Enantioselective Formal Alkenylations of Imines Catalyzed by Axially Chiral Dicarboxylic Acid Using Vinylogous Aza-Enamines
Enantioselective Formal Alkenylations of Imines Catalyzed by Axially Chiral Dicarboxylic Acid Using Vinylogous Aza-Enamines
复制标题
DOI：
10.1002/anie.201003600
复制
发表时间：
2010-01-01
影响因子：
16.6
通讯作者：
Maruoka, Keiji
中科院分区：
文献类型：
--
作者：
Hashimoto, Takuya;Kimura, Hidenori;Maruoka, Keiji
手性烯丙基胺的催化不对称合成因其合成方法的多样性而成为研究的热点。在这种情况下，催化不对称烯基化亚胺，虽然被认为是一个相当简单的过程，最近才成为一个有吸引力的选择，朝着这个目标，不对称烯丙基胺化的流行。[1]快速发展的有机催化领域在这一最新发展中发挥了关键作用，如在不对称Petasis反应中所看到的，[2]该反应产生手性烯丙基胺，其具有从相应的烯基硼物种转移的富电子烯基。[3-6]有机催化的氮杂-Morita-Baylis-Hillman反应，其中a，b-不饱和羰基化合物通过催化产生的离子中间体形式上作为烯基阴离子在其α位上起作用，构成了提供具有吸电子烯烃部分的手性烯丙基胺的另一个重要策略。[7]乙烯基氮杂烯胺（腙;方案1）[8]，其可以通过相应的a，b-不饱和醛和N，N-二烷基肼的缩合容易地制备，已知是一类非极性物质。[9]这些物质在C1和C3-位（B位）表现出亲核性，这是N，N-二烷基氨基给电子的结果。[10]文献中零星报道了它们在C3处与高度亲电试剂的反应，[11，12]并且其反应机理被理解为通过离子中间体的初始形成和连续的去质子化以再生烯烃部分来进行。虽然这种基本理解清楚地暗示了在与乙烯基氮杂烯胺的反应中应用催化活化的前手性底物作为亲电试剂以正式实现不对称烯基化的可能性，但迄今为止还没有报道实现这一吸引人的目标的实例。[13]在本文中，我们报道了利用乙烯基氮杂烯胺在轴向手性二羧酸催化的亚胺的正式烯基化（乙烯基亚胺基氮杂烯胺反应）中的这种有趣但尚未探索的性质，其独特之处在于反应体系产生高度对映体富集的手性烯丙基胺，同时避免了在催化剂和底物中对任何种类的金属源的需要。此外，由于氮杂-烯胺部分可以通过用过酸处理容易地转化为腈基，因此这被认为是一种通过反应性uppolung实现的用丙烯腈及其类似物在本质上缺电子的b-碳原子处进行不对称烯基化的简便方法，因此该方法是对氮杂-森田-贝利斯-希尔曼反应的补充。一般来说，氮杂烯胺在不对称催化中应用的主要障碍在于难以获得高的对映选择性，尽管有一些里程碑式的努力。[14]在这种情况下，我们最近报道了最初在我们的研究小组中开发的轴向手性二羧酸[15]具有在甲酰胺和芳酰胺衍生的氮杂烯胺与各种N-Boc亚胺的不对称加成（亚氨基氮杂烯胺反应）中实现优异水平的对映选择性的显著能力。[14a B，16]基于该研究，我们着手检查乙烯基氮杂烯胺2a（衍生自丙烯醛）与苯甲醛N-Boc亚胺的轴向手性二羧酸催化加成（表1，条目1）。在该初步研究中，立即变得明显的是，在我们先前的研究中优化的反应条件的应用对于该特定的反应体系是完全无效的。反应...
Catalytic asymmetric synthesis of chiral allylic amines has been an extensively studied research field owing to their remarkable synthetic versatility. In this context, catalytic asymmetric alkenylation of imines, though considered to be quite a straightforward process, has only recently become an attractive option toward this end, following the prevalence of asymmetric allylic amination.[1] The rapidly growing field of organocatalysis has played a pivotal role in this latest development as can be seen in the asymmetric Petasis reaction,[2] which gives chiral allylic amines with an electron-rich alkene group being transferred from the corresponding alkenyl boron species.[3–6] The organocatalytic aza-Morita–Baylis–Hillman reaction, wherein a, b-unsaturated carbonyl compounds formally act as an alkenyl anion at their a position via a catalytically generated ionic intermediate, constitutes another important strategy to afford chiral allylic amines with an electron-withdrawing alkene moiety.[7] Vinylogous aza-enamines (hydrazones; Scheme 1),[8] which can be easily prepared by the condensation of the corresponding a, b-unsaturated aldehydes and N, N-dialkylhydrazines, are known to be a class of umpolung species.[9] These species exhibit nucleophilic character at the C1 and C3-positions (b position) as a result of the electron-donation from the N, N-dialkylamino group.[10] Their reactions at C3 with highly electrophilic reagents have been sporadically reported in the literature,[11, 12] and its reaction mechanism is understood to proceed via the initial formation of the ionic intermediate and successive deprotonation to regenerate the alkene moiety. Although this fundamental understanding clearly implies the possibility of applying the catalytically activated prochiral substrates as electrophile in the reaction with vinylogous aza-enamines to formally realize asymmetric alkenylations, there has been no example reported to date realizing this appealing objective.[13] Herein we report the exploitation of this intriguing but yet unexplored property of vinylogous aza-enamines in axially chiral dicarboxylic acid catalyzed formal alkenylation of imines (vinylogous imino aza-enamine reaction), which is distinctive in that the reaction system generates highly enantioenriched chiral allylic amines while obviating the need for any kind of metallic sources in the catalyst and substrates. Furthermore, as an aza-enamines moiety can be easily converted into a nitrile group by treatment with a peracid, this is considered to be a facile method for the asymmetric alkenylation with acrylonitrile and its analogues at the intrinsically electron-deficient b-carbon atom realized by the reactivity umpolung, thus this process is complementary to aza-Morita-Baylis–Hillman reactions. In general, the main obstacle on the use of aza-enamines in asymmetric catalysis lies in the difficulty to attain high enantioselectivities despite some landmark endeavors.[14] In this context, we have recently reported that axially chiral dicarboxylic acid, originally developed in our research group,[15] has a remarkable ability to achieve an excellent level of enantioselectivities in the asymmetric addition of formaldehyde-and arylaldehyde-derived aza-enamines to various N-Boc imines (imino aza-enamine reaction).[14a, b, 16] Based on this study, we set out to examine the axially chiral dicarboxylic acid catalyzed addition of the vinylogous azaenamine 2a (derived from acrolein) to benzaldehyde N-Boc imine (Table 1, entry 1). In this preliminary study, it immediately became obvious that the application of the reaction conditions optimized in our previous study was completely ineffective for this specific reaction system. The reaction …