Catalytic enantioselective and diastereoselective addition of aldehyde-derived enecarbamates to α-oxo aldehydes
Catalytic enantioselective and diastereoselective addition of aldehyde-derived enecarbamates to α-oxo aldehydes
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DOI：
10.1002/anie.200600471
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发表时间：
2006-01-01
影响因子：
16.6
通讯作者：
Kobayashi, Shu
中科院分区：
文献类型：
--
作者：
Matsubara, Ryosuke;Kawai, Nobuyuki;Kobayashi, Shu
催化不对称羟醛缩合反应已被广泛研究，并已报道了许多成功的合成方法。[1]虽然大多数研究采用酮和酯（或其衍生物）作为亲核供体，但使用醛作为亲核试剂是一个具有挑战性的课题，因为会发生副反应，如自缩合和产物的进一步反应。[2]最近，丹麦和Ghosh报道了醛与三氯甲硅烷基烯醇化物的第一个催化非对映选择性和对映选择性交叉羟醛缩合反应，该反应由手性磷酰胺催化剂活化。[3]此外，Northrup和MacMillan报道了脯氨酸催化的醛之间的直接对映选择性交叉羟醛缩合反应，该方法被应用于碳水化合物的简易合成。[4]在以前的出版物中，我们已经表明，烯酰胺和烯氨基甲酸酯可以作为亲核试剂与亚胺，醛和酮的加成反应。[5]特别值得注意的是，烯氨基甲酸酯的反应提供了带有氨基甲酸酯N-保护基团的亚胺产物，例如叔丁氧基羰基（Boc）和苄氧基羰基（Cbz），其可以容易地除去以将那些产物转化为其它含氮化合物。在此，我们报告了不对称催化加成反应的衍生物烯氨基甲酸酯与醛。在大多数情况下，在小于1摩尔%的铜（I）催化剂的存在下，以良好的产率和高的对映选择性获得了醛氧化水平保持不变的产物。我们开始用enecarbamate 2a（方案1）研究该项目。[6]由醛衍生的烯基氨基甲酸酯在水和空气中相当稳定，并且它们容易由相应的醛（2步）或α，β-不饱和羧酸（1锅，4步）制备。当使用来自参考文献[5b]的铜（I）催化剂时，2a几乎立即被消耗，但得到复杂的混合物，并且在水解后没有观察到预期的产物，即醛亚胺或醛缩亚胺型衍生物。1H NMR光谱表明产物是聚合物或低聚物材料。用三氟甲磺酸钪（Sc（OTf）3）在EtOH/CH3CN中处理该粗物质，以中等产率得到具有优异ee值的所需产物3a（参见方案1）。该结果表明，在第一反应中获得的粗材料包括具有4a结构的化合物。然而，对产物的仔细分析表明，发生了过度反应，得到了化合物5。为了抑制5的形成，使用EtOH作为初始反应性酰亚胺产物的捕集试剂。在这些条件下，在没有Sc（OTf）3处理的情况下获得产物3a，但仅以中等产率（参见方案1）。[7]当iPrOH（1当量）与铜催化剂一起沿着使用并且粗产物用Sc（OTf）3处理时，观察到最佳产率（80%）。一旦建立了最佳条件，就探索了反应的范围（表1）。出乎意料的是，当使用单或二取代烯氨基甲酸酯时，即使在不存在醇的情况下也没有观察到过度反应的产物，因此在除条目1之外的所有反应中，省略了醇。发现甚至低至0.1摩尔%的催化剂负载量也足以使反应在1小时内完成，并且以高对映选择性获得产物（表1，条目1）。苯基乙二醛在反应中也表现良好，以中等产率和可接受的ee值获得所需的N，O-缩醛（表1.
Catalytic enantioselective aldol reactions have been widely investigated and many successful syntheses have been reported.[1] While most of the studies employed ketones and esters (or their derivatives) as nucleophilic donors, the use of aldehydes as nucleophiles is a challenging topic because side reactions such as self-condensation and further reactions of products take place.[2] Quite recently, Denmark and Ghosh reported the first catalytic diastereo-and enantioselective crossed aldol reactions of aldehydes with trichlorosilyl enolates which are activated by a chiral phosphoramide catalyst.[3] Additionally Northrup and MacMillan have reported proline-catalyzed direct enantioselective crossed aldol reactions between aldehydes, a method which was applied to the facile synthesis of carbohydrates.[4] In previous publications, we have shown that enamides and enecarbamates may be used as nucleophiles in addition reactions with imines, aldehydes, and ketones.[5] It is especially noteworthy that reactions of enecarbamates afford imine products bearing carbamate N-protecting groups, such as tert-butoxycarbonyl (Boc) and benzyloxycarbonyl (Cbz), which may be readily removed to convert those products into other nitrogen-containing compounds. Herein we report asymmetric catalytic addition reactions of aldehyde-derived enecarbamates with aldehydes. The products, in which the aldehyde oxidation level is conserved, were obtained in good yields with high enantioselectivities in the presence of less than 1 mol% of copper (I) catalysts in most cases. We set about the investigation of this project with enecarbamate 2a (Scheme 1).[6] Enecarbamates that are derived from aldehydes are rather stable in water and air and they are readily prepared from the corresponding aldehydes (2steps) or α, β-unsaturated carboxylic acids (1 pot, 4 steps). When the copper (I) catalyst from reference [5b] was employed, 2a was consumed almost instantaneously, but a complex mixture was obtained and none of the expected products, that is, the aldimine-or aldehyde-type derivatives, were observed after hydrolysis. 1H NMR spectroscopy suggested that the product was a polymeric or oligomeric material. Treatment of this crude material with scandium trifluoromethanesulfonate (Sc (OTf) 3) in EtOH/CH3CN afforded the desired product 3a in a moderate yield with an excellent ee value (see Scheme1). This result indicates that the crude material obtained in the first reaction includes compounds with the structure of 4a. However, careful analysis of the products revealed that overreaction had occurred to give compound 5. In an attempt to suppress the formation of 5, EtOH was used as a trapping reagent for the initial reactive acylimine product. Under these conditions, product 3a was obtained without the Sc (OTf) 3 treatment, but only in moderate yield (see Scheme1).[7] The best yield (80%) was observed when iPrOH (1 equiv) was employed along with the copper catalyst and the crude product was treated with Sc (OTf) 3.Once the optimal conditions were established, the scope of the reaction was explored (Table 1). Unexpectedly, products of overreaction were not observed even in the absence of alcohol when mono-or disubstituted enecarbamates were used, so in all reactions other than that of entry 1, the alcohol was omitted. It was found that even catalyst loading as low as 0.1 mol% was enough to bring the reaction to completion within 1 h, and the product was obtained with high enantioselectivity (Table 1, entry 1). Phenylglyoxal also performed well in the reaction, with the desired N, O-acetal being obtained in moderate yield and with an acceptable ee value (Table 1 …