摘要/Abstract

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's chelation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.
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
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 S_NAr 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, 0.012n₅), phenylboronic acid (2.0 g, 16.3 mmol, 2.5n₅), were added a solution of ketone 5 (1.9 g, 6.5 mmol, 1.0n₅) in 1,4-dioxane (32.0 mL) and H₂O (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, 0.012n₅) and phenylboronic acid (2.0 g, 16.3 mmol, 2.5n₅) 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 modelinstead ofthe 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 magnesium ions were not chelated with the alkoxyl substituent as well as the carbonyl oxygen was due to the intramolecular chelation with fluorine atom. Alcohol 10 underwent intramolecular S_NAr reaction and deprotection to deliver 4,5-spirocycle compound 18.
Key words: Phainanoids, 4,5-spirocycle skeleton, rhodium-catalyzed arylative cyclization, S_NAr, Cram's chelation


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