Asymmetric activation of tropos 2,2′-biphenol with cinchonine generates an effective catalyst for the asymmetric Strecker reaction of N-Tosyl-protected aldimines and ketoimines
Asymmetric activation of tropos 2,2′-biphenol with cinchonine generates an effective catalyst for the asymmetric Strecker reaction of N-Tosyl-protected aldimines and ketoimines
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DOI：
10.1002/anie.200703188
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发表时间：
2007-01-01
影响因子：
16.6
通讯作者：
Feng, Xiaoming
中科院分区：
文献类型：
--
作者：
Wang, Jun;Hu, Xiaolei;Feng, Xiaoming
催化不对称Strecker反应是合成手性α-氨基酸最有效的方法之一。在过去的十年中，人们在这一领域做出了巨大的努力，并披露了许多成功的协议。[1-3]然而，这一领域还需要更多的努力，首先，因为酮亚胺的高效氰化以提供具有重要药用意义的α季氨基酸[4]的前体是困难的，而且很少报道，其次，寻找一种既能作用于醛胺又能作用于酮亚胺的催化剂体系是具有挑战性和有趣的。在此，我们提出了一个高度对映选择性的n -Ts保护（Ts=对甲苯磺酰基）醛胺和酮亚胺的氰化，该氰化是由一种新的催化剂促进的，该催化剂是由轴向柔性2,2 ' -双酚（bipol）与手性活化剂1通过与金属的配位相互作用产生的不对称活化[5]（方案1）。我们的初步研究表明，以三甲基硅氰（TMSCN）为氰化试剂，在甲苯中，在20%催化剂的存在下，在À208C条件下，用cinchonine 1活化的bipol/Ti (OiPr) 4是一种很有前景的N-Ts苯二胺4a氰化催化剂（表1，第1项）。通过筛选几种修饰的双酚衍生物，进一步提高了ee值（表1，条目2-10）。特别是，在3,3 '位置上具有立体要求的芳香取代基的双酚配体极大地提高了对映选择性，达到94-95% ee（表1，条目7 - 10）。考虑到3h的性能优异，制备相对方便，我们以此来优化其他参数。将3h/Ti (OiPr) 4/1的比例调整为1.2:1.2:1后，得到的5a的ee可达97%，收率大于99%（表1，条目11）。然而，当催化剂负载降低时，1.2当量iPrOH[6]的存在对于保持优异的结果是必不可少的（表1，条目12-14）。其他条件如中心金属、溶剂和温度也进行了研究，但没有得到好的结果。在最佳条件下（表1，条目14），测试了一系列从芳香、杂环、α、β不饱和和脂肪醛衍生的亚胺（4a - 40），获得了优异的结果（高达97% ee）（表2，条目1 -）
The catalytic asymmetric Strecker reaction is one of the most powerful strategies for the synthesis of chiral α-amino acids. In the last decade, great endeavors have been devoted to this area and a number of successful protocols have been disclosed.[1–3] However, more efforts are still needed in this area, first, because highly efficient cyanation of ketoimines to afford the precursors of pharmaceutically important αquaternary amino acids [4] is difficult and little reported, and second, as searching for a catalyst system which could work well not only on aldimines but also on ketoimines is challenging and interesting. Herein, we present a highly enantioselective cyanation of N-Ts-protected (Ts= p-toluenesulfonyl) aldimines and ketoimines promoted by a novel catalyst generated from the asymmetric activation [5] of axially flexible 2, 2’-biphenol (bipol) with a chiral activator 1 through coordinative interaction with a metal (Scheme 1). Our initial studies showed that bipol/Ti (OiPr) 4 activated by cinchonine 1 was a promising catalyst for the cyanation of N-Ts benzaldimine 4a using trimethylsilyl cyanide (TMSCN) as the cyanide reagent at À208C in toluene in the presence of 20 mol% catalyst (Table 1, entry 1). Further improvement of ee values was achieved by screening several modified bipol derivatives (Table 1, entries 2–10). Especially, the bipol ligand bearing a sterically demanding aromatic substituent at the 3, 3’-position greatly enhanced the enantioselectivity to 94–95% ee (Table1, entries7–10). Considering the excellent performance and relatively facile preparation of 3h, we used this to optimize the other parameters. After adjusting the ratio of 3h/Ti (OiPr) 4/1 to 1.2: 1.2: 1, 5a was obtained in up to 97% ee and greater than 99% yield (Table1, entry11).However, when the catalyst loading was lowered, the presence of 1.2 equivalents of iPrOH [6] was essential to maintain the excellent results (Table 1, entries 12–14). Other conditions such as the central metal, solvent, and temperature were also investigated, but no superior results were obtained. Under optimal conditions (Table 1, entry 14), a series of imines (4a–4o) derived from aromatic, heterocyclic, α, βunsaturated, and aliphatic aldehydes were tested and excellent results (up to 97% ee) were achieved (Table 2, entries 1–