A triple-aldol cascade reaction for the rapid assembly of polyketides.
A triple-aldol cascade reaction for the rapid assembly of polyketides.
复制标题
DOI：
10.1002/anie.200907076
复制
发表时间：
2010-04-01
影响因子：
16.6
通讯作者：
Yamamoto, Hisashi
中科院分区：
文献类型：
--
作者：
Albert, Brian J.;Yamamoto, Hisashi
长期以来，聚酮类化合物为合成有机化学家提供了各种复杂的结构来构建和开发新的化学工具，并为药物提供了许多有用的药物。大约1%的聚酮具有药物活性，是天然产物平均值的五倍。[1]合成聚酮的一种常见策略是交叉羟醛缩合反应，尽管不受控制的齐聚和脱水反应会使其复杂化。[2]醛的不对称羟醛缩合反应和烯丙化反应的发展取得了重大进展。[3，4]然而，在下一次迭代可以进行之前，通常需要进一步的操作，如酒精保护或氧化还原反应。因此，人们对一锅级联的Aldol反应越来越感兴趣；[5，6]然而，只有一个例子成功地进行了第三次Aldol迭代，并且产率很低。[5A]受到Mukaiyama等人开创性工作的启发，[2a]我们的研究小组报告了一个使用三(三甲基硅基)硅基烯醇醚的Aldol级联反应，例如容易制备的1，[7]，以得到多功能的醛产品2(方案1)。此外，这些醛可以在同一反应罐中与格氏试剂或多卤甲基锂试剂反应生成单保护的二元醇。由于三(三甲基硅基)硅基的极端空间体积，这些化合物的形成具有高度的非对映选择性。[7a，8a，9]值得注意的是，由于(TMS)3SiNTf2·2络合物的空间体积，严格防止了1到2的进一步加成。我们制定了具有挑战性的目标，将这种Aldol级联反应扩展到以最少的步骤将1加成到醛的三个或更多。尽管多次尝试，二甲基丙醛与1(4.0当量)和Tf2NH在二氯甲烷中处理只得到双羟醛产物2a(R=tBU)，没有形成任何三羟醛产物3a(表1，条目1)。加热反应混合物也不能产生所需的三羟醛加合物。显然，需要一种新的方法。简单的溶剂筛选对反应有有趣的影响：在己烷或甲苯中进行反应只得到单一的羟醛加合物(表1，条目2和3)，而当
Polyketides have long provided synthetic organic chemists with a variety of complex architectures to construct and develop new chemical tools for, and provided medicine with, many useful drugs. About 1% of polyketides display drug activity, which is five times the average for natural products.[1] A common strategy in the synthesis of polyketides is the cross-aldol reaction, although it can be complicated by uncontrolled oligomerization and dehydration reactions.[2] There has been significant advances in the development of the asymmetric aldol and allylation reactions of aldehydes.[3, 4] However, further manipulations, such as alcohol protection or redox reactions, are often required before the next iteration can proceed. Therefore, there has been increasing interest in one-pot cascade aldol reactions;[5, 6] however, only one example successfully proceeded to the third aldol iteration, and in low yields.[5a] Inspired by the seminal work of Mukaiyama et al.,[2a] our research group reported an aldol cascade reaction using tris (trimethylsilyl) silyl enol ethers, such as the easily prepared 1,[7] to give versatile aldehyde products 2 (Scheme 1). Moreover, these aldehydes can be treated with Grignard or polyhalomethyllithium reagents in the same reaction pot to generate mono-protected diols.[8] The formation of these compounds is highly diastereoselective because of the extreme steric bulk of the tris (trimethylsilyl) silyl group.[7a, 8a, 9] Significantly, further addition of 1 to 2 is strictly prevented, because of the steric bulk of the (TMS) 3SiNTf2· 2 complex.We set out with the challenging aim of extending this aldol cascade reaction to three or more additions of 1 to an aldehyde for the construction of polyketides in a minimal number of steps. Despite several attempts, treatment of dimethylpropanal with 1 (4.0 equivalents) and Tf2NH in dichloromethane gave only the double-aldol product 2a (R= tBu), without the formation of any triple-aldol product 3a (Table 1, entry 1). Heating the reaction mixture also failed to produce the desired triple aldol adduct. Evidently, a new approach was required. Simple solvent screening had interesting effects on the reaction: performing the reaction in hexane or toluene gave only the mono-aldol adduct (Table 1, entries 2 and 3), whilst when
登录
查看更多内容
影响因子：
15
作者：
Boxer, Matthew B.;Yamamoto, Hisashi
通讯作者：
Yamamoto, Hisashi
影响因子：
3.6
作者：
Denmark, SE;Bui, T
通讯作者：
Bui, T
影响因子：
1.6
作者：
KATO, J;MUKAIYAMA, T
通讯作者：
MUKAIYAMA, T
影响因子：
15
作者：
Iwata, Mitsutaka;Yazaki, Ryo;Shibasaki, Masakatsu
通讯作者：
Shibasaki, Masakatsu
影响因子：
16.6
作者：
Casas, J;Engqvist, M;Córdova, A
通讯作者：
Córdova, A