The total synthesis of (±)-rishirilide B
The total synthesis of (±)-rishirilide B
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DOI：
10.1021/ja003272a
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发表时间：
2001-01-17
影响因子：
15
通讯作者：
Danishefsky, SJ
中科院分区：
文献类型：
--
作者：
Allen, JG;Danishefsky, SJ
里希里里德B和A是1984年由Naki等人从里氏链霉菌OFR-1056中分离得到的。3它们通过选择性地抑制R2-巨球蛋白，从而导致纤溶酶的激活而表现出抗血栓活性。Rishirilide B在本试验中比A有效得多。利什里德A的结构(虽然不是它的绝对构型)由结晶学方法确定为2。结构1与利什里德B的结构没有得到晶体数据的支持，而是建立在其与2的生物起源连接性的假设下。除了它们新的作用机制，作用于一个关键的生物级联外，利什里德的结构使我们有兴趣成为全合成的重点目标。最近，我们已经描述了系统3的用途，作为奎诺二甲胺(4)的可行的等价物，用于与一系列亲双烯化合物的分子间环加成反应(方案1)。5如在3b、5a或5b中，具有取代基(R1*H)的环加成反应速率显著降低。虽然取代的环己酮与5没有发生有效的反应，但我们还是提出了方案1所示的利什利德B的合成路线(见下文)。6该提议成功的核心是需要处理达到1的C6酚羟基所需的周围取代基的严重阻碍效应。特别是，我们试图利用Masamune的发现，7其中一个有策略地放置的羟基可以增强无环R，β-不饱和酮的双烯亲水性，推测是通过内部氢键。我们想知道Masamune效应是否可以通过R‘-羟基环己酮实现，以至于它可以与奎诺二甲胺前体如5反应。这一猜测导致选择66作为推测的双烯亲和者。在这个建模阶段，我们使用容易制备的8 5a作为推测的奎诺二甲胺前体。在这种情况下，5a和6确实在160℃下在15小时内发生了反应(方案2)。粗环加合物在甲醇中用樟脑磺酸回流处理，产率为65%。在下一步中，β处理的羟基7干净地引导异戊基溴化镁反应到酮的β面上，以70%的产率得到8(熔点128~129C)。用X-射线单晶衍射法对该化合物进行了结构表征。
Rishirilides B and A were isolated from Streptomyces rishiriensis OFR-1056 in 1984 by Naki and co-workers. 3 They exhibit antithrombotic activity4 through selective R2-macroglobulin inhibition, thereby leading to the activation of plasmin. Rishirilide B is substantially more potent than A in this assay. The structure of rishirilide A (although not its absolute configuration) was established, by crystallographic means, to be 2. The assignment of structure 1 to rishirilide B was not supported by crystallographic data, but was rendered under the assumption of its biogenetic connectivity to 2. In addition to their novel mechanism of action, impinging on a crucial biological cascade, the structures of the rishirilides interested us as focusing targets for total synthesis. Recently, we have described the use of systems 3 as viable equivalents of quinodimethides (4) for intermolecular cycloaddition reactions with a range of dienophiles (Scheme 1). 5 With peri-substituents (R1* H), as in 3b, 5a, or 5b, the rate of cycloaddition is significantly reduced. Although substituted cyclohexenones failed to react usefully with 5, we nonetheless proposed the synthetic route to rishirilide B shown in Scheme 1 (vide infra). 6Central to the success of the proposal was the need to deal with the serious retardation effect of peri-substituents required to reach the C6 phenolic hydroxyl of 1. In particular, we sought to exploit a discovery of Masamune, 7 wherein a strategically placed hydroxyl group could enhance the dienophilicity of an acyclic R, β-unsaturated ketone, presumably by internal hydrogen bonding. We wondered whether the Masamune effect could be realized with an R′-hydroxylated cyclohexenone, to the extent that it would react with quinodimethide precursors such as 5. This line of conjecture led to the selection of 66 to serve as a putative dienophile. In this modeling phase, we used the readily prepared8 5a as the presumptive quinodimethide precursor. In the event, reaction of 5a and 6 did occur at 160 C over 15 h (Scheme 2). The crude cycloadduct was treated with camphorsulfonic acid in methanol under reflux, providing a 65% yield of 7. In the next step, the β-disposed hydroxyl group of 7 cleanly directed the reaction of isoamylmagnesium bromide to the β face of the ketone to afford 8 (mp 128-129 C) in 70% yield. The structure of this compound was verified by X-ray crystallography.