Organocatalytic Asymmetric Direct C?sp?3?H Functionalization of Ethers: A Highly Efficient Approach to Chiral Spiroethers
Organocatalytic Asymmetric Direct C?sp?3?H Functionalization of Ethers: A Highly Efficient Approach to Chiral Spiroethers
复制标题
醚的有机催化不对称直接C?sp?3?H官能化：手性螺醚的高效方法
DOI：
10.1002/anie.201204274
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发表时间：
2012-01-01
影响因子：
16.6
通讯作者：
Li, Hui
中科院分区：
文献类型：
--
作者：
Jiao, Zhi-Wei;Zhang, Shu-Yu;Li, Hui
手性螺醚存在于许多生物活性天然产物(图1)和药物中，手性螺醚的不对称合成[1]是有机合成中的一项重要工作。在过去的几年里，人们为开发合成螺环醚的方法付出了巨大的努力，[2]虽然已开发的方法中有许多涉及多个步骤，但只有少数是对映体选择性的。因此，仍然需要开发高效、催化和对映体选择性的方法。Csp3±H键的直接和选择性官能化不仅是基础有机化学中一个重要而活跃的研究课题，[3]它也因其原子和步骤经济而成为一种实用的有机合成方法。[4]在已报道的转化方法中，α到杂原子的Csp3±H键的直接官能化的分子内氧化还原过程对于合成结构多样的胺和醚衍生物具有重要意义。[6]在分子内氧化还原过程领域，有许多关于α位置上直接对映体选择性Csp3±H官能化到氮原子的报道。[7]然而，相应的醚类对映体选择性反应的例子很少。2005年，萨姆斯和同事们。报道了Sc(OTf)3或BF3·Et2O可以引发环醚1的Csp3±H键的直接官能化，得到外消旋螺醚2‘(方案1)。这种转化通过串联的1，5-氢化物转移/环化氧化还原过程进行。[5B]这些结果表明，不对称催化变体是可能的，该过程包括将环醚的外消旋混合物转化为对映体富集型螺环醚。有机催化已成为有机化学中的一种重要方法，并已被用于许多对映体选择性转化。[8]为了完成上述对映体选择性C±H键功能化，我们设想，通过含有α，β-不饱和醛的环醚(1)与手性有机催化剂(R1NHR2)反应而形成的亚胺离子将引发1，5-氢化物移动，生成的烯胺和氧卡宾基团将反应生成手性螺醚2‘’(方案1)。在这里，我们介绍了我们在这一目标上取得的成功。我们的研究始于使用四氢呋喃1a作为模型底物，它同时含有α，β不饱和醛和丙二酸二乙酯部分，以确定合适的催化体系。我们设想，需要强酸的存在才能确保亚胺离子具有足够的电泳性，以促进α-氢原子从1a的四氢呋喃部分转移。因此，催化量的(+)-樟脑磺酸(CsA)和一种由脯氨酸衍生的
The asymmetric synthesis of chiral spiroethers, which are present in numerous bioactive natural products (Figure 1) and pharmaceuticals,[1] is an important endeavor in organic synthesis. Tremendous efforts have been made during the past few years toward developing methods for the synthesis of spiroethers,[2] although of the methods developed, many involve multiple steps and only a few are enantioselective.[2d–i] Therefore, the development of methods that are highly efficient, catalytic, and enantioselective is still required. The direct and selective functionalization of inactive Csp3ÀH bonds is not only a significant and actively studied subject in fundamental organic chemistry,[3] it is also becoming a practical method for organic synthesis because of its atom-and step economy.[4] Among the reported transformations, intramolecular redox processes for the direct functionalization of Csp3ÀH bonds that are α to heteroatoms are important for the synthesis of structurally diverse amine and ether derivatives.[5] Furthermore, since the pioneering work of Kim and co-workers,[6] there have many good results reported in the area of intramolecular redox processes for the direct enantioselective Csp3ÀH functionalization at positions α to nitrogen atoms.[7] However, examples of the corresponding enantioselective reaction of ethers are scarce. In 2005, Sames and co-workers. reported that Sc (OTf) 3 or BF3· Et2O could initiate a direct functionalization of Csp3ÀH bonds of cyclic ethers 1 to give racemic spiroethers 2’(Scheme 1). This transformation proceeds through a tandem 1, 5-hydride transfer/cyclization redox process.[5b] These results suggested that an asymmetric catalytic variant should be possible, a process that would involve the conversion of a racemic mixture of a cyclic ether into enantiomerically enriched spiroether. Organocatalysis has emerged as an important method in organic chemistry and it has been used to effect many enantioselective transformations.[8] To accomplish the above enantioselective CÀH bond functionalization, we envisioned that the formation of an iminium ion through the reaction between a cyclic ether containing an α, β-unsaturated aldehyde group (1) and a chiral organocatalyst (R1NHR2) would initiate a 1, 5-hydride shift and that the resulting enamine and oxocarbenium moieties would react to give chiral spiroether 2’’(Scheme 1). Herein, we present our success toward this goal.Our investigation started with the use of tetrahydrofuran 1a, which contains both an α, β-unsaturated aldehyde and a diethylmalonate moiety, as the model substrate for identifying a suitable catalytic system. We envisioned that the presence of strong acid would be required to ensure that the iminium ion would be of sufficient electrophility for facilitating the transfer of the α-hydrogen atom from the THF moiety of 1a. Thus the combination of a catalytic amount of (+)-camphorsulphonic acid (CSA) and a proline-derived