Chiral Ammonium Betaines as Ionic Nucleophilic Catalysts
Chiral Ammonium Betaines as Ionic Nucleophilic Catalysts
复制标题
DOI：
10.1002/anie.201002315
复制
发表时间：
2010-01-01
影响因子：
16.6
通讯作者：
Ooi, Takashi
中科院分区：
文献类型：
--
作者：
Uraguchi, Daisuke;Koshimoto, Kyohei;Ooi, Takashi
不对称亲核催化在过去几十年中得到了广泛的研究，并在现代不对称合成中发挥着越来越重要的作用。 [1]这种催化的一般决定性特征是路易斯碱性催化剂与底物反应，通过形成新的共价键产生反应性离子中间体，该共价键最终将通过催化剂的消除而裂解。在这方面，与常用的电子中性分子相比，阴离子分子可以充当潜在的更亲核的催化剂来引发反应，但它会产生相当稳定的不带电荷的中间体（见下文）。因此，利用阴离子分子的反应性开发新型亲核催化，即对映选择性离子亲核催化的研究取得了有限的成功。 [2, 3] 我们最近引入了手性铵甜菜碱 1 作为一种新的、但有趣的结构基序作为有机分子催化剂。 [4, 5] 其阴离子位点（芳氧基化物）的基本特征和氢键能力其共轭酸（芳基氢氧化物）的存在似乎是实现高度对映选择性曼尼希型反应的关键特征。鉴于芳氧基化物官能团具有亲核特性，我们设想经过适当的结构操作后 1 可以演变成手性亲核试剂。 [6]通过亲核催化剂进行的酰基转移反应是有机合成化学中基本的分子转化。在这些反应中，Steglich重排[7]即将5-恶唑基碳酸酯重排成4-羧基吖内酯，为建立四取代立体中心提供了一个有吸引力的过程，并且还可以作为评估手性亲核催化剂效率的模型系统（方案1）；[8, 9]该领域的开创性工作由Ruble和Fu报道，用于合成DMAP类似物。 [9a]然而，在该反应中使用离子亲核试剂，例如芳氧基化鎓 (Q+OArÀ) 是很困难的，可能是因为原位生成的电子中性芳基酯 (R’COOAr) 对烯醇化鎓 A（左循环）的反应活性较低。相比之下，在甜菜碱催化中，限速碳-碳键的形成将以伪分子内的方式进行，并且独特的离子对中间体B不仅有可能规避反应性问题，而且还可以诱导前所未有的立体控制水平（右循环）。在此，我们提出了使用手性铵甜菜碱作为亲核离子催化剂的高度对映选择性 Steglich 重排。该反应通常通过在258℃下将2-叔丁基-4-苄基-5-恶唑基2,2,2-三氯乙基碳酸酯(2a)的1,4-二恶烷溶液添加到1(2mol%)和粉末状4分子筛[10]在1,4-二恶烷中的搅拌混合物中来进行。 [11]由于最初使用 1a [4] 作为催化剂的尝试表明其在反应活性和立体选择性方面均无效，因此我们制备了 1b，它在芳氧基化物部分 (R2) 的 3 位上缺少取代基，以发挥芳氧基阴离子固有的亲核性。正如预期的那样，在 1b 存在的情况下重排顺利进行，得到所需产物 3a，产率 93%，对映体过量 93%（方案 2）。 [12]值得注意的是，加入一滴 2a 溶液后，甜菜碱 1b 特有的黄色立即变亮，这意味着中间体 B 的形成。事实上，通过 ESI/MS 方法分析该混合物显示出对应于酰化 1b (m/z 592) 的峰，因此证实了
Asymmetric nucleophilic catalysis has been extensively studied over the last several decades and plays an increasingly important role in modern asymmetric synthesis.[1] The general definitive feature of this catalysis is that a Lewis basic catalyst reacts with a substrate to give a reactive ionic intermediate through the formation of a new covalent bond, which will be eventually cleaved by the elimination of the catalyst. In this respect, an anionic molecule could function as a potentially more nucleophilic catalyst for initiating the reaction, compared to the commonly utilized electronically neutral molecules, but it generates a rather stable intermediate bearing no charge (see below). Hence, research toward exploiting the reactivity of anionic molecules for the development of a new type of nucleophilic catalysis, that is, enantioselective ionic nucleophilic catalysis, has met with limited success.[2, 3] We recently introduced the chiral ammonium betaine 1 as a new, yet intriguing structural motif as an organic molecular catalyst.[4, 5] The basic character of its anionic site (aryloxylate) and the hydrogen-bonding capability of its conjugate acid (arylhydroxide) appeared to be the key features for realizing highly enantioselective Mannich-type reactions. Given that the aryloxylate functionality has a nucleophilic character, we envisioned that 1 could be evolved into a chiral nucleophile after appropriate structural manipulations.[6] Acyl transfer reactions by means of nucleophilic catalysts are the fundamental molecular transformation in synthetic organic chemistry. Among these reactions, the Steglich rearrangement,[7] which is the rearrangement of 5-oxazolyl carbonate into 4-carboxyazlactones, offers an attractive process for establishing a tetrasubstituted stereogenic center, and also serves as a model system for evaluating the efficiency of chiral nucleophilic catalysts (Scheme 1);[8, 9] the pioneering work in this field was reported by Ruble and Fu for a synthetic analogue of DMAP.[9a] However, the use of an ionic nucleophile, such as onium aryloxylate (Q+OArÀ), in this reaction has been difficult, probably because of the presumed low reactivity of the in situ generated, electronically neutral aryl ester (R’COOAr) toward the onium enolate A (left cycle). In contrast, in the betaine catalysis, the ratelimiting carbon–carbon bond formation would proceed in a pseudo-intramolecular manner, and the unique ion-pair intermediate B could have the potential to not only circumvent the reactivity problem but also induce an unprecedented level of stereocontrol (right cycle). Herein, we present the highly enantioselective Steglich rearrangement using chiral ammonium betaines as nucleophilic ionic catalysts. The reaction was generally conducted by the addition of a 1, 4-dioxane solution of 2-tert-butyl-4-benzyl-5-oxazolyl 2, 2, 2-trichloroethyl carbonate (2a) to a stirred mixture of 1 (2 mol%) and powdered 4 molecular sieves [10] in 1, 4-dioxane at 258C.[11] Since an initial attempt with 1a [4] as a catalyst showed its ineffectiveness in terms of both reactivity and stereoselectivity, we prepared 1b, which lacks a substituent at the 3 position of the aryloxylate moiety (R2) to bring out the inherent nucleophilicity of the aryloxy anion. As expected, the rearrangement in the presence of 1b proceeded cleanly to give the desired product 3a in 93% yield, and with an enantiomeric excess of 93%(Scheme2).[12] Notably, the characteristic yellow color of betaine 1b instantaneously lightened with the addition of one drop of a solution of 2a, which implies the formation of the intermediate B. Indeed, the analysis of this mixture by ESI/MS methods showed a peak corresponding to acylated 1b (m/z 592), thus corrobo-