3，4-二氢-3-氧代-2H-1，4-苯并噁嗪类化合物以及24-Demethylbafilomycin C_1中C3-C12片断的合成
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摘要
目标分子导向合成在现代有机化学的发展中起着重要的作用。复杂天然产物分子的全合成研究极大地推动了新反应、新试剂、以及新合成策略的建立,丰富了多步有机合成的手段。与之相对应,多样性导向合成是以产生分子结构多样性为目的,是近年发展起来的一个前沿研究方向,与化学生物学或化学基因组学的研究有密切的关系。本论文一部分工作以多样性导向合成的策略和方法合成了含氮、氧的优势杂环化合物。另一部分工作采用目标分子导向合成的策略和方法合成了16元环抗生素24-demethylbafilomycin C_1中C3-C12片断。
第一章首先介绍了多样性导向有机合成、异氰参与的多组分反应、以及微波辅助有机合成。取代2-氨基苯酚是一类廉价、易得的原料,对它们在含氮、氧杂环化合物合成中的例子作了扼要的讨论。然后介绍了plecomacrolide类大环内酯的结构以及文献报道的用于合成bafilomycin A_1全合成的策略。
第二至第四章记载了本论文完成的在微波加热条件下合成一系列3,4-二氢-3-氧代-2H-1,4-苯并噁嗪类杂环及其与2-吲哚酮的轭合物(conjugates)。第二章首先优化了N-芳甲基取代的2-氨基苯酚经微波加热区域选择性地同α-溴代羧酸乙酯环化的最佳条件,合成了4-芳甲基-3,4-二氢-3-氧代-2H-1,4-苯并噁嗪类杂环。第三章将Ugi四组分反应同前述分子内环化反应相结合,实现了微波辅助一锅法合成多官能团化的同类杂环,并且探索了微波加热条件下铜催化的分子内酰胺化反应来合成2-吲哚酮,对酰胺羰基氧参与的分子内芳基化反应的产物进行了鉴定。第四章采用钯催化剂来促进分子内酰胺化反应,优化了反应条件,在微波加热条件以第三章中得到的杂环为底物,快速、高效地合成了一系列3,4-二氢-3-氧代-2H-1,4-苯并噁嗪与2-吲哚酮的轭合物。
第五章阐述了文献中报道的用于建立bafilomycin A_1中C6-C8三个相连手性中心的方法以及本论文工作中采用的Abiko手性丙酸酯衍生的(Z)-型硼烯醇盐参与的反式选择aldol缩合反应。利用1,3-dithiane烷基化反应构筑了甲基酮,从而通过Horner-Wittig反应合成了(E)-1,3-二烯结构单元。最后经其它常规转化反应得到了所需的C3-C12片断,以13步反应,计算的总收率为12.3%。
实验部分罗列了相关的实验步骤及新化合物结构表征数据。原始的~1H和~(13)C核磁共振谱及X-射线单晶结构解析数据收于附录中。
Target-oriented organic synthesis (TOS) has played an important role in the advancement of contemporary organic chemistry. Studies on total synthesis of natural products of structural complexity have been the driving force for development of new reactions, new reagents, and novel synthetic tactics. The latter collectively enrich the tools available for multi-step organic synthesis. In contrast to TOS, diversity-oriented organic synthesis (DOS), aiming for creation of molecular structural diversity, is emerging as a frontier research direction in recent years. It closely associates with research in chemical biology or chemical genetics. This thesis covers studies on the synthesis of nitrogen- and oxygen-containing privileged heterocycles according to the strategy and protocol of DOS and the synthesis of the C3-C12 fragment of a 16-membered ring antibiotic, 24-demethylbafilomycin C_1, by applying the strategy and protocol of TOS.
Chapter 1 briefly introduces DOS, isocyanide-based multicomponent reactions (IMCRs), and microwave-assisted organic synthesis (MAOS). Substituted 2-aminophenols are a class of cheap and readily available starting materials. Selected applications of 2-aminophenols in the synthesis of nitrogen- and oxygen-containing heterocycles are discussed. The structures of the plecomacrolides are then presented and the known strategies in the literature used for synthesis of bafilomycin A_1 are analyzed.
Chapters 2-4 compile the results obtained during this thesis research on synthesis of a series of 3,4-dihydro-3-oxo-2H-1,4-benzoxazines and the conjugates with 2-oxindoles under controlled microwave heating. First, optimization of reaction conditions was performed as given in Chapter 2, leading to regioselective annulation of N-arylmethyl-2-aminophenols with ethylα-bromoalkanoates under microwave heating to produce 4-arylmethyl-3,4-dihydro-3-oxo-2H-1,4-benzoxazines. In Chapter 3, a one-pot synthetic sequence was established by combining Ugi-four-component reaction (U-4CR) with intramolecular S_n2 reaction. It offers an efficient microwave-assisted synthesis of 3,4-dihydro-3-oxo-2H-1,4-benzoxazines appended with a variety of functionalities. The latter allow further annulation to install a 2-oxindole subunit via microwave-assisted Cu-catalyzed intramolecular amidation. The byproduct formed from intramolecular O-arylation of the bulky secondary amides was identified. In order to improve efficiency of the intramolecular amidation, the palladium-catalyzed version was developed in Chapter 4. Under controlled microwave heating, the functionalized 3,4-dihydro-3-oxo-2H-1,4-benzoxazines, prepared by the one-pot U-4CR & intramolecular S_n2 reaction in Chapter 3, underwent a rapid and efficient cyclization to furnish a collection of the conjugates with 2-oxindole linked through a C-N single bond.
Chapter 5 briefs the reports in the literature on establishment of the C6-C8 stereotriad used for total synthesis of bafilomycin A_1. In this thesis work, the anti-selective aldol reaction of the (E)-enolate of the Abiko's chiral propionate was used as the key step for stereochemical control. The alkylation of 1,3-dithiane was selected for formation of the methyl ketone intermediate, which was then used to install the (E)-1,3-diene moiety via Horner-Wittig reaction. By following some common transformations, the C3-C12 fragment was synthesized by a 13-step sequence and in 12.3% overall yield.
The experimental section compiles the synthetic procedures and full characterization data for all new compounds. Copies of original ~1H and ~(13)C NMR spectra, and data of X-ray single crystal structural analysis are found in the Appendix.
第一章首先介绍了多样性导向有机合成、异氰参与的多组分反应、以及微波辅助有机合成。取代2-氨基苯酚是一类廉价、易得的原料,对它们在含氮、氧杂环化合物合成中的例子作了扼要的讨论。然后介绍了plecomacrolide类大环内酯的结构以及文献报道的用于合成bafilomycin A_1全合成的策略。
第二至第四章记载了本论文完成的在微波加热条件下合成一系列3,4-二氢-3-氧代-2H-1,4-苯并噁嗪类杂环及其与2-吲哚酮的轭合物(conjugates)。第二章首先优化了N-芳甲基取代的2-氨基苯酚经微波加热区域选择性地同α-溴代羧酸乙酯环化的最佳条件,合成了4-芳甲基-3,4-二氢-3-氧代-2H-1,4-苯并噁嗪类杂环。第三章将Ugi四组分反应同前述分子内环化反应相结合,实现了微波辅助一锅法合成多官能团化的同类杂环,并且探索了微波加热条件下铜催化的分子内酰胺化反应来合成2-吲哚酮,对酰胺羰基氧参与的分子内芳基化反应的产物进行了鉴定。第四章采用钯催化剂来促进分子内酰胺化反应,优化了反应条件,在微波加热条件以第三章中得到的杂环为底物,快速、高效地合成了一系列3,4-二氢-3-氧代-2H-1,4-苯并噁嗪与2-吲哚酮的轭合物。
第五章阐述了文献中报道的用于建立bafilomycin A_1中C6-C8三个相连手性中心的方法以及本论文工作中采用的Abiko手性丙酸酯衍生的(Z)-型硼烯醇盐参与的反式选择aldol缩合反应。利用1,3-dithiane烷基化反应构筑了甲基酮,从而通过Horner-Wittig反应合成了(E)-1,3-二烯结构单元。最后经其它常规转化反应得到了所需的C3-C12片断,以13步反应,计算的总收率为12.3%。
实验部分罗列了相关的实验步骤及新化合物结构表征数据。原始的~1H和~(13)C核磁共振谱及X-射线单晶结构解析数据收于附录中。
Target-oriented organic synthesis (TOS) has played an important role in the advancement of contemporary organic chemistry. Studies on total synthesis of natural products of structural complexity have been the driving force for development of new reactions, new reagents, and novel synthetic tactics. The latter collectively enrich the tools available for multi-step organic synthesis. In contrast to TOS, diversity-oriented organic synthesis (DOS), aiming for creation of molecular structural diversity, is emerging as a frontier research direction in recent years. It closely associates with research in chemical biology or chemical genetics. This thesis covers studies on the synthesis of nitrogen- and oxygen-containing privileged heterocycles according to the strategy and protocol of DOS and the synthesis of the C3-C12 fragment of a 16-membered ring antibiotic, 24-demethylbafilomycin C_1, by applying the strategy and protocol of TOS.
Chapter 1 briefly introduces DOS, isocyanide-based multicomponent reactions (IMCRs), and microwave-assisted organic synthesis (MAOS). Substituted 2-aminophenols are a class of cheap and readily available starting materials. Selected applications of 2-aminophenols in the synthesis of nitrogen- and oxygen-containing heterocycles are discussed. The structures of the plecomacrolides are then presented and the known strategies in the literature used for synthesis of bafilomycin A_1 are analyzed.
Chapters 2-4 compile the results obtained during this thesis research on synthesis of a series of 3,4-dihydro-3-oxo-2H-1,4-benzoxazines and the conjugates with 2-oxindoles under controlled microwave heating. First, optimization of reaction conditions was performed as given in Chapter 2, leading to regioselective annulation of N-arylmethyl-2-aminophenols with ethylα-bromoalkanoates under microwave heating to produce 4-arylmethyl-3,4-dihydro-3-oxo-2H-1,4-benzoxazines. In Chapter 3, a one-pot synthetic sequence was established by combining Ugi-four-component reaction (U-4CR) with intramolecular S_n2 reaction. It offers an efficient microwave-assisted synthesis of 3,4-dihydro-3-oxo-2H-1,4-benzoxazines appended with a variety of functionalities. The latter allow further annulation to install a 2-oxindole subunit via microwave-assisted Cu-catalyzed intramolecular amidation. The byproduct formed from intramolecular O-arylation of the bulky secondary amides was identified. In order to improve efficiency of the intramolecular amidation, the palladium-catalyzed version was developed in Chapter 4. Under controlled microwave heating, the functionalized 3,4-dihydro-3-oxo-2H-1,4-benzoxazines, prepared by the one-pot U-4CR & intramolecular S_n2 reaction in Chapter 3, underwent a rapid and efficient cyclization to furnish a collection of the conjugates with 2-oxindole linked through a C-N single bond.
Chapter 5 briefs the reports in the literature on establishment of the C6-C8 stereotriad used for total synthesis of bafilomycin A_1. In this thesis work, the anti-selective aldol reaction of the (E)-enolate of the Abiko's chiral propionate was used as the key step for stereochemical control. The alkylation of 1,3-dithiane was selected for formation of the methyl ketone intermediate, which was then used to install the (E)-1,3-diene moiety via Horner-Wittig reaction. By following some common transformations, the C3-C12 fragment was synthesized by a 13-step sequence and in 12.3% overall yield.
The experimental section compiles the synthetic procedures and full characterization data for all new compounds. Copies of original ~1H and ~(13)C NMR spectra, and data of X-ray single crystal structural analysis are found in the Appendix.
引文
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