天然活性產(chǎn)物Daldinin A,B,C和炭球菌素的全合成研究
發(fā)布時(shí)間：2018-08-18 18:59
【摘要】：背景炭球菌素(Concentricolide)是近年來從野生高等真菌炭球菌(Daldinia. Concentrica)的代謝產(chǎn)物中分離得到的天然產(chǎn)物,具有顯著的抗HIV-1活性。同時(shí)又從中分離得到新型的炭球菌素衍生物daldinin A、B和C。和炭球菌素相同,這三種衍生物也具有苯并呋喃和苯并呋喃酮內(nèi)酯這兩個(gè)常見的藥效官能團(tuán),并且目前尚無通用的全合成報(bào)道。本論文通過建立了簡便有效的轉(zhuǎn)移氫化方法合成出手性的二氫苯并呋喃環(huán)化合物,完成了daldinin A、B、C以及炭球菌素的全合成,對該類化合物的研究具有重要的理論意義和應(yīng)用價(jià)值。 目的通過對daldinin A、B、C和炭球菌素四個(gè)天然產(chǎn)物的全合成研究,建立該類化合物通用的、簡單有效的全合成及結(jié)構(gòu)修飾方法,以便后續(xù)深入的研究。 方法以1,3-丙酮二羧酸二甲酯為原料,先與炔醛加成縮合構(gòu)建苯環(huán)上有四個(gè)取代基的2-羥基-4-丙基間苯二甲酸甲酯中間體化合物,然后經(jīng)酚羥基的保護(hù)、芐位的氧化及手性還原試劑還原等反應(yīng)完成苯并呋喃酮內(nèi)酯環(huán)的構(gòu)建。再在堿性條件下通過迪克曼縮合成環(huán),Krapcho反應(yīng)構(gòu)建苯并呋喃環(huán),最終通過在LDA條件下引入異丙醇基,并用手性試劑還原酮羰基完成了daldinin A的全合成。通過對daldinin A進(jìn)行鈀碳催化氫化反應(yīng),合成了daldinin B。在此基礎(chǔ)上通過四氫鋁鋰還原開環(huán)苯并呋喃酮內(nèi)酯環(huán)即可得到daldinin C。此外,通過對daldinin A的羥基進(jìn)行還原消除反應(yīng)得到炭球菌素。 結(jié)果與結(jié)論(1)以便宜易得的市購原料,通過8步反應(yīng),以總產(chǎn)率11.8%完成了daldinin A的全合成,以此為基礎(chǔ),同時(shí)完成了daldinin B和C的全合成(Scheme1),并對其結(jié)構(gòu)進(jìn)行了表征。 (2)在上述路線基礎(chǔ)上,通過還原消除反應(yīng),選擇性地合成了(R)-炭球菌素和(S)-炭球菌素(7.3%yield,97%ee;7.1%yield,98%ee)。此目標(biāo)化合物經(jīng)圖譜NMR確證,并與天然標(biāo)準(zhǔn)樣品的高效液相色譜進(jìn)行對比分析,確定天然產(chǎn)物為S構(gòu)型。 (3)建立了一條碳骨架含有6-氫-1,7-二氧環(huán)戊二烯并[E]茚-8-酮結(jié)構(gòu)母核的天然化合物的全合成方法學(xué),該路線較為便捷可靠,通用性很強(qiáng),各步反應(yīng)條件溫和、產(chǎn)率較高,同時(shí)易獲得高光學(xué)純度的手性化合物,為后續(xù)炭球菌素類化合物的結(jié)構(gòu)修飾和藥效、藥理機(jī)制研究奠定了基礎(chǔ)。
[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.
【學(xué)位授予單位】：新鄉(xiāng)醫(yī)學(xué)院
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2014
【分類號】：R914.5
本文編號：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.
【學(xué)位授予單位】：新鄉(xiāng)醫(yī)學(xué)院
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2014
【分類號】：R914.5
【參考文獻(xiàn)】
相關(guān)期刊論文 前2條
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;李文紅;曹云濤;李媛;;手性VA唑硼烷的研究進(jìn)展及其應(yīng)用[J];有機(jī)化學(xué);2011年01期
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