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研究生:粘富堯
研究生(外文):Fu-YaoNien
論文名稱:快速合成具化學選擇性保護之不對稱α-雙氨基二元酸
論文名稱(外文):An expeditious approach towards preparation of orthogonally protected chiral bis-α-amino acids
指導教授:鄭偉杰
指導教授(外文):Wei-Chieh Cheng
學位類別:碩士
校院名稱:國立成功大學
系所名稱:化學系碩博士班
學門:自然科學學門
學類:化學學類
論文種類:學術論文
論文出版年:2012
畢業學年度:100
語文別:英文
論文頁數:155
中文關鍵詞:雙氨基二元酸選擇性保護氨基二元酸仿氨基酸肽聚醣
外文關鍵詞:bis-α-amino acidsorthogonally protected bis-α-amino acidspeptide mimicspeptidoglycan
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雙氨基二元酸是一種存在於自然界中很獨特的分子,特別是仿氨基酸及細菌的肽聚醣等生物應用上扮演著重要的角色。因此,我們發展一種高效率的方法來合成選擇性保護氨基二元酸(OPBAs),關鍵步驟為結合Schöllkopf bis-lactim ethers和bromide oxazolidines進行立體選擇性的烷化。各種oxazolidines是由不同的氨基酸,例如:絲胺酸、天門冬氨酸和谷氨酸,其經由快速合成得到不同碳鏈長度的oxazolidines,並藉由Wittig 反應得到其他不同環狀的oxazolidines。根據我們於此篇所報導的方法,合成了十種前驅物和六種OPBAs。此外,iE-DAP是一種具有Nucleotide-binding oligomerization domain-containing protein 1 (NOD 1)螯合性的生物分子,經由我們的方法也可以快速的得到iE-DAP。這種方法也已經證實能夠控制掌性中心和調整碳鏈長度做為氨基二元酸的合成及具生物活性之研究。
Naturally occurring and synthetic bis-α-amino acids are structurally unique molecules and they play an important role for biological applications, especially for the studies in peptide mimics, bacterial peptidoglycan, and polypeptides. We developed an efficient method for the preparation of orthogonally protected bis-α-amino acids (OPBAs) through the conjugation of the Schöllkopf bis-lactim ethers with bromide-oxazolidines via a stereospecific alkylation as a key step. Various oxzaolidines bearing a different alkyl spacer were efficiently prepared from the amino acid-based chiral pool such as D-seine, L-serine, L-aspartic acid, and L-glutamic acid. In addition, other oxazolidines containing an unusual spacer were prepared with the construction of proper alkyl chains via the Wittig reaction. Through this concise approach, ten precursors for the conjugation were demonstrated and six OPBAs were prepared. Among those, one biological molecule called iE-meso-DAP as a NOD 1 ligand was also efficiently synthesized based on our strategy. This validated methodology can be extensively applied for the preparation of other bis-amino acids with desired stereogenic centers and an adjusted spacer between two carboxylic acids, or for the synthesis of bis-amino acids containing biologically interesting molecules.
Table of Contents
摘要.......................................................I
Abstract..................................................II
Acknowledgement..........................................III
Table of Contents..........................................V
Index of Figures.........................................VII
Index of Tables.........................................VIII
Index of schemes..........................................IX
Abbreviations..............................................X
Chapter 1. Introduction....................................1
1-1 Introduction.......................................1
1-2 Current known methods for the preparation of OPBAs ...........................................................4
1-3 Motivation.........................................9
Chapter 2. Results and discussion.........................10
2-1 Strategy for the preparation of OPBAs................10
2-1.1 General synthesis of OPBAs.........................10
2-2 Preparation of the protected meso-DAP................11
2-2.1 Preparation of the strategy........................11
2-2.2 Conjugation of 4 and 8.............................13
2-2.3 Selective hydrolysis of the precursors.............14
2-2.4 Obtain the protected meso-DAP......................16
2-3 Synthesis of the other bridge bis-α-amino acids......16
2-3.1 Preparation of oxidazolidine derivatives from D-serine....................................................17
2-3.2 Preparation of oxidazolidine derivatives from aspartic acid.............................................18
2-3.3 Preparation of oxidazolidine derivatives from compound 7, 16, 21........................................18
2-4 Synthesis of γ-D-glutamyl-meso-diaminopimelic acid...22
2-5 Conclusion...........................................24
Chapter 3. Experimental Section..........................25
3-1 General experimental procedures......................25
3-2 Procedures and experimental data.....................26
References................................................65
Appendix..................................................68


Index of Figures
Figure 1.1. Bioactive and natural molecules containing bis-α-amino acids..............................................2
Figure 1.2. SK&F 107647 and differently length of alkyl spacer.....................................................3
Figure 2.1. General structure of OPBAs....................10
Figure 2.3. Structures of Schöllkopf bis lactim ethers 4 and ent-4.....................................................12
Figure 2.4. A set of various oxazolidine-based building blocks....................................................20


Index of Tables
Table 1.1. Asymmetic hydrogenation.........................6
Table 2.1. Conjugation of chiral auxiliary 4 and oxazolidine 8.........................................................14
Table 2.2. Selective hydrolysis of compound 9 to afford compound 10...............................................15
Table 2.4. Conjugation of chiral auxiliary and different bridge of oxazolidine.....................................21


Index of schemes
Scheme 1.1. Kolbe electrolysis approach....................4
Scheme 1.2. Mixture products of dimerizaiotn for Kolbe electrolysis...............................................5
Scheme 1.3. Hiebl’s approach for the preparation of bis-α-amino acids................................................6
Scheme 1.4. Boon’s approach for the preparation of bis-α-amino acids................................................7
Scheme 1.5. Kawasaki A. approach for the preparation of bis-α-amino acids..............................................8
Scheme 1.6. Synthetic routs of Kremminger P................8
Scheme 2.1. Synthesis of chiral auxiliary 4...............11
Scheme 2.2. Synthesis of oxazolidine 8....................12
Scheme 2.3. Synthesis of 9 for orthogonally protected meso-DAP precursor.............................................13
Scheme 2.4. Preparation of orthogonally protected meso-DAP. ..........................................................16
Scheme 2.5. Preparation of oxidazolidine derivatives from D-serine....................................................17
Scheme 2.6. Conjugation of compound 4 and 17 or 18 to generate compound 32a.....................................17
Scheme 2.7. Preparation of oxidazolidine derivatives from aspartic acid.............................................18
Scheme 2.8. Preparation of oxazolidines 26, 27, and 28....19
Scheme 2.9. Preparation of oxazolidine 31.................19
Scheme 2.10. General synthesis of OPBAs...................22
Scheme 2.11. Synthesis of the iE-DAP......................22

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