Palladium-catalyzed asymmetric allylation of prochiral nucleophiles: Synthesis of 3-allyl-3-aryl oxindoles
Palladium-catalyzed asymmetric allylation of prochiral nucleophiles: Synthesis of 3-allyl-3-aryl oxindoles
复制标题
DOI：
10.1002/anie.200460335
复制
发表时间：
2005-01-01
影响因子：
16.6
通讯作者：
Frederiksen, MU
中科院分区：
文献类型：
--
作者：
Trost, BM;Frederiksen, MU
通过控制绝对立体化学生成季中心是有机合成中的一个基本挑战。[1]在这方面，我们已经研究了不对称烯丙基烷基化（AAA）的能力，以控制立体化学在前手性亲核试剂，一个特别艰巨的挑战，因为它的直接攻击在面对的烯丙基片段相反，绑定到金属。我们在几类亲核试剂上取得的成功，例如β-酮酯、[2]酮、[3]等，[4-6]鼓励我们研究具有特别重要意义的新型亲核试剂，例如内酰胺烯醇化物。3-烷基-3-芳基羟吲哚结构基序是许多具有生物活性的天然产物的突出特征，例如重氮酰胺A [7]和leptosin D [8]以及几种药物活性化合物。[9]尽管这一结构主题的重要性，很少有一般的方法存在其建设。除了由Overman及其同事开发的优雅的不对称分子内Heck反应[10]之外，仅报道了基于Pd催化的α芳基化[11]和不对称酰基转移的分散实例。[12]Pd催化的AAA代表了这一重要结构类别的概念新颖和灵活的方法，特别是当与Hartwig及其同事开发的用于合成3-芳基羟吲哚的强大Pd催化的α-芳基化方案相结合时。[11当协同使用时，这些方法将容易地从简单且容易获得的起始材料获得具有季立体中心的结构复杂的羟吲哚[等式（1）]。在此，我们报告这一战略的成功发展。我们的研究开始于在我们的标准配体组5-7的存在下，在羟吲哚8到形式9的Pd催化的AAA反应中对碱基进行全面的矩阵筛选（表1）。[14]这些实验揭示了产率和对映体选择性的大的变化，例如，与配体5-7结合使用碳酸钾显示出产率和ee值（表1，条目1-3）相对于其它抗衡离子（结果未显示）的显著增加。较弱的碱显示出与该反应更好的相容性（表1，条目4和5）。有趣的是，10mol%KF给出了与化学计量反应基本相同的结果（表1，条目5和6）。当使用非金属碱如Et 3 N（表1，条目7和8）时，也观察到这种趋势。当使用BSA时，ee值显著增加36%，当碱负荷从1当量降低到0.1当量时，观察到了（从40到76%ee（表1，条目9和10）。这些观察结果与AcOK在该反应中的熟练程度相结合表明，仅需要加入催化量的碱来引发烯醇化，乙酸烯丙酯的电离保持了碱的催化浓度。然而，烯醇化物或烯醇可充当亲核试剂。当羟吲哚互变异构为羟基吲哚时，似乎有理由探索是否实际上是后者充当了羟吲哚的异构体。
The generation of quaternary centers with control of absolute stereochemistry represents a fundamental challenge in synthetic organic chemistry.[1] In this area, we have examined the ability of asymmetric allylic alkylation (AAA) to control stereochemistry at prochiral nucleophiles, a particularly daunting challenge given its direct attack at the face of the allyl fragment opposite to that bound to the metal. Our success with a few classes of nucleophiles exemplified by β-ketoesters,[2] ketones,[3] among others,[4–6] encouraged us to examine new classes of nucleophiles of particular significance such as lactam enolates. The 3-alkyl-3-aryl oxindole structural motif is a prominent feature in a number of biologically active natural products, for example, diazonamide A [7] and leptosin D,[8] as well as several pharmaceutically active compounds.[9] In spite of the importance of this structural motif, few general methods exist for its construction. Aside from the elegant asymmetric intramolecular Heck reaction developed by Overman and co-workers,[10] only scattered examples based on Pd-catalyzed α arylation [11] and asymmetric acyl transfer have been reported.[12] Pdcatalyzed AAA represents a conceptually novel and flexible approach to this important structural class, especially when combined with the powerful Pd-catalyzed α-arylation protocols for the synthesis of 3-aryl oxindoles developed by Hartwig and co-workers.[11, 13] When used in concert, these processes would readily give access to structurally complex oxindoles endowed with a quaternary stereocenter from simple and readily available starting materials [Eq (1)]. Herein we report the successful development of this strategy. Our studies commenced with a comprehensive matrix screen of bases in the presence of our standard set of ligands 5–7 in the Pd-catalyzed AAA reaction of oxindole 8 to form 9 (Table 1).[14] These experiments revealed large variations in yield and enantioselectivity, for example, the use of potassium carbonate in conjunction with ligands 5–7 showed a dramatic increase in both yield and ee values (Table 1, entries 1–3) relative to other counterions (results not shown). Weaker bases showed better compatibility with this reaction (Table 1, entries 4 and 5). Interestingly, 10 mol% KF gave essentially identical results to the stoichiometric reaction (Table1, entries 5 and 6). This trend was also observed when nonmetal bases such as Et3N (Table 1, entries 7 and 8) were used. When BSA was utilized, a spectacular increase in the ee value by 36%(from 40 to 76% ee) was observed when the base loading was lowered from 1 to 0.1 equivalent (Table1, entries 9 and 10).These observations combined with the proficiency of AcOK in this reaction suggested that the addition of only a catalytic amount of base was necessary to initiate the enolization, as ionization of allyl acetate maintained the catalytic concentration of base. However, either the enolate or enol may function as the nucleophile. As oxindoles tautomerize to hydroxyindoles, it seemed reasonable to probe whether it was in fact the latter that acted as the