Gold(I)-catalyzed bis-spiroketalization: synthesis of the trioxadispiroketal-containing A-D rings of azaspiracid.
Gold(I)-catalyzed bis-spiroketalization: synthesis of the trioxadispiroketal-containing A-D rings of azaspiracid.
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DOI：
10.1002/anie.200601963
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发表时间：
2007
影响因子：
--
通讯作者：
Yongfeng Li;F. Zhou;C. Forsyth
中科院分区：
文献类型：
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作者：
Yongfeng Li;F. Zhou;C. Forsyth
阿司匹酸是一类海洋毒素，1995年在荷兰首次被认为是人类中毒的罪魁祸首。[1]这些毒素对小鼠的肝脏、胰腺、胸腺和脾显示出显著的急性和慢性影响。[2]此外，阿司匹酸引起了人们对其神经毒性和促进肿瘤潜力的关注。[2]阿司匹酸的结构(1，方案1)最初提出于1998年[3]，随后由Nicolaou等人修改。在2004年完成了令人印象深刻的全合成。[4]在这里，我们报道了一种新的含三氧二吡酮的氮杂阿司匹酸A-D结构域的组装，其特点是前所未有的AuCl催化的[5]双螺酮化和高效的钴介导的分子内醚化反应，如Inoti和Mukaiyama所描述的那样。[6]与最初的结构分配相反，氮杂阿司匹酸的含三氧二吡酮的A-D环已被证明采用了热力学上有利的构型和构象。[4，7]因此，人们认识到，在平衡条件下组装三氧二氢吡酮缩醛应该有利于这种体系的传递。8]利用炔在脱水状态下类似于酮(酮)的氧化状态这一事实，我们以前通过双分子内杂-Michael加成构建了氮杂阿司匹酸C10螺酮中心。[7]然而，炔的双双羟基加成也可以通过AUI或AuIII催化完成，而不需要炔和羰基之间的共轭。这一事实在AuIII催化的炔烃水合反应[9]以及炔烃转化为甲基烯醇醚[9]和二甲基[9，10]或分子内桥联的[11]酮中得到了例证。在氮杂阿司匹酸A-D结构域中形成三氧杂二异丙酮体系(1，方案2)的背景下[5]，我们预计AUI催化的2的C6羟基跨C10±C11的6-exo加成将导致瞬时的C10±C11烯醇醚(方案2)。然后，这种烯醇醚可以在质子条件下与C13缩酮氧原子接合，形成1的双螺酮。在C10上使用炔烃作为酮的替代物，可以降低C7±C8烯烃异构化到C8±C9位置的可能性，如果确实存在酮，则可能发生这种情况。三氧杂二异丙酮化前体2包含完整的C和D环，其中C13中心处于正确的缩酮氧化态，以及A环的C6氧原子和Z烯烃在非环链中(方案2)。C5-C9侧链3将通过铜介导烯丙基化与自行车4相连。[12]后者将由羟基烯5通过Inoki和Mukaiyama报道的钴催化的氧醚化反应合成2，5-反式稠合三取代四氢呋喃D环[6]。
The azaspiracids are a family of marine toxins that were first recognized as being responsible for human poisonings in the Netherlands in 1995.[1] These toxins showed significant acute and chronic effects on the liver, pancreas, thymus, and spleen in mice.[2] Moreover, the azaspiracids have raised concerns over their neurotoxic and tumor-promoting potential.[2] The structure of azaspiracid (1, Scheme 1) was originally proposed in 1998 [3] and was subsequently revised by Nicolaou et al. in 2004 upon completion of an impressive total synthesis.[4] Herein we report a novel assembly of the trioxadispiroketal-containing A–D domain of azaspiracid which features an unprecedented AuCl-catalyzed [5] bis-spiroketalization and an efficient cobalt-mediated intramolecular etherification, as described by Inoti and Mukaiyama, to close the D ring.[6] Contrary to the initial structural assignment, the trioxadispiroketal-containing A–D rings of the azaspiracids have been shown to adopt a thermodynamically favored configuration and conformation.[4, 7] Thus, it was recognized that assembly of the trioxadispiroketal moiety under equilibrating conditions should favor the delivery of such a system.[4, 7, 8] By taking advantage of the fact that an alkyne resembles the oxidation state of a ketone (ketal) in its dehydrated form, we previously constructed the azaspiracid C10 spiroketal center through a double intramolecular hetero-Michael addition.[7] However, the geminal bis-hydroxy addition to an alkyne can also be accomplished by AuI or AuIII catalysis, without needing conjugation between the alkyne and a carbonyl moiety. This fact was exemplified in the AuIII-catalyzed hydration of alkynes,[9] as well as in the conversion of alkynes into methyl enol ethers [9] and dimethyl [9, 10] or intramolecularly bridged [11] ketals. An advance in the emergent methodology of homogeneous Aucatalyzed addition to alkynes [5] was targeted in the context of forming the trioxadispiroketal system (1, Scheme 2) in the azaspiracid A–D domain.We anticipated that an AuI-catalyzed 6-exo addition of the C6 hydroxy group of 2 across the C10ÀC11 alkyne would result in a transient C10ÀC11 enol ether (Scheme 2). This enol ether could then engage the C13 ketal oxygen atom under protic conditions to form the bis-spiroketal of 1. The use of an alkyne as a surrogate for a ketone at C10 reduces the likelihood of the C7ÀC8 alkene isomerizing into the C8ÀC9 position, which might occur if a ketone was actually present. Trioxadispiroketalization precursor 2 contains the intact C and D rings with the C13 center at the correct ketal oxidation state as well as the C6 oxygen atom and the Z alkene of the A ring in an acyclic chain (Scheme 2). The C5–C9 side chain 3 would be conjoined with bicycle 4 through a copper-mediated alkyne allylation.[12] The latter would be elaborated from hydroxy alkene 5 through the synthesis of the 2, 5-trans-fused trisubstituted tetrahydrofuran D ring using a cobalt-catalyzed oxyetherification reported by Inoki and Mukaiyama.[6]