Org. Chem. 2017, 3681–3688.
58.Brimble, M. A.; Bryant, C. J. Synthesis and assignment of the absolute configuration of the anti-Helicobacter pylori agents CJ-12,954 and CJ-13,014. Org. Biomol. 2007, 5, 2858–2866.
59.Ley, S. V.; Tackett, M. N.; Maddess, M. L.; Anderson, J. C.; Brennan, P. E.; Cappi, M. W.; Heer, J. P.; Helgen, C.; Kori, M.; Kouklovsky, C.; Marsden, S. P.; Norman, J.; Osborn, D. P.; Palomero, M. Á.; Pavey, J. B. J.; Pinel, C.; Robinson, L. A.; Schnaubelt, J.; Scott, J. S.; Spilling, C. D.; Watanabe, H.; Wesson, K. E.; Willis, M. C. Total Synthesis of Rapamycin. Chem. Eur. J. 2009, 15, 2874–2914.
60.Lin, C.-K.; Hsieh, B.-H.; Wu, C.-F. Total Synthesis of Citreochlorol Monochloro Analogues via a Catalytically Enantioselective Carbonyl Allylation. Synthesis 2021, 54, 1321–1328.
61.Mohapatra, D. K.; Pulluri, K.; Gajula, S.; Yadav, J. S. 13-Step total synthesis of Dendrodolide K following iterative Bartlett–Smith iodocarbonate cyclization. Tetrahedron Lett. 2015, 56, 6377–6380.
62.Shu, Y.; Yanagita, R. C.; Tokuda, H.; Suzuki, N.; Irie, K. Synthesis of Antineoplastic Analogs of Aplysiatoxin with Various Side Chain Structures. Heterocycles 2012, 86, 281–304.
63.Druais, V.; Hall, M. J.; Corsi, C.; Wendeborn, S. V.; Meyer, C.; Cossy, J. A Convergent Approach toward the C1−C11 Subunit of Phoslactomycins and Formal Synthesis of Phoslactomycin B. Org. Lett. 2009, 11, 935–938.
64.Smith, A. B.; Lin, Q.; Doughty, V. A.; Zhuang, L.; McBriar, M. D.; Kerns, J. K.; Boldi, A. M.; Murase, N.; Moser, W. H.; Brook, C. S.; Bennett, C. S.; Nakayama, K.; Sobukawa, M.; Lee Trout, R. E. Spongipyran synthetic studies. Total synthesis of (+)-spongistatin 2. Tetrahedron 2009, 65, 6470–6488.
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