Asymmetric nucleophilic glyoxylation through a metalated α-aminonitrile derivative in Michael additions to nitroalkenes
Asymmetric nucleophilic glyoxylation through a metalated α-aminonitrile derivative in Michael additions to nitroalkenes
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DOI：
10.1002/anie.200604802
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发表时间：
2007-01-01
影响因子：
16.6
通讯作者：
Raabe, Gerhard
中科院分区：
文献类型：
--
作者：
Enders, Dieter;Bonten, Maurice Hubert;Raabe, Gerhard
献给汉斯-约阿希姆盖斯教授65岁生日之际，a-酮酸及其衍生物在有机合成中发挥着重要作用。[1]它们已成功整合到肽分子中，产生蛋白水解酶（例如丝氨酸、半胱氨酸和天冬氨酰蛋白酶）的有效抑制剂。[2]它们也有效地作为白三烯A4水解酶的抑制剂。[3]此外，它们是许多生物活性天然产物如3-脱氧-d-甘露-2-辛酮糖酸（KDO）、3-脱氧-d-甘油-d-半乳糖-2-壬酮糖酸（KDN）和N-乙酰神经氨酸的组成部分。[1，4]在这些化合物中引入酮酸结构在合成上具有挑战性，并且已经开发了不同的方法来构建该部分，其中包括α-亚甲基酯的臭氧分解，[5]使用强碱[6]或通过二醇环状亚硫酸酯的B消除用MoO 5· Py· HMPA（MoOPH; Py=吡啶，HMPA=六甲基磷酰胺）氧化α-烷氧基酯。[7]在几种方法中，已应用Umpolung [8]的概念，其允许亲核引入酮酸系统。1994年，Takahashi等人引入了一种保护的氰醇作为乙醛酸烷基酯的酰基阴离子等价物[9a]，后来用于合成KDO和KDN。[9b]施密特及其同事能够通过立体选择性地应用二乙基硫缩醛保护的乙醛酸烷基酯作为C2亲核试剂成功地合成3-脱氧-d-阿拉伯糖基-2-庚酮糖酸（DAH），其在微生物和植物中的氨基酸生物合成中起重要作用。[10]此外，已报道了锂化的1，3-二噻烷保护的乙醛酸烷基酯的几种烷基化反应。[11]据我们所知，还没有开发出不对称亲核乙二醛化的方法。此外，提供对映体富集的α-酮酯的直接方法的数量也相当有限。[12]这一事实促使我们开发了第一种不对称方法，使用金属化乙醛酸氨基腈B作为亲核乙醛酸d1合成子A的手性等价物（图1）。金属化氨基腈[13]作为掩蔽酰基阴离子[14]的等价物的合成用途是众所周知的。使用对映体纯的仲胺（S，S）-1作为手性助剂已被证明在许多亲核酰化反应中与不同的迈克尔受体产生优异的不对称诱导。[15]在我们尝试合成乙醛酸氨基腈2的过程中，我们首先尝试了以乙醛酸酯、纯仲胺（S，S）-1和氰化钾在水中开始的不对称Strecker反应。[16]该尝试失败可能是因为在这些条件下形成醛水合物。[17]我们发现的最佳方法是纯仲胺（S，S）-1与氯乙腈反应，[18]并通过加入二叔丁基二异丙基氯化铵（Boc 2 O）进一步官能化，随后用两当量的二异丙基氨基锂（LDA）处理。[19]该两步转化以良好的产率（73%;方案1）得到相应的氨基腈2，为差向异构体混合物。为了确定手性乙醛酸氨基腈2的金属化的最佳条件，我们首先用甲基碘进行了测试烷基化反应，其中我们发现碱如LDA或叔丁基锂是不合适的，并且仅提供痕量的甲基化产物。然而，强，受阻碱钾二异丙基酰胺（KDA）允许几乎定量转化2成其甲基化衍生物。接下来，我们用各种方法捕获了金属化氨基腈。
Dedicated to Professor Hans-Joachim Gais on the occasion of his 65th birthday a-Keto acids and their derivatives play an important role in organic synthesis.[1] They have been successfully incorporated into peptidic molecules to generate potent inhibitors of proteolytic enzymes such as serine, cysteine, and aspartyl proteases.[2] They are also effective as inhibitors of leukotriene A4 hydrolase.[3] Furthermore, they are an integral part of many biologically active natural products such as 3-deoxyd-manno-2-octulosonic acid (KDO), 3-deoxy-d-glycero-dgalacto-2-nonulosonic acid (KDN) and N-acetylneuraminic acid.[1, 4] The introduction of the keto acid structure in these compounds is synthetically challenging and different methodologies to build up this moiety have already been developed, which include ozonolysis of a-methylene esters,[5] oxidation of a-alkoxy esters with MoO5· Py· HMPA (MoOPH; Py= pyridine, HMPA= hexamethylphosphoramide) using a strong base [6] or through b elimination of a diol cyclic sulfite.[7] In several methods, the concept of Umpolung [8] has been applied, which allows the nucleophilic introduction of the aketo acid system. In 1994, Takahashi et al. introduced a protected cyanohydrin as an acyl anion equivalent of alkyl glyoxylate [9a] that was later on used in the synthesis of KDO and KDN.[9b] Schmidt and co-workers were able to successfully synthesize 3-deoxy-d-arabino-2-heptulosonic acid (DAH), which plays an important role in the biosynthesis of amino acids in microorganisms and plants, by stereoselectively applying a diethyl thioacetal protected alkyl glyoxylate as the C2 nucleophile.[10] Furthermore, several alkylation reactions of lithiated 1, 3-dithiane-protected alkyl glyoxylates have been reported.[11] To the best of our knowledge, a method for asymmetric nucleophilic glyoxylation has not yet been developed. In addition, the number of methods that offer a direct approach to enantioenriched a-keto esters are also rather limited.[12] This fact encouraged us to develop the first asymmetric method by using a metalated glyoxylate aminonitrile B as a chiral equivalent of a nucleophilic glyoxylate d1 synthon A (Figure 1).The synthetic utility of metalated aminonitriles [13] as equivalents of masked acyl anions [14] is well known. Use of the enantiomerically pure secondary amine (S, S)-1 as a chiral auxiliary has already proven to give excellent asymmetric induction in many nucleophilic acylation reactions with different Michael acceptors.[15] In our attempts to synthesize the glyoxylate aminonitrile 2, we first tried an asymmetric Strecker reaction starting with the glyoxylic acid ester, the pure secondary amine (S, S)-1, and potassium cyanide in water.[16] This attempt failed probably because of formation of the aldehyde hydrate under these conditions.[17] The best method we found was the reaction of the pure secondary amine (S, S)-1 with chloroacetonitrile,[18] and further functionalization through the addition of di-tert-butyl dicarbonate (Boc2O) and subsequent treatment with two equivalents of lithium diisopropylamide (LDA).[19] This twostep conversion led to the corresponding aminonitrile 2 as an epimeric mixture in good yield (73%; Scheme 1). To determine the best conditions for metalation of the chiral glyoxylate aminonitrile 2, we first carried out test alkylation reactions with methyl iodide, in which we found that bases such as LDA or tert-butyllithium were not suitable and only afforded traces of the methylation product. However, the strong, hindered base potassium diisopropylamide (KDA) allowed an almost quantitative conversion of 2 into its methylated derivative. Next we trapped the metalated aminonitrile with various …