Phainanoids的4,5-螺环骨架的合成探索  

Synthetic Study Toward the 4,5-Spirocycle Skeleton of Phainanoids

作　　者：江崇国 陈斯嘉 龚建贤 杨震 Jiang Chongguo;Chen Sijia;Gong Jianxian;Yang Zhen(Laboratory of Chemical Genomics,State Key Laboratory of Chemical Oncogenomics,School of Chemical Biology and Biotechnology,Peking University Shenzhen Graduate School,Shenzhen 518055,China;College of Chemistry and Molecular Engineering of Peking University,Beijing 100871,China;Shenzhen Bay Laboratory,Shenzhen 518055,China)

机构地区：[1]北京大学深圳研究生院化学生物学与生物技术学院省部共建肿瘤化学基因组学国家重点实验室广东省化学基因组学重点实验室,深圳518055 [2]北京大学化学与分子工程学院,北京100871 [3]深圳湾实验室,深圳518055

出　　处：《化学学报》2020年第9期928-932,共5页Acta Chimica Sinica

基　　金：国家自然科学基金(Nos.21632002,21772008);国家重点研发计划(No.2018YFC0310905);深圳市科技计划(No.JCYJ20170818090044432);深港脑科学创新研究院项目计划(No.2019SHIBS0004)资助。

摘　　要：本工作报道了用铑(I)催化芳基化环化反应和芳香亲核取代反应为关键步骤,合成天然产物Phainanoids的4,5-螺环骨架的探索.从已知化合物1出发,经过结构修饰得到炔酮5,在铑(I)催化条件下,与苯硼酸发生芳基化环化反应,构建了多取代环丁烯6.随后经过羟基保护和臭氧解反应得到α-烷氧基环丁酮8,其与格氏试剂9发生加成反应得到环丁醇10.最后在碱性条件下发生芳香亲核取代反应,在酸性条件下脱除乙氧基甲基(ethoxymethyl, EOM)和缩酮保护基,得到了4,5-螺环骨架结构18.格氏试剂9与邻烷氧基环丁酮8未能按照Cram’schelation模型进行与天然产物Phainanoids中螺环手性中心一致的立体选择性加成.综合文献报道和相关实验,可能的原因是:邻烷氧基环丁酮8的相对刚性结构,增加了镁离子与羰基氧原子和邻位烷氧基螯合过渡态的能垒;以及格氏试剂9中的氟原子与镁离子发生分子内螯合,抑制了镁离子与羰基邻位的烷氧基的螯合作用.Attempts to synthesize the 4,5-spirocycle skeleton of Phainanoids by rhodium-catalyzed arylative cyclization of alkynone 5 and the addition of Grignard reagent 9 to α-alkoxyl cyclobutone 8, followed by intramolecular SNAr reaction are reported. Phainanoids, highly modified triterpenoids, were isolated from Phyllanthus hainanensis by Yue and co-workers. They have been found to show intriguing immunosuppressive activities. The most potent of them, Phainanoid F, inhibit the proliferation of T cells with an IC50 value of(2.04±0.01) nmol/L and B cells with an IC50 value <(1.60±0.01) nmol/L. The noteworthy activities and the lack of Phainanoids in nature resources make the synthesis of them for further biological evaluation a challenge for chemists. Our synthesis started from known compound 1, after Birch reduction and alkylation to give alkynone 5. The rhodium-catalyzed arylative cyclization of alkynone 5 to deliver tetrasubstituted cyclobutene 6 was performed by the following procedure. Under an atmosphere of Ar, to an oven-dried Schlenk tube with [Rh(OH)(cod)]2(35.5 mg, 0.078 mmol, 0.012 n5), phenylboronic acid(2.0 g, 16.3 mmol, 2.5 n5), were added a solution of ketone 5(1.9 g, 6.5 mmol, 1.0 n5) in 1,4-dioxane(32.0 mL) and H2 O(0.3 mL) at room temperature. The mixture was stirred at 35 ℃ for 12 h. Another [Rh(OH)(cod)]2(35.5 mg, 0.078 mmol, 0.012 n5) and phenylboronic acid(2.0 g, 16.3 mmol, 2.5 n5) was added to the mixture. The mixture was stirred at 35 ℃ for 12 h. Subsequently, hydroxyl group was protected with ethoxymethyl(EOM) group to furnish 7, followed by ozonolysis to generate ketone 8. Ketone 8 was reacted with fresh prepared Grignard reagent 9 in Felkin-Anh model instead of the Cram’s chelation-control model to deliver alcohol 10. The explanation of the diastereoselectivity of this reaction could be illustrated from two aspects:(1) the rigid structure of α-alkoxyl cyclobutone 8 increased the energy barrier for the transition state of chelation between magnesium ions and alkoxyl substituent;(2) the

关 键 词：Phainanoids 4 5-螺环骨架 铑催化芳基化环化 芳香亲核取代 Cram’s chelation 

分 类 号：O626[理学—有机化学]