Enantioselective phase-transfer-catalyzed intramolecular Aza-Michael reaction: Effective route to pyrazino-indole compounds
Enantioselective phase-transfer-catalyzed intramolecular Aza-Michael reaction: Effective route to pyrazino-indole compounds
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DOI：
10.1002/anie.200705685
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发表时间：
2008-01-01
影响因子：
16.6
通讯作者：
Umani-Ronchi, Achille
中科院分区：
文献类型：
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作者：
Bandini, Marco;Eichholzer, Astrid;Umani-Ronchi, Achille
3，4-二氢吡嗪并[1，2-a]吲哚-1（2 H）-酮1（参见方案1）由于其广泛的生物活性（即，其抗真菌性质、非竞争性抗组胺活性和对组胺能受体的特异性抑制）而引起了广泛的关注。[2]此外，最近的专利报道了相应的1，2，3，4-四氢吡嗪并[1，2-a]吲哚2（方案1）作为抗肥胖剂以及在治疗和预防非胰岛素依赖性糖尿病中的有效性。[3]从这些研究中，立体中心的绝对构型对药理活性的重要性清楚地显现出来。此外，由于哌嗪化合物2可容易地由1 [3]获得，因此开发一种有效的立体选择性合成吡嗪并-吲哚-1-酮1的路线将是非常有价值的。手性池的使用和外消旋体的拆分是迄今为止1和2的唯一合成路线。[3-5]在我们正在进行的多环吲哚官能化研究中，[6]我们最近通过区域和对映选择性C3-烯丙基亲核烷基化（高达97%ee）传达了一种有效的Pd催化四氢-β-咔啉方法。[7]不幸的是，我们所有尝试利用这种方法进行对映选择性吲哚基-N1闭环反应都是不成功的。在这里，我们描述了第一个高度对映选择性合成的分子图案的类型1通过相转移催化[8]氮杂迈克尔加成。[9]无金属方法的使用[10]源于我们最近对分子内碱催化合成1的发现，从容易获得的前体3（方案2）。[11]然而，在本发明的闭环反应中使用刘易斯酸催化失败，可能是由于α，β-不饱和酯的差的亲电特性和由于起始材料/产物抑制（即，由强配位酰胺基团施加的金属中毒效应）导致的低催化剂周转率。寻找一个对映选择性的变体，我们首先把我们的注意力转向手性有机碱，如金鸡纳生物碱和金雀花碱，这给了令人失望的结果在环化3a（X= H;甲苯，回流，48小时，0%ee）。我们推断，不令人满意的立体诱导可归因于奎宁环的铵盐和亲核吲哚中间体之间形成灵活且不够紧密的离子对（图1a）。
3, 4-Dihydropyrazino [1, 2-a] indol-1 (2H)-ones 1 (see Scheme 1) have attracted much attention due to the broad scope of their biological activities (that is, their antifungal properties, noncompetitive antihistamine activity, and specific inhibition of serotonergic receptors).[2] Moreover, recent patents reported the effectiveness of the corresponding 1, 2, 3, 4-tetrahydropyrazino [1, 2-a] indoles 2 (Scheme 1) as antiobesity agents and in the treatment and prevention of noninsulin-dependent diabetes.[3] From these studies, the importance of the absolute configuration of the stereocenters on the pharmacological activity emerged clearly. Moreover, since the piperazine compounds 2 are readily obtainable from 1,[3] the development of an effective stereoselective synthetic route to pyrazino-indol-1-ones 1 would be extremely valuable. The use of chiral pools and the resolution of racemates are the only synthetic routes to 1 and 2 to date.[3–5] During our ongoing research addressing the functionalization of polycyclic indoles,[6] we recently communicated an efficient Pd-catalyzed approach to tetrahydro-β-carbolines through regio-and enantioselective C3-allylic nucleophilic alkylation (up to 97% ee).[7] Unfortunately, all our attempts to exploit such an approach to perform enantioselective indolyl-N1 ring-closing reactions were unsuccessful. Herein, we describe the first highly enantioselective synthesis of molecular motifs of type 1 through a phase-transfer-catalyzed [8] aza-Michael addition.[9] The employment of a metal-free approach [10] stems from our recent findings on the intramolecular base-catalyzed synthesis of 1, from readily available precursors 3 (Scheme 2).[11] However, the use of Lewis acid catalysis in the present ring-closing reaction failed, probably due to the poor electrophilic character of the α, β-unsaturated ester and to low catalyst turnover as a result of starting material/product inhibition (that is, a metallo-poisoning effect exerted by the strongly coordinating amide group). Searching for an enantioselective variant, we firstly turned our attention to chiral organic bases such as the Cinchona alkaloids and sparteine, which gave disappointing results in the cyclizations of 3a (X= H; toluene, reflux, 48 h, 0% ee). We reasoned that the unsatisfactory stereoinduction could be ascribable to the formation of flexible and not sufficiently tight ion pairs between the ammonium salt of the quinuclidine ring and the nucleophilic indolate intermediate (Figure 1a).