基于4，6-二氯嘧啶-5-醛的多样性导向合成
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摘要
本论文共分四章,开发了以4,6-二氯嘧啶-5-醛为起始原料的多样性导向合成(DOS),共合成了三类结构新颖的嘧啶并环化合物,并在此基础上构建了结构多样的化合物库。
第一章介绍了多样性导向合成以及选题背景。多样性导向合成在设计合成结构复杂多样的小分子化合物库方面发挥着重要的指导作用,其与化学遗传学的结合使用可以高效地解决生物学问题。嘧啶并环化合物具有多种的药理活性,设计开发新的合成路线,合成结构新颖、多样的嘧啶并环化合物对于发现优化先导化合物,创制新药具有重要意义。
第二章中,最初设计用嘧啶醛与二级胺生成亚甲胺叶立德然后与烯烃发生分子内[3+2]环加成反应,合成一类新型嘧啶并环分子。但是产物经1H NMR判断不是预期产物,经单晶衍射表征确定为四氢嘧啶并[4,5-d]嘧啶分子。我们对这一新发现进行了系统的研究。以4,6-二氯嘧啶-5-醛为起始原料,经一级胺和苯硫酚连续两次亲核取代反应合成了四种反应前体4-胺基-6-苯硫基嘧啶-5-醛,然后与十种二级胺在二甲苯回流的条件下发生关环反应,以10-78%的适中产率合成了17个四氢嘧啶并[4,5-d]嘧啶化合物。该反应具有如下特点:(1)嘧啶醛上的取代基团对反应的影响不大,二级胺上的取代基团越大则反应时间越长但是对产率影响不大;(2)由于二级胺取代基团的不同,产物会得到一对区域异构体而且没有明显的区域选择性。根据实验结果,我们提出了以亚胺离子异构化反应为关键关环步骤的反应机理。嘧啶醛与二级胺形成亚胺离子后发生异构化反应形成了不同的亚胺离子,然后再关环进而生成了不同的区域异构体。四氢嘧啶并[4,5-d]嘧啶的5位苯硫基团通过侧链硫氧化为砜然后与胺发生亲核取代反应合成了5位胺基取代的四氢嘧啶并[4,5-d]嘧啶衍生物,表明其5位芳香砜基团具有较高的亲核取代反应活性,推断其也可以被其它亲核试剂(醇类、硫醇等)取代转换成其它基团。以上研究为构建含有多个取代基的四氢嘧啶并[4,5-d]嘧啶衍生物库提供了一条有效的合成策略。
第三章中,通过对4-烯丙基氨基嘧啶-5-醛与一系列芳胺的亚胺Diels-Alder反应的研究,建立了快速合成六氢苯[b]嘧啶[4,5-h][1,6]萘啶分子骨架的有效方法,并研究了反应的规律。以4,6-二氯嘧啶-5-醛为起始原料,经亲核取代反应合成了七种关键前体4-烯丙基氨基嘧啶-5-醛,然后与十九种芳胺在三氟乙酸催化、乙腈和水的混合溶剂中室温条件下发生关环反应,以49-98%的高产率得到了23个六氢苯[b]嘧啶[4,5-h][1,6]萘啶化合物。该反应具有如下特点:(1)芳胺上连有吸电子基团时反应时间短;(2)芳胺的邻位有取代基时反应时间长,甚至于不反应;(3)芳胺间位取代基的电子效应强(强的吸电子或推电子基团),则反应具有专一的区域选择性;(4)二级芳胺的亚胺DA反应需要在甲苯回流带水的条件下反应,比一级芳胺反应条件剧烈;(5)产物通过单晶衍射以及1H NMR确定为顺式结构,表明该关环反应具有立体专一性。关环产物六氢苯[b]嘧啶[4,5-h][1,6]萘啶通过侧链硫氧化为亚砜,然后与亲核试剂(胺、醇、酚和硫)发生取代反应合成了6个6位取代的六氢苯[b]嘧啶[4,5-h][1,6]萘啶衍生物,表明其6位芳香亚砜基团具有较高的亲核取代反应活性,可转换成多种取代基团。上述研究为合成六氢苯[b]嘧啶[4,5-h][1,6]萘啶分子库提供了一条有效的合成策略。
第四章中,通过对4-烯丙基氨基嘧啶-5-醛与一系列一级胺的亚胺Ene反应的研究,建立了快速合成桥亚胺嘧啶并[4,5-b]分子骨架的有效方法,并研究了反应的规律。根据亚胺Ene反应文献总结,得出发生亚胺DA反应的底物(4-烯丙基氨基嘧啶-5-醛)也符合亚胺Ene反应的要求。通过反应条件摸索,我们发现底物与一级胺在对甲苯磺酸催化、甲苯回流带水的条件下可以专一的、高产率的发生亚胺Ene反应。在优化的反应条件下研究了十一种底物与九种一级胺发生亚胺Ene关环反应,结果以44-97%的高产率合成了16个桥亚胺嘧啶[4,5-b]并化合物。该反应具有如下特点:(1)嘧啶醛的电子云密度对反应影响很大,只有当电子云密度足够低时才能发生亚胺Ene反应,且电子云密度越低产率越高;(2)胺上连有推电子基团时反应进行的快,但对产率影响不大;(3)一级芳胺的邻位有取代基团时反应时间增加且产率降低。此外我们还研究了4-烯丙基氨基嘧啶-5-醛自身的羰基Ene反应,建立了快速合成环氧嘧啶并[4,5-b]分子骨架的有效方法。九种底物在二甲苯回流的条件下以72-95%的高产率合成了9个环氧嘧啶并[4,5-b]化合物,结果显示羰基Ene反应比亚胺Ene反应所需的温度高、反应时间长。上述研究为合成桥亚胺嘧啶并[4,5-b]或环氧嘧啶并[4,5-b]分子库提供了一条有效的合成策略。
This four-chapter dissertation focus on the strategy of diversity-oriented synthesis (DOS) and its application in the construction of three different kinds of pyrimidine-fused heterocyclic scaffolds from the same starting material ( 4,6-dichloropyrimidine-5-carbaldehyde).
In Chapter One, the development of diversity-oriented synthesis is reviewed. As an important and widely applied strategy in the design and syntheses of complex and diversed libraries, DOS can merge with chemical genetics and provide efficient solutions to biological and medical challenges. Developing methodologies for the syntheses of novel diversed pyrimidine-fused heterocycles with potential pharmacological properties is a good practice of DOS, and the resulted compound libraries are the bases for screening against biological targets.
In Chapter Two, a novel iminium ion isomerization reaction is discussed. To apply the DOS strategy, an initial design of intramolecular azomethine ylide [3+2] cycloaddition reaction with pyrimidine carbaldehyde as starting material was performed and an unexpected new product was acquired. The structure was determined to possess tetrahydro pyrimido[4,5-d]pyrimidine scaffold by X-ray crystallography. Following this, a systematic study of this reaction is discussed. The precursor 4-amino-6-phenylthiopyrimidin-5-carbaldehyde was prepared by amine and subsequent thiophenol substitution of the 4,6-dichloropyrimidine-5-carbaldehyde. The precursor was then reacted with ten selected secondary amines in refluxing xylene and led to tetrahydropyrimido[4,5-d]pyrimidine derivatives with 10-78% yields. The reaction results can be summarized as follow: (1) Reaction of pyrimidine aldehyde containing various N-substitutents proceed well; (2) The reactions are slow when secondary amine contains a large group; (3) The various substitutents of secondary amines led to two regioisomers without significant selectivity. The isolation and characterization of regioisomers supported an iminium ion isomerization mechanism. In addition, the oxidation of 6-phenylthio group to the corresponding sulfone compound results in 70% yields, and the sulfones can be further derivatized via nucleophilic substitution with 67-90% yields. Thus an efficient methodology to access structurally diverse library of tetrahydropyrimido [4,5-d]pyrimidines was developed.
In Chapter Three, the discussed DOS method focused on imino Diels-Alder reaction to develop novel hexahydrobenzo[b]pyrimido[4,5-h][1,6]naphthyridine scaffold. The key step of this method can be considered as a tandem reaction, imines formed in situ from allylaminopyrimidinealdehydes and anilines, followed by the intramolecular inverse electron demand hetero Diels-Alder reaction. Seven key precursors 4-allylaminopyrimidine-5-carbaldehydes were prepared via the nucleophilic substitution of various allylamines to 4,6-dichloropyrimidine-5- carbaldehyde. The desired hexahydrobenzo[b]pyrimido[4,5-h][1,6]naphthyridine derivatives were obtained by this one-pot reaction under the catalysis of trifluoroacetic acid with 49-98% yields. The reaction results can be summarized as follow: (1) The reactions with aromatic amines containing electron-withdrawing groups were faster than those with electron-donating groups; (2) When the anilines had an ortho substituent, the reactions were either slow or resulted no desired product; (3) When the anilines had a strong electro-effect substituent, the reactions were extremely regioselective; (4) The reaction of secondary aryl amines could yield the desired products in refluxing toluene with p-toluenesufonic acid using a Dean-Stark apparatus; (5) All the products were determined to be cis-con gured by comparison of 1H NMR spectra with the X-ray confirmed compound. In addition, the oxidation of 6-phenylthio group to the corresponding sulfoxide compound results in 75% yields, and the sulfoxides can be further derivatized to the corresponding 6-substituted hexahydrobenzo[b] pyrimido[4,5-h][1,6] naphthyridines via nucleophilic substitutions with 55-98% yields. Thus an efficient methodology to access structurally diverse library of hexahydrobenzo[b]pyrimido[4,5-h][1,6]naphthyridine was developed.
In Chapter Four, another strategy using ene reaction to access epiminopyrimido[4,5-b]azepine scaffold was developed. The key intermediate for this synthetic route was same as the hetero Diels-Alder reaction discussed in Chapter Three. Under the catalysis of p-toluenesufonic acid, the reactions were heated in refluxing toluene with a Dean-Stark apparatus. The titled compounds were acquired via an intramolecular imine Ene reaction following the in situ imine formation of allylaminopyrimidinealdehydes and primary amines. Sixteen epiminopyrimido[4,5-b] azepine derivatives were synthesized with 44-97% yields. The reaction results can be summarized as follow: (1) The electron density of pyrimidine aldehyde has great influence on the reaction outcome. When the electron density is lower, the reaction yield is higher; (2) The reactions with primary amines containing electron-donating groups are faster than those with electron-withdrawing groups; (3) When the primary anilines had an ortho substituent, the reactions were slow and low yielding. Besides, the key precursors were treated in refluxing xylene, and epoxypyrimido[4,5-b]azepine derivatives were isolated with 72-95% yields via carbonyl Ene reaction. Carbonyl Ene reaction demands higher reaction temperature. Another DOS method was developed utilizing Imine-Ene reaction and Carbonyl-Ene reaction.
第一章介绍了多样性导向合成以及选题背景。多样性导向合成在设计合成结构复杂多样的小分子化合物库方面发挥着重要的指导作用,其与化学遗传学的结合使用可以高效地解决生物学问题。嘧啶并环化合物具有多种的药理活性,设计开发新的合成路线,合成结构新颖、多样的嘧啶并环化合物对于发现优化先导化合物,创制新药具有重要意义。
第二章中,最初设计用嘧啶醛与二级胺生成亚甲胺叶立德然后与烯烃发生分子内[3+2]环加成反应,合成一类新型嘧啶并环分子。但是产物经1H NMR判断不是预期产物,经单晶衍射表征确定为四氢嘧啶并[4,5-d]嘧啶分子。我们对这一新发现进行了系统的研究。以4,6-二氯嘧啶-5-醛为起始原料,经一级胺和苯硫酚连续两次亲核取代反应合成了四种反应前体4-胺基-6-苯硫基嘧啶-5-醛,然后与十种二级胺在二甲苯回流的条件下发生关环反应,以10-78%的适中产率合成了17个四氢嘧啶并[4,5-d]嘧啶化合物。该反应具有如下特点:(1)嘧啶醛上的取代基团对反应的影响不大,二级胺上的取代基团越大则反应时间越长但是对产率影响不大;(2)由于二级胺取代基团的不同,产物会得到一对区域异构体而且没有明显的区域选择性。根据实验结果,我们提出了以亚胺离子异构化反应为关键关环步骤的反应机理。嘧啶醛与二级胺形成亚胺离子后发生异构化反应形成了不同的亚胺离子,然后再关环进而生成了不同的区域异构体。四氢嘧啶并[4,5-d]嘧啶的5位苯硫基团通过侧链硫氧化为砜然后与胺发生亲核取代反应合成了5位胺基取代的四氢嘧啶并[4,5-d]嘧啶衍生物,表明其5位芳香砜基团具有较高的亲核取代反应活性,推断其也可以被其它亲核试剂(醇类、硫醇等)取代转换成其它基团。以上研究为构建含有多个取代基的四氢嘧啶并[4,5-d]嘧啶衍生物库提供了一条有效的合成策略。
第三章中,通过对4-烯丙基氨基嘧啶-5-醛与一系列芳胺的亚胺Diels-Alder反应的研究,建立了快速合成六氢苯[b]嘧啶[4,5-h][1,6]萘啶分子骨架的有效方法,并研究了反应的规律。以4,6-二氯嘧啶-5-醛为起始原料,经亲核取代反应合成了七种关键前体4-烯丙基氨基嘧啶-5-醛,然后与十九种芳胺在三氟乙酸催化、乙腈和水的混合溶剂中室温条件下发生关环反应,以49-98%的高产率得到了23个六氢苯[b]嘧啶[4,5-h][1,6]萘啶化合物。该反应具有如下特点:(1)芳胺上连有吸电子基团时反应时间短;(2)芳胺的邻位有取代基时反应时间长,甚至于不反应;(3)芳胺间位取代基的电子效应强(强的吸电子或推电子基团),则反应具有专一的区域选择性;(4)二级芳胺的亚胺DA反应需要在甲苯回流带水的条件下反应,比一级芳胺反应条件剧烈;(5)产物通过单晶衍射以及1H NMR确定为顺式结构,表明该关环反应具有立体专一性。关环产物六氢苯[b]嘧啶[4,5-h][1,6]萘啶通过侧链硫氧化为亚砜,然后与亲核试剂(胺、醇、酚和硫)发生取代反应合成了6个6位取代的六氢苯[b]嘧啶[4,5-h][1,6]萘啶衍生物,表明其6位芳香亚砜基团具有较高的亲核取代反应活性,可转换成多种取代基团。上述研究为合成六氢苯[b]嘧啶[4,5-h][1,6]萘啶分子库提供了一条有效的合成策略。
第四章中,通过对4-烯丙基氨基嘧啶-5-醛与一系列一级胺的亚胺Ene反应的研究,建立了快速合成桥亚胺嘧啶并[4,5-b]分子骨架的有效方法,并研究了反应的规律。根据亚胺Ene反应文献总结,得出发生亚胺DA反应的底物(4-烯丙基氨基嘧啶-5-醛)也符合亚胺Ene反应的要求。通过反应条件摸索,我们发现底物与一级胺在对甲苯磺酸催化、甲苯回流带水的条件下可以专一的、高产率的发生亚胺Ene反应。在优化的反应条件下研究了十一种底物与九种一级胺发生亚胺Ene关环反应,结果以44-97%的高产率合成了16个桥亚胺嘧啶[4,5-b]并化合物。该反应具有如下特点:(1)嘧啶醛的电子云密度对反应影响很大,只有当电子云密度足够低时才能发生亚胺Ene反应,且电子云密度越低产率越高;(2)胺上连有推电子基团时反应进行的快,但对产率影响不大;(3)一级芳胺的邻位有取代基团时反应时间增加且产率降低。此外我们还研究了4-烯丙基氨基嘧啶-5-醛自身的羰基Ene反应,建立了快速合成环氧嘧啶并[4,5-b]分子骨架的有效方法。九种底物在二甲苯回流的条件下以72-95%的高产率合成了9个环氧嘧啶并[4,5-b]化合物,结果显示羰基Ene反应比亚胺Ene反应所需的温度高、反应时间长。上述研究为合成桥亚胺嘧啶并[4,5-b]或环氧嘧啶并[4,5-b]分子库提供了一条有效的合成策略。
This four-chapter dissertation focus on the strategy of diversity-oriented synthesis (DOS) and its application in the construction of three different kinds of pyrimidine-fused heterocyclic scaffolds from the same starting material ( 4,6-dichloropyrimidine-5-carbaldehyde).
In Chapter One, the development of diversity-oriented synthesis is reviewed. As an important and widely applied strategy in the design and syntheses of complex and diversed libraries, DOS can merge with chemical genetics and provide efficient solutions to biological and medical challenges. Developing methodologies for the syntheses of novel diversed pyrimidine-fused heterocycles with potential pharmacological properties is a good practice of DOS, and the resulted compound libraries are the bases for screening against biological targets.
In Chapter Two, a novel iminium ion isomerization reaction is discussed. To apply the DOS strategy, an initial design of intramolecular azomethine ylide [3+2] cycloaddition reaction with pyrimidine carbaldehyde as starting material was performed and an unexpected new product was acquired. The structure was determined to possess tetrahydro pyrimido[4,5-d]pyrimidine scaffold by X-ray crystallography. Following this, a systematic study of this reaction is discussed. The precursor 4-amino-6-phenylthiopyrimidin-5-carbaldehyde was prepared by amine and subsequent thiophenol substitution of the 4,6-dichloropyrimidine-5-carbaldehyde. The precursor was then reacted with ten selected secondary amines in refluxing xylene and led to tetrahydropyrimido[4,5-d]pyrimidine derivatives with 10-78% yields. The reaction results can be summarized as follow: (1) Reaction of pyrimidine aldehyde containing various N-substitutents proceed well; (2) The reactions are slow when secondary amine contains a large group; (3) The various substitutents of secondary amines led to two regioisomers without significant selectivity. The isolation and characterization of regioisomers supported an iminium ion isomerization mechanism. In addition, the oxidation of 6-phenylthio group to the corresponding sulfone compound results in 70% yields, and the sulfones can be further derivatized via nucleophilic substitution with 67-90% yields. Thus an efficient methodology to access structurally diverse library of tetrahydropyrimido [4,5-d]pyrimidines was developed.
In Chapter Three, the discussed DOS method focused on imino Diels-Alder reaction to develop novel hexahydrobenzo[b]pyrimido[4,5-h][1,6]naphthyridine scaffold. The key step of this method can be considered as a tandem reaction, imines formed in situ from allylaminopyrimidinealdehydes and anilines, followed by the intramolecular inverse electron demand hetero Diels-Alder reaction. Seven key precursors 4-allylaminopyrimidine-5-carbaldehydes were prepared via the nucleophilic substitution of various allylamines to 4,6-dichloropyrimidine-5- carbaldehyde. The desired hexahydrobenzo[b]pyrimido[4,5-h][1,6]naphthyridine derivatives were obtained by this one-pot reaction under the catalysis of trifluoroacetic acid with 49-98% yields. The reaction results can be summarized as follow: (1) The reactions with aromatic amines containing electron-withdrawing groups were faster than those with electron-donating groups; (2) When the anilines had an ortho substituent, the reactions were either slow or resulted no desired product; (3) When the anilines had a strong electro-effect substituent, the reactions were extremely regioselective; (4) The reaction of secondary aryl amines could yield the desired products in refluxing toluene with p-toluenesufonic acid using a Dean-Stark apparatus; (5) All the products were determined to be cis-con gured by comparison of 1H NMR spectra with the X-ray confirmed compound. In addition, the oxidation of 6-phenylthio group to the corresponding sulfoxide compound results in 75% yields, and the sulfoxides can be further derivatized to the corresponding 6-substituted hexahydrobenzo[b] pyrimido[4,5-h][1,6] naphthyridines via nucleophilic substitutions with 55-98% yields. Thus an efficient methodology to access structurally diverse library of hexahydrobenzo[b]pyrimido[4,5-h][1,6]naphthyridine was developed.
In Chapter Four, another strategy using ene reaction to access epiminopyrimido[4,5-b]azepine scaffold was developed. The key intermediate for this synthetic route was same as the hetero Diels-Alder reaction discussed in Chapter Three. Under the catalysis of p-toluenesufonic acid, the reactions were heated in refluxing toluene with a Dean-Stark apparatus. The titled compounds were acquired via an intramolecular imine Ene reaction following the in situ imine formation of allylaminopyrimidinealdehydes and primary amines. Sixteen epiminopyrimido[4,5-b] azepine derivatives were synthesized with 44-97% yields. The reaction results can be summarized as follow: (1) The electron density of pyrimidine aldehyde has great influence on the reaction outcome. When the electron density is lower, the reaction yield is higher; (2) The reactions with primary amines containing electron-donating groups are faster than those with electron-withdrawing groups; (3) When the primary anilines had an ortho substituent, the reactions were slow and low yielding. Besides, the key precursors were treated in refluxing xylene, and epoxypyrimido[4,5-b]azepine derivatives were isolated with 72-95% yields via carbonyl Ene reaction. Carbonyl Ene reaction demands higher reaction temperature. Another DOS method was developed utilizing Imine-Ene reaction and Carbonyl-Ene reaction.
引文
[1]张健,张启虹,王晓晨, et al.药物合成策略的近期发展[J].药学进展, 2008, 32(20): 433-40.
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