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研究生： 巴來吉
Dangeti Balaji Chandrasekhar
論文名稱： 利用「骨牌式反應」合成「吡喃-2-酮」、「α-胺基酸」、「脫氧醣」以及設計與製備具含生物活性之「奈米球」
Domino reactions in the Syntheses of Chroman-2-ones, α-Amino Acids, and Deoxy Sugars as well as Preparation of Nano-Bullets containing Biologically Active Compounds
指導教授： 胡紀如
Hwu, Jih-Ru
口試委員: 林俊成
Lin, Chun-Cheng
韓建中
Han, Chien-Chung
張家靖
Chia-Ching Chang
謝發坤
Shieh, Fa-Kuen
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： 2017
畢業學年度： 105
語文別： 英文
論文頁數： 265
中文關鍵詞： 利用「骨牌式反應」合成 、吡喃-2-酮 、α-胺基酸 、脫氧醣
外文關鍵詞： Domino reactions, chroman-2-one, 2-deoxy sugars, nano bullets
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    • 骨牌反應應用於合成苯并二氫吡喃、胺基酸及脫氧醣衍生物暨
    含生物活性分子之奈米藥用子彈
    摘要
    有機合成最重要的目標之一是將簡單之化合物組裝合成至較複雜之化合物。常用的步驟為一步接著一步完成目標分子內的鍵結；然而我們可以藉由在單一序列的反應上不純化分離中間物、添加反應物、改變反應條件來提升效率。骨牌反應為一個不錯的方法可以進行如此高效率的合成複雜化合物，藉由免除中間步驟之純化與分離步驟來達到大程度的減少操作時間與開銷。
    許多胺基苯并二氫吡喃和胺基二芳基丙胺酸化合物擁有生物活性。於此，一個新的骨牌反應方法應用於高效率合成這些衍生物。首先將各式各樣的酚、吖内酯及三氯化鋁在甲苯以動力學控制反應於攝氏八十度產生預期的胺基苯并二氫吡喃，產率為百分之六十五至九十。這個在同一個反應瓶內發生的連結反應包含傅里德-克拉夫茨反應及後續的轉酯反應。以其他路易士酸替換三氯化鋁會無法得到同樣的產物。接著，以小蘇打進行水解胺基苯并二氫吡喃於四氫呋喃與水的混合溶液來得到α-(N-苯甲酰)胺基酸。
    N端保護的α-胺基酸分子於蛋白質體學及合成化學領域上相當的有用，其上的羥基及羧基可以讓他們接上其他核酸、胺基酸和藥物分子。在接上之後，N端保護基可以去除以露出胺基。利用此特性，我們可以溫和的方式從苯并二氫吡喃來合成N端保護的α-胺基酸，隨後以鹽酸甲醇溶液去除保護基來得到對應的α-胺基酸；產率分布於百分之八十至八十八之間。在優化的條件下，α-N-苯甲酰及α-胺基酸上的α-碳並未出現差向異構的現象。這些發現提供了一個非常好的方法來進行高度立體專一性地合成3、4取代的苯并二氫吡喃及二芳基丙胺酸衍生物。
    脫氧醣為天然物中重要且豐富的的碳水化合物之一，其衍生物有相當多的生物功能，諸如抗生素及抗癌活性等等。在本研究中，我們以骨牌反應方法來將胺基醛醣及酮醣轉化成脫氧醣，其中在溫和反應中產生的苯炔來當作後續關鍵步驟的還原劑。胺基醛醣及酮醣與二硫化碳及乙酸酐反應而轉化成對應的1,3-噻唑啉-2-硫酮，其上面的羥基全部都帶有保護基。在關鍵的步驟中，這些噻唑啉-2-硫酮和2-(三甲基硅)苯基三氟甲烷磺酸鹽及氟化銫於乙腈溶劑內進行常溫反應生成非環狀的烯醇乙酸酯。烯醇乙酸和甲醇中的甲醇鈉進行皂化反應而在原位進一步發生分子內環化反應產生預期產物D-2-脫氧醣。在骨牌式還原去胺反應中的關鍵步驟中，1,3-噻唑啉-2-硫酮和苯炔之間發生[3+2]環加成反應之機構，接下來的偶極體進行逆[3+2]開環反應生成對應的烯醇乙酸酯。
    標靶藥物傳遞是一個輸送藥物分子的聰明的方法來提升藥物到達病灶的濃度。利用奈米科技來產生奈米結構當作傳輸載具可以解決這方面的問題。金奈米粒子提供了相當棒的奈米載具供作合成鷹架，因為金奈米多才多藝、良好的生物相容性以及低毒性。另外，光提供了外部的刺激來打斷可被光裂解的鍵結，這個反應可以應用於奈米載具的化學性應答。為了有選擇性的瞄準癌症，我們開發了可同時對抗癌症及DNA切割彈頭的奈米子彈。
    抗癌藥物接在可光解的連接分子上，並以共駕鍵結接著在金奈米粒子上。第二個連接分子帶有季銨鹽以離子鍵結抓取寡核苷酸並接著在金奈米粒子上。生成的奈米粒子都會經過後續分析，如紫外線光譜、電子顯微鏡、核磁共振光譜儀、紅外線光譜儀以及表面電位量測。初步的光啟動將金奈米粒子轉化為抗癌症藥物也已執行，光激發金奈米釋放藥物tegafur可以在紫外線光譜發現在272 nm有吸收波峰，而 tegafur的吸收最大波長274 nm。

    三個主題會在論文內詳細討論。第一，一個新的骨牌反應方法應用於高效率合成胺基苯并二氫吡喃和胺基二芳基丙胺酸。第二，有活性的苯炔在原位生成並形成去胺反應的還原劑，此方法已成功應用於從胺基醛醣及酮醣合成脫氧醣之關鍵步驟。最後，發展含有生物活性分子之奈米子彈可以解決在許多疾病中久而未決的藥物傳輸問題。

    Domino reactions in the Syntheses of Chroman-2-ones, α-Amino Acids, and Deoxy Sugars as well as Preparation of Nano-Bullets containing
    Biologically Active Compounds
    Dangeti Balaji Chandrasekhar
    Abstract
    One of the fundamental objectives of organic synthesis is the construction of complex molecules from simpler ones. The usual procedure for the synthesis of organic compounds is stepwise formation of the individual bonds within the target molecule. However, it would be much more efficient, if one can form several bonds in a single sequence without isolating the intermediates, changing the reaction conditions, or adding additional reagents. Domino reactions allow such highly efficient synthesis of complex organic compounds , as these processes take place without intermediate recovery steps, their use drastically reduces operating times and costs as well as the consumption of chemicals and use of energy.
    Many 3-aminochroman-2-ones and β,β-diarylalanines exhibit significant biological activities. A new domino method was thus developed for the syntheses of these compounds with high efficiency. First, treatment of various phenols with the Erlenmeyer–Plochl (Z)-azlactones and AlCl3 in toluene at 80 °C produced the desired cis-3-aminochroman-2-ones in 65–90% yields under kinetic control. This coupling reaction involved Friedel–Crafts alkylation followed by transesterification, which took place in a single-flask. The same products could not be obtained by the replacement of AlCl3 with protonic acid as the catalyst. Second, hydrolysis of 3-amino-4-arylchroman-2-ones by NaHCO3 in a mixture of THF and water gave α-(N-benzoyl) amino acids.
    The N-protected -amino acids area class of valuable compounds in proteomic and synthetic chemistry. The free hydroxyl and carboxyl groups therein allow them to be coupled with nucleic acids, various drugs, and other amino acids. Afterwards, the N-protected group can be removed to give free amines. On the basis of this advantage, it encouraged us to find mild conditions for the generation of N-protected -amino acids from chroman-2-ones. Deprotection of these isolated compounds with aqueous hydrogen chloride (12 N) and in methanol produced the corresponding free amino acids in 80–88% yields. Under these optimized conditions, epimerization did not occur at the α carbons of α-(N-benzoyl)- and free α-amino acids. These new findings provide a convenient avenue of producing 3,4-disubstituted choman-2-ones and β, β-diarylalanines derivatives with very high steroselectivity.
    Deoxy sugars constitute an important class of carbohydrates that occur widely in natural products, many of which exhibit antibiotics and anti-cancer activities as well as play versatile and essential biological roles. A domino method was developed by using benzyne, generated under mild condition, as a reducing agent in the key step to convert amino sugars and ketoses to deoxy sugars. By reacting with CS2 and then acetic anhydride, amino sugars and ketoses can be readily converted to the corresponding 1,3-thiazolidine-2-thiones with all hydroxyl groups therein protected. In the key step, these thiazolidine-2-thiones were treated with 2-trimethylsilylphenyl triflate (2.0 equiv) and CsF (3.0 equiv) in acetonitrile at room temperature to produce acyclic enol acetates in good yields (51–63%). Saponification of enol acetates with NaOMe in MeOH followed by intramolecular cyclization in situ gave the desired targets D-2-deoxy-sugars. The key step in the domino reductive deamination involved a mechanism of [3+2] cycloaddition between benzyne and 1,3-thiazolidine-2-thione, followed by retro [3+2] ring opening of the resultant ylide to afford the corresponding enol acetate.
    Targeted drug delivery is a smart method to deliver therapeutics in such a way to increase the concentration of the drug specifically only in some portions of the body. The fundamental challenge in targeted drug delivery can be addressed with nanotechnology using nanostructures as delivery vehicles (nanocarriers). Gold nanoparticles (Au NPs) provide an attractive synthetic scaffold for the creation of nanocarriers due to their functional versatility, better biocompatibility, and low toxicity. Furthermore, light provide a highly orthogonal external stimulus and used to break photo-cleavable bonds to produce chemical responses from nanocarriers. For the selective targeting of cancer, we developed nano-bullets capable of holding both an anticancer drug and DNA cleaving warhead with an oligonucleotide on a gold nanoparticle.
    The anticancer drug was attached to a photo cleavable linker and hooked to gold nanoparticle through a covalent bond. A second linker having tetrammonium salt for holding the oligonucleotide through ionic bond was prepared and attached to the gold nanoparticle. The nano particle prepared were well characterized by using UV, TEM, 1H-NMR, IR and zeta potential. Preliminary assessment of the light-triggered conversion of Au-NPs to anticancer drug was performed, Au-NPs with drug were displayed photoliberation to tegafur by observing a peak at 272 nm which is consistent with the UV absorption of tegafur at 274 nm.
    Three major issues discussed in this dissertation, first, a new domino method was developed for the syntheses of 3-aminochroman-2-ones and β,β-diarylalanines with high efficiency. Second, active benzyne generated in situ was developed as a reducing reagent for deamination. This method was applied successfully as the key step in the synthesis of deoxy sugars in an optically active form from 2-amino sugars and 2-ketoses. Alternatively, the development of nano-bullets containing biologically active compounds can efficiently resolve the long-lasting drug delivery problems in tackling various diseases. In addition, the conjugation of gold nanoparticles with oligonucleotide containing warhead groups are currently ongoing and the results will be reported in the near future.

    ACKNOWLEDGEMENTS There are many people to thank. All of whom have made this possible. First and foremost, I would like to thank Prof. Jih Ru Hwu for granting me the opportunity to pursue my Ph.D. work in his lab without a moment’s hesitation, and for that I am eternally grateful. I am thankful for his patience and respect for my academic growth. He promotes the exchange of ideas without fear of judgment. Various discussions have cultivated in me a sense of independent thinking towards research. His drive for understanding chemical problems and discovering novel chemistry imparted on me a desire to understand, analyze, and circumvent multiple synthetic difficulties which I encountered during my graduate studies. Working in the Prof. Hwu’s laboratory has been a real treat. I credit a great group of people for maintaining an entertaining and hardworking environment. Past and present members include: Dr. V. Raju, Dr. S. Y. Lin, Dr. Yung, Dr. S. Babu, Dr. Tapan, Dr. Mohit, Huang, Nitesh, Avijit, Animesh, Chuang, Shih, Yang, Tsai, Wang, Chan, Chou, Watson, Uttam, Bohara, and Kumar. My Special thanks to Dr. Ravi, Dr. Poliraju, Naresh, Karthik, Kalyan, Chandu, and Chiru. My sincere thanks to Prof. Dar Bin Shieh and his student Li Xing Yang from National Cheng Kung University, Tainan, for their help in cytotoxic determination assays for newly fabricated gold nanoparticles. I warmly acknowledge Alankara Rao sir and Dr. Saravanan for their moral support. I want to thank all my friends from India: Sivaramakrishna, Dr. Pavan, Dr. Sudhakar, Sai, Murali, Kishore, Kasi, Ravi, Krishna Mohan, Ugandhar, Suresh, and Mehar for their boundless friendship. Finally last but not least, I want to thank my family for their encouragement, support, and love bestowed upon me throughout my life. Words alone cannot even begin to describe how grateful I am to have such wonderful parents, father D. Suryanarayana Murthy and my mother Manga Devi. They have always done everything in their power and made selfless sacrifices to help me achieve my goals. They allowed me to make my own decisions and always trusted that I’d make the best choice. I owe my deepest gratitude towards my first sister and brother-in-law, Anantha Lakshmi (baby) and V. Trinadh Rao, second elder sister and brother-in-law, Jyothi and R. Srinivas their infallible love and support has always been my strength. Without their help, I would not have been able to complete much of what I have done and become who I am. I am so blessed to have wonderful in-laws. I have been fortunate to be marrying into such a great family. I really appreciate all of the time, energy, and love that they put into supporting and believing in me over the last five years. Most importantly, my wife Archana has been by my side for the last six years of my graduate career, and I could not have gotten through this challenging process without her love and unwavering support. She has a remarkable way of remaining patient when the hours were long and the days were worse. This dissertation never would have been possible without them. It is to them, I dedicate my scientific work. Thank you one and all. Content Abstract (in English)………………………………………………………………… i Abstract (in Chinese)………………………………………………………………. iv Acknowledgement ………………………………………………………………… vii Content ……………………………………………………………………………. viii List of Figures ……………………………………………………………………. xxix List of Tables …………………………………………………………………... …xxx List of Schemes …………………………………………………………………….xxxi 1. Introduction ………………………………………………………....................... 1 Part I. Synthesis of chroman-2-ones and -amino acids through a domino process………………………………………....................... 1 Part II. Benzyne-induced domino process and synthesis of 2-deoxy sugars by deamination reaction………………....................... 22 Part III. Preparation of Nano-Bullets containing Biologically Active Compounds………………………………………...................... 34 2. Results …………………………………………………………………………….. 40 2.1 Synthesis of chroman-2-ones ……………………………………………... 40 2.2 Synthesis of -disubstituted arylalanines and N-protected derivatives…………… ………………………………..... 48 2.3 Synthesis of Deoxy Sugars from Amino Sugars and Ketons……………..53 2.4 Synthesis of Nano-Bullets ……………………………………………….. 59 3. Discussion ………………………………………………………………………. 64 4. Conclusion ……………………………………………………………………… 69 5. Experimental …………………………………………………………………… 71 Standard Procedure 1 for the Syntheses of chroman-2-one Derivatives …..... 72 cis-4-Phenyl-3-(N-benzoylamino)chroman-2-one (217)………………………73 cis-6-Methyl-4-phenyl-3-(N-benzoylamino)chroman-2-one (218)…………….74 cis-7-Methyl-4-phenyl-3-(N-benzoylamino)chroman-2-one (219)……………..75 cis-5,7-dimethyl-4-phenyl-3-(N-benzoylamino)chroman-2-one (220)…………76 cis-6-tert-Butyl-4-phenyl-3-(N-benzoylamino)chroman-2-one (221)………….76 cis-6-Methoxy-4-phenyl-3-(N-benzoylamino)chroman-2-one (222)……………77 cis-6-Methoxy-4-(4′-methylphenyl)-3-(N-benzoylamino)chroman-2-one (223)..78 cis-6-Methoxy-4-(2′-methoxyphenyl)-3-(N-benzoylamino)chroman-2-one (224)..79 cis-6-Methoxy-4-(3′-methoxyphenyl)-3-(N-benzoylamino)chroman-2-one (225)..80 cis-6-Methoxy-4-(4′-methoxyphenyl)-3-(N-benzoylamino)chroman-2-one (226)..81 cis-6-Methoxy-4-(3′,2′-dimethoxyphenyl)-3-(N-benzoylamino)chroman-2-one (227)..82 cis-6-Methoxy-4-(4′-fluorophenyl)-3-(N-benzoylamino)chroman-2-one (228)……83 cis-6-Methoxy-4-methyl-3-(N-benzoylamino)chroman-2-one (229)………………84 cis-6-Methoxy-4-ethyl-3-(N-benzoylamino)chroman-2-one (230)…………….84 cis-6-Methoxy-4-isobutyl-3-(N-benzoylamino)chroman-2-one (231)…………85 cis-6,7-Methylenedioxy-4-phenyl-3-(N-benzoylamino)chroman-2-one (232)….86 cis-6-Iodo-4-phenyl-3-(N-benzoylamino)chroman-2-one (233)…………………87 cis-1-Phenyl-2-(N-benzoylamino)-3H-benzo[f]chromen-3-one (234)…………..88 cis-2-(N-benzoylamino)-3-(2-hydroxy-3,5-dimethylphenyl)-3-phenyl-propionic acid (237)……………………………………………………………………………..89 cis-2-(N-benzoylamino)-3-(2-hydroxy-5-methoxyphenyl)-3-phenyl-propionic acid (238)……………………………………………………………………………..90 cis-2-(N-benzoylamino)-3-(2-hydroxy-5-methoxyphenyl)-3-(4-fluorophenyl)-propionic acid (239)………………………………………………………………………..91 cis-2-(N-benzoylamino)-3-(2-hydroxy-5-methoxyphenyl)-pentanoic acid (240)..91 cis-2-(N-benzoylamino)-3-(2-hydroxy-5-methoxyphenyl)-4-methyl-pentanoic acid (241)……………………………………………………………………………..92 cis-2-(N-benzoylamino)-3-(2-hydroxy-4,5-methylenedioxyphenyl)-3-phenyl-propionic acid (242)…………………………………………………………………………93 cis-2-amino-3-(2-hydroxy-3,5-dimethylphenyl)-3-phenyl-propionic acid (243)…94 cis-2-amino-3-(2-hydroxy-5-methoxyphenyl)-3-phenyl-propionic acid (244)……95 cis-2-amino-3-(2-hydroxy-5-methoxyphenyl)-3-(4-fluorophenyl)-propionic acid (245)………………………………………………………………………………95 cis-2-amino-3-(2-hydroxy-5-methoxyphenyl)-pentanoic acid (246)……………..97 cis-2-amino-3-(2-hydroxy-5-methoxyphenyl)-5-methyl-hexanoic acid (247)…….97 cis-2-amino-3-(2-hydroxy-4,5-methylenedioxyphenyl)-3-phenyl-propionic acid (248)……………………………………………………………………………….98 Standard Procedure 1 for the Reduction of Schiff Bases………………………….98 Standard Procedure 2 for the Selective C(1)-O-Deacetylation…………………….99 Standard Procedure 3 for Syntheses of 4-Substituted 5-(Acetoxy)thiazolidine-2 -thiones……………………………………………………………………………..99 Standard Procedure 4 for the Hynes Rearrangement………………………………99 Standard Procedure 5 for Syntheses of Enol Acetates…………………………….100 Standard Procedure 6 for Syntheses of 2-Deoxy Sugars………………………… 100 2-Deoxy-2-benzylideneamino-1,3,4,6-tetra-O-acetyl-β-D-galactopyranose (250b)..100 2-Deoxy-2-benzylamino-1,3,4,6-tetra-O-acetyl-β-D-galactopyranose (251a)…….101 2-Deoxy-2-benzylamino-3,4,6-tri-O-acetyl-D-galactopyranose (251)……………..101 5-(R&S)-Acetoxy-4-(1,2,3,4-tetra-O-acetyl-D-lyxo-tetritol-1-yl)-3-benzylthiazolidine-2-thione (252)…………………………………………………………………………102 (E)-1,3,4,5,6-Penta-O-acetyl-2-deoxy-D-lyxo-hex-1-en (253)……………………..103 (+)-2-Deoxy-D-Galactose (254)…………………………………………………….104 3,4,6-Tri-O-benzyl-1-tert-butyldimethylsilyl-2-deoxy-2-(p-methoxybenzyl)amino-D-glucopyranoside (256b)…………………………………………………………….104 3,4,6-Tri-O-benzyl-2-(p-methoxybenzyl)amino-2-deoxy-D-glucosamine (256)…..105 5-(R&S)-Acetoxy-4-(1,2,4-tri-O-benzyl-3-O-acetyl-D-arabino-tetritol-1-yl)-3-benzylthiazolidine-2-thione (257)………………………………………………….106 (E)-1,5-Di-O-acetyl-3,4,6-(tri-O-benzyl-2-deoxy-D-arabino)hex-1-en (258)……..107 (+)-2-Deoxy-D-Glucose (259)……………………………………………………..108 1,3-Di-O-acetyl-4,6-O-benzylidene-2-benzylamino-2-deoxy-β-D-glucopyranoside (260b)………………………………………………………………………………108 4,6-O-Benzylidene-2-benzylamino-2-deoxy-β-D-glucopyranose (260)…………..109 5-(R&S)-Acetoxy-4-(1,3-di-O-acetyl-2,4-O-benzylidene-D-arabino-tetritol-1-yl)-3- benzylthiazolidine-2-thione (261)…………………………………………………109 (E)-1,3,5-Tri-O-acetyl-4,6-O-benzylidene-2-deoxy-D-arabino-hex-1-en (262)….110 2,6-Dideoxy-1,3,4-tri-O-acetyl-2-benzylideneamino-D-glucopyranoside (264b)..112 2,6-Dideoxy-1,3,4-tri-O-acetyl-2-benzylamino-D-glucopyranoside (264c)………113 2,6-Dideoxy-3,4-di-O-acetyl-2-benzylamino-D-glucopyranose (264)……………114 5-(R&S)-Acetoxy-4-(1,2,3,-tri-O-acety-4-deoxyl-D-arabino-tetritol-1-yl)-3-benzylthiazolidine-2-thione (265)…………………………………………………114 (E)-1,3,4,5,-Tetra-O-acetyl-6,2-dideoxy-D-arabino-hex-1-en (266)……………..115 (+)-Olivose (267)………………………………………………………………….116 2,6-Dideoxy-1,3,4-tri-O-acetyl-2-(p-methoxybenzylidene)amino-D-galactopyranoside (269b)……………………………………………………………………………….117 2,6-Dideoxy-1,3,4-tri-O-acetyl-2-(p-methoxybenzyl)amino-D- galactopyranose (269c)……………………………………………………………..118 2,6-Dideoxy-3,4-di-O-acetyl-2-(p-methoxybenzyl)amino-D-galactopyranose (269)………………………………………………………………………………...118 5-(R&S)-Acetoxy-4-(1,2,3,-tri-O-acety-4-deoxyl-D-lyxo-tetritol-1-yl)-3-benzylthiazolidine-2-thione (270)…………………………………………………119 (E)-1,3,4,5,-Tetra-O-acetyl-6,2-dideoxy-D-lyxo-hex-1-en (271)………………….120 (+)-Oliose (272)…………………………………………………………………….121 5-(R&S)-Acetoxy-4-(1,2,3,4-tetra-O-acetyl-D-arabino-tetritol-1-yl)-3-benzylthiazolidine-2-thione (276)……………………………………………………………………….121 (E)-1,3,4,5,6-Penta-O-acetyl-2-deoxy-D-arabino-hex-1-en (277)………………….122 2-Benzylamino-2-deoxy-D-gulosamine (279)………………………………………123 5-(R&S)-Acetoxy-4-(1,2,3,4-tetra-O-acetyl-L-xylo-tetritol-1-yl)-3-benzylthiazolidine-2-thione (280)………………………………………………………………………….123 (E)-1,3,4,5,6-Penta-O-acetyl-2-deoxy-L-xylo-hex-1-en (281)………………………124 α-D-Glucopyranosyl-(1→6)-N-benzyl-D-glucosamine (284)………………………125 5-(R&S)-Acetoxy-4-[1,2,3-tri-O-acetyl-4-O-(2',3',4',6'-tetra-O-acetyl-α-D-glucopyranosyl)-D-arabino-tetritol-1-yl]-N-benzyl-1,3-thiazolidine-2-thione (285)..125 (–)-(2'S,3'S,4'S)-2,3,4,6-Tetra-O-acetyl-1-O-(2',3',4',6'-tetraacetoxy-5'-trans-hexen-1-yl)--D-glucopyranoside (286)………………………………………………………..127 5-(R&S)-Acetoxy-4-[1,3,4-tri-O-acetyl-2-O-(2',3',4',6'-tetra-O-acetyl-β-D-galactopyranosyl)-D-arabino-tetritol-1-yl]-N-benzyl-1,3-thiazolidine-2- thione (290)………………………………………………………………………127 (–)-(2'S,3'S,4'S)-2,3,4,6-Tetra-O-acetyl-3'-O-(1',2',4',6'-tetraacetoxy-5'-trans-hexen-1-yl)-β-D-galactopyranoside (291)…………………………………………………….129 (+)-2-deoxy-lactose (292)………………………………………………………..130 11-(4-Methoxytriphenyl)methylsulfanyl-1-O-methanesulfonyl-3,6,9- trioxaundecane (297)…………………………………………………………….130 11-(4-Methoxytriphenyl)methylsulfanyl-3,6,9-trioxaundecan-1-N,N,N-trimethylammonium sulfonate (298)…………………………………………….131 11-Mercapto-3,6,9-trioxaundecan-1-N,N,N-trimethylammonium sulfonate (300)…131 11-(4-Methoxytriphenyl)methylsulfanyl-1-N,N-dimethyl-3,6,9-trioxaundecan (299)…132 5-Fluoro-1-N-(4-hydroxymethyl-2-nitrobenzyl)-3-N-(2-tetrahydrofuryl)uracil (303)..133 5-Fluoro-1-N-(4-chloromethyl-2-nitrobenzyl)-3-N-(2-tetrahydrofuryl)uracil (304)….134 5-Fluoro-1-N-(4-[11-(4-methoxytriphenyl)methylsulfanyl-1-N,N-dimethylammoniumchloride-3,6,9-trioxaundecan]-methyl-2-nitrobenzyl)-3-N-(2-tetrahydrofuryl)uracil (305)……………………………………………………………..135 5-Fluoro-1-N-(4-[11marcapto-1-N,N-dimethylammoniumchloride-3,6,9-trioxaundecan]-methyl-2-nitrobenzyl)-3-N-(2-tetrahydrofuryl)uracil (306)…..136 Au-Nanoparticles Containing Dummy Ligand (307)……………………………138 Au-Nanoparticles Containing Drug Ligand (308)………………………………138 Au-Nanoparticles Containing Drug (306) + Dummy (300) (1:5) Ligands (309)..138 Au-Nanoparticles Containing Drug (306) + Dummy (300) (1:10) Ligands (310)..139 Au-Nanoparticles Containing Drug (306) + Dummy (300) (1:20) Ligands (311)..139 6. References …………………………………………………………………...... 144 7. Spectra ………………………………………………………………………… 154 1H NMR Spectrum of cis-4-Phenyl-3-(N-benzoylamino)chroman-2-one (217)…………………………………………………………………………………155 13C NMR Spectrum of cis-4-Phenyl-3-(N-benzoylamino)chroman-2-one (217)…………………………………………………………………………………155 1H NMR Spectrum of cis-6-Methyl-4-phenyl-3-(N-benzoylamino)chroman-2-one (218)…………………………………………………………………………………157 13C NMR Spectrum of cis-6-Methyl-4-phenyl-3-(N-benzoylamino)chroman-2-one (218)…………………………………………………………………………………157 1H NMR Spectrum of cis-7-Methyl-4-phenyl-3-(N-benzoylamino)chroman-2-one (219)………………………………………………………………………………....159 13C NMR Spectrum of cis-7-Methyl-4-phenyl-3-(N-benzoylamino)chroman-2-one (219)…………………………………………………………………………………159 1H NMR Spectrum of cis-5,7-dimethyl-4-phenyl-3-(N-benzoylamino)chroman-2-one (220)…………………………………………………………………………………161 13C NMR Spectrum of cis-5,7-dimethyl-4-phenyl-3-(N-benzoylamino)chroman-2-one (220)……………………………………………………………………………..….161 1H NMR Spectrum of cis-6-tert-Butyl-4-phenyl-3-(N-benzoylamino)chroman-2-one (221)…………………………………………………………………………………163 13C NMR Spectrum of cis-6-tert-Butyl-4-phenyl-3-(N-benzoylamino)chroman-2-one (221)…………………………………………………………………………………163 1H NMR Spectrum of cis-6-Methoxy-4-phenyl-3-(N-benzoylamino)chroman-2-one (222)…………………………………………………………………………………165 13C NMR Spectrum of cis-6-Methoxy-4-phenyl-3-(N-benzoylamino)chroman-2-one (222)…………………………………………………………………………………165 1H NMR Spectrum of cis-6-Methoxy-4-(4′-methylphenyl)-3-(N-benzoylamino)chroman-2-one (223)……………………………..………………….167 13C NMR Spectrum of cis-6-Methoxy-4-(4′-methylphenyl)-3-(N-benzoylamino)chroman-2-one (223)……………………………..………………….167 1H NMR Spectrum of cis-6-Methoxy-4-(2′-methoxyphenyl)-3-(N-benzoylamino)chroman-2-one (224)……………………………..…………………169 13C NMR Spectrum of cis-6-Methoxy-4-(2′-methoxyphenyl)-3-(N-benzoylamino)chroman-2-one (224)…………………………………..……………169 1H NMR Spectrum of cis-6-Methoxy-4-(3′-methoxyphenyl)-3-(N-benzoylamino)chroman-2-one (225)..........................................................................171 13C NMR Spectrum of cis-6-Methoxy-4-(3′-methoxyphenyl)-3-(N-benzoylamino)chroman-2-one (225)……………………………..………………….171 1H NMR Spectrum of cis-6-Methoxy-4-(4′-methoxyphenyl)-3-(N-benzoylamino)chroman-2-one (226)…………………………………………….......173 13C NMR Spectrum of cis-6-Methoxy-4-(4′-methoxyphenyl)-3-(N-benzoylamino)chroman-2-one (226)…………………………………………...……173 1H NMR Spectrum of cis-6-Methoxy-4-(3′,2′-dimethoxyphenyl)-3-(N-benzoylamino)chroman-2-one (227).…………………………………………….…175 13C NMR Spectrum of cis-6-Methoxy-4-(3′,2′-dimethoxyphenyl)-3-(N-benzoylamino)chroman-2-one (227).………………………………………..………175 1H NMR Spectrum of cis-6-Methoxy-4-(4′-fluorophenyl)-3-(N-benzoylamino)chroman-2-one (228)……………………………………………..….177 13C NMR Spectrum of cis-6-Methoxy-4-(4′-fluorophenyl)-3-(N-benzoylamino)chroman-2-one (228) ………………………………………….…….177 1H NMR Spectrum of cis-6-Methoxy-4-methyl-3-(N-benzoylamino)chroman-2-one (229) ………………………………………………………………………………...179 13C NMR Spectrum of cis-6-Methoxy-4-methyl-3-(N-benzoylamino)chroman-2-one (229) ………………………………………………………………………………...179 1H NMR Spectrum of cis-6-Methoxy-4-ethyl-3-(N-benzoylamino)chroman-2-one (230) ………………………………………………………………………………...181 13C NMR Spectrum of cis-6-Methoxy-4-ethyl-3-(N-benzoylamino)chroman-2-one (230) ………………………………………………………………..……………….181 1H NMR Spectrum of cis-6-Methoxy-4-isobutyl-3-(N-benzoylamino)chroman-2-one (231) ………………………………………………………………..……………….183 13C NMR Spectrum of cis-6-Methoxy-4-isobutyl-3-(N-benzoylamino)chroman-2-one (231) ……………………………………………………………………………..….183 1H NMR Spectrum of cis-6,7-Methylenedioxy-4-phenyl-3-(N-benzoylamino)chroman-2-one (232) ………………………………………………………………………….185 13C NMR Spectrum of cis-6,7-Methylenedioxy-4-phenyl-3-(N-benzoylamino)chroman-2-one (232) …………………………………….………….185 1H NMR Spectrum of cis-6-Iodo-4-phenyl-3-(N-benzoylamino)chroman-2-one (233) ……………………………………………………………………………………….187 13C NMR Spectrum of cis-6-Iodo-4-phenyl-3-(N-benzoylamino)chroman-2-one (233) ……………………………………………………………………………………….187 1H NMR Spectrum of cis-1-Phenyl-2-(N-benzoylamino)-3H-benzo[f]chromen-3-one (234) …………………………………………………………………...……………189 13C NMR Spectrum of cis-1-Phenyl-2-(N-benzoylamino)-3H-benzo[f]chromen-3-one (234) …………………………………………………………………...……………189 1H NMR Spectrum of cis-2-(N-benzoylamino)-3-(2-hydroxy-3,5-dimethylphenyl)-3-phenyl-propionic acid (237)…………………………………………………….……191 13C NMR Spectrum of cis-2-(N-benzoylamino)-3-(2-hydroxy-3,5-dimethylphenyl)-3-phenyl-propionic acid (237)………………………………………………….………191 1H NMR Spectrum of cis-2-(N-benzoylamino)-3-(2-hydroxy-5-methoxyphenyl)-3-phenyl-propionic acid (238) ……………………………………………..…………193 13C NMR Spectrum of cis-2-(N-benzoylamino)-3-(2-hydroxy-5-methoxyphenyl)-3-phenyl-propionic acid (238) …………………………………………………………193 1H NMR Spectrum of cis-2-(N-benzoylamino)-3-(2-hydroxy-5-methoxyphenyl)-3-(4-fluorophenyl)-propionic acid (239)………………………………………………….195 13C NMR Spectrum of cis-2-(N-benzoylamino)-3-(2-hydroxy-5-methoxyphenyl)-3-(4-fluorophenyl)-propionic acid (239) ……………………………………………….…195 1H NMR Spectrum of cis-2-(N-benzoylamino)-3-(2-hydroxy-5-methoxyphenyl)-pentanoic acid (240)………………………………………………………….………197 13C NMR Spectrum of cis-2-(N-benzoylamino)-3-(2-hydroxy-5-methoxyphenyl)-pentanoic acid (240)……………………………………………………………….…197 1H NMR Spectrum of cis-2-(N-benzoylamino)-3-(2-hydroxy-5-methoxyphenyl)-4-methyl-pentanoic acid (241)…………………………………………………………199 13C NMR Spectrum of cis-2-(N-benzoylamino)-3-(2-hydroxy-5-methoxyphenyl)-4-methyl-pentanoic acid (241)…………………………………………………………199 1H NMR Spectrum of cis-2-(N-benzoylamino)-3-(2-hydroxy-4,5-methylenedioxyphenyl)-3-phenyl-propionic acid (242)………………………….…201 13C NMR Spectrum of cis-2-(N-benzoylamino)-3-(2-hydroxy-4,5-methylenedioxyphenyl)-3-phenyl-propionic acid (242)………………………….…201 1H NMR Spectrum of cis-2-amino-3-(2-hydroxy-3,5-dimethylphenyl)-3-phenyl-propionic acid (243)………………………………………………………………….203 13C NMR Spectrum of cis-2-amino-3-(2-hydroxy-3,5-dimethylphenyl)-3-phenyl-propionic acid (243) …………………………………………………………………203 1H NMR Spectrum of cis-2-amino-3-(2-hydroxy-5-methoxyphenyl)-3-phenyl-propionic acid (244) …………………………………………………………………205 13C NMR Spectrum of cis-2-amino-3-(2-hydroxy-5-methoxyphenyl)-3-phenyl-propionic acid (244) …………………………………………………………………205 1H NMR Spectrum of cis-2-amino-3-(2-hydroxy-5-methoxyphenyl)-3-(4-fluorophenyl)-propionic acid (245)………………………………………………….207 13C NMR Spectrum of cis-2-amino-3-(2-hydroxy-5-methoxyphenyl)-3-(4-fluorophenyl)-propionic acid (245)………………………………………………….207 1H NMR Spectrum of cis-2-amino-3-(2-hydroxy-5-methoxyphenyl)-pentanoic acid (246)………………………………………………………………………………....209 13C NMR Spectrum of cis-2-amino-3-(2-hydroxy-5-methoxyphenyl)-pentanoic acid (246)………………………………………………………………………………....209 1H NMR Spectrum of cis-2-amino-3-(2-hydroxy-5-methoxyphenyl)-5-methyl-hexanoic acid (247)…………………………………………………………………..211 13C NMR Spectrum of cis-2-amino-3-(2-hydroxy-5-methoxyphenyl)-5-methyl-hexanoic acid (247)…………………………………………………………..………211 1H NMR Spectrum of cis-2-amino-3-(2-hydroxy-4,5-methylenedioxyphenyl)-3-phenyl-propionic acid (248)………………………………………………………….213 13C NMR Spectrum of cis-2-amino-3-(2-hydroxy-4,5-methylenedioxyphenyl)-3-phenyl-propionic acid (248)………………………………………………………….213 1H NMR Spectrum of 2-Deoxy-2-benzylideneamino-1,3,4,6-tetra-O-acetyl-β-D-galactopyranose (250b)…………………………………………………………...…214 13C NMR Spectrum of 2-Deoxy-2-benzylideneamino-1,3,4,6-tetra-O-acetyl-β-D-galactopyranose (250b)………………………………………………………….…..214 1H NMR Spectrum of 2-Deoxy-2-benzylamino-1,3,4,6-tetra-O-acetyl-β-D-galactopyranose (251a)…………………………………………………...…………215 13C NMR Spectrum of 2-Deoxy-2-benzylamino-1,3,4,6-tetra-O-acetyl-β-D-galactopyranose (251a)………………………………………………………..……215 1H NMR Spectrum of 5-(R&S)-Acetoxy-4-(1,2,3,4-tetra-O-acetyl-D-lyxo-tetritol-1-yl)-3-benzylthiazolidine-2-thione (252)…………………………………………………216 13C NMR Spectrum of 5-(R&S)-Acetoxy-4-(1,2,3,4-tetra-O-acetyl-D-lyxo-tetritol-1-yl)-3-benzylthiazolidine-2-thione (252)……………………………………………..216 1H NMR Spectrum of (E)-1,3,4,5,6-Penta-O-acetyl-2-deoxy-D-lyxo-hex-1-en (253)…………………………………………………………………………………217 13C NMR Spectrum of (E)-1,3,4,5,6-Penta-O-acetyl-2-deoxy-D-lyxo-hex-1-en (253)…………………………………………………………………………………217 1H NMR Spectrum of 3,4,6-Tri-O-benzyl-2-(p-methoxybenzyl)amino-2-deoxy-D-glucosamine (256)…………………………………………………………………...218 13C NMR Spectrum of 3,4,6-Tri-O-benzyl-2-(p-methoxybenzyl)amino-2-deoxy-D-glucosamine (256)…………………………………………………………………...218 1H NMR Spectrum of 5-(R&S)-Acetoxy-4-(1,2,4-tri-O-benzyl-3-O-acetyl-D-arabino-tetritol-1-yl)-3-benzylthiazolidine-2-thione (257)………………………………………………………………………………..219 13C NMR Spectrum of 5-(R&S)-Acetoxy-4-(1,2,4-tri-O-benzyl-3-O-acetyl-D-arabino-tetritol-1-yl)-3-benzylthiazolidine-2-thione (257)………………………………………………………………..……………….219 1H NMR Spectrum of (E)-1,5-Di-O-acetyl-3,4,6-(tri-O-benzyl-2-deoxy-D-arabino)hex-1-en (258)……………………………………………………..………220 13C NMR Spectrum of (E)-1,5-Di-O-acetyl-3,4,6-(tri-O-benzyl-2-deoxy-D-arabino)hex-1-en (258)…………………………………………………….……….220 1H NMR Spectrum of 1,3-Di-O-acetyl-4,6-O-benzylidene-2-benzylamino-2-deoxy-β-D-glucopyranoside (260b)……………………………………………………….….221 13C NMR Spectrum of 1,3-Di-O-acetyl-4,6-O-benzylidene-2-benzylamino-2-deoxy-β-D-glucopyranoside (260b)………………………………………………………..….221 1H NMR Spectrum of 5-(R&S)-Acetoxy-4-(1,3-di-O-acetyl-2,4-O-benzylidene-D-arabino-tetritol-1-yl)-3- benzylthiazolidine-2-thione (261)……………………..…..222 13C NMR Spectrum of 5-(R&S)-Acetoxy-4-(1,3-di-O-acetyl-2,4-O-benzylidene-D-arabino-tetritol-1-yl)-3- benzylthiazolidine-2-thione (261)…………………………222 1H NMR Spectrum of (E)-1,3,5-Tri-O-acetyl-4,6-O-benzylidene-2-deoxy-D-arabino-hex-1-en (262)…………………………………………………………………….…223 13C NMR Spectrum of (E)-1,3,5-Tri-O-acetyl-4,6-O-benzylidene-2-deoxy-D-arabino-hex-1-en (262)……………………………………………………………….………223 1H NMR Spectrum of 2,6-Dideoxy-1,3,4-tri-O-acetyl-2-benzylideneamino-D-glucopyranoside (264b)……………………………………………………………...224 13C NMR Spectrum of 2,6-Dideoxy-1,3,4-tri-O-acetyl-2-benzylideneamino-D-glucopyranoside (264b)………………………………………………………….….224 1H NMR Spectrum of 2,6-Dideoxy-1,3,4-tri-O-acetyl-2-benzylamino-D-glucopyranoside (264c)…………………………………………………….………..225 13C NMR Spectrum of 2,6-Dideoxy-1,3,4-tri-O-acetyl-2-benzylamino-D-glucopyranoside (264c)…………………………………………………………..….225 1H NMR Spectrum of 2,6-Dideoxy-3,4-di-O-acetyl-2-benzylamino-D-glucopyranose (264)……………………………………………………………………………...….226 13C NMR Spectrum of 2,6-Dideoxy-3,4-di-O-acetyl-2-benzylamino-D-glucopyranose (264)…………………………………………………………………………………226 1H NMR Spectrum of 5-(R&S)-Acetoxy-4-(1,2,3,-tri-O-acety-4-deoxyl-D-arabino-tetritol-1-yl)-3-benzylthiazolidine-2-thione (265)……………………………….…..227 13C NMR Spectrum of 5-(R&S)-Acetoxy-4-(1,2,3,-tri-O-acety-4-deoxyl-D-arabino-tetritol-1-yl)-3-benzylthiazolidine-2-thione (265)…………………………………..227 1H NMR Spectrum of (E)-1,3,4,5,-Tetra-O-acetyl-6,2-dideoxy-D-arabino-hex-1-en (266)…………………………………………………………………………………228 13C NMR Spectrum of (E)-1,3,4,5,-Tetra-O-acetyl-6,2-dideoxy-D-arabino-hex-1-en (266)…………………………………………………………………………………228 1H NMR Spectrum of 2,6-Dideoxy-1,3,4-tri-O-acetyl-2-(p-methoxybenzylidene)amino-D-galactopyranoside (269b)………………………..…229 13C NMR Spectrum of 2,6-Dideoxy-1,3,4-tri-O-acetyl-2-(p-methoxybenzylidene)amino-D-galactopyranoside (269b)…………………………..229 1H NMR Spectrum of 2,6-Dideoxy-1,3,4-tri-O-acetyl-2-(p-methoxybenzyl)amino-D-galactopyranose (269c)……………………………………………………………...230 13C NMR Spectrum of 2,6-Dideoxy-1,3,4-tri-O-acetyl-2-(p-methoxybenzyl)amino-D-galactopyranose (269c)………………………………………………………………230 1H NMR Spectrum of 2,6-Dideoxy-3,4-di-O-acetyl-2-(p-methoxybenzyl)amino-D-galactopyranose (269)…………………………………………………………….....231 13C NMR Spectrum of 2,6-Dideoxy-3,4-di-O-acetyl-2-(p-methoxybenzyl)amino-D-galactopyranose (269)…………………………………………………………….....231 1H NMR Spectrum of 5-(R&S)-Acetoxy-4-(1,2,3,-tri-O-acety-4-deoxyl-D-lyxo-tetritol-1-yl)-3-benzylthiazolidine-2-thione (270)……………………………………..……232 13C NMR Spectrum of 5-(R&S)-Acetoxy-4-(1,2,3,-tri-O-acety-4-deoxyl-D-lyxo-tetritol-1-yl)-3-benzylthiazolidine-2-thione (270)…………………………………..232 1H NMR Spectrum of (E)-1,3,4,5,-Tetra-O-acetyl-6,2-dideoxy-D-lyxo-hex-1-en (271)…………………………………………………………………………………233 13C NMR Spectrum of (E)-1,3,4,5,-Tetra-O-acetyl-6,2-dideoxy-D-lyxo-hex-1-en (271)…………………………………………………………………………………233 1H NMR Spectrum of 5-(R&S)-Acetoxy-4-(1,2,3,4-tetra-O-acetyl-D-arabino-tetritol-1-yl)-3-benzylthiazolidine-2-thione (276)…………………………………………..234 13C NMR Spectrum of 5-(R&S)-Acetoxy-4-(1,2,3,4-tetra-O-acetyl-D-arabino-tetritol-1-yl)-3-benzylthiazolidine-2-thione (276)……………………………………………………………………………..…234 1H NMR Spectrum of (E)-1,3,4,5,6-Penta-O-acetyl-2-deoxy-D-arabino-hex-1-en (277)………………………………………………………………………………...235 13C NMR Spectrum of (E)-1,3,4,5,6-Penta-O-acetyl-2-deoxy-D-arabino-hex-1-en (277)…………………………………………………………………………………235 1H NMR Spectrum of 5-(R&S)-Acetoxy-4-(1,2,3,4-tetra-O-acetyl-L-xylo-tetritol-1-yl)-3-benzylthiazolidine-2-thione (280)………………………………………………...236 13C NMR Spectrum of 5-(R&S)-Acetoxy-4-(1,2,3,4-tetra-O-acetyl-L-xylo-tetritol-1-yl)-3-benzylthiazolidine-2-thione (280)………………………….…………………236 1H NMR Spectrum of (E)-1,3,4,5,6-Penta-O-acetyl-2-deoxy-L-xylo-hex-1-en (281)…………………………………………………………………………………237 13C NMR Spectrum of (E)-1,3,4,5,6-Penta-O-acetyl-2-deoxy-L-xylo-hex-1-en (281)…………………………………………………………………………..……..237 1H NMR Spectrum of α-D-Glucopyranosyl-(1→6)-N-benzyl-D-glucosamine (284)………………………………………………………………………..………238 13C NMR Spectrum of α-D-Glucopyranosyl-(1→6)-N-benzyl-D-glucosamine (284)………………………………………………………………………….…….238 1H NMR Spectrum of 5-(R&S)-Acetoxy-4-[1,2,3-tri-O-acetyl-4-O-(2',3',4',6'-tetra-O-acetyl-α-D-glucopyranosyl)-D-arabino-tetritol-1-yl]-N-benzyl-1,3-thiazolidine-2-thione (285)……………………………………………………………………….…239 13C NMR Spectrum of 5-(R&S)-Acetoxy-4-[1,2,3-tri-O-acetyl-4-O-(2',3',4',6'-tetra-O-acetyl-α-D-glucopyranosyl)-D-arabino-tetritol-1-yl]-N-benzyl-1,3-thiazolidine-2-thione (285)…………………………………………………………………………239 1H NMR Spectrum of (–)-(2'S,3'S,4'S)-2,3,4,6-Tetra-O-acetyl-1-O-(2',3',4',6'-tetraacetoxy-5'-trans-hexen-1-yl)--D-glucopyranoside (286)……………………...240 13C NMR Spectrum of (–)-(2'S,3'S,4'S)-2,3,4,6-Tetra-O-acetyl-1-O-(2',3',4',6'-tetraacetoxy-5'-trans-hexen-1-yl)--D-glucopyranoside (286)……………………...240 1H NMR Spectrum of 5-(R&S)-Acetoxy-4-[1,3,4-tri-O-acetyl-2-O-(2',3',4',6'-tetra-O-acetyl-β-D-galactopyranosyl)-D-arabino-tetritol-1-yl]-N-benzyl-1,3-thiazolidine-2-thione (290)………………………………………………………………………….241 13C NMR Spectrum of 5-(R&S)-Acetoxy-4-[1,3,4-tri-O-acetyl-2-O-(2',3',4',6'-tetra-O-acetyl-β-D-galactopyranosyl)-D-arabino-tetritol-1-yl]-N-benzyl-1,3-thiazolidine-2-thione (290)………………………………………………………………………….241 1H NMR Spectrum of (–)-(2'S,3'S,4'S)-2,3,4,6-Tetra-O-acetyl-3'-O-(1',2',4',6'-tetraacetoxy-5'-trans-hexen-1-yl)-β-D-galactopyranoside (291)………………………………………………………………...……………….242 13C NMR Spectrum of (–)-(2'S,3'S,4'S)-2,3,4,6-Tetra-O-acetyl-3'-O-(1',2',4',6'-tetraacetoxy-5'-trans-hexen-1-yl)-β-D-galactopyranoside (291)…………………….242 1H NMR Spectrum of 11-(4-Methoxytriphenyl)methylsulfanyl-3,6,9-trioxaundecan-1-N,N,N-trimethylammonium sulfonate (298)………………………………………....243 13C NMR Spectrum of 11-(4-Methoxytriphenyl)methylsulfanyl-3,6,9-trioxaundecan-1-N,N,N-trimethylammonium sulfonate (298)……………………………………....243 1H NMR Spectrum of 11-(4-Methoxytriphenyl)methylsulfanyl-1-N,N-dimethyl-3,6,9-trioxaundecan (299)…………………………………………………………..……..244 13C NMR Spectrum of 11-(4-Methoxytriphenyl)methylsulfanyl-1-N,N-dimethyl-3,6,9-trioxaundecan (299)…………………………………………………………...244 1H NMR Spectrum of 5-Fluoro-1-N-(4-hydroxymethyl-2-nitrobenzyl)-3-N-(2-tetrahydrofuryl)uracil (303)………………………………………………………….245 13C NMR Spectrum of 5-Fluoro-1-N-(4-hydroxymethyl-2-nitrobenzyl)-3-N-(2-tetrahydrofuryl)uracil (303)………………………………………………………….245 1H NMR Spectrum of 5-Fluoro-1-N-(4-chloromethyl-2-nitrobenzyl)-3-N-(2-tetrahydrofuryl)uracil (304)………………………………………………………….246 13C NMR Spectrum of 5-Fluoro-1-N-(4-chloromethyl-2-nitrobenzyl)-3-N-(2-tetrahydrofuryl)uracil (304)……………………………………………………….…246 1H NMR Spectrum of 5-Fluoro-1-N-(4-[11-(4-methoxytriphenyl)methylsulfanyl-1-N,N-dimethylammoniumchloride-3,6,9-trioxaundecan]-methyl-2-nitrobenzyl)-3-N-(2-tetrahydrofuryl)uracil (305)……………………………...……247 13C NMR Spectrum of 5-Fluoro-1-N-(4-[11-(4-methoxytriphenyl)methylsulfanyl-1-N,N-dimethylammoniumchloride-3,6,9-trioxaundecan]-methyl-2-nitrobenzyl)-3-N-(2-tetrahydrofuryl)uracil (305)………247 8. Crystallographic Data ………………………………………………………... 330 List of Figures Figure 1. Falling domino pieces………………………………………………………1 Figure 2. Chroman-2-one’s display pharmacological properties……………………..9 Figure 3. During catabolic reactions, proteins are broken down into amino acids, lipids are broken down into fatty acids, and polysaccharides are broken down into monosaccharides……………………………..................................................14 Figure 4. Representative examples of -disubstituted arylalanines………………...15 Figure 5. Deoxy sugars in the diological system………………………………………30 Figure 6. Deoxy hexoses in antibiotics and anti-cancer agents………………………..31 Figure 7. Oxidation and reduction of Benzyne………………………………………...32 Figure 8. Traditional drug delivery system…………………………………………….34 Figure 9. Targeted drug delivery……………………………………………………….35 Figure 10. Nanostructures as delivery vehicles………………………………………..35 Figure 11. Passive and active targeting of nanocarriers……………………………….36 Figure 12. Covalent and non-covalent attachment of drugs to nanocarrier…………....37 Figure 13. Gold nanoparticles in drug delivery system………………………………..38 Figure 14. Paclitaxel-conjugated iron oxide and gold nanoparticles………………….39 Figure 15. Synthesis of nano-bullets containing biologically active compounds……..40 Figure 16. ORTEP diagram of compound 220 as determined by X-ray analysis…….47 Figure 17. Experimental design of MTT assay………………………………………..63 Figure 18. Cytotoxity of different AuNPs in OECM cells by MTT assay……………63 Figure 19. Cytotoxity of different AuNPs in HUVEC cells by MTT assay………….64 List of Tables Table 1. Conditions applied to optimize the yield for the coupling of with phenol (44, R2 = p-OMe, 1.0 equivalents) and (Z)-azlactone 45 (R2 = Ph) to give disubstituted chroman-2-one 46 (R3 = Ph, R2 = p-OMe) in the presence of different acids as the catalyst and various solvents……………………………………………..41 Table 2. Starting materials and products in the synthesis of cis-chromane-2-ones 46 from phenols 44 and azlactons 45 by use of the optimized conditions to be obtained……………………………………………………………………...44 Table 3. Various conditions and yields for the hydrolysis of cis-chroman-2-one 222 to give -(N-benzoyl)amino acid 238………………………………………….49 Table 4. Optimization of reaction conditions for the hydrolysis of -(N-benzoyl)amino acid 238 to give free -amino acid 244 with minimal epimerization……….51 Table 5. Structures of the products and their isolated yields in the hydrolysis of cis- chroman-2-ones to give isolated -(N-benzoyl)amino acids 237–242, and following next step of debenzoylation of protected amino acids 237–242 to give the desired free -amino acids 243–248, respectively………………..52 Table 6. Conditions to be applied for optimizing the yield for the conversion of 1,3-thiazolidine-2-thiones 252 to enol acetate 253..................................54 Table 7. Starting aminosugars and intermediates in the conversion of 2-amino sugars to 2- deoxy aldoses……………………………………………………………56 Table 8. Starting ketoses and intermediates in the conversion of 2-ketoes to 2-deoxy aldoses via 2-amino sugars……………………………………………………….58 List of Schemes Scheme 1. The enzymatic cyclisation of oxidosqualene to lenosterol…………………….3 Scheme 2. Domino reaction in the synthesis of tropinone………………………………...4 Scheme 3. Domino reaction in the synthesis of Daphnilactone A………………………...4 Scheme 4. Intramolecular domino reactions occur to generate steroids. Several characteristics and benefits associated with the domino process are described……………….5 Scheme 5. Reaction of -silylphenyl triflates with allenylsilanes to generate (-phenanthrenyl)vinylsilanes…………………………………………………6 Scheme 6. An aryne-induced 1,3-dipolar cycloaddition reaction for the synthesis of imidazolidines from -silylphenyl triflates and Schiff bases…………………7 Scheme 7. Synthesis of amino-containing 3,4-disubstituted chroman-2-ones…………..10 Scheme 8. Bayer–Villiger oxidation in the synthesis of 3,4-dihydrocoumarin…………10 Scheme 9. Kolbe electrolysis of 3,3-diphenylpropanoic acid…………………………..11 Scheme 10. Sequential Friedel-Crafts acylation, esterification and bromoarylation hydrogenation,……………………………………………………………..11 Scheme 11. Synthesis of dihydrocoumarins by lactonisation…………………………..11 Scheme 12. Synthesis of 3,4-disubstituted chroman-2-one by metal catalyzed [3+2] cycloaddition................................................................................................12 Scheme 13. Synthesis of 3,4-disubstituted chroman-2-one by Michael-acetalization …12 Scheme 14. Synthesis of 3,4-disubstituted chroman-2-one by Michael-aldol reaction…12 Scheme 15. Synthesis of dihydrocoumarin by oxidative cleavage……………………...13 Scheme 16. Synthesis of dihydrocoumarin via sequential Ugi and Michael reactions….13 Scheme 17. Armstrong’s Regioselective ring opening of an aziridine-2-carboxylate…..15 Scheme 18. Nucleophilic substitution reactions at -hydroxytyrosine esters…………...16 Scheme 19. Synthesis of -arylated -amino acids via Pd-catalyzed C– H arylation……16 Scheme 20. C(sp3)-H activation using catalyst-bound ligands to govern selectivity……17 Scheme 21. The carboxamide-directed Pd(OAc)2-catalyzed oxidative conversion……...17 Scheme 22. Selective monoarylation of the methyl group by 2-thiomethylaniline derivative…………………………………………………………………….17 Scheme 23. Diarylation of methyl and monoarylation of methylene functionalities…….18 Scheme 24. Asymmetric 1,4-Michael addition to imide conjugate………………………18 Scheme 25. Asymmetric synthesis of -substituted tryptophans via Michael addition of a chiral nickel(II) complex…………………………………………………….19 Scheme 26. One-Pot Aza-Darzens/Ring-Opening Reactions with Arenes……………….19 Scheme 27. Asymmetric hydrogenation of tetrasubstituted olefins to nonsymmetrically substituted N-protected β,β-diaryl-α-amino esters………………………….20 Scheme 28. Asymmetric Friedel–Crafts alkylation of indoles with nitroacrylates……...20 Scheme 29. Reaction of Sulfonylindole with Glycine Ester…………………………….21 Scheme 30. Ring opening of chroman-2-ones to -amino acids ………….…………….21 Scheme 31. Stereospecific Benzyne-Induced Olefination from -Amino Alcohols……22 Scheme 32: The benzyne-induced olefination strategy as the key step in the synthesis of deoxy sugars……......................................................................23 Scheme 33. Oxidative deamination of unbranched primary amines……………………24 Scheme 34. Oxidative cleavage of benzylic C–N bonds using TBAI and H2O2………..25 Scheme 35. Deamination with isopropyl N,N-difluorocarbamate………………………25 Scheme 36. Deamination with nitrosyl acetate in the synthesis of sialic acid derivatives……………………………………………………….25 Scheme 37. Reductive deamination of phenylalanine derivatives………………………26 Scheme 38. Multistep protocol for the deamination of primary amines…………………26 Scheme 39. Conversion of D-glucosamine hydrochloride to chitose……………………27 Scheme 40. Oxidative deamination of -aminophosphonates…………………………27 Scheme 41. Oxidative deamination of cephalosporin C………………………………..27 Scheme 42. β-Deamination of L-lysine to L-pipecolic acid……………………………28 Scheme 43. L-Lysine was oxidized with L-amino-acid oxidase (LAO) or L-lysine oxidase (LO) into 2-keto-lysine……………………………………………………28 Scheme 44. Deamination of amino acids by pyridoxal phosphate cofactor……………29 Scheme 45. Deamination in DNA bases ………………………………………………29 Scheme 46. Strategy designed for deamination of amino sugars by benzyne and its procedure...........................................................................33 Scheme 47. Synthesis of arylhydrazones……………………………………………...39 Scheme 48. p-Toluenesulfonic acid-catalyzed coupling of azlactones with napthols to give five-membered naphtho[2,1-b]furan-2(1H)-ones at high temperature; and a synthetic method to generate chroman-2-ones from phenols and azlactones……………………………………………………………….41 Scheme 49. Hydrolyses of disubstituted cis-chroman-2-ones to give isolated N- protected -amino acids and then free -amino acids….............. ….....48 Scheme 50. Conversion of galactosamine hydrochloride to deoxy-galactose...........54 Scheme 51. Conversion of ketose to deoxy-glucose via 2-aminoaldose and the reaction mechanism of the deamination key step...................................57 Scheme 52. Synthesis of ligands…………………………………………………….59 Scheme 53. Synthesis of photocleable ligand with tegafur………………………….60 Scheme 54. Synthesis of AuNPs……………………………………………………61 Scheme 55. Photo liberation of tegafur……………………………………………..62 Scheme 56. The design and a plausible mechanism on the formation of cis- chorman-2-ones from phenols and azlactone through a Lewis- catalyzed omino reaction, which includes Friedel–Crafts alkylation/1,4-AlCl3 shift/ transesterfication/protonation……..65 Scheme 57. The reaction mechanism of the deamination key step................68

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