Organocatalyzed conjugate umpolung of α,β-unsaturated aldehydes for the synthesis of γ-butyrolactones
Organocatalyzed conjugate umpolung of α,β-unsaturated aldehydes for the synthesis of γ-butyrolactones
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DOI：
10.1002/anie.200461572
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发表时间：
2004-01-01
影响因子：
16.6
通讯作者：
Glorius, F
中科院分区：
文献类型：
--
作者：
Burstein, C;Glorius, F
有机合成中的大多数反应都是极性的，可以描述为亲核试剂（供体d）与亲电试剂（受体a）的反应。[1]官能团的“天然”反应性的推测[2]为一组新的反应开辟了一条途径。长期以来，人们已经知道亲电醛的聚合可能是通过使用催化剂如氰化物或噻唑卡宾来实现的。[3]所得到的d1-亲核试剂可以与芳香醛反应（苯偶姻缩合[4]）或与贫电子的极化烯烃反应（Stetter反应[5]）。[6]与此a1-to-d1-umpolung相反，术语“共辄”umpolung描述了通过亲核催化剂攻击醛官能团将a，b-不饱和醛转化为d3-亲核体（高烯醇化物当量[7]）（方案1）。本文中，我们报道了共轭“umpoled”a，b-不饱和醛与芳族醛和酮的有机催化的化学和立体选择性反应，得到g-丁内酯1和4（参见方案1和4）。我们从肉桂醛和4-氯苯甲醛的反应开始我们的研究。作为两种醛的有机催化的聚合的结果，可以形成许多产物（方案2，R1= 4-ClC 6 H4，R2= Ph）。使用市售的噻唑鎓盐2 [8]作为催化剂不提供内酯1a，但导致以低产率形成几种苯偶姻产物（表1，条目1）。最近，咪唑鎓衍生的N-杂环卡宾（NHC）已经非常成功地用作过渡金属催化[9]中的配体和酯交换反应的有机催化剂。[10]我们很高兴地发现，使用1，3-二（2，4，6-三甲基苯基）咪唑啉-2-亚基（IMes），由3通过去质子化，结果在选择性形成g-丁内酯1a。在优化的条件下，将IMes（5mol%）滴加到醛的1：1混合物中，并将反应物在环境温度下搅拌16小时，从而分别以44%和9%的产率分离1a的顺式和反式非对映异构体（表1，条目2）。大量的氰化钾也会催化这种转化。KCN（30摩尔%）和[18]冠-6 [11]（10摩尔%）的组合导致以33%产率形成内酯1a（表1，条目3）。通过该方法可以合成多种不同取代的内酯。除2-氯苯甲醛（表1，条目10）外，在所有情况下主要形成顺式非对映异构体[12]（表1，图1）。目前，涉及醛的聚合的反应范围，例如安息香缩合或Stetter反应，通常受到限制[13]，因为需要自缩合或分子内反应以获得良好的化学选择性。与此形成鲜明对比的是，芳族醛与共轭的umpoled a，b-不饱和醛的反应允许两种不同的醛以分子间的方式选择性连接，代表具有两个新的立体中心的g-丁内酯的一步形成。[14个]
Most reactions in organic synthesis are polar and can be described as the reaction of a nucleophile (donor d) with an electrophile (acceptor a).[1] The umpolung [2] of the “natural” reactivity of a functional group opens up an avenue to a new set of reactions. It has been known for a long time that the umpolung of electrophilic aldehydes is possibly by using catalysts such as cyanide or thiazolium carbenes.[3] The resulting d1-nucleophiles can react with aromatic aldehydes (benzoin condensation [4]) or with electron-poor, polarized olefins (Stetter reaction [5]).[6] In contrast to this a1-to-d1-umpolung, the term “conjugate” umpolung describes the transformation of a, b-unsaturated aldehydes into d3-nucleophiles (homoenolate equivalents [7]) by attack of nucleophilic catalysts on the aldehyde function (Scheme 1). Herein we report the organocatalyzed, chemo-and stereoselective reaction of conjugate “umpoled” a, b-unsaturated aldehydes with aromatic aldehydes and ketones to give g-butyrolactones 1 and 4 (see Schemes 1 and 4). We started our investigation with the reaction of cinnamaldehyde and 4-chlorobenzaldehyde. As a result of the organocatalyzed umpolung of both aldehydes, numerous products can be formed (Scheme2, R1= 4-ClC6H4, R2= Ph). The use of the commercially available thiazolium salt 2 [8] as a catalyst does not provide lactone 1a, but results in the formation of several benzoin products in low yield (Table 1, entry 1). Recently, imidazolium derived N-heterocyclic carbenes (NHCs) have been very successfully used as ligands in transition-metal catalysis [9] and as organocatalysts of transesterification reactions.[10] We were pleased to find that the use of 1, 3-di (2, 4, 6-trimethylphenyl) imidazolin-2-ylidene (IMes), derived from 3 by deprotonation, results in the selective formation of g-butyrolactone 1a. Under optimized conditions, IMes (5mol%) was added dropwise to a 1: 1 mixture of the aldehydes, and the reaction was stirred at ambient temperature for 16 h, allowing the isolation of the cis and trans diastereomers of 1a in 44% and 9% yield, respectively (Table 1, entry 2). Larger amounts of potassium cyanide also catalyze this transformation. A combination of KCN (30 mol%) and [18] crown-6 [11](10 mol%) leads to the formation of lactone 1a in 33% yield (Table 1, entry 3). A variety of differently substituted lactones can be synthesized through this method. With the exception of 2-chlorobenzaldehyde (Table1, entry10), the cis diastereomer [12] was formed predominantly in all cases (Table 1, Figure 1). Currently, the scope of reactions that involve the umpolung of aldehydes, for example, the benzoin condensation or the Stetter reaction, is generally [13] limited, as self-condensation or intramolecular reactions are required for good chemoselectivity. In stark contrast, the reaction of aromatic aldehydes with conjugate umpoled a, b-unsaturated aldehydes allows the selective linking of two different aldehydes in an intermolecular manner, representing a one-step formation of g-butyrolactones with two new stereocenters.[14]