A Doubly Axially Chiral Phosphoric Acid Catalyst for the Asymmetric Tandem Oxyfluorination of Enamides
A Doubly Axially Chiral Phosphoric Acid Catalyst for the Asymmetric Tandem Oxyfluorination of Enamides
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DOI：
10.1002/anie.201205383
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发表时间：
2012-01-01
影响因子：
16.6
通讯作者：
Toste, F. Dean
中科院分区：
文献类型：
--
作者：
Honjo, Takashi;Phipps, Robert J.;Toste, F. Dean
碳氟键的选择性构建引起了药物化学家的极大兴趣，因为用碳氟键取代碳氢键仍然是开发具有改善的物理和代谢特征以及生物活性的生物活性分子的有效途径。为此，在过去的十年里，已经报道了一些令人印象深刻的催化不对称氟化的例子。[2，3]我们的实验室最近引入了一种新的基于相转移催化的不对称氟化策略，该策略使用基于BINOL衍生的磷酸盐的手性阴离子催化剂[等式(1)]。5]由于β-氟胺基序在药物化学中的重要性，我们采用这一策略开发了环烯胺的高度不对称氟化，使我们能够分离稳定但高度通用的富含对映体的α-氟-N-酰亚胺。[4B]鉴于BINOL磷酸催化剂已被证明有能力控制亚胺的加成，[6]我们假设醛衍生的烯胺应该特别感兴趣，因为我们的方案在烯胺氟化后，将首先生成质子化的N-酰亚胺离子[式(2)]。这种中间体应该表现出与手性磷酸阴离子的氢键作用，允许外部的氧亲核试剂在催化剂的控制下加成，构成烯胺的氧氟化。[7]由此得到的立体定义的α-氟-N，O-氨基将特别引起人们的兴趣，因为手性N，O-氨基普遍存在于天然产品中，据我们所知，氟引入对这个基元的影响到目前为止还没有被探索。[8]关于现有的不对称N，O-胺的合成，Antilla和他的同事已经报道了磷酸催化的醇[9]和氢过氧化物[10]与N-酰亚胺的加成反应。尽管提供高对映体选择性的例子仅限于芳香亚胺，而且在任何情况下都不能使用简单的水作为亲核剂来获得半胺。我们意识到，我们的目标是利用单一催化剂进行连续两次的对映选择性转化，这带来了复杂性。催化剂不仅必须能够促进两个反应，而且来自初始安装的立体中心的固有的非立体控制可能与用于形成第二立体中心的催化剂控制匹配或不匹配。然而，这种同样的效应可能会使双重立体分化的效果被利用，在某些情况下可能导致极高的立体控制力。此外，在我们之前的研究中观察到，尽管在真空下在808℃下干燥，但在我们的氟化中使用的选择氟含有内在的水分，我们假设这些水分可能足以原位形成半纤维。我们开始我们的研究使用(E)构型的N-苯甲酰胺(E)-1(表1)。使用TRIP或C8-TRIP作为催化剂，我们得到了理想的α-氟-N，O-氨基3，对合成的非对映异构体具有很好的选择性(条目1和2)。[11]然而，考虑到我们以前对环烯胺的研究结果，缺乏任何显著的对映体选择性是令人失望的。[12]通过使用我们以前报道的环己基取代催化剂TCYP(2c)，[13]在次要的非对映异构体中观察到了有希望的对映选择性，而主要的对映体仍然很低，但有所改善(条目3)。令人鼓舞的是，2-萘基取代催化剂2d具有高的非对映选择性和中等的对映选择性(53%ee)，尽管这不能通过使用1-萘基(2e)或9-蒽基(2f)变体来改善(条目5和6)。耐人寻味的是，…
The selective construction of carbon–fluorine bonds is of great interest to medicinal chemists because the replacement of a carbon–hydrogen bond with a carbon–fluorine bond continues to be an effective approach to the development of biologically active molecules with improved physical and metabolic profiles and biological activities.[1] To this end, a number of impressive examples of catalytic enantioselective fluorination have been reported over the last decade.[2, 3] Our laboratory has recently introduced a novel strategy for asymmetric fluorination based on phase-transfer catalysis using chiral anionic catalysts based on BINOL-derived phosphates [Eq.(1)].[4, 5] Motivated by the importance of the β-fluoroamine motif in medicinal chemistry we employed this strategy to develop a highly asymmetric fluorination of cyclic enamides, allowing us to isolate stable but highly versatile enantioenriched α-fluoro-N-acylimines.[4b] Given the proven ability of BINOL phosphoric acid catalysts to control addition to imines,[6] we posited that aldehyde-derived enamides should be of particular interest as our protocol, upon enamide fluorination, would generate in the first instance a protonated N-acyliminium ion [Eq.(2)]. This intermediate should exhibit hydrogen-bonding interactions with the chiral phosphate anion, allowing catalyst-controlled addition of an external oxygen nucleophile, constituting an oxyfluorination of enamides.[7] The resulting stereodefined α-fluoro-N, O-aminal would be of particular interest as chiral N, O-aminals are prevalent in natural products and the effect of fluorine introduction on this motif remains, to the best of our knowledge, thus far unexplored.[8] With regard to existing asymmetric N, O-aminal synthesis, Antilla and co-workers have reported the phosphoric acid-catalyzed addition of alcohols [9] and hydroperoxides [10] to N-acylimines, although examples delivering high enantioselectivity were restricted to aromatic imines and in no cases could simple water be used as nucleophile in order to obtain a hemiaminal. We were aware that our aim of utilizing a single catalyst to carry out two consecutive enantioselective transformations presented complications. Not only must the catalyst be capable of promoting both reactions, but the inherent diastereocontrol from the initially installed stereocenter could be matched or mismatched with the catalyst control for formation of the second stereocenter. However, this same effect might enable the effect of double stereodifferentiation to be exploited, potentially leading to extremely high stereocontrol in certain cases. Furthermore, observations during our previous studies suggested that, despite drying at 808C under vacuum, the Selectfluor employed in our fluorination contains intrinsic moisture that we hypothesized may be sufficient to enable in situ formation of the hemiaminal. We began our investigations employing (E)-configured N-benzoyl enamide (E)-1 (Table 1). Using TRIP or C8-TRIP as catalysts, the desired α-fluoro-N, O-aminal 3 was isolated with excellent selectivity for the syn-diastereomer (entries 1 and 2).[11] However, the lack of any significant enantioselectivity was disappointing, given our previous results with cyclic enamides.[12] By using our previously reported cyclohexylsubstituted catalyst TCYP (2c),[13] promising enantioselectivity was observed in the minor diastereomer, while the major remained low but improved (entry3). Encouragingly, 2-naphthyl-substituted catalyst 2d gave high diastereoselectivity as well as moderate enantioselectivity (53% ee), although this could not be improved upon by use of the 1-naphthyl (2e) or 9-anthracyl (2 f) variants (entries 5 and 6). Intriguingly, the …