Synthesis of β-hydroxyaldehydes with stereogenic quaternary carbon centers by direct organocatalytic asymmetric aldol reactions
Synthesis of β-hydroxyaldehydes with stereogenic quaternary carbon centers by direct organocatalytic asymmetric aldol reactions
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DOI：
10.1002/anie.200353546
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发表时间：
2004-01-01
影响因子：
16.6
通讯作者：
Barbas, CF
中科院分区：
文献类型：
--
作者：
Mase, N;Tanaka, F;Barbas, CF
24202004Wiley-VCH Verlag GmbH&Co.KGaA，Weinheim DOI：10.1002/anie.安格鲁200353546号。化学。内部艾德[2]L-脯氨酸和其他手性胺最近被证明是不对称分子间羟醛缩合反应的有效催化剂[3]以及其他各种基于亚胺和烯胺的反应。[4-7]虽然令人印象深刻，但L-脯氨酸的合成范围不足以解决所有方面的羟醛缩合反应。[3B]例如，含季碳原子的化合物的合成是目前不对称有机化学中最具挑战性的课题之一，L-脯氨酸催化没有有效地解决这一问题。L-脯氨酸催化的羟醛反应主要集中在利用α单烷基或α杂原子取代的羰基化合物作为给体。使用α，α-二烷醛供体应能直接获得具有季碳原子的对映体富集物。然而，将该方法应用于α，α-二烷醛给体的反应并没有得到令人满意的结果。由于胺催化的羟醛反应是通过烯胺中间体进行的，所以加速烯胺中间体的形成可能是改进α，α-二烷基羟醛产物结构的关键。最近，我们展示了一种荧光检测系统[10]用于监测马来酰亚胺1和丙酮(2)反应中C±C键的形成过程。这种迈克尔型反应可以用作其他基于烯胺的反应的替代-报告反应。通过监测荧光产物3(图1)的形成，评价了烯胺形成的催化剂，并确定了一种有效的吡咯烷/醋酸双功能催化剂，用于α，α二烷基醛作为羟醛供体。[11]本研究为我们提供了为这类重要的羟醛反应寻找不对称催化剂的动力。在这里，我们通过高通量荧光筛选研究了α，α-二烷基醛与芳香醛的直接不对称分子间羟醛反应的结果。为了评价手性胺4-8在不同酸性添加剂存在下的催化效率，如刘易斯、Brnsted和有机酸，我们在每个催化剂的存在下进行了1与丙酮的反应，并监测了荧光的增强(图1)。在催化剂8与酸性添加剂三氟磺酸(RUN 74，RFU=160.0 S±1)、[12]和催化剂8与酸性添加剂三氟乙酸(RUN 78，RFU=152.5 S±1)的反应中，反应效果最好。与催化剂8在无酸条件下相比，这些酸的加入显著提高了反应速度(RUN 65，RFU=35.0RFU S±1)。L-脯氨酸(4，RUN 1，RFU=79.2 S±1)和L-脯氨酸(5，RUN 17，RFU=73.9 S±1)催化反应的初始速率不受任何酸的影响。催化剂6具有较大的二苯羟甲基取代基，在无酸条件下反应速率较低(RUN 33，RFU=1.6 S±1)，加酸时反应速率仍然较低。对于催化剂7，添加醋酸可提高反应速率(无酸时反应速率为14.8 S±1，无酸时反应速率为85.5 S±1，无酸反应时反应速率为63)。手性-胺/酸组合也在不同的溶剂中进行了评价，如二甲基亚砜(DMSO)、N，N-二甲基甲酰胺、1，4-二氧六环、丙酮、
2420 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim DOI: 10.1002/anie. 200353546 Angew. Chem. Int. Ed. 2004, 43, 2420–2423 after in catalytic asymmetric intramolecular aldol reactions.[2] L-Proline and other chiral amines have recently been shown to be efficient catalysts of asymmetric intermolecular aldol reactions [3] and a variety of other imine-and enamine-based reactions.[4–7] Although impressive, the synthetic scope of L-proline is not sufficient to address all aspects of the aldol reaction.[3b] For example, the synthesis of compounds with quaternary carbon atoms is currently one of the most challenging topics in asymmetric organic chemistry that is not addressed efficiently with L-proline catalysis.[8, 9] L-Proline-catalyzed aldol reactions have focused on the use of αmonoalkyl-substituted or α-heteroatom-substituted carbonyl compounds as donors. The use of α, α-dialkyl aldehyde donors should provide direct access to enantiomerically enriched products with a quaternary carbon atom. However, the application of this approach to reactions of α, α-dialkyl aldehyde donors has not provided satisfactory results. Since an amine-catalyzed aldol reaction proceeds via an enamine intermediate, acceleration of the formation of the enamine intermediate can be key to improving the construction of α, α-dialkyl aldol products. Recently we demonstrated the utility of a fluorescence detection system [10] for monitoring the progress of CÀC bond formation in the reaction of the maleimide 1 and acetone (2). This Michael-type reaction can then be used as a surrogate-reporter reaction for other enamine-based reactions. By monitoring the formation of the fluorescent product 3 (Figure 1), catalysts of enamine formation were evaluated, and an effective pyrrolidine/acetic acid bifunctional catalyst was identified for the use of α, αdialkyl aldehydes as aldol donors.[11] This study provided us with the incentive to find asymmetric catalysts for this important class of aldol reactions. Herein we present the results of our investigation of direct asymmetric intermolecular aldol reactions of α, α-dialkyl aldehydes with aryl aldehydes through high-throughput fluorescence-based screening.To evaluate the catalytic efficiency of the chiral amines 4–8 in the presence of various acid additives, such as Lewis, Brønsted, and organic acids, the reaction of 1 with acetone was performed in the presence of each of these catalysts, and the increase in fluorescence was monitored (Figure 1). The best results were observed in the reactions with the catalyst 8 and the acid additive trifluorosulfonic acid (run 74, RFU= 160.0 sÀ1),[12] and with the catalyst 8 and the acid additive trifluoroacetic acid (run 78, RFU= 152.5 sÀ1). The addition of these acids significantly improved the reaction rate relative to that with the catalyst 8 in the absence of an acid (run 65, RFU= 35.0 sÀ1). The initial rate of reactions catalyzed by L-proline (4, run 1, RFU= 79.2 sÀ1) and L-prolinol (5, run 17, RFU= 73.9 sÀ1) were not increased by the addition of any of the acids. The reaction with the catalyst 6, which has a bulky diphenylhydroxymethyl substituent, had a low rate in the absence of an acid (run33, RFU= 1.6 sÀ1), and the rates remained low even when acids were added. For the catalyst 7, the rate was enhanced by the addition of acetic acid (RFU= 14.8 sÀ1 without acid, run 49 and RFU= 85.5 sÀ1 with acetic acid, run 63). The chiral-amine/acid combinations were also evaluated in different solvents, such as dimethyl sulfoxide (DMSO), N, N-dimethylformamide, 1, 4-dioxane, acetone,