新型「抗癌複合藥物」之研發暨具光學活性「3-吡咯啉」合成法之開創

簡易檢索 / 詳目顯示

回結果列表

研究生：	亞維傑 Avijit, Panja
論文名稱：	新型「抗癌複合藥物」之研發暨具光學活性「3-吡咯啉」合成法之開創 Development of New Anticancer Codrugs and a Method for Synthesis of Optically Active 3-Pyrrolines
指導教授：	胡紀如 Hwu, Jih-Ru
口試委員:	陳貴通 Tan, Kui-Thong 蔡福源 Cai, FuYuan 謝發坤 Shieh, Fa-Kuen 許銘華 Hsu, Ming-Hua 蔡淑貞 Tsay, Shwu-Chen
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：	2019
畢業學年度：	107
語文別：	英文
論文頁數：	193
中文關鍵詞：	藥物傳遞、藥物傳遞、抗癌、不對稱合成、協同作用、拮抗作用
外文關鍵詞：	Drug delivery, Drug delivery, Anticancer, Asymmetric synthesis, Synergism, Antagonism
相關次數：	點閱：5 下載：0
分享至:	分享至facebook 分享至twitter

查詢本校圖書館目錄查詢臺灣博碩士論文知識加值系統勘誤回報

近來新穎藥物設計方法之開發，已成為全球最受關注，極具潛力之研究標的，人們開始研究如何利用各種高效率之合成法，以及不同藥物傳遞方式設計並製造高療效藥物。我們利用骨牌式反應及精準藥物傳遞設計高療效之抗癌複合藥物。骨牌式反應因其高產率且環保，一直為有機合成化學中之重要研究領域。藥物傳遞方式之研究探討將具生物活性之化合物準確送至人體患部，以提高藥效。
我們所設計之新型抗癌複合藥物，包含四項關鍵部份：紫杉醇（抗癌藥物），來那度胺（具協同作用之免疫調節藥物），D-呋喃核糖（對人體無害之化學橋接基團），磷酸二酯部分則具有可控釋藥功能。此複合藥物之合成共7個步驟，總產率為33％。其對OECM1細胞之效力為8.82-9.93nM，對正常細胞的毒性為685.5->1000nM。其中磷酸二酯部分促進該藥物於正常細胞下抑制癌細胞之選擇性。複合藥物中來那度胺與紫杉醇之比例為1：1。與單一藥物相比，複合藥物之水溶性較好。複合藥物之協同作用從0.721-0.867顯著改善至0.336-0.395，拮抗作用適中（1.038-1.277）。此新型複合藥物之生物活性與單一藥物時相比提升近一百倍。
不對稱合成是現代有機化學中之重要反應，骨牌式反應可提高效率，降低毒性，且過程環保。對合成化學家而言，分離出特定異構物仍然是一項艱鉅任務。因此，我們開發了一種新型骨牌式反應，於單一燒瓶中完成四個連續步驟，其利用（三甲基甲矽烷基）芳基三氟甲磺酸酯，席夫鹼和炔烴，成功合成出具有生物活性之3-吡咯啉。該等新反應產率極佳（75-87％），且生成單一異構產物，具高立體選擇性。該反應利用1,4-分子內質子轉移和Hüisgen 1,3-偶極環加成反應，及不對稱反應催化劑(R)-()-1,1'-binaphthyl-2,2'-diyl hydrogenphosphate，得到高光學純度之鏡像異構產物，鏡像異構比例高達98.5：1.5。
本篇論文探討了兩大重要主題，首先為新型複合藥物之設計與合成及其協同與拮抗作用之新發現。此外，我們利用「芐誘導反應」，成功研發出具光學活性「3-吡咯啉」之新合成方法。以上所述之豐富研究成果，可幫助學者專家們擬定藥物設計策略，並利用所發展之新合成法高效率研發及製造具生物活性化合物以對抗新興RNA病毒疾病。

Novel design of highly efficient drugs for the treatment of various diseases poses a significant challenge and a high-priority task in medicinal chemistry. Therefore, the synthesis of biologically active compounds by use of various methods and modifications for the known medications are closely related to each other. Drug delivery and domino reactions both have their significant importance for medicinal and synthetic organic chemistry. Drug delivery refers to the transport of a biologically active compound to the target site in the body and have its desired therapeutic effect.
Although the physical combination is efficient, only few codrugs possess anticancer activity without synergistic and antagonistic effects. We designed a novel anticancer codrug that contains four crucial elements: paclitaxel (a potent anticancer drug), lenalidomide (a immunomodulatory drug exerting synergistic effect), D-ribofuranose (a pharmacologically safe joint), and phosphodiester moiety as the trigger for the selective delivery. The synthesis of codrug involves seven steps in 33% overall yield. Its potency against OECM1 cells was found 8.82–9.93 nM and toxicity toward normal cells was 685.5 – >1000 nM. The phosphodiester moiety therein facilitates this drug to exhibit appealing selectivity against cancer cells in the presence of normal cells. Water solubility of codrug increased compared with the individual drugs. The synergism of codrug is significantly improved from 0.721–0.867 to 0.336–0.395 in comparison with the physical combination of lenalidomide with paclitaxel in a 1:1 ratio. The breakthrough in biological activity is that the antagonism is moderate (1.038–1.277) for the physical combination. It is raised greatly in two-order higher (40.01–130.9).
Enantioselective synthesis is a key process in modern organic chemistry. In the past decade, asymmetric catalysis has grown rapidly to become one of the most fascinating and current fields in organic chemistry. Increased efficiency, reduced toxicity and eco-friendly process are some of the striking features of domino reaction. Isolation of a particular isomer still remains a difficult task for the synthetic chemists. Therefore, we developed a domino reaction for the synthesis of 3-pyrrolines, a class of compounds with biological activities, directly from (trimethylsilyl)aryl triflates, Schiff bases, and alkynes by an eco-friendly method. The key features of this new reaction include the generation of a single product in very good yields (7587%) with high stereo- and enantio-selectivity. The reaction involves completion of four sequential steps in a single flask, which are formation of arynes, their alkylation by Schiff bases, an unusual 1,4-intramolecular proton transfer, and a Hüisgen 1,3-dipolar cycloaddition. The addition of the chiral catalyst (R)-()-1,1'-binaphthyl-2,2'-diyl hydrogenphosphate to some of the reaction mixtures leads to the formation of optically active 3-pyrrolines with enantiomeric ratio as high as 98.5:1.5.
Two major challenges are discussed and addressed in this dissertation. These includes the design and syntheses of novel codrugs and new findings of synergism and antagonism effects of the new drug conjugates. On the other hand, development of a method for the synthesis of optically active 3-pyrrolines by benzyne-induced reactions. These results and compounds provide a way for further optimization, design, and synthesis of new biologically active compounds for the emerging RNA viral diseases.

Abstract (in English)     i
Abstract (in Chinese)     iii
Acknowledgement     v
Content     vii
List of Figures     ..xxiii
List of Tables     xxiv
List of Schemes     xxv
1.  Introduction     1
2.  Results     14
2.1          Synthesis of codrug 1 starting with paclitaxel (3)     14
2.2         Synthesis of codrug 1 starting with lenalidomide derivative 19     16
2.3         The successful synthesis of the codrug 1     17
2.3.1      Attachment of two anticancer drugs on ribose core unit     17
2.3.2      Attachment of cyclic phosphate ester on ribose core unit     18
2.4         Spectroscopic analysis for the structure identification of codrug 1     19
2.5         Hydrolysis study of the codrug 1 and liberation of lenalidomide (2), paclitaxel
(3), and D-ribose (4)     20
2.6         Establishment of drug release mechanism from hydrolysis graph     21
2.7         Biological activities against OECM1 cancer cells and normal Huvec cells     23
2.8         Synthesis of 3-pyrrolines from silylaryl triflates 29, Schiff bases 30, and alkynes
31     26
2.9         Optimization of reaction condition for the syntheses of 3-pyrroline 32     27
2.10       Syntheses of various substituted 3-pyrrolines     28
2.11       Optimization Conditions for Asymmetric Synthesis of 3-Pyrroline 32n     33
2.12       Development of sustainable method for the synthesis of 3-pyrrolines 32     40
2.13       Spectroscopic analysis for the structure identification of 3-pyrroline 32e     40
3.  Discussion     42
3.1         Determination of synergism and antagonism     42
3.2         Plausible mechanism for the synthesis of 3-pyrroline 32     43
3.3         Catalyst used in aryne-induced reaction to generate important products     46
3.4         Identification of asymmetric induction step and particular catalyst for the
synthesis of optically active 3-pyrrolines     47
3.5         Plausible mechanism for asymmetric induction to generate optically active
3-pyrrolines     49
4.  Conclusion     51
5.  Experimental     53
2,3-O-benzylidene-5-(4-nitrophenyl-oxycarbonyl)oxymethyl-oxolane-1-ol (15)     55
2,3-O-benzylidene-5-(2ʹ-Paclitaxeyl-oxycarbonyl)oxymethyl-oxolane-1-ol (16)     56
2,3-O-benzylidene-1-(4-nitrophenyl-oxycarbonyl)oxy-5-(2ʹ-Paclitaxeyl-oxycarbonyl)oxy- oxolane (17)     57
2,3-O-benzylidene-5-(N-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindoline-4-yl)-piperidine-(carbamoyl)oxymethyl-oxolane-1-ol (20)     58
5-(N-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindoline-4-yl)-piperidine (carbamoyl)oxymethyl-2,3-hydrogenphosphate-oxolane-1-ol (21)     59
2,3-O-benzylidene-5-(N-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindoline-4-yl)-
piperidine-(carbamoyl)oxymethyl-oxolane-1-ol (23)     60
2,3-O-benzylidene-5-(N-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindoline-4-yl)-
piperidine-(carbamoyl)oxymethyl)-1-(4-nitrophenyl-oxycarbonyl)oxy-oxolane (24)     61
2,3-O-benzylidene-5-(N-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindoline-4-yl)-
piperidine-(carbamoyl)oxymethyl)-1-(2’-Paclitaxeyl-oxycarbonyl)oxy-oxolane (25)     62
5-(N-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindoline-4-yl)-piperidine-(carbamoyl)oxymethyl)-1-(2’-Paclitaxeyl-oxycarbonyl)oxy-oxolane-2,3-diol (26)     64
5-(N-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindoline-4-yl)-piperidine-(carbamoyl)oxymethyl)-1-(2’-Paclitaxeyl-oxycarbonyl)oxy-oxolane-2-3-ammonium phosphate (1)     65
Standard Procedure 1 for the Preparation of Schiff Bases     66
Standard Procedure 2 for the Single-Flask Synthesis of 3-Pyrrolines     67
Standard Procedure 3 for Asymmetric Synthesis of Optically Active 3-Pyrrolines     67
Standard Procedure 4 for the Sustainable Synthetic Route of 3-Pyrrolines     67
Standard Procedure 5 for the Sustainable Synthetic Route of Optically Active
3-Pyrrolines     68
(E)-Methyl N-(3-bromobenzylidene)--alanate (30d)     68
(E)-N-(4-Methylbenzylidene)-(2-methoxy)ethan-1-amine (30e)     69
(E)-N-(4-Methoxybenzylidene)-(2-methoxy)ethan-1-amine (30f)     69
(E)-N-(4-Methoxybenzylidene)-(2-cyano)ethan-1-amine (30g)     70
cis-3,4-Dimethoxycarbonyl-5-(2'-methoxy-2'-oxoethyl)-2-phenyl-N-phenyl-3-pyrroline    (32a)     71
cis-3,4-Diethoxycarbonyl-5-(2'-methoxy-2'-oxoethyl)-2-phenyl-N-phenyl-
3-pyrroline (32b)     72
cis-3,4-Dimethoxycarbonyl-5-(2'-methoxy-2'-oxoethyl)-2-(4''-methylphenyl)-N-
phenyl-3-pyrroline (32c)     73
cis-3,4-Diethoxycarbonyl-5-(2'-methoxy-2'-oxoethyl)-2-(4''-methylphenyl)-N-phenyl
-3-pyrroline (32d)     74
cis-3,4-Dimethoxycarbonyl-5-(2'-methoxy-2'-oxoethyl)-2-(4''-methoxyphenyl)-N-phenyl-
3-pyrroline (32e)     75
cis-3,4-Diethoxycarbonyl-5-(2'-methoxy-2'-oxoethyl)-2-(4''-methoxyphenyl)-N-phenyl-
3-pyrroline (32f)     77
cis-2-(3''-Bromophenyl)-3,4-dimethoxycarbonyl-5-(2'-methoxy-2'-oxoethyl)-N-phenyl-
3-pyrroline (32g)     78
cis-2-(3''-Bromophenyl)-3,4-diethoxycarbonyl-5-(2'-methoxy-2'-oxoethyl)-N-phenyl-
3-pyrroline (32h)     79
cis-2-(3''-Bromophenyl)-3-ethoxycarbonyl-5-(2'-methoxy-2'-oxoethyl)-N-phenyl-
3-pyrroline (32i)     80
cis-3,4-Dimethoxycarbonyl-5-(1′-methoxymethyl)-2-(4′′-methylphenyl)-N-phenyl-
3-pyrroline (32j)     81
cis-3,4-Diethoxycarbonyl-5-(1′-methoxymethyl)-2-(4′′-methylphenyl)-N-phenyl-
3-pyrroline (32k)     83
cis-3-Methoxycarbonyl-5-(1'-methoxymethyl)-2-(4′′-methylphenyl)-N-phenyl-
3-pyrroline (32l)     85
cis-3-Ethoxycarbonyl-5-(1'-methoxymethyl)-2-(4′′-methylphenyl)-N-phenyl-
3-pyrroline (32m)     86
cis-3,4-Dimethoxycarbonyl-5-(1′-methoxymethyl)-2-(4′′-methoxyphenyl)-N-phenyl-
3-pyrroline (32n)     87
cis-3,4-Diethoxycarbonyl-5-(1′-methoxymethyl)-2-(4′′-methoxyphenyl)-N-phenyl-
3-pyrroline (32o)     89
cis-3-Methoxycarbonyl-5-(1'-methoxymethyl)-2-(4′′-methoxyphenyl)-N-phenyl-
3-pyrroline (32p)     91
cis-3-Ethoxycarbonyl-5-(1'-methoxymethyl)-2-(4′′-methoxyphenyl)-N-phenyl-
3-pyrroline (32q)     92
cis-3,4-Diethoxycarbonyl-N-3′′′,4′′′-dimethoxyphenyl-5-(1′-methoxymethyl)-
2-(4′′-methoxyphenyl)-3-pyrroline (32r)     94
cis-N-(Benzo[d][1''',3''']dioxol-5'''-yl)-3,4-dimethoxycarbonyl-5-(2'-methoxy-2'-oxoethyl)-
2-(4''-methoxyphenyl)-3-pyrroline (32s)     96
cis-5-(1′-Cyanomethyl)-3,4-diethoxycarbonyl-2-(4′′-methoxyphenyl)-N-phenyl-
3-pyrroline (32t)     97
Large-Scale Synthesis of Optically Active 3-Pyrrolines 32n and 32o as well as Catalyst
Recovery    100
Calculation of Atom Economy and Atom Efficiency for the 3-Pyrroline (4n)     101
6.  References     101
7.  Spectra     110
1H NMR spectrum of 2,3-O-benzylidene-5-(4-nitrophenyl-oxycarbonyl)oxymethyl-oxolane-1-ol (15)     111
HRMS spectrum of 2,3-O-benzylidene-5-(4-nitrophenyl-oxycarbonyl)oxymethyl-
oxolane-1-ol (15)     111
1H NMR spectrum of 2,3-O-benzylidene-5-(2ʹ-Paclitaxeyl-oxycarbonyl)oxymethyl-oxolane-1-ol (16)     112
HRMS spectrum of 2,3-O-benzylidene-5-(2ʹ-Paclitaxeyl-oxycarbonyl)oxymethyl-
oxolane-1-ol (16)     112
1H NMR spectrum of 2,3-O-benzylidene-1-(4-nitrophenyl-oxycarbonyl)oxy-5-(2ʹ-Paclitaxeyl-oxycarbonyl)oxy-oxolane (17)     113
HRMS spectrum of 2,3-O-benzylidene-1-(4-nitrophenyl-oxycarbonyl)oxy-5-(2ʹ-
Paclitaxeyl-oxycarbonyl)oxy-oxolane (17)     113
1H NMR spectrum of 2,3-O-benzylidene-5-(N-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindoline-4-yl)-piperidine-(carbamoyl)oxymethyl-oxolane-1-ol (20)     114
HRMS spectrum of 2,3-O-benzylidene-5-(N-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindoline-4-yl)-piperidine-(carbamoyl)oxymethyl-oxolane-1-ol (20)     114
1H NMR spectrum of 5-(N-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindoline-4-yl)-piperidine-(carbamoyl)oxymethyl-2,3-hydrogenphosphate-oxolane-1-ol (21)     115
HRMS spectrum of 5-(N-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindoline-4-yl)-
piperidine-(carbamoyl)oxymethyl-2,3-hydrogenphosphate-oxolane-1-ol (21)     115
1H NMR spectrum of 2,3-O-benzylidene-5-(N-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindoline-4-yl)-piperidine-(carbamoyl)oxymethyl-oxolane-1-ol (23)     116
13C NMR spectrum of 2,3-O-benzylidene-5-(N-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindoline-4-yl)-piperidine-(carbamoyl)oxymethyl-oxolane-1-ol (23)     116
1H NMR spectrum of 2,3-O-benzylidene-5-(N-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindoline-4-yl)-piperidine-(carbamoyl)oxymethyl)-1-(4-nitrophenyl-oxycarbonyl)
oxy-oxolane (24)     117
13C NMR spectrum of 2,3-O-benzylidene-5-(N-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindoline-4-yl)-piperidine-(carbamoyl)oxymethyl)-1-(4-nitrophenyl-oxycarbonyl)
oxy-oxolane (24)     117
1H NMR spectrum of 2,3-O-benzylidene-5-(N-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindoline-4-yl)-piperidine-(carbamoyl)oxymethyl)-1-(2’-Paclitaxeyl-oxycarbonyl
)oxy-oxolane (25)     118
13C NMR spectrum of 2,3-O-benzylidene-5-(N-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindoline-4-yl)-piperidine-(carbamoyl)oxymethyl)-1-(2’-Paclitaxeyl-oxycarbonyl)
oxy-oxolane (25)     118
HRMS spectrum of  5-(N-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindoline-4-yl)-piperidine-(carbamoyl)oxymethyl)-1-(2’-Paclitaxeyl-oxycarbonyl)oxy-oxolane-2,3-diol (26)     119
1H NMR spectrum of 5-(N-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindoline-4-yl)-piperidine-(carbamoyl)oxymethyl)-1-(2’-Paclitaxeyl-oxycarbonyl)oxy-oxolane-2-3-ammonium phosphate (1)     119
13C NMR spectrum of 5-(N-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindoline-4-yl)-piperidine-(carbamoyl)oxymethyl)-1-(2’-Paclitaxeyl-oxycarbonyl)oxy-oxolane-2-3-ammonium phosphate (1)     120
31P NMR spectrum of 5-(N-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindoline-4-yl)-piperidine-(carbamoyl)oxymethyl)-1-(2’-Paclitaxeyl-oxycarbonyl)oxy-oxolane-2-3-ammonium phosphate (1)     120
1H NMR spectrum of (E)-Methyl N-(3-bromobenzylidene)--alanate (30d)     121
13C NMR spectrum of (E)-Methyl N-(3-bromobenzylidene)--alanate (30d)     121
1H NMR spectrum of (E)-N-(4-Methylbenzylidene)-(2-methoxy)ethan-1-amine
(30e)     122
13C NMR spectrum of (E)-N-(4-Methylbenzylidene)-(2-methoxy)ethan-1-amine
(30e)     122
1H NMR spectrum of (E)-N-(4-Methoxybenzylidene)-(2-methoxy)ethan-1-amine
(30f)     123
13C NMR spectrum of (E)-N-(4-Methoxybenzylidene)-(2-methoxy)ethan-1-amine
(30f)     123
1H NMR spectrum of (E)-N-(4-Methoxybenzylidene)-(2-cyano)ethan-1-amine
(30g)     124
13C NMR spectrum of (E)-N-(4-Methoxybenzylidene)-(2-cyano)ethan-1-amine
(30g)     124
1H NMR spectrum of cis-3,4-Dimethoxycarbonyl-5-(2'-methoxy-2'-oxoethyl)-2-phenyl
-N-phenyl-3-pyrroline (32a)     125
13C NMR spectrum of cis-3,4-Dimethoxycarbonyl-5-(2'-methoxy-2'-oxoethyl)-2-phenyl-
N-phenyl-3-pyrroline (32a)     125
1H NMR spectrum of cis-3,4-Diethoxycarbonyl-5-(2'-methoxy-2'-oxoethyl)-2-phenyl-
N-phenyl-3-pyrroline (32b)     126
13C NMR spectrum of cis-3,4-Diethoxycarbonyl-5-(2'-methoxy-2'-oxoethyl)-2-phenyl-
N-phenyl-3-pyrroline (32b)     126
1H NMR spectrum of cis-3,4-Dimethoxycarbonyl-5-(2'-methoxy-2'-oxoethyl)-2-(4''-methylphenyl)-N-phenyl-3-pyrroline (32c)     127
13C NMR spectrum of cis-3,4-Dimethoxycarbonyl-5-(2'-methoxy-2'-oxoethyl)-2-(4''-methylphenyl)-N-phenyl-3-pyrroline (32c)     127
1H NMR spectrum of cis-3,4-Diethoxycarbonyl-5-(2'-methoxy-2'-oxoethyl)-2-(4''-methylphenyl)-N-phenyl-3-pyrroline (32d)     128
13C NMR spectrum of cis-3,4-Diethoxycarbonyl-5-(2'-methoxy-2'-oxoethyl)-2-(4''-methylphenyl)-N-phenyl-3-pyrroline (32d)     128
1H NMR spectrum of cis-3,4-Dimethoxycarbonyl-5-(2'-methoxy-2'-oxoethyl)-2-(4''-methoxyphenyl)-N-phenyl-3-pyrroline (32e)     129
13C NMR spectrum of cis-3,4-Dimethoxycarbonyl-5-(2'-methoxy-2'-oxoethyl)-2-(4''-methoxyphenyl)-N-phenyl-3-pyrroline (32e)     129
1H NMR spectrum of cis-3,4-Diethoxycarbonyl-5-(2'-methoxy-2'-oxoethyl)-2-(4''-methoxyphenyl)-N-phenyl-3-pyrroline (32f)     130
13C NMR spectrum of cis-3,4-Diethoxycarbonyl-5-(2'-methoxy-2'-oxoethyl)-2-(4''-methoxyphenyl)-N-phenyl-3-pyrroline (32f)     130
1H NMR spectrum of cis-2-(3''-Bromophenyl)-3,4-dimethoxycarbonyl-5-(2'-methoxy
-2'-oxoethyl)-N-phenyl-3-pyrroline (32g)     131
13C NMR spectrum of cis-2-(3''-Bromophenyl)-3,4-dimethoxycarbonyl-5-(2'-methoxy
-2'-oxoethyl)-N-phenyl-3-pyrroline (32g)     131
1H NMR spectrum of cis-2-(3''-Bromophenyl)-3,4-diethoxycarbonyl-5-(2'-methoxy-
2'-oxoethyl)-N-phenyl-3-pyrroline (32h)     132
13C NMR spectrum of cis-2-(3''-Bromophenyl)-3,4-diethoxycarbonyl-5-(2'-methoxy-
2'-oxoethyl)-N-phenyl-3-pyrroline (32h)     132
1H NMR spectrum of cis-2-(3''-Bromophenyl)-3-ethoxycarbonyl-5-(2'-methoxy-2'-oxoethyl)-N-phenyl-3-pyrroline (32i)     133
13C NMR spectrum of cis-2-(3''-Bromophenyl)-3-ethoxycarbonyl-5-(2'-methoxy-2'-oxoethyl)-N-phenyl-3-pyrroline (32i)     133
1H NMR spectrum of cis-3,4-Dimethoxycarbonyl-5-(1′-methoxymethyl)-2-(4′′-methylphenyl)-N-phenyl-3-pyrroline (32j)     134
13C NMR spectrum of cis-3,4-Dimethoxycarbonyl-5-(1′-methoxymethyl)-2-(4′′-methylphenyl)-N-phenyl-3-pyrroline (32j)     134
1H NMR spectrum of cis-3,4-Diethoxycarbonyl-5-(1′-methoxymethyl)-2-(4′′-methylphenyl)-N-phenyl-3-pyrroline (32k)     135
13C NMR spectrum of cis-3,4-Diethoxycarbonyl-5-(1′-methoxymethyl)-2-(4′′-methylphenyl)-N-phenyl-3-pyrroline (32k)     135
1H NMR spectrum of cis-3-Methoxycarbonyl-5-(1'-methoxymethyl)-2-(4′′-
methylphenyl)-N-phenyl-3-pyrroline (32l)     136
13C NMR spectrum of cis-3-Methoxycarbonyl-5-(1'-methoxymethyl)-2-(4′′-
methylphenyl)-N-phenyl-3-pyrroline (32l)     136
1H NMR spectrum of cis-3-Ethoxycarbonyl-5-(1'-methoxymethyl)-2-(4′′-
methylphenyl)-N-phenyl-3-pyrroline (32m)     137
13C NMR spectrum of cis-3-Ethoxycarbonyl-5-(1'-methoxymethyl)-2-(4′′-
methylphenyl)-N-phenyl-3-pyrroline (32m)     137
1H NMR spectrum of cis-3,4-Dimethoxycarbonyl-5-(1′-methoxymethyl)-2-(4′′-methoxyphenyl)-N-phenyl-3-pyrroline (32n)     138
13C NMR spectrum of cis-3,4-Dimethoxycarbonyl-5-(1′-methoxymethyl)-2-(4′′-methoxyphenyl)-N-phenyl-3-pyrroline (32n)     138
1H NMR spectrum of cis-3,4-Diethoxycarbonyl-5-(1′-methoxymethyl)-2-(4′′-methoxyphenyl)-N-phenyl-3-pyrroline (32o)     139
13C NMR spectrum of cis-3,4-Diethoxycarbonyl-5-(1′-methoxymethyl)-2-(4′′-methoxyphenyl)-N-phenyl-3-pyrroline (32o)     139
1H NMR spectrum of cis-3-Methoxycarbonyl-5-(1'-methoxymethyl)-2-(4′′-methoxyphenyl)-N-phenyl-3-pyrroline (32p)     140
13C NMR spectrum of cis-3-Methoxycarbonyl-5-(1'-methoxymethyl)-2-(4′′-methoxyphenyl)-N-phenyl-3-pyrroline (32p)     140
1H NMR spectrum of cis-3-Ethoxycarbonyl-5-(1'-methoxymethyl)-2-(4′′-
methoxyphenyl)-N-phenyl-3-pyrroline (32q)     141
13C NMR spectrum of cis-3-Ethoxycarbonyl-5-(1'-methoxymethyl)-2-(4′′-
methoxyphenyl)-N-phenyl-3-pyrroline (32q)     141
1H NMR spectrum of cis-3,4-Diethoxycarbonyl-N-3′′′,4′′′-dimethoxyphenyl-5-(1′-methoxymethyl)-2-(4′′-methoxyphenyl)-3-pyrroline (32r)     142
13C NMR spectrum of cis-3,4-Diethoxycarbonyl-N-3′′′,4′′′-dimethoxyphenyl-5-(1′-methoxymethyl)-2-(4′′-methoxyphenyl)-3-pyrroline (32r)     142
1H NMR spectrum of cis-N-(Benzo[d][1''',3''']dioxol-5'''-yl)-3,4-dimethoxycarbonyl-
5-(2'-methoxy-2'-oxoethyl)-2-(4''-methoxyphenyl)-3-pyrroline (32s)     143
13C NMR spectrum of cis-N-(Benzo[d][1''',3''']dioxol-5'''-yl)-3,4-dimethoxycarbonyl-
5-(2'-methoxy-2'-oxoethyl)-2-(4''-methoxyphenyl)-3-pyrroline (32s)     143
1H NMR spectrum of cis-5-(1′-Cyanomethyl)-3,4-diethoxycarbonyl-2-(4′′-methoxyphenyl)-N-phenyl-3-pyrroline (32t)     144
13C NMR spectrum of cis-5-(1′-Cyanomethyl)-3,4-diethoxycarbonyl-2-(4′′-methoxyphenyl)-N-phenyl-3-pyrroline (32t)     144
8.  HPLC Chromatogram     145
HPLC chromatogram for enatioenriched 2,3-O-benzylidene-5-(N-(2-(2,6-
dioxopiperidine-3-yl)-1-oxoisoindoline-4-yl)-piperidine-(carbamoyl)oxymethyl)-1-(4-nitrophenyl-oxycarbonyl)oxy-oxolane (24)     146
HPLC chromatogram for hydrolysis of 5-(N-(2-(2,6-dioxopiperidine-
3-yl)-1-oxoisoindoline-4-yl)-piperidine-(carbamoyl)oxymethyl)-1-(2’-Paclitaxeyl-oxycarbonyl)oxy-oxolane-2-3-ammonium phosphate (1) after 0 h     147
HPLC chromatogram for hydrolysis of 5-(N-(2-(2,6-dioxopiperidine-
3-yl)-1-oxoisoindoline-4-yl)-piperidine-(carbamoyl)oxymethyl)-1-(2’-Paclitaxeyl-oxycarbonyl)oxy-oxolane-2-3-ammonium phosphate (1) after 6.0 h     148
HPLC chromatogram for hydrolysis of 5-(N-(2-(2,6-dioxopiperidine-
3-yl)-1-oxoisoindoline-4-yl)-piperidine-(carbamoyl)oxymethyl)-1-(2’-Paclitaxeyl-oxycarbonyl)oxy-oxolane-2-3-ammonium phosphate (1) after 12 h     149
HPLC chromatogram for hydrolysis of 5-(N-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindoline
-4-yl)-piperidine-(carbamoyl)oxymethyl)-1-(2’-Paclitaxeyl-oxycarbonyl)oxy-oxolane-2-3-ammonium phosphate (1) after 18 h     150
HPLC chromatogram for hydrolysis of 5-(N-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindoline
-4-yl)-piperidine-(carbamoyl)oxymethyl)-1-(2’-Paclitaxeyl-oxycarbonyl)oxy-oxolane-2-3-ammonium phosphate (1) after 24 h     151
HPLC chromatogram for hydrolysis of 5-(N-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindoline
-4-yl)-piperidine-(carbamoyl)oxymethyl)-1-(2’-Paclitaxeyl-oxycarbonyl)oxy-oxolane-2-3-ammonium phosphate (1) after 30 h     152
HPLC chromatogram for hydrolysis of 5-(N-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindoline
-4-yl)-piperidine-(carbamoyl)oxymethyl)-1-(2’-Paclitaxeyl-oxycarbonyl)oxy-oxolane-2-3-ammonium phosphate (1) after 36 h     153
HPLC chromatogram for hydrolysis of 5-(N-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindoline
-4-yl)-piperidine-(carbamoyl)oxymethyl)-1-(2’-Paclitaxeyl-oxycarbonyl)oxy-oxolane-2-3-ammonium phosphate (1) after 42 h     154
HPLC chromatogram for hydrolysis of 5-(N-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindoline
-4-yl)-piperidine-(carbamoyl)oxymethyl)-1-(2’-Paclitaxeyl-oxycarbonyl)oxy-oxolane-2-3-ammonium phosphate (1) after 48 h     155
HPLC chromatogram for racemic cis-3,4-Dimethoxycarbonyl-5-(2'-methoxy-2'-
oxoethyl)-2-(4''-methylphenyl)-N-phenyl-3-pyrroline (32c)     156
HPLC chromatogram for enatioenriched cis-3,4-Dimethoxycarbonyl-5-(2'-methoxy-
2'-oxoethyl)-2-(4''-methylphenyl)-N-phenyl-3-pyrroline (32c)     157
HPLC chromatogram for racemic cis-3,4-Diethoxycarbonyl-5-(2'-methoxy-2'-oxoethyl)
-2-(4''-methylphenyl)-N-phenyl-3-pyrroline (32d)     158
HPLC chromatogram for enatioenriched cis-3,4-Diethoxycarbonyl-5-(2'-methoxy-2'-
oxoethyl)-2-(4''-methylphenyl)-N-phenyl-3-pyrroline (32d)     159
HPLC chromatogram for racemic cis-3,4-Dimethoxycarbonyl-5-(2'-methoxy-2'-oxoethyl)
-2-(4''-methoxyphenyl)-N-phenyl-3-pyrroline (32e)     160
HPLC chromatogram for enatioenriched cis-3,4-Dimethoxycarbonyl-5-(2'-methoxy-2'-
oxoethyl)-2-(4''-methoxyphenyl)-N-phenyl-3-pyrroline (32e)     161
HPLC chromatogram for racemic cis-3,4-Diethoxycarbonyl-5-(2'-methoxy-2'-oxoethyl)
-2-(4''-methoxyphenyl)-N-phenyl-3-pyrroline (32f)     162
HPLC chromatogram for enatioenriched cis-3,4-Diethoxycarbonyl-5-(2'-methoxy-2'-
oxoethyl)-2-(4''-methoxyphenyl)-N-phenyl-3-pyrroline (32f)     163
HPLC chromatogram for racemic cis-3,4-Dimethoxycarbonyl-5-(1′-methoxymethyl)-2-(4′′-methylphenyl)-N-phenyl-3-pyrroline (32j)     164
HPLC chromatogram for enatioenriched cis-3,4-Dimethoxycarbonyl-5-(1′-methoxymethyl)-2-(4′′-methylphenyl)-N-phenyl-3-pyrroline (32j)     165
HPLC chromatogram for racemic cis-3,4-Diethoxycarbonyl-5-(1′-methoxymethyl)-2-
(4′′-methylphenyl)-N-phenyl-3-pyrroline (32k)     166
HPLC chromatogram for enatioenriched cis-3,4-Diethoxycarbonyl-5-(1′-methoxymethyl)
-2-(4′′-methylphenyl)-N-phenyl-3-pyrroline (32k)     167
HPLC chromatogram for racemic cis-3-Methoxycarbonyl-5-(1'-methoxymethyl)-2-
(4′′-methylphenyl)-N-phenyl-3-pyrroline (32l)     168
HPLC chromatogram for enatioenriched cis-3-Methoxycarbonyl-5-(1'-methoxymethyl)-
2-(4′′-methylphenyl)-N-phenyl-3-pyrroline (32l)     169
HPLC chromatogram for racemic cis-3-Ethoxycarbonyl-5-(1'-methoxymethyl)-2-
(4′′-methylphenyl)-N-phenyl-3-pyrroline (32m)     170
HPLC chromatogram for enatioenriched cis-3-Ethoxycarbonyl-5-(1'-methoxymethyl)-
2-(4′′-methylphenyl)-N-phenyl-3-pyrroline (32m)     171
HPLC chromatogram for racemic cis-3,4-Dimethoxycarbonyl-5-(1′-methoxymethyl)
-2-(4′′-methoxyphenyl)-N-phenyl-3-pyrroline (32n)     172
HPLC chromatogram for enatioenriched cis-3,4-Dimethoxycarbonyl-5-(1′-methoxymethyl)
-2-(4′′-methoxyphenyl)-N-phenyl-3-pyrroline (32n)     173
HPLC chromatogram for racemic cis-3,4-Diethoxycarbonyl-5-(1′-methoxymethyl)-
2-(4′′-methoxyphenyl)-N-phenyl-3-pyrroline (32o)     174
HPLC chromatogram for enatioenriched cis-3,4-Diethoxycarbonyl-5-(1′-methoxymethyl)
-2-(4′′-methoxyphenyl)-N-phenyl-3-pyrroline (32o)     175
HPLC chromatogram for racemic cis-3-Methoxycarbonyl-5-(1'-methoxymethyl)-2-
(4′′-methoxyphenyl)-N-phenyl-3-pyrroline (32p)     176
HPLC chromatogram for racemic cis-3-Methoxycarbonyl-5-(1'-methoxymethyl)-2-
(4′′-methoxyphenyl)-N-phenyl-3-pyrroline (32p)     177
HPLC chromatogram for racemic cis-3-Ethoxycarbonyl-5-(1'-methoxymethyl)-2-(4′′-
methoxyphenyl)-N-phenyl-3-pyrroline (32q)     178
HPLC chromatogram for enatioenriched cis-3-Ethoxycarbonyl-5-(1'-methoxymethyl)-
2-(4′′-methoxyphenyl)-N-phenyl-3-pyrroline (32q)     179
HPLC chromatogram for racemic cis-3,4-Diethoxycarbonyl-N-3′′′,4′′′-
dimethoxyphenyl-5-(1′-methoxymethyl)-2-(4′′-methoxyphenyl)-3-pyrroline (32r)     180
HPLC chromatogram for enatioenriched racemic cis-3,4-Diethoxycarbonyl-N-3′′′,4′′′-
dimethoxyphenyl-5-(1′-methoxymethyl)-2-(4′′-methoxyphenyl)-3-pyrroline (32r)     181
9.  Crystallographic data     182

List of Figures
Figure 1.  Diagrammatic representation of codrug action     2
Figure 2.  Major advantages of codrug     3
Figure 3.  Marketed codrugs for various diseases     4
Figure 4.  Codrugs possess anticancer activity     5
Figure 5.  C-3 carbon of piperidine-2,6-dione undergoes recemization     7
Figure 6.  3-Pyrrolines family shows various bioactivities     10
Figure 7.  Nine conventional methods and a novel domino asymmetric method (red arrows) for the syntheses of 3-pyrroline targets     11
Figure 8.  Novel domino reaction for the syntheses of 3-pyrrolines and its asymmetric
induction     14
Figure 9.  Hydolysis of codrug 1 and determination of the half-life (t1/2) period     20
Figure 10.  Catalysts used for establishment of asymmetric induction for 3-pyrrolines     33
Figure 11.  ORTEP diagram of compound 32e, obtained by X-ray analysis     41

List of Tables
Table 1.  IC50 (nM), values of co-drug 1, its major intermediate, individual drugs and, physical combination 1:1 individual drugs     22
Table 2.  Ratio of IC50 values for different drugs on the same cell lines after 24 and 48 h     25
Table 3.  Potency versus toxicity of various drugs for different cell lines after incubation of drugs     25
Table 4.  Optimization of yield for reaction 29a + 30c + 31a  32e in Scheme 12 by use of various solvents, fluorides, temperatures, and reaction times     28
Table 5.  Structures of reactants 29–31 and products cis-3-pyrrolines 32 as well as the isolated yields of newly developed domino reaction     29
Table 6.  Optimization conditions of asymmetric synthesis of 3-pyrroline 32n by use of various metal salts, chiral catalysts, solvents, temperatures, and reaction times     34
Table 7.  Reaction times, yields, and %ee of asymmetric synthesis of cis-3-pyrrolines 32 with 10 mol% of (R)-()-BNPPA (35a) in domino reactions     38
Table 8.  Optimization conditions of asymmetric synthesis of 3-pyrroline 32n by use of various chiral catalysts, additives, solvents, temperatures, and reaction times     39
Table 9.  Description of synergism and antagonism effects in codrug 1 combination drugs 2 + 4 (1:1) and conjugated drug (18) analyzed with the combination index method after 24 and
48 h     43
Table 10.  Hydrolysis study of codrug 1 determination of area percentage from HPLC analysis in 048 h     99

List of Schemes
Scheme 1.  Design of the new codrug 1 and functions of each components     6
Scheme 2.  Olefin metathesis by ruthenium-phosphabicyclononane complex     11
Scheme 3.  Asymmetric intermolecular Heck reaction of aryl halides for the syntheses of
3-pyrrolies     12
Scheme 4.  Representative reactions of arynes     13
Scheme 5.  Attempt to synthesize codrug 1 starting with paclitaxel (4)     15
Scheme 6.  Attempt to synthesize codrug 1 starting with a lenalidomide derivative 19     16
Scheme 7.  Successful attachment of two drugs on ribose and synthesis of conjugate
drug 25     17
Scheme 8.  Installation of cyclic phosphate ester on ribose C-2’ and C-3’ position to obtained codrug 1     18
Scheme 9.  Drug release mechanism of codrug 1     21
Scheme 10.  Syntheses of cis-3-pyrrolines 32 from (trimethylsilyl)aryl triflates 29 Schiff bases 30, and alkynes 31 by a “single-flask” method     26
Scheme 11.  Optimization conditions for the synthesis of 3-pyrroline 32e     27
Scheme 12.  A plausible mechanism for the synthesis of 3-pyrrolines 32 from -silylphenyl triflates 29, Schiff bases 30, and alkynes 31 through a domino process     44
Scheme 13.  Imine alkylation through intermolecular proton transfer     46
Scheme 14.  Use of palladium catalyst in the aryne-induced reaction     47
Scheme 15.  Use of copper catalyst in the aryne-induced reaction     47
Scheme 16.  Mechanistic explanation of enantioselective [3 + 2] dipolar cycloaddition
catalyzed by (R)-BNPPA (35a) to generate cis-3-pyrrolines in optically active form     50
Scheme 17.  Syntheses of new Schiff bases 30 from aldehydes 52 and amines 53     66

                                

(1) Tallarida, R. J. Genes Cancer. 2011, 3, 10031008.
(2) Foucquier, J.; Guedj, M. Pharma. Res. Per. 2015, 3, e00149.
(3) Chou, T.-C. Pharmacol Rev. 2006, 58, 621681.
(4) Bigioni, M.; Benzo, A.; Irrissuto, C.; Lopez, G.; Curatella, B.; Maggi, C. A. Cancer Chemother. Pharmacol. 2008, 62, 6219.
(5) Lenz, T. L.; Hilleman, D. E.; Ann. Pharmacother. 2000, 34, 12831290.
(6) Breeze, S. Expert Rev Clin. Pharmacol. 2012, 5, 613615.
(7) Liu, Y.; Hu, B.; Fu, C.; Chen, X. Bioinformatics. 2010, 26, 587588.
(8) Albers, G. W.; Amarenco, P. Stroke. 2001, 32, 29482949.
(9) Bezin, J.; Pariente, A.; Lassalle, R.; Dureau-Pournin, C.; Abouelfath, A.; Robinson, P. Eur. J. Clin. Pharmacol. 2014, 70, 429436.
(10) Singh, S.; Bouzinbi, N.; Chaturvedi, V.; Godreuil, S.; Kremer, L. Clin. Microbiol. Infect. 2014, 20, 11241127.
(11) Lee, H. Z.; Miller, B.W.; Kwitkowski, V. E.; Ricci, S.; DelValle, P.; Saber, H. Clin. Cancer Res. 2014, 20, 39023907.
(12) Patankar, N. A.; Pritchard, J.; van Grinsven, M.; Osooly, M.; Bally, M. B. Clin. Cancer Res. 2013, 19, 865877.
(13) Cavalli, A.; Bolognesi, M.L.; Minarini, A.; Rosini, M.; Tumiatti, V.; Recanatini, M.; Melchiorre, C. J. Med. Chem. 2008, 51, 347372.
(14) Bhosle, D.; Bharambe, S.; Gairola, N.; Dhaneshwar, S. S. Indian J. Pharm. Sci. 2006, 68, 286294.
(15) Baltzer, B.; Binderup, E.; Daehne, W. V.; Godtfredsen, W. O.; Kansen. K.; Nielsen, B.;
Sorensen. H.; Vangedal, S. J. Antibiot. 1980, 33, 11831192.
(16) Jones, R. N. Eur. J. Clin. Microbiol. Infect. Dis. 1990, 9, 4358.
(17) Svartz, N. Acta. Med. Scand. 1942, 110, 577598.
(18) Croft, D. N.; Cuddigan, J. H.; Sweetland, C. Br. Med. J. 1972, 3, 545547.
(19) Adnan, S.; Paterson, D. L.; Lipman, J.; Roberts, J. A. Int. J. Antimicrob. Ag. 2013, 42, 384389.
(20) Katselou, M.; Papoutsis, I.; Nikolaou, P.; Qammaz, S.; Spiliopoulou, C.; Athanaselis, S. Basic Clin. Pharmacol. Toxicol. 2016, 119, 133140.
(21) Gottesman, M. M. Annu. Rev. Med. 2002, 53, 615627.
(22) Foo, J.; Michor, F. PLoS Comput. Biol. 2009, 5, e1000557.
(23) Das, N.; Dhanawat, M.; Dash, B.; Nagarwal, R. C.; Shrivastava, S. K. Eur. J. Pharm. Sci. 2010, 41, 571588.
(24) Syed, Y. Y. Drugs. 2017, 13, 14731480.
(25) Mathew, P.; Tannir, N.; Tu, S. M.; Carter, C. M.; Bekele, N. B.; Pagliaro, L. Cancer Chemother. Pharmacol. 2010, 65, 811815.
(26) Dimopoulos, M.; Spencer, A.; Attal, M. N. Engl. J. Med. 2007, 357, 21232132.
(27) Richardson, P. G.; Weller, E.; Lonial, S.; Jakubowiak, A. J.; Jagannath, S.; Raje, N. S.; Avigan, D. E.; Xie, W.; Ghobrial, I. M.; Schlossman, R. L.; Mazumder, A.; Munshi, N. C.; Vesole, D. H.; Joyce, R.; Kaufman, J. L.; Doss, D.; Warren, D. L.; Lunde, L. E.; Kaster, S.; DeLaney, C.; Hideshima, T.; Mitsiades, C. S.; Knight, R.; Esseltine, D.-L.; Anderson, K.C. Blood. 2010, 116, 679686.
(28) Amraoui, K.; Belhadj, K.; Maître, B.; Jannière-Nartey, C.; Dupuis, J. Eur. Respir. J. 2013, 22, 9395.
(29) Richardson, P. G.; Mitsiades, C.; Hideshima, T.; Anderson, K. C. Exp. Rev. Anticancer Ther. 2006, 6, 11651173..
(30) Walz, S.; Weis, S.; Franz. M.; Rominger, F.; Trapp, O. Electrophoresis. 2015, 36, 796804.
(31) Szabó, Z.-I.; Foroughbakhshfasaei, M.; Gál, R.; Horváth, P.; Komjáti, B.; Noszál, B.; Tóth, G. J. Sep. Sci. 2018, 41, 1414-1423.
(32) Jacquesa, V.; Czarnika, A. W.; Judgeb, T. M.; Van der Ploega, L. H. T.; DeWitta, D. R. Proc. Natl. Acad. Sci. U S A. 2015, 112, e14711479.
(33) Wei, Y.; Pu, X.; and Zhao, L. Oncol. Rep. 2017, 37, 31593166.
(34) Meng, Z.; Lv, Q.; Lu, J.; Yao, H.; Lv, X.; Jiang, F.; Lu, A.; Zhang, G. Int. J. Mol. Sci. 2016, 17, 796.
(35) Marupudi, N. I.; Han, J. E.; Li, K. W.; Renard, V. M.; Tyler, B. M.; Brem, H. Expert Opin. Drug Saf. 2007, 6, 609621.
(36) Dugas, H.; Penney, C. In Bioorganic Chemistry, A Chemical Approach to Enzyme Action; Cantor, C. R., Eds.; SpringerVerlag: Berlin, 1981; p 36.
(37) Tietze, L. F. Chem. Rev. 1996, 96, 115136.
(38) Padwa, A. Chem. Soc. Rev. 2009, 38, 30723081.
(39) Ardkhean, R.; Caputo, D. F. J.; Morrow, S. M.; Shi, H.; Xiong, Y.; Anderson, E. A. Chem. Soc. Rev. 2016, 45, 15571569.
(40) Pellissier, H. Adv. Synth. Catal. 2012, 354, 237294.
(41) Enders, D.; Grondal, C.; Hüttl, M. R. M. Angew. Chem. Int. Ed. 2007, 46, 15701581.
(42) Grondal, C.; Jeanty, M.; Enders, D. Nat. Chem. 2010, 2, 167178.
(43) Nicolaou, K. C.; Chen, J. S. Chem. Soc. Rev. 2009, 38, 2993–3009.
(44) Hulme, C.; Gore, V. Curr. Med. Chem. 2003, 10, 5180.
(45) Halpern, J.; Trost, B. M. Proc. Natl. Acad. Sci. U. S. A. 2004, 101, 5347.
(46) Green, M. P.; Prodger, J. C.; Hayes, C. J. Tetrahedron Lett. 2002, 43, 66096611.
(47) Chogii, I.; Njardarson, J. T. Angew. Chem. Int. Ed. 2015, 54, 1370613710.
(48) Di Bussolo, V.; Frau, I.; Crotti, S.; Uccello-Barretta, G.; Balzano, F.; Pineschi, M.; Crotti, P. Org. Lett. 2013, 15, 60266029.
(49) Shi, F.; Xing, G.-J.; Tan, W.; Zhu, R.-Y.; Tu, S. Org. Biomol. Chem. 2013, 11, 14821489.
(50) Wang, Y.-X.; Mabic, S.; Castagnoli Jr, N. Bioorg. Med. Chem. 1998, 6, 143149.
(51) Lange, U. E. W.; Baucke, D.; Hornberger, W.; Mack, H.; Seitz, W.; Höffken, H. W. Bioorg. Med. Chem. Lett. 2006, 16, 26482653.
(52) Lee, Y.; Ling, K.-Q.; Lu, X.; Silverman, R. B.; Shepard, E. M.; Dooley, D. M.; Sayre, L. M. J. Am. Chem. Soc. 2002, 124, 1213512143.
(53) Mou, Q.-Y.; Chen, J.; Zhu, Y.-C.; Zhou, D.-H.; Chi, Z.-Q.; Long, Y.-Q. Bioorg. Med. Chem. Lett. 2002, 12, 22872290.
(54) Cox, C. D.; Breslin, M. J.; Whitman, D. B.; Coleman, P. J.; Garbaccio, R. M.; Fraley, M. E.; Zrada, M. M.; Buser, C. A.; Walsh, E. S.; Hamilton, K.; Lobell, R. B.; Tao, W.; Abrams, M. T.; South, V. J.; Huber, H. E.; Kohl, N. E.; Hartman, G. D. Bioorg. Med. Chem. Lett. 2007, 17, 26972702.
(55) Brichacek, M.; Njardarson, J. T. Org. Biomol. Chem. 2009, 7, 17611770.
(56) Kagoshima, H.; Akiyama, T. J. Am. Chem. Soc. 2000, 122, 1174111742.
(57) Sai, M.; Matsubara, S. Org. Lett. 2011, 13, 46764679.
(58) Zhu, X.-F.; Henry, C. E.; Kwon, O. Tetrahedron 2005, 61, 62766282.
(59) Li, G.-Y.; Chen, J.; Yu, W.-Y.; Hong, W.; Che, C.-M. Org. Lett. 2003, 5, 21532156.
(60) Zhang, D.-H.; Yao, L.-F.; Wei, Y.; Shi, M. Angew. Chem. Int. Ed. 2011, 50, 25832587.
(61) Ma, L.; Li, W.; Xi, H.; Bai, X.; Ma, E.; Yan, X.; Li, Z. Angew. Chem. Int. Ed. 2016, 55, 1041010413.
(62) Boeda, F., Clavier, H.; Jordaan, M.; Meyer, W. H.; Nolan, S. P. J. Org. Chem. 2008, 73, 259263.
(63) Wu, C.; Zhou, J. J. Am. Chem. Soc. 2014, 136, 650652.
(64) Bhunia, A.; Yetra, S. R.; Biju, A. T. Chem. Soc. Rev. 2012, 41, 31403152.
(65) E. Yoshikawa, K. V. Radhakrishnan and Y. Yamamoto, J. Am. Chem. Soc. 2000, 122, 72807286.
(66) Du, C.-J. F.; Hart, H.; Ng, K.-K. D. J. Org. Chem. 1986, 51, 31623165.
(67) Dubrovskiy, A. V.; Markina N. A.; Larock, R. C. Org. Biomol. Chem. 2013, 11, 191218.
(68) Henderson, J. L.; Edwards, A. S.; Greaney, M. F. J. Am. Chem. Soc. 2006, 128, 74267427.
(69) Yoshioka, E.; Kohtani, S.; Miyabe, H. Molecules 2014, 19, 863880.
(70) Shi, J.; Qiu, D.; Wang, J.; Xu, H.; Li, Y. J. Am. Chem. Soc. 2015, 137, 56705673.
(71) Castillo, J.-C.; Quiroga, J.; Abonia, R.; Rodriguez, J.; Coquerel, Y. Org. Lett. 2015, 17, 33743377.
(72) Qiu, D.; He, J.; Yue, X.; Shi, J.; Li, Y. Org. Lett. 2016, 18, 31303133.
(73) Hwu, J. R.; Hsu, Y. C. Chem. Eur. J. 2011, 17, 47274731.
(74) Hwu, J. R.; Chandrasekhar, D. B.; Hwang, K. C.; Lin, C.-C.; Horng, J.-C.; Shieh, F.-K. ChemistryOpen 2017, 6, 331335.
(75) Hsu, Y. C.; Hwu, J. R. Chem. Eur. J. 2012, 18, 76867690.
(76) Hwu, J. R.; Swain, S. P. Chem. Eur. J. 2013, 19, 65566560.
(77) Swain, S. P.; Shih, Y.-C.; Tsay, S.-C.; Jacob, J.; Lin, C.-C.; Hwang, K. C.; Horng, J.-C.; Hwu, J. R. Angew. Chem. Int. Ed. 2015, 54, 99269930.
(78) Tadross, P. M.; Stoltz, B. M. Chem. Rev. 2012, 112, 35503577 and reference there in.
(79) Ghan, L.; Just, G. Tetrahedron. 1990, 46, 151162.
(80) Pitsch, S.; Spinner, C.; Atsum, K.; Ermert, P. Chimia 1999, 53, 291294.
(81) Hwu, J. R.; Lin, Y. S.; Josephrajan, J; Hsu, M.-H.; Cheng, F.-Y.;Yeh, C,-S.; Su, W,-C.; Shieh, D.-B. J. Am. Chem. Soc. 2009, 131, 6668.

(82) Hakimelahi, G. H.; MoosaviMovahedi, A. A.; Sadeghi, M. M.; Tsay, S.-C.; Hwu, J. R. J. Med. Chem. 1995, 38, 46484659.
(83) Razzel, W. E.; Khorana, H. G. idbi, 1961, 236, 1144.
(84) Fettiplace, M, R.; Lis, K.; Ripper, R.; Kowal, K.; Pichurko, A.; Vitello, D.; Rubinstein, I.; Schwartz, D.; Akpa, B. S.; Weinberg, W. J. Control. Release 2015, 198, 6270.
(85) Shigematsu, M.; Kawamura, T.; Kirino, Y. Front. Genet. 2018, 9, 562.
(86) Shamis, M.; Lode, H, N,; Shabat, D. J. Am. Chem. Soc. 2004, 126, 17261731.
(87) Freimoser, F. M.; Jakob, C. A.; Aebi, M.; Tour, U. Appl. Environ. Microbiol. 1999, 65, 37273729.
(88) Gad, S. C.; Conroy, W. J.; McKelvey, J. A.; Turney, K. A. Drug Chem. Toxicol. 1978, 1, 339353.
(89) Husinec, S.; Savic, V. Tetrahedron: Asymmetry 2005, 16, 20472061.
(90) Hashimoto T.; Maruoka, K. Chem. Rev. 2015, 115, 53665412.
(91) Nájera, C.; Sansano, J. M. Angew. Chem. Int. Ed. 2005, 44, 62726276.
(92) Yu, S.-B.; Hua, X.-P.; Deng, J.; Wang, D.-Y.; Duan, Z.-C.; Zheng, Z. Tetrahedron: Asymmetry 2009, 16, 621625.
(93) Hong, L.; Sun, W.; Yang, D.; Li G.; Wang, R. Chem. Rev. 2016, 116, 40064123.
(94) Bohen, J. M.; Joullié, M. M.; Kaplan, F. A.; Love, B. J. Chem. Educ. 1973, 50, 367368.
(95) Peterson, E. A.; Dillon, B.; Raheem, I.; Richardson, P.; Richter, D.; Schmidte, R.; Sneddonf, H. F. Green Chem. 2014, 16, 40604075.
(96) Li, C.-J.; Trost, B. M. Proc. Natl. Acad. Sci. U. S. A. 2008, 105, 1319713202.
(97) Sheldon, R. A. Pure Appl. Chem. 2009, 72, 12331246.
(98) Hong, Y. J.; Tantillo, D. J. J. Am. Chem. Soc. 2015, 137, 41344140.
(99) Wang, Y.; Cai, P.-J.; Yu, Z.-X. J. Org. Chem. 2017, 82, 46044612.
(100) Ross, S. P.; Hoye, T. R. Nat. Chem. 2017, 9, 523530.
(101) Zhang, J.; Chen, Z.-X.; Du, T.; Li, B.; Gu, Y.; Tian, S.-K. Org. Lett. 2016, 18, 48724875.
(102) Xu, H.-D.; Cai, M.-Q.; He, W.-J.; Hu, W.-H.; Shen, M.-H. RSC Adv. 2014, 4, 76237626.
(103) Chen, J.; Palani, V.; Hoye. T. R. J. Am. Chem. Soc. 2016, 138, 43184321.
(104) GarcíaLópez, J.-A.; Greaney, M. F. Chem. Soc. Rev. 2016, 45, 67666798.
(105) Jayanth, T. T.; Cheng, C.-H. Chem. Commun. 2006, 894–896.
(106) Peng, X.; Ma, C.; Tung, C.-H.; Xu, Z. Org. Lett. 2016, 18, 4154−4157.
(107) Yao, T.; He, D. Org. Lett. 2017, 19, 842−845.
(108) Yang, W.-L.; Tang, F.-F.; He, F.-S.; Li, C.-Y.; Yu, X.; Deng, W.-P. Org. Lett. 2015, 17, 48224825.
(109) Cayuelas, A.; Ortiz, R.; Nájera, C.; Sansano, J. M.; Larrañaga, O.; de Cózar, A.; Cossío, F. P. Org. Lett. 2016, 18, 29262929.
(110) Wang, H.; Deng, Q.; Zhou, Z.; Hu, S.; Liu, Z.; Zhou, L.-Y. Org. Lett. 2016, 18, 404407.
(111) Poulsen, P. H.; Vergura, S.; Monleón, A.; Jørgensen, D. K. B.; Jørgensen, K. A. J. Am. Chem. Soc. 2016, 138, 64126415.
(112) Zhang, Z.; Sun, W.; Zhu, G.; Yang, J.; Zhang, M.; Hong, L.; Wang, R. Chem. Commun. 2016, 52, 13771380.
(113) Arpa, E. M.; González–Esguevillas, M.; Pascual-Escudero, A.; Adrio, J.; Carretero, J. C. J. Org. Chem. 2016, 81, 61286135.
(114) Shi, F.; Luo, S.-W.; Tao, Z.-L.; He, L.; Yu, J.; Tu, S.-J.; Gong, L.-Z. Org. Lett. 2011, 13, 46804683.
(115) Shi, F.; Xing, G.-J.; Tan, W.; Zhu, R.-Y.; Tu, S. Org. Biomol. Chem. 2013, 11, 14821489.
(116) Parmar, D.; Sugiono, E.; Raja, S.; Rueping, M. Chem. Rev., 2014, 114, 90479153.
(117) Akiyama, T.; Itoh, J.; Fuchibe, K. Adv. Synth. Catal. 2006, 348, 9991010.
(118) Cabrera, S.; Arrayás, R. G.; Carretero, J. C. J. Am. Chem. Soc. 2005, 127, 1639416395.
(119) Bohen, J. M.; Joullié, M. M.; Kaplan, F. A.; Love, B. J. Chem. Educ. 1973, 50, 367368.
(120) For compounds 30a, 30b, and 30c, see: Kumar, S.; Painter, T. O.; Pal, B. K.; Neuenswander, B.; Malinakova, H. C. ACS Comb. Sci. 2011, 13, 466477.
(121) Xu, J.-K.; Li, S.-J.; Wang, H.-Y.; Xu, W.-C. Tian, S.-K. Chem. Comm. 2017, 53, 17081711.
(122) Tambar, U. K.; Stoltz, B. M. J. Am. Chem. Soc. 2005, 127, 53405341.

簡易檢索 / 詳目顯示

相關論文