Progress in the Synthesis of 3-Substituted Phthaides

Abstract

3-Substituted phthalides are widely distributed in plants and fungi. They are active ingredients in traditional Chinese herbal medicines, and have attracted much attention in modern medicinal chemistry. The synthetic methods of 3-substituted phthalides are reviewed, especially those in enantioselective manners. The main approach involves: (a) construction of lactones from C-C bond formation reactions, e.g. an aldol/lactonization cascade reaction of 2-acylbenzoates and alikes, (b) construction of lactones via C-O bond formation reactions, e.g. reductive lactonization of 2-acylbenzoates or reduction of 3-alkenyl phthalides, intramolecular oxidation/lactonization, or intramolecular redox/lactonization. These methods are of great significance for the high stereoselective synthesis of phthalides and drug research. Keywords phthalide; isobenzofuran-1(3H)-one; synthesis; enantioselectivity; natural product 天然产物在药物研发中发挥了关键作用, 许多现代 药物的开发受到了各种天然产物的启发 [1][2] . 苯酞, 即异 苯并呋喃-1(3H)-酮, 为具有 γ-内酯与苯稠合的双环结构 物质(图 1, 1). 某些植物(如川芎和当归)以及真菌中就含 有这类化合物 [3] . 目前, 已分离鉴定出近两百种含苯酞 骨架的天然化合物, 这些化合物在取代基的性质、位置 以及苯环的氧化程度方面表现出差异. 根据苯酞单元的 结构特征, 通常分为三类 [4][5] : (a) 3-未取代的苯酞, (b) 3-取代的苯酞和(c)苯酞二聚物. 这些物质显示出重要的 临床特性, 例如抗血小板聚集、抗血栓形成、防止脑缺 血、抗心绞痛、调节心脏功能及中枢神经系统的作 用 [4,[6][7][8] . 这类分子的生物活性归因于苯酞中的环内酯结 构 [9] . 尽管苯酞类化合物的结构和生物多样性引起了人 们广泛的兴趣, 但是大规模从天然产物中获取这类化合 物并不现实, 因此采用化学方法合成这些化合物具有重 要意义. 本综述将简述苯酞类化合物的结构多样性、生 物活性, 总结在生物活性方面更为重要的 3-取代苯酞的 代表性合成方法, 为相关研究提供参考. 生物活性具有苯酞结构骨架的霉酚酸(图 1, 2)是一种免疫抑 制剂, 用于器官移植(如肾脏移植)的术后恢复 [10][11] ; 化 合物 3 能抑制前列腺素 E 2 的生成 [12] ; 4 具有抗癌和抗抑 郁活性 [13] .大多数天然苯酞类化合物属于 3-取代的苯酞(图 1, 5～11), 这些化合物往往具有丰富的药理活性. 具有芹 菜特有气味的丁苯酞 5 (NBP, 图 1), 能够抑制血小板凝 集、改善微循环、减轻缺血性脑损伤, 是治疗缺血性脑 卒中的药物 [14] , (S)-NBP 在某些情况下效果更佳 [15] ; 化

Flexible and Convergent Enantioselective Total Synthesis of (R)-Juglanaloids A and B: Two Phthalide Spiro Alkaloids with Potential Alzheimer’s Disease Inhibitory Activity

“…In the variegated panorama of natural products, the chiral phthalide framework is a recurrent structural motif that is frequently associated with relevant and diverse biological activities and therefore object of continuous effort in developing stereoselective synthetic methodologies. , On our side, given the large availability of simple phthalide building blocks, we have pursued over the past few years a strategy for building more complex structures based on the stereocontrolled formation of a C–C bond at the γ-site of the lactone ring. , …”

A convenient and efficient synthesis of 3-benzofuryl-substituted phthalides

“…17 As such, the construction of 3-substituted phthalides has attracted significant interest over the years. 18,19 Despite that a variety of synthetic approaches have been developed, the majority of these protocols generally suffer from the requirement of excess amounts of substrates, harsh conditions, and/or use of expensive or toxic transition-metal catalysts. 5,20 Of the various strategies, Friedel-Crafts/ lactonization of 2-formylbenzoates and nucleophiles is probably the most easily conceivable mode for formation of 3substituted phthalides.…”

TfOH-Catalyzed Cascade Reaction: Metal-Free Access to 3,3-Disubstituted Phthalides from o-Alkynylbenzoic Acids

“…For these reasons, the synthesis of phthalides is of great interest. Notably, the construction of the γ-butyrolactone scaffold is the key step in the synthesis of phthalides, and the common approaches to γ-butyrolactone synthesis comprise the cyclization of 2-(1-hydroxyalkyl)-benzaldehyde and its derivatives, the cyclization of o -aroylbenzoic acids, and other methods. Moreover, the intramolecular cyclization of o -alkynylbenzoic acids or their derivatives is a useful route for the synthesis of 3-substituted phthalides (Scheme a) . Different transition metal salts, such as Pd, Ag, Cu salts, and I 2 -complexes, were reported to be able to catalyze the reaction.…”