Catalytic Asymmetric Total Synthesis of ent-Hyperforin
Catalytic Asymmetric Total Synthesis of ent-Hyperforin
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DOI：
10.1002/anie.200906678
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发表时间：
2010-01-01
影响因子：
16.6
通讯作者：
Shibasaki, Masakatsu
中科院分区：
文献类型：
--
作者：
Shimizu, Yohei;Shi, Shi-Liang;Shibasaki, Masakatsu
天然存在的多环聚异戊二烯化酰基间苯三酚（PPAP：方案1）通常具有高度取代的双环[3.3。 1]壬酮核心。[1] Hyperforin (1) 是该家族的代表，从草本植物贯叶连翘 (Hypericum perforatum) 中分离出来。[2a] Hyperforin 具有多种生物活性，包括轻度抗抑郁活性、[3] 抗疟活性、[4] 人组蛋白脱乙酰酶抑制活性、[5] 和 CYP3A4 诱导活性。 [6]通过结构修饰增强特定的生物活性是药物发现研究的一个重要方向，因此建立灵活的、不对称的全合成路线是一个基本前提。其结构复杂性和作为药物先导化合物的潜在效用使PPAP成为非常有吸引力的合成靶点。已完成加苏贝林A(2)、[7]、克卢西亚酮(3)、[8]和纳莫罗松(4)[8d]的全合成。 [9]使用优雅的仿生方法来构建双环核心，导致其中一些外消旋合成时间较短，并且适用于生产结构多样的类似物。 [8b, e, 9e] 然而，PPAP 的催化不对称合成仍然是一项艰巨的挑战；只有一种 PPAP 的不对称合成（3），其中涉及使用化学计量的手性氨基锂进行后期动力学拆分。[8c] Hyperforin (1) 与 2-4 相比，在 C8 处包含一个额外的手性四元中心，因此
Naturally occurring polycyclic polyprenylated acylphloroglucinols (PPAPs: Scheme 1) commonly have a highly substituted bicyclo [3.3. 1] nonanone core.[1] Hyperforin (1), a representative of this family, was isolated from the herb St. John s wort (Hypericum perforatum).[2a] Hyperforin exhibits various biological activities, including mild antidepressant activity,[3] antimalarial activity,[4] human histone deacetylase inhibitory activity,[5] and CYP3A4 induction activity.[6] Enhancement of a specific biological activity through structural modification is an important direction in drug-discovery research, and thus establishing a flexible, asymmetric total synthetic route is a fundamental prerequisite.Their structural complexity and potential utility as pharmaceutical leads make PPAPs very attractive synthetic targets. The total syntheses of garsubellin A (2),[7] clusianone (3),[8] and nemorosone (4)[8d] have been accomplished.[9] The use of elegant biomimetic approaches to construct the bicyclic core has resulted in some of these racemic syntheses being short and applicable for the production of structurally diverse analogues.[8b, e, 9e] The catalytic asymmetric synthesis of PPAPs, however, remains a daunting challenge; there is only one asymmetric synthesis of PPAPs (that of 3), which involved a late-stage kinetic resolution using a stoichiometric amount of chiral lithium amide.[8c] Hyperforin (1) contains an additional chiral quaternary center at C8 compared to 2–4, thus