博碩士論文 110223047 詳細資訊




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姓名 張聿辰(Yu-Chen Chang)  查詢紙本館藏   畢業系所 化學學系
論文名稱 從手性N-亞磺醯胺進行非對映選擇性磷酯基化反應建構高度選擇性的α-胺基磷酸酯
(Synthesis of α-amino phosphonate from chiral N-sulfinyl imine via highly diastereoselective hydrophosphonylation)
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摘要(中) 普多維克反應是一種製備α-胺基磷酸酯的非鏡像選擇性磷酯基化反應,藉由該反應,我們希望能夠開發得到單一立體選擇性的α-胺基磷酸酯的合成方法。一般在進行普多維克反應需使用手性配位基來控制反應的立體選擇性,然而我們則是在手性胺基醛引入具備手性助劑特性的叔丁基亞磺醯胺,來有效控制反應的進行與否。研究結果說明,在左旋胺基醛引入具備手性助劑特性的官能基(R)-(+)-叔丁基亞磺醯胺,可有效進行反應,得到高立體選擇性產物。若是將左旋胺基醛起始物換成右旋胺基醛,則須引入(S)-(-)-叔丁基亞磺醯胺,方可以進行反應。這樣的化學反應就像模擬酵素生合成,具有立體選擇性及基質專一性。此外,該反應也不須在嚴苛條件下進行,只需要利用碳酸銫來促進反應,以溫和的條件下與各種天然與非天然胺基酸進行反應生成良好到優異產率的α-胺基磷酸酯。該方法同時展示反應基質的可用性、簡易實驗操作和原子經濟性等優點。
摘要(英) Pudovik reaction is a well-known diastereoselective C-P bond formation method for the synthesis of α-amino phosphonates. Despite the success of these reactions, there are still some limitations that must be addressed. Therefore, we would like to develop a user-friendly approach for the synthesis of α-amino phosphonates with high stereoselectivity. In general, chiral ligands are used to control the stereoselective Pudovik-type reactions. In this thesis, we demonstrated a Cs2CO3-mediated hydrophosphonylation for diastereoselective synthesis of α-amino phosphonates from the chiral sulfinimide. We used chiral 2-methyl-2-propanesulfinamide as a chiral auxiliary to prepare chiral sulfinimide from chiral α-amino aldehydes. This approach can achieve highly pronounced dichotomous selectivities for substrates, providing the diastereoisomers of the products in high yields. In addition, not only (S)-amino aldehydes can be suitable for the reaction by using (R)-(+)-2-methyl-2-propanesulfinamide, but (R)-amino aldehydes can also be reacted by using (S)-(-)-2-methyl-2-propanesulfinamide. Furthermore, this diastereoselective hydrophosphonylation is simple protocol using Cs2CO3-mediated reactions under mild reaction conditions from various natural and unnatural amino acids can be reacted to generate relative α-amino phosphonates. The method also shows the advantages of substrate scopes, user-friendly experimental operation and atom economy.
關鍵字(中) ★ α-胺基磷酸酯
★ 磷酯基化反應
★ 普多維克反應
★ 手性助劑
關鍵字(英) ★ α-amino phosphonate
★ hydrophosphonylation
★ Pudovik-type reaction
★ chiral auxiliary
論文目次 目次

摘要.........................................ii
Abstract........................iii
誌謝.................................….............................iv
目次...................................................................v
圖次................................................................vi
表次......................................................................viii
簡稱用語對照表…………………………………………………………………….……....viii
第一章 緒論........................................................................1
1-1胺基酸與相關衍生物 1
1-2沙利度胺事件 2
1-3 α-胺基磷酸酯的合成方法 3
1-3-1米歇爾–阿爾布佐夫(Michaelis–Arbuzov)反應 4
1-3-2 Perkow反應 5
1-3-3米歇爾–貝克(Michaelis–Becker)反應 6
1-3-4 卡巴其尼克-菲爾次(Kabachnik–Fields)反應 6
1-3-5普多維克(Pudovik)反應 7

1-4手性助劑 7
1-5 α-胺基磷酸酯的文獻回顧 10
1-6 研究動機 13
1-7 實驗設計 14

第二章 實驗結果與討論.....................................................................................................…16
2-1 胺基醇的合成 16
2-2 N-亞磺醯胺的合成 19
2-3 條件篩選 21
2-4 底物範圍 24
2-5 結構鑑定 26
2-6 非鏡像基質立體選擇性實驗 27
2-7 反應機構 28

第三章 結論............................................................................................................................30
第四章 實驗部分 ..................................................................................................................32
參考文獻...............................................73

圖次

圖 1、胺基酸衍生物[1] 1
圖2、胺基磷酸及沙利度胺[1] 3
圖3、以化學鍵形成的方式區分α-胺基磷酸酯的合成方法[1] 4
圖4、阿爾布佐夫反應之反應機構[9] 5
圖5、Perkow反應之反應機構[10] 5
圖6、米歇爾–貝克反應示意圖[11] 6
圖7、卡巴其尼克-菲爾次反應路徑示意圖[12] 6
圖8、形成手性環境以利於進行立體選擇性普多維克反應的四種方法[13] 7
圖9、手性助劑應用於不對成合成示意圖[14] 8
圖10、常見的手性助劑結構 9
圖11、以醛類為起始物引入叔丁基亞磺醯胺進行縮合反應 9
圖12、以叔丁基亞磺醯醛亞胺進行格林納反應 9
圖13、以叔丁基亞磺醯醛亞胺進行格林納反應之過渡態 9
圖14、叔丁基亞磺醯胺的酸化水解 9
圖15、使用對甲苯磺醯胺建構手性N-亞磺醯胺進行磷酯基化反應[17] 10
圖16、N-對甲苯亞磺醯胺進行磷酯基化之推測過渡態[17] 10
圖17、從手性N-亞磺醯胺化合物1合成脯胺酸磷酸酯衍生物藉由磷酯基化反應[18] 11
圖18、使用叔丁基亞磺醯胺建構手性N-亞磺醯胺進行磷酯基化反應[20] 11
圖19、手性N-亞磺醯胺進行磷酯基化反應過渡態[20] 12
圖20、化合物9進行磷酯基化反應得到環化胺基磷酸酯化合物10[21] 12
圖21、α,β-不飽合亞磺醯胺化合物11進行磷酯基化反應得到化合物13[22] 13
圖22、雙環亞胺化合物16進行磷酯基化反應得到化合物17[23] 13
圖23、使用接上手性助劑的單醣進行巴比耶反應的立體及基質選擇性[24] 14
圖24、N-亞磺醯胺分別進行巴比耶反應和磷酯基化反應 14
圖25、需要加上胺基保護基的胺基酸 15
圖26、本實驗所使用胺基酸的四種胺基保護基 16
圖27、化合物19aa合成路徑 16
圖28、化合物19ba–19bg合成路徑[16] 17
圖29、化合物19ca-19cd合成路徑 17
圖30、化合物19da合成路徑[25] 17
圖31、化合物19bh–19bi合成路徑 18
圖32、化合物19ch–19ci合成路徑 18
圖33、化合物21aa合成路徑篩選 19
圖34、化合物21ba–21bi合成路徑 20
圖35、化合物21ca–21cd合成路徑 20
圖36、化合物21da合成路徑 20
圖37、化合物 (S,R,R)-22bd的雙晶結構 27
圖38、非鏡像基質磷酯基化反應控制實驗 28
圖39、右旋胺基N-亞磺醯胺磷酯基化反應控制實驗 28
圖40、亞磷酸酯與磷酸酯互變異構化 29
圖41、推測磷酯基化的過渡體 30


表次

表1、磷酯基化反應保護基篩選 22
表2、磷酯基化反應鹼試劑篩選 22
表3、磷酯基化反應碳酸銫當量數篩選 23
表4、磷酯基化反應溫度篩選 23
表5、磷酯基化反應亞磷酸二乙酯的當量數篩選 24
表6、叔丁氧羰基保護胺基磷酸酯底物範圍 25
表7、乙醯基保護胺基磷酸酯底物範圍 26
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[3] Stamper, C.; Bennett, B.; Edwards, T.; Holz, R.C.; Ringe, D.; Petsko, G. “Inhibition of the aminopeptidase from aeromonas proteolytica by L-leucinephosphonic acid. Spectroscopic and crystallographic characterization of the transition state of peptide hydrolysis.” Biochemistry 2001, 40, 7035–7046.

[4] Kafarski, P.; Lejczak, B.; Szewczyk, J. “Optically active 1-aminoalkanephosphonic acids. Dibenzoyl-l-tartaric anhydride as an effective agent for the resolution of racemic diphenyl 1-aminoalkanephosphonates.” Can. J. Chem. 1983, 61, 2425–2430.

[5] Solodenko, A.; Kukhar, P. “Stereoselective papain-catalyzed Synthesis of Alafosfalin.” Tetrahedron Lett. 1989, 30, 6917–6918.

[6] Poliak, M.S. “Antibiotics of the phosphonic acid group.” Antibiot. Med Biotechnol. 1987, 32, 66–75.

[7] van Toorn, R.; Solomons, R. “Update on the diagnosis and management of tuberculous meningitis in children.” Semin. Pediatr. Neurol. 2014, 21, 12–18.

[8] Yang C.-S.; Kim, C.; Antaya, J. “Review of thalidomide use in the pediatric population.” J. Am. Acad. Dermatol. 2015, 72, 703–711.

[9] Landuer, S. R.; Rydon, H. N. “The organic chemistry of phosphorus. part I. Some new methods for the preparation of alkyl halides.” J. Chem. Soc. 1953, 2224–2234.

[10] Oldrich, P.; Karel P.; Stanislav, K.; Antonin, K.; Vladislav, K. “New modification of the Perkow reaction: halocarboxylate anions as leaving groups in 3-acyloxyquinoline-2,4(1H,3H)-dione compounds.” Beilstein J. Org. Chem. 2005, 1, 17.

[11] Fletcher, M.D. & Murphy, P.J. (Ed.) Organophosphorus Reagents; University Press., Oxford, 2002, pp. 185.

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[13] Engel, R. “Phosphorus addition at sp2 carbon.” Org. React. 2004, 36, 175–248.

[14] Glorius, F.; Gnas, Y. “Chiral auxiliaries–principles and recent applications.” Synthesis 2006, 12, 1899–1930.

[15] Liu, G.-C.; Cogan, A.; Ellman, J. A. “Catalytic asymmetric synthesis of tert -butanesulfinamide. application to the asymmetric synthesis of amines.” J. Am. Chem. Soc. 1997, 119, 9913–9914.

[16] Ellman, J. A.; Owens, T. D.; Tang, T. P. “N-tert-Butanesulfinyl imines: versatile intermediates for the asymmetric synthesis of amines.” Acc. Chem. Res. 2002, 35, 984–995.

[17] Davis, F. A.; Lee, S.; Hong, X.-Y.; Donald, D. T. “Asymmetric synthesis of quaternary α-amino phosphonates using sulfinimines.” Org. Lett. 2001, 3, 11.
[18] Davis, F. A.; Lee, S.-H.; Xu, H. “Asymmetric synthesis of cyclic α-amino phosphonates using masked oxo sulfinimines (N-sulfinyl imines).” J. Org. Chem. 2004, 69, 3774–3781.

[19] Davis, F. A.; Lee, S.; Zhang, H.-M.; Dean L. F. “Applications of the sulfinimine-mediated asymmetric strecker synthesis to the synthesis of α-alkyl α-amino acids.” J .Org. Chem. 2000, 65, 25.

[20] Chen, Q.; Li, J.-F.; Yuan, C.-G. “Sulfinimine-mediated asymmetric synthesis of acyclic and cyclic α-aminophosphonates.” Synthesis 2008, 18, 2986–2990.

[21] Khan, H. A.; Ellman, J. A. “Asymmetric synthesis of α-amino phosphonate esters by the addition of dialkyl phosphites to tert-butanesulfinyl imines.” Synth. 2013, 45, 3147–3150.

[22] Li, P.; Jiang, M.; Liu, J.-T. “Asymmetric Pudovik reaction of chiral fluoroalkyl α,β-unsaturated ketimines and diphenyl phosphite.” Chin. J. Chem. 2014, 32, 1003–1006.

[23] Julia P.; Nicolai C. “Enantioselective C−H functionalization−addition sequence delivers densely substituted 3 azabicyclo[3,1,0]hexanes.” J. Am. Chem. Soc. 2017, 139, 12398−12401.

[24] Lin, L.-Z.; Yang, S.; Liu, W.-H.; Shie, J.-J. “Dichotomous selectivity in indium-mediated aza-barbier-type allylation of 2-N-acetyl glycosyl sulfinylimines in brine: convenient access to potent anti-influenza agents.” J. Org. Chem. 2022, 87, 2324–2335.

[25] Maria, V.; Isabella, C.; Peter, G.; Matthias, W.; Christian, S.; Katharina, B. “Amino alcohol-derived chiral ionic liquids: structural investigations toward chiral recognition.” Tetrahedron Lett. 2015, 26, 1069–1082.
指導教授 謝俊結 侯敦仁(Jiun-Jie Shie Duen-Ren Hou) 審核日期 2023-8-21
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