天然活性产物Daldinin A,B,C和炭球菌素的全合成研究
发布时间：2018-08-18 18:59
【摘要】：背景炭球菌素(Concentricolide)是近年来从野生高等真菌炭球菌(Daldinia. Concentrica)的代谢产物中分离得到的天然产物,具有显著的抗HIV-1活性。同时又从中分离得到新型的炭球菌素衍生物daldinin A、B和C。和炭球菌素相同,这三种衍生物也具有苯并呋喃和苯并呋喃酮内酯这两个常见的药效官能团,并且目前尚无通用的全合成报道。本论文通过建立了简便有效的转移氢化方法合成出手性的二氢苯并呋喃环化合物,完成了daldinin A、B、C以及炭球菌素的全合成,对该类化合物的研究具有重要的理论意义和应用价值。 目的通过对daldinin A、B、C和炭球菌素四个天然产物的全合成研究,建立该类化合物通用的、简单有效的全合成及结构修饰方法,以便后续深入的研究。 方法以1,3-丙酮二羧酸二甲酯为原料,先与炔醛加成缩合构建苯环上有四个取代基的2-羟基-4-丙基间苯二甲酸甲酯中间体化合物,然后经酚羟基的保护、苄位的氧化及手性还原试剂还原等反应完成苯并呋喃酮内酯环的构建。再在碱性条件下通过迪克曼缩合成环,Krapcho反应构建苯并呋喃环,最终通过在LDA条件下引入异丙醇基,并用手性试剂还原酮羰基完成了daldinin A的全合成。通过对daldinin A进行钯碳催化氢化反应,合成了daldinin B。在此基础上通过四氢铝锂还原开环苯并呋喃酮内酯环即可得到daldinin C。此外,通过对daldinin A的羟基进行还原消除反应得到炭球菌素。 结果与结论(1)以便宜易得的市购原料,通过8步反应,以总产率11.8%完成了daldinin A的全合成,以此为基础,同时完成了daldinin B和C的全合成(Scheme1),并对其结构进行了表征。 (2)在上述路线基础上,通过还原消除反应,选择性地合成了(R)-炭球菌素和(S)-炭球菌素(7.3%yield,97%ee;7.1%yield,98%ee)。此目标化合物经图谱NMR确证,并与天然标准样品的高效液相色谱进行对比分析,确定天然产物为S构型。 (3)建立了一条碳骨架含有6-氢-1,7-二氧环戊二烯并[E]茚-8-酮结构母核的天然化合物的全合成方法学,该路线较为便捷可靠,通用性很强,各步反应条件温和、产率较高,同时易获得高光学纯度的手性化合物,为后续炭球菌素类化合物的结构修饰和药效、药理机制研究奠定了基础。
[Abstract]:BACKGROUND Concentricolide is a natural product isolated from the metabolites of wild higher fungus Daldinia. Concentrica in recent years. It has remarkable anti-HIV-1 activity. At the same time, new carbon cocci derivatives, daldinin A, B and C, are isolated from it, which are the same as carbon cocci derivatives. These three derivatives also have the same properties. Benzofuran and benzofuranolactone are two common pharmacodynamic functional groups, and there is no general report of total synthesis at present. In this paper, a simple and effective transfer hydrogenation method was established to synthesize chiral dihydrobenzofuran ring compounds, and the total synthesis of daldinin A, B, C and carbococcus was completed. The research has important theoretical significance and application value.
OBJECTIVE To establish a general, simple and effective method for the total synthesis and structural modification of daldinin A, B, C and carbococcus by studying the total synthesis of daldinin A, B, C and carbococcus.
METHODS Benzofuranolactone ring was synthesized from dimethyl 1,3-pyruvate dicarboxylate by addition condensation with acetylene aldehyde to form methyl 2-hydroxy-4-propyl isophthalate intermediate with four substituents on the benzene ring. Then benzofuranolactone ring was synthesized by phenolic hydroxyl protection, benzyl oxidation and chiral reductant reduction. Benzofuran rings were synthesized by Dickmann condensation and Krapcho reaction. Finally, isopropyl alcohol was introduced into the ring under LDA condition, and daldinin A was synthesized by reducing ketone carbonyl with chiral reagent. Daldinin B was synthesized by palladium-carbon catalytic hydrogenation of daldinin A. On this basis, ring-opening benzene was reduced by lithium aluminum tetrahydroxide. Daldinin C can be obtained from the ring of furanolactone. In addition, carbococcus can be obtained by reducing the hydroxyl group of daldinin A.
RESULTS AND CONCLUSION (1) Total synthesis of daldinin A was completed in 8 steps with a total yield of 11.8%. On this basis, total synthesis of daldinin B and C (Scheme1) was completed and its structure was characterized.
(2) On the basis of the above-mentioned route, (R) - Carbococcin and (S) - Carbococcin (7.3% yield, 97% ee; 7.1% yield, 98% ee) were selectively synthesized by reduction elimination reaction. The target compound was confirmed by NMR and compared with the natural standard sample by high performance liquid chromatography (HPLC).
(3) A total synthesis method of natural compounds with 6-hydro-1,7-diocyclopentadienyl [E] indene-8-one structure as the parent nucleus has been established. The method is convenient, reliable, versatile, mild reaction conditions, high yield, and easy to obtain chiral compounds with high optical purity. It is the junction of subsequent carbococcus compounds. It laid a foundation for the study of structure modification, pharmacodynamics and pharmacological mechanism.
【学位授予单位】：新乡医学院
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R914.5
本文编号：2190377
[Abstract]:BACKGROUND Concentricolide is a natural product isolated from the metabolites of wild higher fungus Daldinia. Concentrica in recent years. It has remarkable anti-HIV-1 activity. At the same time, new carbon cocci derivatives, daldinin A, B and C, are isolated from it, which are the same as carbon cocci derivatives. These three derivatives also have the same properties. Benzofuran and benzofuranolactone are two common pharmacodynamic functional groups, and there is no general report of total synthesis at present. In this paper, a simple and effective transfer hydrogenation method was established to synthesize chiral dihydrobenzofuran ring compounds, and the total synthesis of daldinin A, B, C and carbococcus was completed. The research has important theoretical significance and application value.
OBJECTIVE To establish a general, simple and effective method for the total synthesis and structural modification of daldinin A, B, C and carbococcus by studying the total synthesis of daldinin A, B, C and carbococcus.
METHODS Benzofuranolactone ring was synthesized from dimethyl 1,3-pyruvate dicarboxylate by addition condensation with acetylene aldehyde to form methyl 2-hydroxy-4-propyl isophthalate intermediate with four substituents on the benzene ring. Then benzofuranolactone ring was synthesized by phenolic hydroxyl protection, benzyl oxidation and chiral reductant reduction. Benzofuran rings were synthesized by Dickmann condensation and Krapcho reaction. Finally, isopropyl alcohol was introduced into the ring under LDA condition, and daldinin A was synthesized by reducing ketone carbonyl with chiral reagent. Daldinin B was synthesized by palladium-carbon catalytic hydrogenation of daldinin A. On this basis, ring-opening benzene was reduced by lithium aluminum tetrahydroxide. Daldinin C can be obtained from the ring of furanolactone. In addition, carbococcus can be obtained by reducing the hydroxyl group of daldinin A.
RESULTS AND CONCLUSION (1) Total synthesis of daldinin A was completed in 8 steps with a total yield of 11.8%. On this basis, total synthesis of daldinin B and C (Scheme1) was completed and its structure was characterized.
(2) On the basis of the above-mentioned route, (R) - Carbococcin and (S) - Carbococcin (7.3% yield, 97% ee; 7.1% yield, 98% ee) were selectively synthesized by reduction elimination reaction. The target compound was confirmed by NMR and compared with the natural standard sample by high performance liquid chromatography (HPLC).
(3) A total synthesis method of natural compounds with 6-hydro-1,7-diocyclopentadienyl [E] indene-8-one structure as the parent nucleus has been established. The method is convenient, reliable, versatile, mild reaction conditions, high yield, and easy to obtain chiral compounds with high optical purity. It is the junction of subsequent carbococcus compounds. It laid a foundation for the study of structure modification, pharmacodynamics and pharmacological mechanism.
【学位授予单位】：新乡医学院
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R914.5
【参考文献】
相关期刊论文 前2条
1 ;Novel Chromone Derivatives from Marine Fungus Aspergillus versicolor Isolated from the Sponge Xestospongia exigua[J];Chinese Chemical Letters;2001年03期
2 汪泳;李文红;曹云涛;李媛;;手性VA唑硼烷的研究进展及其应用[J];有机化学;2011年01期
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